Treatment of moderate-to-severe asthma by administering rilzabrutinib

Abstract

Methods for treating patients with moderate-to-severe asthma comprising administering a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof are disclosed.

Description

TREATMENT OF MODERATE-TO-SEVERE ASTHMA BY ADMINISTERING RILZABRUTINIB

[0001] Disclosed herein are methods for treating moderate-to-severe asthma. BTK inhibitors and pharmaceutical compositions comprising the same are also disclosed.

[0002] Asthma is a chronic inflammatory disease of the airways characterized by airway hyperresponsiveness, acute and chronic bronchoconstriction, airway edema and mucus plugging. The inflammation component of asthma is thought to involve many cell types including epithelial cells, T lymphocytes, eosinophils, mast cells, neutrophils, innate lymphoid cells type 2 (ILC2) and their biological products. Patients with asthma most often present with symptoms of wheezing, shortness of breath, cough, and chest tightness (Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, Updated 2019, Updated 2020, Updated 2021).

[0003] Despite current treatment options, uncontrolled asthma continues to carry a significant burden, with more than 1 million moderate-to-severe asthmatic adolescent and adults in the U.S. having uncontrolled symptoms on inhaled corticosteroids (ICS) combined with a second controller or systemic corticosteroid therapy (Chung KF et al., 2014; Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, Updated 2019, Updated 2020, Updated 2021). These patients are prone to severe exacerbations and contribute disproportionately to the overall morbidity in this condition, including more hospital days, emergency room visits, and lost work / school days than matched controls with good asthma control. Additionally, they are likely to experience comorbidities such as anxiety, depression, and insomnia (Bahadori K et al., 2009; To T et al., 2012). Furthermore, systemic corticosteroids, while clinically effective, are associated with significant side effects, such as fluid retention and swelling, glaucoma, increased blood pressure, increased risk of infections, diabetes, osteoporosis, and impaired growth in children (McCracken JL et al., 2016).

[0004] For severe uncontrolled asthma patients, there are several currently approved biologies (Pelaia C et al., 2020). In the severe, corticosteroid-refractory allergy-induced asthma population, the anti-immunoglobulin E (IgE) agent omalizumab (Xolair®) has shown efficacy. Xolair is associated with a black box warning of potential for anaphylaxis. In the severe population with an eosinophilic phenotype, the two currently approved anti-interleukin(IL)-5 agents, mepolizumab (Nucala®) and reslizumab (Cinqair®), and the anti-IL5 receptor benralizumab (Fasenra™) have shown efficacy as well. These anti-IL5 agents now provide additional therapeutic options with important limitations though. Even in the high eosinophilic group, 36% of patients on mepolizumab had no decrease in oral corticosteroid (OCS) dose or had a lack of asthma control (Bel EH et al., 2014), suggesting that targeting a single cytokine in a heterogenous disease such as asthma is not sufficient. Despite the advent of biologies in the past decade, there remains a significant unmet need for effective asthma treatments. In support of this, up to 60% of patients remain uncontrolled despite treatment with ICS / LABA.

[0005] The main objectives for new therapies are to improve asthma symptoms, lung function, and prevent exacerbations, while optimizing adherence to the treatment. As noted above, one of the reasons for the poor response to medication in some patients with severe asthma may be the heterogeneity of the disease, namely the mixed eosinophilic and neutrophilic inflammation, only partly responding to the current targeted therapies. Underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations are all important mechanisms to target with novel treatments (Custovic A et al., 2013). Thus, there is an important need for new therapeutic options for patients with asthma.

[0006] Compound (I) is a BTK inhibitor of the following structure:wherein *C is a stereochemical center. See PCT Publication No. WO 2014 / 039899, which is incorporated herein by reference, e.g., Example 31.

[0007] (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2-enenitrile, having the following structure:is also known as PRN1008 and rilzabrutinib. This compound has been disclosed in several patent publications, such as, e.g., PCT Publication Nos. WO 2014 / 039899, WO 2015 / 127310, WO 2016 / 100914, WO 2016 / 105531, WO 2018 / 005849, and WO 2021 / 150723, the contents of each of which are incorporated by reference herein.

[0008] Rilzabrutinib is a novel, highly selective, and potent small molecule inhibitor of non-T cell white blood cell signaling via B-cell receptor, FcyR, and / or FceR signaling of the BTK pathway. In the context of ITP, rilzabrutinib has the potential to (1) inhibit B cell activation and (2) interrupt antibody-coated cell phagocytosis by FCyR in the spleen and liver (Bradshaw et al. 2021, Langrish et al. 2021, Owens et al. 2022).

[0009] Rilzabrutinib functions as a reversible covalent BTK inhibitor and is capable of both non-covalently and covalently binding to its target; in particular, its reversible cysteine binding enables high selectivity and precise BTK inhibition without a permanent modification of proteins and peptides (Langrish et al. 2021, Owens et al. 2022, Smith PF et al. 2017). Taken together, these properties allow for enhanced selectivity and extended inhibition with low systemic exposure. In comparison to first and second generation BTKi, rilzabrutinib has shown minimal cross-reactivity with other molecules and is low risk for off- target effects (Smith PF et al. 2017). Importantly, rilzabrutinib ’s reversible binding minimizes the likelihood of permanently modified peptides (Serafimova IM 2012). In addition, rilzabrutinib shows improved kinase selectivity relative to the covalent BTK inhibitor ibrutinib. Preclinical studies in a broad kinase enzyme inhibition panel showed that 1 pM rilzabrutinib achieved >90% inhibition of just 6 of 251 kinases sharing a common cysteine in their active site. By contrast, 1 pM ibrutinib inhibited 21 kinases. Rilzabrutinib ’s IC50 values were 1.3 nM for BTK, 0.8 nM for tyrosine protein kinase TEC, 1.0 nM for bone marrow tyrosine kinase on chromosome X (BMX), 1.2 nM for receptor-like kinase (RLK), 6.3 nM for B cell lymphocyte kinase (BLK), and 11 nM for ERBB4. Further preclinical assays withrilzabrutinib showed that binding to BTK persisted while that for other TEC family members decayed rapidly over time.

[0010] Rilzabrutinib has shown encouraging results for the treatment of immune- mediated diseases. In humans, rilzabrutinib is rapidly absorbed following oral administration, with a fast half-life (3-4 h) and variable pharmacokinetics (Smith PF et al., 2017).

[0011] In Phase 1 studies of rilzabrutinib with 114 healthy volunteers, target BTK occupancy levels were safely and consistently exceeded, suggesting rilzabrutinib may be highly effective in treating autoimmune diseases. Moreover, preclinical and clinical pharmacokinetic and pharmacodynamic data showed that treatment effects endured even after the compound was cleared from circulation, consistent with an extended target residence time (Hill R et al., 2015) and high target occupancy rate (> 90% within four hours and high sustained occupancy over 24 h) (Smith PF et al., 2015).

[0012] Rilzabrutinib has also demonstrated a favorable safety profile in clinical studies. In contrast with non-selective, irreversible BTK inhibitors, rilzabrutinib does not alter platelet aggregation in healthy volunteers or patients with ITP and thus does not lead to bleeding problems (Langrish et al. 2021, von Hundelshausen and Seiss 2021). As an additional point of contrast with irreversible BTK inhibitors, rilzabrutinib treatment does not exert clinically relevant effects on cardiac repolarization (electrocardiogram parameters including corrected QT interval) in healthy volunteers (N=51), even when administered at supratherapeutic doses (Lipsky and Lamanna 2020). Indeed, the most commonly reported adverse events in healthy volunteers were gastrointestinal adverse events, including nausea / vomiting and diarrhea. No serious adverse events or deaths were reported, and no participants discontinued treatment due to an adverse event (Smith PF 2017).

[0013] The clinical efficacy of rilzabrutinib was further demonstrated in an openlabel, Phase 1 / 2 study in immune thrombocytopenic purpura (ITP). In this trial, 50% of participants achieved the primary response endpoint after treatment with rilzabrutinib for at least 12 weeks. Furthermore, there were no treatment-emergent serious adverse events (TESAEs) observed. Collectively, these and other studies have shown rilzabrutinib to be a safe and effective inhibitor of BTK.

[0014] Accordingly, disclosed herein are methods of treating asthma in a human patient in need thereof, comprising administering to the human patient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3- (2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof.

[0015] Further disclosed herein are methods of treating asthma in a human patient in need thereof, comprising administering to the human patient a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and a long-acting P2 adrenergic agonist (LABA).

[0016] Further disclosed herein is the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for treating asthma in a human patient in need thereof.

[0017] Further disclosed herein is the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for treating asthma in a human patient in need thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).

[0018] Further disclosed herein is the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating asthma in a human patient in need thereof.

[0019] Further disclosed herein is the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating asthma in a human patient in needthereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).

[0020] Further disclosed herein is a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin- 1 -yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2- enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for use in treating asthma in a human patient in need thereof.

[0021] Further disclosed herein is a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin- 1 -yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2- enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for use in treating asthma in a human patient in need thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).

[0022] Further disclosed herein is a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin- 1 -yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2- enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for use in the manufacture of a medicament for treating asthma in a human patient in need thereof.

[0023] Further disclosed herein is a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin- 1 -yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2- enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for use in the manufacture of a medicament for treating asthma in a human patient in need thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).BRIEF DESCRIPTION OF DRAWINGS

[0024] Fig. 1 shows a graphical representation of the study design for the 400 mg BID cohort.

[0025] Fig. 2 shows a graphical representation of the study design for the 400 mg TID cohort.

[0026] Figs. 3A and B show a Kaplan-Meier plot of time to LOAC postrandomization for the 400 mg BID (A) and 400 mg TID (B) cohorts (mITT population).

[0027] Figs. 4A and B show a plot of mean change from baseline in prebronchodilator FEV 1 (L) over time for the 400 mg BID (A) and 400 mg TID (B) cohorts (onsite conventional spirometry, as observed; mITT population).

[0028] Figs. 5A and B show a plot of LS mean change from baseline in prebronchodilator FEV 1 over time, reduced model, for the 400 mg BID (A) and 400 mg TID (B) cohorts (mITT population).

[0029] Figs. 6A and B show a plot of LS mean change from baseline in prebronchodilator percent predicted FEV1 (L) over time, reduced model, for the 400 mg BID (A) and 400 mg TID (B) cohorts (mITT population).

[0030] Fig. 7 shows a plot of LS mean change from inhalations / day of albuterol or levalbuterol for symptom relief over time for the 400 mg BID cohort (mITT population).

[0031] Fig. 8 shows a plot of LS mean change from inhalations / day of albuterol or levalbuterol for symptom relief over time, reduced model, for the 400 mg BID cohort (mITT population).

[0032] Figs. 9A and B show a plot of LS mean change from ACQ-5 over time for the400 mg BID (A) and 400 mg TID (B) cohorts (mITT population).

[0033] Fig. 10 shows a plot of the proportion of participants with ACQ-5 score less than 0.75 over time for the 400 mg BID cohort (ITT population).

[0034] Figs. 11A and B show a plot of LS mean change from baseline in ACQ-5 frequency of awakening by asthma over time for the 400 mg BID (A) and 400 mg TID (B) cohorts (mITT population).

[0035] Figs. 12A and B show a plot of LS mean change from baseline in ACQ-5 asthma symptoms when woke up over time for the 400 mg BID (A) and 400 mg TID (B) cohorts (mITT population).

[0036] Figs. 13A and B show a plot of LS mean change from baseline in ACQ-5 limitation of activities by asthma over time for the 400 mg BID (A) and 400 mg TID (B) cohorts (mITT population).

[0037] Figs. 14A and B show a plot of LS mean change from baseline in ACQ-5 shortness of breath experienced over time for the 400 mg BID (A) and 400 mg TID (B) cohorts (mITT population).

[0038] Figs. 15A and B show a plot of LS mean change from baseline in ACQ-5 wheeze over time for the 400 mg BID (A) and the 400 mg TID (B) cohorts (mITT population).

[0039] Figs. 16A and B show a plot of LS mean change from AQLQ global score over time for the 400 mg BID (A) and 400 mg TID (B) cohorts (mITT population).Definitions:

[0040] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meanings. All undefined technical and scientific terms used in this Application have the meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0041] As used herein, “a” or “an” entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound unless stated otherwise. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

[0042] As used herein, the term “about” is used herein to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 5%. With regard to specific values, it should be understood that specific values described herein for subject populations (e.g., the subject of the described clinical trial) represent median, mean, or statistical numbers, unless otherwise provided. Accordingly, aspects of the present disclosure requiring a particular value in a subject are supported herein by population data in which the relevant value is assessed to be a meaningful delimitation on the subject population.

[0043] As used herein, the term “active pharmaceutical ingredient” or “therapeutic agent” (“API”) refers to a biologically active compound.

[0044] As used herein, the term “approved treatment” refers to a medication that has received regulatory authorization, in any country, for its intended use.

[0045] As used herein, the terms “administer,” “administering,” or “administration” herein refer to providing, giving, dosing, and / or prescribing by either a health practitioner or an authorized agent and / or putting into, taking, or consuming by the patient or person himself or herself. For example, “administration” of an API to a patient refers to any route (e.g., oraldelivery) of introducing or delivering the API to the patient. Administration includes selfadministration and administration by another.

[0046] As used herein, the term “baseline” refers to a measurement obtained within four weeks prior to initiating rilzabrutinib treatment.

[0047] As used herein, “BID” and “bid” are used interchangeably to refer to twice a day. As used herein, 400 mg BID refers to a total dose of 800 mg per day.

[0048] As used herein, the term “in combination with,” when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other during a treatment period. Unless specified otherwise, the two or more compounds, agents, or active pharmaceutical ingredients may be administered on different schedules during the treatment period, such as, e.g., with one or more compounds, agents, or active pharmaceutical ingredients being administered once a day and one or more other compounds, agents, or active pharmaceutical ingredients being administered twice a day.

[0049] As used herein, an amount expressed in terms of “mg of [X]” refers to the total amount in milligrams of [X], i.e., the free base. In some embodiments, rilzabrutinib may be administered as a pharmaceutically acceptable salt of rilzabrutinib, in which case an amount expressed in terms of “mg of rilzabrutinib” refers to the total amount in milligrams of rilzabrutinib, i.e., the free base, plus the equivalent amount of one or more pharmaceutically acceptable salts of rilzabrutinib based on the weight of free base therein. For example, “400 mg of at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof’ includes 400 mg of rilzabrutinib and a concentration of one or more pharmaceutically acceptable salts of rilzabrutinib equivalent to 400 mg of rilzabrutinib.

[0050] As used herein, a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, and neither biologically nor otherwise undesirable, such as, e.g., a carrier or an excipient that is acceptable for mammalian pharmaceutical use.

[0051] As used herein, the term “pharmaceutically acceptable salt” refers to a salt form, e.g., an acid addition salt, of an active pharmaceutical agent that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the API of which the salt is made. Pharmaceutically acceptable salts are well known in the art and include those derived from suitable inorganic and organic acids. Such salts include, but are not limited to,salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, and the like. S. M. Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0052] As used herein, the terms “PRN1008,” “rilzabrutinib,” “(R)-2-[3-[4-amino-3- (2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl- 4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile;” “the compound of Formula (I);” and “2- [(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]-pyrimidin-l-yl]piperidine- l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile” are used interchangeably to refer to a compound having the structure:which is also referred to as 2-[(3R)-2-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin- 1 -yl]piperdine- 1 -carbonyl]-4-methyl-4[4-(oxetan-3 -yl)piperazin- 1 -yl]-(E and Z)- pent-2-enenitrile; (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin- 1 -yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2- enenitrile; 1 -piperidinepropanenitrile, 3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl]-a-[2-methyl-2-[4-(3-oxetanyl)-l-piperazinyl]propylidene]-P- oxo-, (3R)-; (EZ)-2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4- d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-yl]pent-2- enenitrile; and also by the International Nonproprietary Names for Pharmaceutical Substances (INN) as published by the World Health Organization https: / / cdn.who.int / media / docs / default-source / international-nonproprietary-names- (inn) / pll21.pdf?sfyrsn=69617906 15&download=true) having the following structure:The compound of Formula (I) includes E and Z isomers, as indicated by the wavy bond in the structure shown above. The compound of Formula (I) may be present as a salt form.

[0053] An isomer of rilzabrutinib may contain the corresponding (Z) isomer as an impurity in less than about 1% by weight; a dose of the (Z) isomer of rilzabrutinib may contain the corresponding (E) isomer as an impurity in less than about 1% by weight. When rilzabrutinib is denoted as a mixture of (E) and (Z) isomers of (R)-2-[3-[4-amino-3-(2-fluoro- 4-phenoxy-phenyl)pyrazolo[3 ,4-d]pyrimidin- 1 -yl]piperidine- 1 -carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile, it means that the amount of (E) or (Z) isomer in the mixture is greater than about 1% by weight. In some embodiments, the molar ratio of (E) to (Z) isomer is 9: 1. rilzabrutinib or a pharmaceutically acceptable salt thereof may also be referred to herein as a “drug,” “active agent,” “a therapeutically active agent,” or “API.”

[0054] As used herein, the term “therapeutically effective amount” refers to that of a compound that produces the desired effect for which it is administered (e.g., improvement in asthma or a symptom of asthma, or lessening the severity of asthma or a symptom of asthma). The exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0055] As used herein, “TID” and “tid” are used interchangeably to refer to three times a day. As used herein, 400 mg TID refers to a total dose of 1200 mg per day.

[0056] As used herein, the term “treat,” “treating,” or “treatment,” when used in connection with a disorder or condition, includes any effect, e.g., lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the disorder or condition. Improvements in or lessening the severity of any symptom of the disorder or condition can be readily assessed according to standard methods and techniques known in the art.

[0057] The present disclosure provides methods of treating asthma in a human patient in need thereof. In some embodiments, the methods comprise administering to the humanpatient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof.

[0058] In some embodiments, the human patient has mild asthma. In some embodiments, the human patient has moderate-to-severe asthma. In some embodiments, the human patient has moderate asthma. In some embodiments, the human patient has severe asthma. In some embodiments, the human patient has asthma that is not well controlled. In some embodiments, the human patient has asthma that is not well controlled for one or more symptoms. In some embodiments, the one or more symptoms is selected from frequency of awakening by asthma, asthma symptoms when woke up, limitation of activities by asthma, shortness of breath, and wheeze. In some embodiments, the one or more symptom is frequency of awakening by asthma. In some embodiments, the one or more symptom is asthma symptoms when woke up. In some embodiments, the one or more symptom is limitation of activities by asthma. In some embodiments, the one or more symptom is shortness of breath. In some embodiments, the one or more symptom is wheeze. In some embodiments, the human patient is receiving treatment with step 3, 4, or 5 of the Global Initiative for Asthma (GINA). In some embodiments, the human patient is receiving treatment with step 3 of GINA. In some embodiments, the human patient is receiving treatment with step 4 of GINA. In some embodiments, the human patient is receiving treatment with step 5 of GINA. In some embodiments, the human patient has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA). In some embodiments, the human patient has asthma that is not well controlled by treatment with an ICS. In some embodiments, the human patient has asthma that is not well controlled by treatment with an LABA.

[0059] In some embodiments, the human patient is withdrawn from ICS / LABA therapy. In some embodiments, the human patient is not withdrawn from ICS / LABA therapy.

[0060] In some embodiments, the human patient does not experience a >30% reduction from baseline in morning PEF.

[0061] In some embodiments, the human patient does not require >6 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol within a 24-hour period for two consecutive 24-hour periods. In some embodiments, the human patient does notrequire >6 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol within a 24-hour period. In some embodiments, the human patient does not require >5 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol within a 24- hour period. In some embodiments, the human patient does not require >4 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol within a 24-hour period. In some embodiments, the human patient does not require >3 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol within a 24-hour period. In some embodiments, the human patient does not require >2 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol within a 24-hour period.

[0062] In some embodiments, the human patient does not require an increase in ICS >4 times the last prescribed ICS dose. In some embodiments, the human patient does not require an increase in ICS >3 times the last prescribed ICS dose. In some embodiments, the human patient does not require an increase in ICS >2 times the last prescribed ICS dose. In some embodiments, the human patient does not require an increase in ICS >50% of the last prescribed ICS dose. In some embodiments, the human patient does not require an increase in ICS dose. In some embodiments, the human patient achieves a decrease in ICS dose.

[0063] In some embodiments, the human patient does not require the use of systemic steroid treatment, optionally wherein the systemic steroid treatment comprises oral or parenteral treatment.

[0064] In some embodiments, the human patient does not require hospitalization or an emergency room visit for asthma exacerbation.

[0065] In some embodiments, the human patient achieves an increase in prebronchodilator FEV1 relative to baseline pre-bronchodilator FEV1. In some embodiments, the human patient achieves an increase in the percent predicted pre-bronchodilator FEV1 prior to baseline pre-bronchodilator FEV 1.

[0066] In some embodiments, the human patient achieves a reduction in Asthma Control Questionnaire-5 (ACQ-5) score relative to a baseline ACQ-5 score. In some embodiments, the human patient achieves a reduction in ACQ-5 of >0.5 relative to baseline ACQ-5. In some embodiments, the human patient achieves an ACQ-5 score of <0.75.

[0067] In some embodiments, the human patient achieves an increase in Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ(S)) relative to baseline AQLQ(S).

[0068] In some embodiments, the human patient achieves a reduction in asthma daytime symptom diary (ADSD) relative to baseline ADSD. In some embodiments, the human patient achieves a reduction in asthma nighttime symptom diary (ANSD) relative to baseline ANSD. In some embodiments, wherein the human patient achieves a reduction in ADSD relative to baseline ADSD and / or a reduction in ANSD relative to baseline ANSD, the patient receives concomitant treatment with ICS and / or LABA.

[0069] In some embodiments, the human patient achieves a reduction in inhalations / day of albuterol or levalbuterol for symptom relief relative to baseline inhalations / day. In some embodiments, wherein the human patient achieves a reduction in inhalations / day of albuterol or levalbuterol for symptom relief relative to baseline inhalations / day, the patient receives concomitant treatment with ICS / LABA.

[0070] In some embodiments, the human patient achieves a reduction in Patient Global Impression of Severity (PGIS) relative to baseline PGIS. In some embodiments, the human patient achieves an improvement in Patient Global Impression of Change (PGIC).

[0071] In some embodiments, the human patient has had asthma for at least 12 months.

[0072] In some embodiments, the human patient is being treated with a moderate to high dose of ICS therapy in combination with LABA. In some embodiments, the human patient is being treated with a moderate dose of ICS therapy in combination with LABA. In some embodiments, the human patient is being treated with a high dose of ICS therapy in combination with LABA. In some embodiments, the ICS is fluticasone propionate and the human patient is being treated with >250 pg of fluticasone propionate BID or comparable ICS daily dosage to a maximum of 2000 pg / day of fluticasone propionate or clinically comparable ICS. In some embodiments, the human patient has received treatment with the ICS for at least 3 months. In some embodiments, the human patient has received treatment with a stable dose of the ICS for at least 1 month.

[0073] In some embodiments, the human patient has a baseline reversibility of at least 12% and 200 mL in FEV1 15 to 30 minutes after administration of 200-400 pg of albuterol / salbutamol or levalbuterol / levosalbutamol. In some embodiments, the human patient has a history reversibility of at least 12% and 200 mL in FEV1 15 to 30 minutes after administration of 200-400 pg of albuterol / salbutamol or levalbuterol / levosalbutamol within the 5 years prior to initiation rilzabrutinib treatment. In some embodiments, the human patient has a history of positive response to methacholine challenge within the 5 years priorto initiation rilzabrutinib treatment. In some embodiments, the human patient has a history of one or more of the following within the 2 years prior to initiation of rilzabrutinib treatment: (a) treatment with a systemic steroid for worsening asthma, optionally wherein the systemic steroid treatment comprises oral or parenteral treatment; and (b) hospitalization or an emergency room visit for asthma exacerbation.

[0074] In some embodiments, the treatment period is at least 12 weeks.

[0075] In some embodiments, the at least one compound consists of at least one compound chosen from the (E) isomer of rilzabrutinib and pharmaceutically acceptable salts thereof. In some embodiments, the at least one compound consists of at least one compound chosen from the (Z) isomer of rilzabrutinib and pharmaceutically acceptable salts thereof. In some embodiments, the at least one compound consists of a mixture of (E) and (Z) isomers of rilzabrutinib or a pharmaceutically acceptable salt of the foregoing.

[0076] In some embodiments, the methods comprise administering rilzabrutinib to the human patient twice a day. In some embodiments, the methods comprise administering to the human patient 400 mg of rilzabrutinib twice a day. In some embodiments, the methods comprise administering rilzabrutinib to the human patient three times a day. In some embodiments, the methods comprise administering to the human patient 400 mg of rilzabrutinib three times a day.

[0077] In some embodiments, the at least one compound is the (E) isomer of rilzabrutinib. In some embodiments, the at least one compound is the (Z) isomer of rilzabrutinib. In some embodiments, the at least one compound consists of a mixture of (E) and (Z) isomers of rilzabrutinib.

[0078] In some embodiments, the at least one compound is orally administered to the human patient. In some embodiments, the at least one compound is administered to the human patient in the form of at least one tablet. In some embodiments, the at least one compound is administered with water.

[0079] In some embodiments, the at least one compound is rilzabrutinib.

[0080] In some embodiments, the methods comprise administering to the human patient a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperi dine- 1 -carbonyl]- 4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof, wherein the human patient in need thereof hasasthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA)

[0081] The present disclosure provides for the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for treating asthma in a human patient in need thereof.

[0082] The present disclosure provides for the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for treating asthma in a human patient in need thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).

[0083] The present disclosure provides for the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating asthma in a human patient in need thereof.

[0084] The present disclosure provides for the use of a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating asthma in a human patient in need thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).

[0085] The present disclosure provides for a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for use in treating asthma in a human patient in need thereof.

[0086] The present disclosure provides for a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for use in treating asthma in a human patient in need thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).

[0087] The present disclosure provides for a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for use in the manufacture of a medicament for treating asthma in a human patient in need thereof.

[0088] The present disclosure provides for a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for use in the manufacture of a medicament for treating asthma in a human patient in need thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).Pharmaceutical Compositions:

[0089] In some embodiments of the present disclosure, rilzabrutinib is administered as part of a pharmaceutical composition comprising: at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in the form of at least one tablet.

[0090] In some embodiments of the present disclosure, rilzabrutinib is orally administered as part of a pharmaceutical composition comprising: at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in the form of at least one tablet.

[0091] In some embodiments, rilzabrutinib is administered in the form of a film- coated tablet.

[0092] In some embodiments of the present disclosure, rilzabrutinib is administered in the form of at least one tablet comprising: at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable excipient. In some embodiments, rilzabrutinib is administered in the form of at least one tablet comprising: at least one compound chosen from rilzabrutinib and pharmaceutically acceptable salts thereof; at least one filler; at least one disintegrant; at least one lubricant; and at least one film coating.

[0093] In some embodiments, rilzabrutinib is administered with a glass of water.

[0094] The proportion and nature of any pharmaceutically acceptable excipient may be determined by the chosen route of administration and standard pharmaceutical practice. Except insofar as any conventional pharmaceutically acceptable excipient is incompatible with rilzabrutinib, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically composition, its use is contemplated to be within the scope of this disclosure.

[0095] Some non-limiting examples of materials which may serve as pharmaceutically acceptable excipients include: (1) sugars, such as, e.g., lactose, glucose, and sucrose; (2) starches, such as, e.g., com starch and potato starch; (3) cellulose and its derivatives, such as, e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as, e.g., cocoa butter and suppository waxes; (9) oils, such as, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as, e.g., propylene glycol; (11) polyols, such as, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as, e.g., ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as, e.g., magnesium hydroxide and aluminum hydroxide; (15) alginic acid;(16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol;(20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0096] One skilled in the art can readily select the proper form and route of administration depending upon the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances.EXAMPLES

[0097] The following example is intended to be illustrative and is not meant in any way to limit the scope of the disclosure.Abbreviations:ACQ-5 Asthma Control Questionnaire-5 AD Atopic dermatitis ADSD Asthma daytime symptom diary AE Adverse event AESI Adverse event of special interest ANSD Asthma nighttime symptom diary AQLQ(S) Asthma Quality of Life Questionnaire withStandardized ActivitiesATC Anatomical therapeutic chemical BD Bronchodilator BDR Bronchodilator response BID Twice daily BTK Bruton's tyrosine kinase CI Confidence interval CS CorticosteroidCSICF Core study informed consent form CYP Cytochrome P450 DPI Dry powder inhaler ECG El ectrocardi ogram EOT End of treatment ETD Early treatment discontinuation FcyR Fc-gamma receptorFcsR Fc-epsilon receptor FEF Forced expiratory flow FVC Forced vital capacity HIV Human immunodeficiency virus HR Hazard ratio HRT Hormonal replacement therapy ICS Inhaled corticosteroidIgG4-RD Immunoglobin G4-related disease IL InterleukinILC2 Innate lymphoid cells type 2 IMP Investigational medicinal product IRT Interactive response technology ITP Immune thrombocytopenia ITT Intent-to-treat LABA Long-acting P2 adrenergic agonist LAR Legally authorized representativeLOAC Loss of asthma control LOCF Last observation carried forward LS Least squared MCID Minimal clinically important differenceMDI Metered dose inhalerPg micrograms mg milligrams ocs Oral corticosteroid PBMC Peripheral blood mononuclear cell PC SA Potentially clinically significant abnormality PD Pharmacodynamics PEF Peak exploratory flow PGIC Patient global impression of change PGIS Patient global impression of severity PK Pharmacokinetics PO Orally RD Risk difference SAE Serious adverse event SUSAR Suspected unexpected serious adverse reactionTB Tuberculosis TBI Tuberculosis infection TEAE Treatment-emergent adverse event TID Three times a day V Visit wAIHA Warm autoimmune hemolytic anemiaWk Week WOCBP Woman of childbearing potential WONCBP Woman of non-childbearing potentialExample 1: A randomized, double-blind, placebo-controlled, parallel-group, 12-week proof-of-concept (PoC) study to assess the efficacy, safety, and tolerability of rilzabrutinib in patients with moderate-to-severe asthma who are not well controlled on inhaled corticosteroid (ICS) plus long-acting pi adrenergic agonist (LABA) therapy Study Design

[0098] This is a global, multicenter, Phase 2, double-blind, 2 arm, parallel treatment, placebo-controlled randomized, proof-of-concept (PoC) study with 2 staggered cohorts (2 arms in each cohort) evaluating the efficacy and safety of rilzabrutinib in adult participants (aged 18-70 years, inclusive) with moderate-to-severe asthma who are not well controlled on inhaled corticosteroid (ICS) plus long-acting P2 adrenergic agonist (LABA) therapy.

[0099] Approximately 192 adult participants meeting the inclusion / exclusion criteria were to be stratified by IgE levels at screening (IgE < 100 lU / mL versus IgE >100 lU / mL) and by region and were to be randomized in a 1 : 1 allocation ratio to either rilzabrutinib or matching placebo. An enrollment cap was to ensure that at least 60% of the participants have IgE > 100 lU / mL at screening.

[0100] Participants were to be enrolled into 2 staggered dose regimen cohorts: a 400 mg BID cohort and a 400 mg TID cohort, starting with the 400 mg BID cohort. These 2 dosing regimen cohorts were to be evaluated with the same double-blind fashion and planned assessments in this study. Participants could only be enrolled in one cohort and were not to be allowed to participate in the 400 mg TID cohort if they had already enrolled in the 400 mg BID cohort.

[0101] Study treatment was to include IMP (rilzabrutinib or placebo) added-on to a background therapy of ICS / LABA (fluticasone / salmeterol (non-investigational medicinal product), standardized at screening). Background therapy of ICS / LABA was to be withdrawn during the 12-week randomized treatment period and resumed at the end of the IMP treatment period, as outlined below:• Screening period (4 weeks (D-28-D-1))• Randomized IMP treatment period (12 weeks ± 3 days) o Background therapy stabilization phase (4 weeks) o Background therapy withdrawal phase (4-5 weeks) o No background therapy phase (3-4 weeks)• Post IMP treatment safety follow-up period (4 weeks ± 3 days)

[0102] At screening, participants must have been using at least moderate to high doses of ICS therapy (>250 pg of fluticasone propionate BID or comparable ICS daily dosage (1) to a maximum of 2000 pg / day of fluticasone propionate or clinically comparable) in combination with a LABA for at least 3 months with a stable dose >1 month prior to Screening Visit 1.

[0103] During the Screening period, participants were to be:• Trained on using electronic questionnaires (e-diary) at the Screening visit (Visit 1) and will record ANSD (Asthma Nighttime Symptom Diary) and ADSD (Asthma Daytime Symptom Diary), compliance with background treatment starting after the screening visit and continuing through the study period using this e-diary. Clinical site staff were to check patient data collected on the e-diary at each visit.• Trained on the use of the electronic home PEF meter / spirometry device. Clinical site staff were to check patient data collected on the home PEF meter / spirometry device at each visit.Queried on personal history of comorbid atopic conditions as well as history of allergy (including aeroallergens, dust mites, and molds). Results of historical skintesting specifying the technique (prick / puncture (percutaneous) or intradermal (intracutaneous) or RAST) was to be collected.

[0104] After completion of screening procedures, all eligible participants were to be switched to clinically comparable doses of the study-specific ICS / LABA combination therapy with fluticasone / salmeterol, as approved by local Health Authority:• Fluticasone / salmeterol - DPI: o 1 inhalation of 250 / 50 pg BID or o 1 inhalation of 500 / 50 pg BIDOR• Fluticasone / salmeterol - MDI: o 2 inhalations of 115 / 21 pg (230 / 42 pg) BID or o 2 inhalations of 230 / 21 pg (460 / 42 pg) BID OR• Fluticasone / salmeterol - MDI: o 2 inhalations of 125 / 25 pg (250 / 50 pg) BID or o 2 inhalations of 250 / 25 pg (500 / 50 pg) BID

[0105] Participants who satisfied the inclusion and exclusion criteria were to be randomized (1 : 1 ratio) to either rilzabrutinib (400 mg) or matching placebo, administered orally BID for 12 weeks.Background therapy (ICS / LABA) withdrawal phase

[0106] At Week 4 (Visit 6), the LABA component (salmeterol) was to be withdrawn, and participants were to be switched from their BID fluticasone / salmeterol combination therapy to a clinically comparable ICS dose of fluticasone BID monotherapy, as approved by local Health Authority:• Fluticasone (DPI formulation): o 1 inhalation of 250 pg BID or o 2 inhalations of 250 pg (500 pg) BID, OR• Fluticasone (MDI formulation): o 2 inhalations of 110 pg (220 pg) BID or o 2 inhalations of 220 pg (440 pg) BIDOR• Fluticasone (MDI formulation): o 2 inhalations of 125 pg (250 ig) BID or o 2 inhalations of 250 ig (500 pig) BID

[0107] The ICS component (fluticasone) was to be withdrawn by a stepwise dose reduction starting at Week 6 (Visit 8) and was to continue at each Week 7 (Visit 9), Week 8 (Visit 10), and, in those being tapered from high dose ICS, Week 9 (Visit 11), provided that participants did not experience an LOAC event (Table 1).

[0108] Table 1. Withdrawal of fluticasone - downward titration doses (administered twice a day).

[0109] Participants were to use the same inhaler type (either DPI or MDI) throughout the study.

[0110] Participants that met the criteria for a LOAC, at any time during the randomized IMP treatment phase, were to (be):• Discontinue early from IMP treatment,• Evaluated and receive treatment by the Investigator with standard of care according to standard medical practice. If practicable and safe, the participant was to undergo EOT Visit (Visit 14) assessment prior to the administration of rescue medications.• Resume their individual prescreening ICS / LABA background therapy and,• Followed for safety during a 4-week Post IMP Treatment Period.Early treatment discontinuation (ETD) follow-up

[0111] Participants who discontinued IMP treatment prior to completing the 12-week IMP treatment (due to LOAC or due to early treatment discontinuation), were to be evaluated as soon as possible at the individual participant’s EOT Visit and using procedures as planned for the EOT Visit at Week 12 (Visit 14). At their EOT visit, participants were to resume theirprescreening ICS / LABA background therapy or appropriate therapy as needed per treating physician were to be resumed after the EOT study assessments had been performed and entered the 4-week safety follow-up period / Post IMP Treatment Period, concluding with the EOS Visit (Visit 16).Post IMP treatment follow-up

[0112] Participants who completed the 12-week randomized IMP treatment period at Week 12 (Visit 14) EOT visit, as per protocol, were to resume their prescreening ICS / LABA therapy and enter the 4-week safety follow-up period / Post IMP Treatment Period concluding with the EOS Visit (Visit 16).

[0113] At EOT visit, if a participant’s asthma could be adequately controlled by the prescreening ICS / LABA therapy, additional controller therapies may also have been prescribed based on the Investigator’s clinical judgement.Objectives and Endpoints

[0114] Objectives and endpoints for this study are described in Table 2 below.

[0115] Table 2. Objectives and endpoints.Appropriateness of Measurements

[0116] The assessments used in this study are all standard endpoints in evaluation of disease activity and response to therapy in asthma.

[0117] The general construct of this 12-week Loss of Asthma Control (LOAC) study consisted of a 4-week standardized ICS / LABA background therapy stabilization phase, a 4-or 5-week background therapy withdrawal phase and a 3- or 4-week no background therapy phase, followed by a 4-week post IMP treatment safety follow-up period at the beginning of which, pre-screening asthma controller medications are restarted. Participants had access to short-acting P-agonist (SABA) reliever medication at all times during the protocol. The primary endpoint of this study is defined as the proportion of participants with an LOAC event during the treatment period, which consists of any of the following: 1) A 30% or greater reduction from baseline in morning PEF on 2 consecutive days; 2) 6 or more additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; 3) Increase in ICS >4 times the last prescribed ICS dose (or >50% of the prescribed ICS dose at V2 if background therapy withdrawal completed); 4) Requiring use of systemic (oral and / or parenteral) steroid treatment; or 5) Requiring hospitalization or emergency room visit for asthma exacerbation.

[0118] This approach allowed for a relatively brief study capable of rapidly identifying the loss of asthma control and minimizing the duration of patient exposure to loss of controller therapy.

[0119] Spirometry is a standard test to measure patients’ lung function. It was to be performed in accordance with the American Thoracic Society (ATS) / European Respiratory Society (ERS) guidelines (Graham BL et al., 2019).

[0120] The ACQ-5 was designed to measure both the adequacy of asthma control and change in asthma control which may have occurred either spontaneously or as a result of treatment. Measurement properties such as reliability and ability to detect change have been documented in the literature (Juniper et al. 2005).

[0121] The AQLQ(S) is a self-administered patient reported outcome to measure the functional impairments that are most troublesome to adolescents and adults>12 years of age as a result of their asthma. The instrument has been used in many clinical trials, and it has been shown to be reliable, valid (patient interviews), and sensitive to change. The MCID for AQLQ(S) is 0.5 (Juniper et al. 1994).

[0122] ADSD and ANSD are PRO measures developed by the PRO Consortium’ Asthma Working Group. Both instruments have been designed to measure asthma symptoms in adult and adolescent (12 years of age and older) patients diagnosed with mild to severe asthma. ADSD and ANSD assess asthma severity based on patient self-report of asthma core symptoms. They have demonstrated adequate evidence of content validity and cross-sectionalmeasurement properties (z.e., internal consistency reliability, test-retest reliability, convergent validity, and known-groups validity) to measure symptoms of asthma (Gater et al. 2016).

[0123] In terms of safety, TEAEs, SAEs, adverse events of special interest (AESIs), vital signs, and laboratory analyses were to be reported.Study Population

[0124] Inclusion criteria are summarized in Table 3. Participants were eligible to be included in the study only if all of the criteria applied.

[0125] Table 3. Inclusion Criteria.1A male condom and an additional highly effective contraceptive method when having sexual intercourse with a woman of childbearing potential who is not currently pregnant; or a male condom when engaging in any activity that allows for passage of ejaculate to another person.2A WOCBP must have had a negative highly sensitive pregnancy test ((urine or serum) as required by local regulations) within 28 days before the first administration of study intervention. If a urine test could not be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test was to be required. In such cases, the participant must have been excluded from participation if the serum pregnancy result was positive.

[0126] Exclusion criteria are summarized in Table 4. Participants were excluded from the study if any of the criteria applied.

[0127] Table 4. Exclusion criteria.3Strong CYP3 A inducers include apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, and St. John’s wort. Moderate CYP3A inducers include Bosentan, efavirenz, etravirine, phenobarbital, and primidone. Source: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers, U.S. Food and Drug Administration..4Strong CYP3 A inhibitors include boceprevir, clarithromycin, cobicistat, danoprevir / ritonavir, elvitegravir / ritonavir, grapefruit juice, idelalisib, indinavir / ritonavir, itraconazole, ketoconazole, lopinavir / ritonavir, nefazodone, nelfinavir, paritaprevir / ritonavir and ombitasvir and / or dasabuvir, posaconazole, ritonavir, saquinavir / ritonavir, telaprevir, telithromycin, tipranavir / ritonavir, troleandomycin, and voriconazole. Moderate CYP3 A inhibitors include aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, and verapamil. Source: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers, U.S. Food and Drug Administration.5A one-time retest value at screening may have been performed by the Investigator if abnormal laboratory test values are found.6Participants with positive hepatitis C antibody due to prior resolved disease could be enrolled, only if a confirmatory negative Hepatitis C RNA test was obtained.Lifestyle Considerations

[0128] Participants were to refrain from consumption of grapefruit or grapefruit juice, from 7 days before the start of study intervention until the completion of the final dose.

[0129] No restriction of caffeine or activity was required. Smoking was not permitted during the trial and current smokers were excluded from participation.Retesting: Laboratory Inclusion / Exclusion Criteria

[0130] If a participant did not meet certain laboratory inclusion / exclusion criteria at Screening due to the following laboratory results, the Investigator may have repeated one or more of these tests once during the screening period:• ALT or AST > 1.5 x ULN (may have been repeated if 1.5 to 3 x ULN)• Total bilirubin > 1.5 x ULN (may have been repeated if 1.5 to 3 x ULN)• Absolute neutrophils count <1.5 x 109 / L (may have been repeated if 1.2 to 1.5 x 109 / L)• A platelet count <150,000 / pL (may have been repeated if 120,000 / pL to 150,000 / pL)• Positive result for SARS-CoV-2 infection

[0131] If the participant met the laboratory eligibility criteria on the second assessment, he or she was to be permitted to enter the study. It was not to be considered a retesting if blood samples had to be redrawn because of sample handling problems, breakage, sample integrity, or laboratory error.

[0132] If a hematology / chemistry lab value fell outside the normal range and was judged by the Investigator to be clinically significant and was NOT one of explicit exclusionary laboratory testing, it may have been repeated once and if the repeat value was no longer considered clinically significant then that specific laboratory testing result should not have disqualified a participant from the study.Study Intervention(s) and Concomitant Therapy

[0133] Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol (Tables 5-6).

[0134] Rilzabrutinib and placebo tablets were supplied ready for use; no preparation was needed. Participants were to use study medication directly from the dispensed bottles.

[0135] Participants were to administer rilzabrutinib or placebo by mouth twice daily (400 mg BID cohort) or three times daily (400 mg TID cohort). Consecutive doses should ideally have been administered approximately 12 hours apart (and not less than 8 hours apart) for 400 mg BID dosing, and ideally approximately 6 hours apart (and not less than 4 hours apart) for 400 mg TID dosing. Tablets should not have been broken or crushed.

[0136] Study intervention was to be dispensed at the study visits. The study intervention to be taken by a participant was to be allocated using an IRT. The site was to contact the IRT prior to the start of study intervention administration for each participant. The site was to record the intervention assignment on the applicable case report form, if required.

[0137] Table 5. Overview of study interventions administered.

[0138] Table 6. Arms and associated interventions.

[0139] Participants were to continue their background therapy of ICS / LAB A (fluticasone / salmeterol (non-investigational medicinal product), standardized at screening). Background therapy of ICS / LAB A was to be withdrawn during the 12-week randomized treatment period and resumed at the end of the IMP treatment period (Figures 1-2 and Table 7).

[0140] Table 7. Background therapy.

[0141] Participants were to use the same inhaler type (either DPI or MDI) throughout the study.Dose Modification

[0142] Rilzabrutinib dose modification was not allowed.Concomitant Therapy

[0143] Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and / or herbal supplements) that the participant was receiving at the time of enrollment or received during the study must have been recorded along with:• Reason for use• Dates of administration including start and end dates• Dosage information including dose and

[0144] The Medical Monitor should have been contacted if there were any questions regarding concomitant or prior therapy.

[0145] Participants were to have abstained from taking prescription or nonprescription drugs (including vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study intervention until completion of the follow-up visit, unless, in the opinion of the Investigator, the medication would not interfere with the study.

[0146] Medications that were not listed as exclusion criteria were permitted for use during the trial.

[0147] These include the following:• Oral corticosteroid rinses (mouth washes) were allowed, as are ocular, intranasal, and topical corticosteroids.• Clinically relevant drugs that are substrates of cytochrome P450 (CYP)3 A, including those considered to be sensitive CYP3 A substrates7were permitted. Appropriate caution was to be used when co-administering sensitive CYP3 A substrates with rilzabrutinib and a benefit-risk assessment was to be conducted for each medication. Consideration should also have been given to avoidance of high doses, dose reduction, or replacement of sensitive and narrow therapeutic index CYP3 A substrate drugs. Systemic moderate or strong inhibitors (including foods such as grapefruit juice) and inducers of CYP3 A should have been avoided.• Histamine 2 (H2) receptor blocking drugs were permitted provided they could have been given 2-3 hours after administration of rilzabrutinib or placebo. For patients receiving the IMP three times a day, H2-receptor blockers must have been taken once daily only, 2-3 hours after the evening dose of rilzabrutinib or placebo.7Sensitive CYP3 A substrates include Alfentanil, avanafil, budesonide, buspirone, conivaptan, darifenacin, darunavir, dasatinib, dronedarone, ebastine, eletriptan, eplerenone, everolimus, felodipine, ibrutinib, indinavir, lomitapide, lovastatin, lurasidone, maraviroc, midazolam, naloxegol, nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, ticagrelor, tolvaptan, tipranavir, triazolam, and vardenafil. Source: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers, U.S. Food and Drug Administration. This list is not intended to be exhaustive and may be out of date. For updated information, please refer to https: / / www.fda.gov / drugs / drug- interactionslabeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and- inducers or product labeling.• Antacids were permitted provided they were given 2 hours or more apart from rilzabrutinib or placebo.• Previously initiated immunotherapy was to be allowed to continue during the study.

[0148] The following concomitant treatments were not permitted during the screening or treatment phases:• Any inhaled steroid other than the standardized fluticasone / salmeterol or fluticasone• background therapy administered as per protocol• Systemic steroids (except systemic steroids to treat asthma exacerbations)• LABA other than the salmeterol component of the fixed dose combination administered per protocol• Ipratropium bromide or other inhaled anti-cholinergic agents (tiotropium)*• Methylxanthines (theophylline, aminophyllines)*• Inhaled mucolytic*• Leukotriene receptor antagonists or leukotriene synthesis inhibitors*• Lipoxygenase inhibitors• Cromones• Anti-IL4R mAb (eg, dupilumab (Dupixent®))• Anti-IL5 or IL-5R mAb (eg, benralizumab (Fasenra®), mepolizumab (Nucala®), or reslizumab (Cinqair®))• Anti-IgE mAb (eg, omalizumab (Xolair®))• Anti-TSLP mAb (eg, tezepelumab)• Systemic immunosuppressant (e.g., methotrexate, any anti-TNF mAbs, B and / or T cell targeted immunosuppressive therapies)• Bronchial thermoplasty• Intravenous Ig (IVIG) therapy• Live Attenuated Vaccines8• Beta-adrenergic receptor blockers (except for a selective beta-1 adrenergic receptor blocker used with stable dose at least 1 month prior to Visit 1)8Live (attenuated) vaccines include Chickenpox (Varicella), Intranasal influenza, Measles (Rubeola), Measles-mumps-rubella (MMR) combination, Mumps, Oral polio (Sabin), Oral typhoid, Rubella, Smallpox (Vaccinia), Shingles (Herpes zoster), Bacille Calmette-Guerin, Yellow fever. Note: Shingrix is allowed for Shingles as a non-live Varicella vaccine.• Asthma relievers other than salbutamol / albuterol or levosalbutamol / levalbuterol: their use was not recommended during the study period. In case of use in exceptional circumstances (e.g., prescribed by a physician not participating in the study), their use was to be documented in the patient's file and reported in the eCRF.• Initiation of immunotherapy• Other investigational drugs• Use of proton-pump inhibitor drugs such as omeprazole and esomeprazole (allowed during screening provided they were stopped within 3 days of Day 1).• Use of known systemic strong-to-moderate inducers or inhibitors of CYP3A (allowed during screening provided they were stopped days within 14 days or 5 half-lives (whichever is longer) of Day 1).

[0149] * The third controller was not allowed to be used for an additional 2 weeks prior to screening visit (VI).Rescue Medicine

[0150] If medically necessary, participants may have received rescue therapy for asthma at the discretion of the Investigator as an LOAC event. If practicable and safe, the participant should have undergone EOT Visit (Visit 14) assessment prior to the administration of rescue medications. Participants who discontinued IMP treatment prior to completing the 12-week IMP treatment (due to LOAC or due to other early treatment discontinuation), were to be evaluated as soon as possible at the individual participants’ EOT Visit, using procedures as planned for the EOT Visit at Week 12 (Visit 14). At their EOT visit, participants were to resume their prescreening ICS / LABA background therapy and enter the 4-week safety follow-up period / Post IMP Treatment Period. If a participant’s asthma could not be consistently controlled on his / her original ICS / LABA therapy, and there was a safety concern, additional controller therapies may have been prescribed based on the Investigator’s clinical judgement.Efficacy Assessments

[0151] The following efficacy parameters were to be analyzed for assessing the primary and secondary endpoints.

[0152] The primary endpoint was the proportion of patients with LOAC. The key secondary endpoint for the study was change in pre-bronchodilator FEV1 from baseline at EOT.

[0153] Other efficacy endpoints included:• Change from baseline in pre- and post-bronchodilator FEV1 and other lung function measurement (peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25-75%) at each spirometry endpoint.• Asthma Control Questionnaire-5 (ACQ-5) score change from baseline at EOT and at each assessment time point.• Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ(S)) Self- Administered score change from baseline at EOT and at each assessment time point.• Change from baseline at EOT and change from baseline at each week for asthma symptom scores in the morning and evening (ADSD and ANSD). Questionnaire was to be administered daily and score averaged weekly for analysis.• Change from baseline at EOT and change from baseline at each week in number of inhalations / day of albuterol or levalbuterol for symptom relief.Disease-Specific Efficacy MeasuresSpirometry

[0154] Spirometry was to be performed in accordance with the American Thoracic Society (ATS)ZEuropean Respiratory Society (ERS) guidelines (Graham et al. 2019) and prior to administration of IMP at the planned time point. For prebronchodilator measured parameters, including FEV1, PEF, FVC and FEF 25%-75%, spirometry was to be performed after a wash out period of bronchodilators according to their action duration, for example, withholding the last dose of salbutamol / albuterol or levosalbutamol / levalbuterol for at least 6 hours and withholding the last dose of LABA for at least 12 hours.

[0155] Reversibility is defined as an increase of the absolute FEV1 after administration of bronchodilator and is measured by spirometry as postbronchodilator increase in FEV1 in percent of the prebronchodilator FEV1. After spirometry for measuring prebronchodilator FEV1, participants were to receive 2-4 puffs of albuterol / salbutamol or levalbuterol / levosalbutamol from a primed MDI. The postbronchodilator spirometry may have been repeated several times within 30 minutes after administration of bronchodilator. Alternatively, and only if it was consistent with usual office practice (to be documented),reversibility may have been performed using inhalation of nebulized albuterol / salbutamol or levalbuterol / levosalbutamol.ACQ-5 (Asthma Control Questionnaire, 5-Question Version)

[0156] The ACQ-5 is a questionnaire that measures the adequacy of asthma control and any changes in asthma control that may occur spontaneously or as a result of treatment. The ACQ-5 has five questions on the asthma symptoms and patients are asked to recall how their asthma has been during the previous week and to respond on a 7-point scale for each question (0 = no impairment, 6 = maximum impairment). The ACQ-5 score is the mean of the 5 questions and, therefore, between 0 (totally controlled) and 6 (severely uncontrolled). A high score indicates low asthma control. Participants with a score below 1.0 reflected adequately controlled asthma and participants with scores above 1.0 reflected inadequately controlled asthma. On the 7-point scale of the ACQ-5, a change or difference in score of 0.5 is the smallest change that can be considered clinically important, corresponding to the Minimal Clinically Important Difference (MCID) defined by the developer.

[0157] Measurement properties such as reliability and ability to detect change have been documented in the literature (Juniper et al. 2005). Participants were to complete the questionnaire in an electronic diary during onsite visits.Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ(S)) selfadministered (>12 years)

[0158] The AQLQ(S) was designed as a self-administered patient reported outcome to measure the functional impairments that are most troublesome to adolescents and adults >12 years of age as a result of their asthma. The instrument is comprised of 32 items, each rated on a 7-point Likert scales from 1 to 7. The AQLQ(S) has 4 domains. The domains and the number of items in each domain are as follows:• Symptoms (12 items)• Activity limitation (11 items)• Emotional function (5 items)• Environmental stimuli (4 items)

[0159] A global score is calculated ranging from 1 to 7 and a score by domain. Higher scores indicate better quality of life. The instrument has been used in many clinical trials, and it has been shown to be reliable, valid (patient interviews), and sensitive to change. TheMCID for AQLQ(S) is 0.5 (Juniper et al. 1994). Patients were to complete the questionnaire in an electronic diary during on-site visits.Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD)

[0160] The ADSD and ANSD are PRO measures developed by the PRO Consortium’ Asthma Working Group. Both instruments have been designed to measure asthma symptoms in adult and adolescent (12 years of age and older) patients diagnosed with mild to severe asthma. ADSD and ANSD assess asthma severity based on patient self-report of asthma core symptoms, z.e., difficulty of breathing; wheezing; shortness of breath; chest tightness; chest pain; and cough. Patients were asked to complete the ADSD every night before they went to bed, thinking about their asthma symptoms on that day, from when they got up this morning until then; the ANSD when getting up, thinking about their asthma symptoms from the previous night from when they went to bed until then. They have demonstrated adequate evidence of content validity and cross-sectional measurement properties (z.e., internal consistency reliability, test-retest reliability, convergent validity, and known-groups validity) to measure symptoms of asthma.

[0161] Both the ADSD and ANSD are composed of 6 items rated using an 11 -point NRS that ranges from 0 = None to 10 = As bad as you can imagine (Gater et al. 2016). The participants were to record their daytime and nighttime asthma symptoms in an electronic diary, once in the evening and once in the morning, respectively. The participants were to complete the ADSD and the ANSD.Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC)

[0162] The Patient Global Impression of Severity (PGIS) is a 1-item questionnaire that asks participants to provide a self-assessment of their overall asthma severity for the past week on a 4-point scale. Response choices are: “None”, “Mild”, “Moderate” and “Severe”.

[0163] The Patient Global Impression of Change (PGIC) is a 1-item questionnaire that asks the participant to provide a self-assessment of overall change in their asthma since the participant started taking the study medication on a 7-point scale. The response options range from “Very Much Better” to “Very Much Worse.”

[0164] Participants were to complete the 2 items in an electronic diary during on-site visits.Electronic diary / PEF meter

[0165] The electronic diary / PEF meter was to be dispensed at Visit 1 and recorded information was to be downloaded from this device on the other indicated days. The electronic diary / PEF meter was to be used for daily recording of salbutamol / albuterol or levosalbutamol / levalbuterol use, asthma controller drug use, ADSD / ANSD, and AM and PM PEF.

[0166] On a daily basis throughout the study, the participant was to use an electronic diary / PEF meter to:• Measure morning and evening PEF.• Respond to the morning and evening asthma symptom score ADSD / ANSD questions.• Indicate the number of inhalations / day of salbutamol / albuterol or levosalbutamol / levalbuterol for symptom relief.• Record the number of inhalations / day of ICS / LAB A or ICS background therapy.

[0167] At screening (Visit 1), participants were to be issued an electronic diary and PEF meter. Participants were to be instructed on the use of the devices, and written instructions on the use of the electronic PEF meter were to be provided to the participants. In addition, the Investigator was to instruct the participants on how to record the following variables in the electronic PEF meter:• AM PEF performed within 15 minutes after arising (between 5:30 AM and 12 PM).• PM PEF performed in the evening (between 5:30 PM and 12 AM).• Participants were to try to withhold albuterol or levalbuterol for at least 6 hours prior to measuring their PEF.• Three PEF efforts were to be performed by the participants; all 3 values were to be recorded by the electronic PEF meter, and the highest value was to be used for evaluation.

[0168] Baseline AM PEF was to be the mean AM measurement recorded for the 7 days prior to the first dose of IMP, and baseline PM PEF was to be the mean PM measurement recorded for the 7 days prior to the first dose of IMP. Period stability limit is defined as the respective mean AM or PM PEF obtained over the last 7 days prior to Day 1. There should have been at least 4 days of measurements for setting up the stability limit, and the first dosing visit may have been rescheduled until data for 4 days are available.

[0169] The following efficacy parameters (described in more detail below) were to be analyzed for assessing exploratory endpoints: fractional exhaled nitric oxide (FeNo) and oscillometry.Fractional exhaled nitric oxide (FeNO)

[0170] FeNO levels (ppb) were to be collected on site with a dedicated medical device such as a commercially available hand worn device (NIOX VERO®). Participants were to inhale to total lung capacity through the device and then exhale for 10 seconds at 50 mL / sec.Oscillometry

[0171] Oscillometry is a complementary technique to spirometry determining the physiological behavior of the lung in asthmatics. Oscillometry was to be conducted during tidal breathing using the tremoflo® device (Thorasys, Montreal, Canada) according to ERS recommended guidelines (Oostveen et al. 2003). A minimum of 3 recordings that achieve coefficient of variation of <15% were required for quality control (Peters et al. 2016). Only these data were to be used for the data analysis. The individual measurements could have been reviewed manually to confirm that a quality measurement was indeed performed.Safety Assessments

[0172] Safety assessments included physical examinations, measurements of vital signs, electrocardiograms, clinical safety laboratory assessments, and pregnancy testing.Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting AE definition

[0173] An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention.SAE definition

[0174] An SAE is defined as any adverse event that, at any dose:• Resulted in death• Was life-threatening• Required inpatient hospitalization or prolongation of existing hospitalization.• Resulted in persistent or significant disability / incapacity.• Was a congenital anomaly / birth defect.• Other situations such as significant medical events that may have jeopardized the participant or may have required medical or surgical intervention to prevent one of the other outcomes listed in the above definition (e.g., invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalization, or development of drug dependency or drug abuse).AESI definition

[0175] An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was required. Such events may have required further investigation in order to characterize and understand them. Adverse events of special interest may have been added, modified or removed during a study by protocol amendment. AESIs include the following:• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a female partner of a male participant entered in a study with IMP.• Symptomatic overdose (serious or nonserious) with IMP.• Other project-specific AESI(s), including: severe infections including opportunistic infections; tuberculosis or initiation of medications for suspected tuberculosis; active COVID-19 infection as documented by a positive COVID-19 molecular test; major hemorrhagic events, including symptomatic bleeding in a critical area or organ such as the CNS, or intraocular bleeding, resulting in an SAE; serious adverse events (or non-serious adverse events with a severity level consistent with Grade 3 CTCAE of cytopenia; and atrial fibrillation.Populations for Analyses

[0176] The populations for analyses are defined in Table 8.

[0177] Table 8. Populations for Analyses.

[0178] Participants exposed to study intervention before or without being randomized were not to be considered randomized and were not to be included in any analysis population. The safety experience of these participants was to be reported separately.

[0179] Randomized participants for whom it was unclear whether they took the study intervention were not to be considered as exposed and were to be included in the safety population as randomized.

[0180] For any participant randomized more than once, only the data associated with the first randomization was to be used in any analysis population. The safety experience associated with any later randomization was to be reported separately.Statistical Analyses

[0181] This section is a summary of the planned statistical analyses of the most important endpoints including primary and key secondary endpoints.General considerations

[0182] The baseline value is defined as the last available value before the first dose of double-blind IMP. For participants randomized but not treated, the baseline value is defined as the last available value before randomization.

[0183] Unless otherwise specified, analyses were to be performed by intervention group (and overall for baseline and demographics characteristics).

[0184] Continuous data were to be summarized using the number of available data, mean, standard deviation (SD), median, QI, Q3, minimum and maximum for each intervention group. Categorical and ordinal data were to be summarized using the number and percentage of patients in each intervention group.

[0185] The observation period was to be divided into 3 segments:• The pre-treatment period is defined as the period up to the first IMP administration.• The on-treatment period is defined as the period from the first IMP administration to the last IMP administration + 1 day.• The post-treatment period is defined as the period from the end of the on-treatment period up to the follow-up visit.

[0186] The treatment-emergent period consisted of on-treatment period and posttreatment period.Primary endpoint(s)

[0187] The primary endpoint was proportion of participants with LOAC during the 12-week treatment period.

[0188] The incidence of LOAC was to be analyzed between rilzabrutinib and placebo. The primary analysis was to be performed using a logistic regression model with treatment (Cramer 2002), baseline IgE strata, region (pooled country), and number of asthma exacerbation events (as defined in I 06) within 2 years prior to screening as the covariates. Note that if the number of participants in some regions was too low, these regions may have been pooled with other regions. This strategy also applied to all the rest of the analyses where region was one of the covariates.

[0189] The following comparisons were to be tested without control for type I error:• Rilzabrutinib 400 mg TID versus its matching placebo.• Rilzabrutinib 400 mg BID versus its matching placebo.

[0190] Comparison may also have been done on the pooled 400 mg BID and 400 mg TID dose level groups of rilzabrutinib versus placebo.

[0191] The odds ratio, 95% confidence interval (CI) and nominal p-value for each comparison was to be estimated from this model.Sensitivity analysis

[0192] Sensitivity analyses using all observed values were also to be conducted.Supportive analyses

[0193] Time to LOAC post-randomization was to be analyzed using a Cox regression model with treatment (Cox 1972), baseline IgE strata, and region (pooled country) as covariates. The Kaplan-Meier (KM) method was to be used to estimate the probabilities of the event at specific time points for each treatment group (Kaplan and Meier 1958). Nominal p-value from log-rank test stratified by baseline IgE strata and region was also to be provided.Subgroup analysis

[0194] To assess the consistency in treatment effects across different subgroup levels, subgroup analyses were to be performed for the primary efficacy endpoint with respect to age group, gender, region, and other factors.Secondary endpoint(s)

[0195] A summary of the primary estimand for key secondary endpoints is shown inTable 9 below.

[0196] Table 9. Summary of primary estimand for key secondary endpoints.Secondary efficacy endpoints

[0197] Secondary efficacy endpoints included:• Post-bronchodilator FEV1 change from baseline at EOT.• The absolute change in the percent predicted FEV1 from baseline to EOT (pre-and postbronchodilator).• Change from baseline in pre- and post-bronchodilator FEV1 and in other lung function measurement (peak expiratory flow (PEF), forced vital capacity (FVC), forced expiratory flow (FEF) 25-75%) at each spirometry endpoint.• Asthma Control Questionnaire-5 (ACQ-5) score change from baseline at EOT and at each assessment time point.• Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ(S)) Selfadministered score change from baseline at EOT and at each assessment time point.• Change from baseline at EOT and change from baseline at each week for asthma daytime symptom diary and asthma nighttime symptom diary scores.• Change from baseline at EOT and change from baseline at each week in numbers of inhalations / day of albuterol or levalbuterol for symptom relief.

[0198] Other secondary efficacy endpoints (e.g., FEV1, FVC, PEF, ACQ-5 score, AQLQ, asthma symptom scores) were to be analyzed using the same approach as for the key secondary endpoint, except for that age, gender and height were to be only included in the models for spirometry variables as response variable.Multiplicity considerations

[0199] No adjustments for multiplicity across secondary efficacy endpoints were planned for this Phase 2 study. Nominal p-values were to be reported.Other safety analysis

[0200] The safety variables, including AEs, vital signs, physical examination, and laboratory values were to be summarized using descriptive statistics in each treatment group in the safety population.

[0201] The summary of safety results were to be presented by treatment group. All safety analyses were to be performed on the safety population. The baseline value is defined generally as the last available value before the first dose of IMP.Adverse events

[0202] In general, AEs were to be analyzed in the following 3 categories:• Pre-treatment AEs: AEs that developed, worsened, or became serious during the pretreatment period.• TEAEs: AEs that developed, worsened, or became serious during the treatment- emergent period.• Post-treatment AEs: AEs that developed, worsened, or became serious during the post-treatment period.Example 2: Rilzabrutinib in Asthma

[0203] A study was initiated to evaluate the effect of rilzabrutinib treatment in N=196 patients with moderate-to-severe asthma uncontrolled by ICS / LABA. Over the course of this 12-week PoC withdrawal study, N=64 patients were administered 400 mg BID rilzabrutinib or a placebo, while N=132 patients were administered 400 mg TID rilzabrutinib or placebo.

[0204] The primary endpoint for this study was the proportion of participants with an LOAC event during the treatment period. Secondary endpoints included pre-bronchodilator FEV1 change from baseline at EOT, ACQ-5 score change from baseline, and AQLQ score change from baseline. Other secondary and exploratory endpoints are described in Table 2.

[0205] Compared to patients who received the placebo, patients who received 400 mg BID or 400 mg TID rilzabrutinib exhibited a marked and meaningful improvement in symptoms despite ICS / LABA withdrawal (Table 10). Rilzabrutinib-treated patients experienced a numerical reduction in LOAC events, a significant and meaningful improvement in asthma symptoms (ACQ-5), and an improvement in quality of life as measured by AQLQ. Furthermore, patients did not exhibit any change in FEV1 following ICS / LABA withdrawal.

[0206] Additionally, rilzabrutinib was generally safe, with no evidence of new safety concerns.

[0207] Table 10. Summary of the primary and key secondary endpoints (mITT population).Parameter Placebo Rilzabrutinib Difference P-value PlaceboRilzabrutinibDifferenceP-valueBID 400 mg BID vs. TID 400 mg TID vs.(N=32) (N=32) placebo (N=68) (N=64) placeboPrimary endpointOdds ratio 16 12 (37.5%) 0.570 0.2880 20 12 (18.8%) 0.584 0.2083 incidence of (50.0%) (0.202, (29.4%) (0.253,LOAC 1.608) 1.349)Key secondary endpointLS Mean -0.08 -0.07 (0.08) 0.01 (- 0.9466 -0.04 -0.13 (0.05) -0.09 (- 0.1523 change from (0.08) 0.17, 0.19) (0.05) 0.21, 0.03) baseline in pre- bronchodilator FEV1 (L) at Week 12Patient Demographics

[0208] The 132 and 64 patients enrolled in the 400 mg TID and 400 mg BID cohorts, respectively, were characterized by the demographic information provided in Tables 11-19. The median age of enrolled patients in the 400 mg TID cohort was 50 years, while the median age of enrolled patients in the 400 mg BID cohort was 52 years. For all patients in the 400 mg TID cohort, the median time since first diagnosis of asthma was 17.96 years. For all patients in the 400 mg BID cohort, the median time since first diagnosis of asthma was 20.79 years.

[0209] Table 11. Analysis population.400 mg BID cohort 400 mg TID cohort n (%) Placebo Rilzabrutinib All BID Placebo Rilzabrutinib All TIDBID 400 mg BID TID 400 mg TIDRandomized population 32 (100) 32 (100) 64 (100) 68 (100) 64 (100) 132(100)Efficacy populationModified intent-to-treat 32 (100) 32 (100) 64 (100) 68 (100) 64 (100) 132(mITT) (100)Safety population 32 32 64 68 64 132Pharmacokinetic (PK) 0 31 (96.9) 31 (48.4) 0 64 (100) 64 (48.5) population

[0210] Table 12. Participant disposition.400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib All n (%) BID 400 mg BID (N=64) TID 400 mg TID (N=132)Exposed but not 0 0 0 0 0 0 randomizedRandomized and 0 0 0 0 0 0 not exposedRandomized and 32 (100) 32 (100) 64 (100) 68 (100) 64 (100) 132 (100) exposedStill on study 0 0 0 0 0 0 intervention or missing EOT page400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib All n (%) BID 400 mg BID (N=64) TID 400 mg TID (N=132)(N=32) (N=32) (N=68) (N=64)Completed the 18 (56.3) 18 (56.3) 36 (56.3) 45 (66.2) 44 (68.8) 89 (67.4) study intervention periodDid not 14 (43.8) 14 (43.8) 28 (43.8) 23 (33.8) 20 (31.3) 43 (32.6) complete the study intervention periodReason for permanent study intervention discontinuationAdverse event 2(6.3) 2(6.3) 4(6.3) 2(2.9) 5(7.8) 7(5.3)Related to 2(6.3) 0 2(3.1) 1 (1.5) 3(4.7) 4(3.0)COVID-19Not related to 0 2(6.3) 2(3.1) 1 (1.5) 2(3.1) 3(2.3)COVID-19Lack of 0 0 0 1 (1.5) 1 (1.6) 2(1.5) efficacyPoor 1 (3.1) 1 (3.1) 2(3.1) 0 1 (1.6) 1 (0.8) compliance to protocolWithdrawal by 0 1 (3.1) 1 (1.6) 1 (1.5) 3(4.7) 4(3.0) subjectLoss of asthma 10 (31.3) 8 (25.0) 18 (28.1) 18 (26.5) 10 (15.6) 28 (21.2) control (LOAC)Other 1 (3.1) 2(6.3) 3(4.7) 1 (1.5) 0 1 (0.8)Related to 0 0 0 0 0 0COVID-19 Not related to 1 (3.1) 2(6.3) 3(4.7) 1 (1.5) 0 1 (0.8)COVID-19Reason for study intervention withdrawal by subjectAdverse event 0 1 (3.1) 1 (1.6) 0 2(3.1) 2(1.5)Study 0 0 0 0 0 0 procedure Inconvenience 0 0 0 0 0 0 of device useOther 0 0 0 0 0 0Related to 0 0 0 0 0 0COVID-19 Not related to 0 0 0 0 0 0COVID-19400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib All n (%) BID 400 mg BID (N=64) TID 400 mg TID (N=132)(N=32) (N=32) (N=68) (N=64)Completed the 31 (96.9) 30 (93.8) 61 (95.3) 67 (98.5) 60 (93.8) 127 (96.2) study periodDid not complete 1 (3.1) 2 (6.3) 3 (4.7) 1 (1.5) 4 (6.3) 5 (3.8) the study periodReason for study discontinuationAdverse event 0 1 (3.1) 1 (1.6) 0 0 0Related to 0 0 0 0 0 0COVID-19Not related to 0 1 (3.1) 1 (1.6) 0 0 0COVID-19Poor 1 (3.1) 0 1 (1.6) 0 0 0 compliance to protocolWithdrawal by 0 0 0 1 (1.5) 4 (6.3) 5 (3.8) subject Site terminated 0 0 0 0 0 0 by sponsorStudy 0 1 (3.1) 1 (1.6) 0 0 0 terminated by sponsorOther 0 0 0 0 0 0Related to 0 0 0 0 0 0COVID-19Not related to 0 0 0 0 0 0COVID-19Status at last 32 (100) 31 (96.9) 63 (98.4) 68 (100) 64 (100) 132 (100) contactAlive 32 (100) 31 (96.9) 63 (98.4) 68 (100) 64 (100) 132 (100)Dead 0 0 0 0 0 0

[0211] Table 13. Demographic and participant characteristics at baseline (randomized population).400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib AllBID 400 mg BID (N=64) TID 400 mg TID (N=132)Age (years) Number 32 32 64 68 64 132Mean (SD) 50.8 (12.3) 48.0 (13.4) 49.4 (12.8) 48.6 (13.7) 48.8 (13.3) 48.7 (13.5)Median 53.5 51.5 52.0 48.5 50.0 50.0Min ; Max 28 ; 70 21 ; 70 21 ; 70 18 ; 70 18 ; 68 18 ; 70Age group 1 (years)[n (%)]Number 32 32 64 68 64 132< 45 10 (31.3) 12 (37.5) 22 (34.4) 29 (42.6) 25 (39.1) 54 (40.9)> 45 22 (68.8) 20 (62.5) 42 (65.6) 39 (57.4) 39 (60.9) 78 (59.1)Age group 2 (years)[n (%)]Number 32 32 64 68 64 132< 65 28 (87.5) 29 (90.6) 57 (89.1) 57 (83.8) 56 (87.5) 113 (85.6)> 65 4 (12.5) 3 (9.4) 7 (10.9) 11 (16.2) 8 (12.5) 19 (14.4)Sex [n (%)] Number 32 32 64 68 64 132Male 8 (25.0) 14 (43.8) 22 (34.4) 27 (39.7) 25 (39.1) 52 (39.4)Female 24 (75.0) 18 (56.3) 42 (65.6) 41 (60.3) 39 (60.9) 80 (60.6)Height (cm) Number 32 32 64 68 64 132Mean (SD) 164.9 166.0 (8.8) 165.4 (9.5) 167.9 169.5 (11.9) 168.6 (11.8)(10.2) (11.8)Median 165.0 164.5 165.0 169.5 169.0 169.0Min ; Max 148 ; 185 150 ; 184 148 ; 185 140 ; 194 146 ; 194 140 ; 194Weight (kg) Number 32 32 64 68 64 132Mean (SD) 77.0 (13.1) 78.0 (15.2) 77.5 (14.0) 77.2 (14.1) 83.2 (12.4) 80.1 (13.6)Median 76.5 75.5 76.0 78.0 83.7 81.9Min ; Max 50 ; 117 54 ; 126 50 ; 126 48 ; 104 54 ; 112 48 ; 112Weight by category(kg) [n (%)]Number 32 32 64 68 64 132< 60 4 (12.5) 3 (9.4) 7 (10.9) 12 (17.6) 2 (3.1) 14 (10.6)> 60 - < 90 25 (78.1) 23 (71.9) 48 (75.0) 40 (58.8) 41 (64.1) 81 (61.4)> 90 3 (9.4) 6 (18.8) 9 (14.1) 16 (23.5) 21 (32.8) 37 (28.0)BMI (kg / m2) Number 32 32 64 68 64 132Mean (SD) 28.39 28.18 (4.01) 28.29 27.46 29.08 (4.29) 28.24 (4.59)(4.79) (4.38) (4.75)400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib AllBID 400 mg BID (N=64) TID 400 mg TID (N=132)Median 27.60 27.75 27.65 26.75 28.90 27.55Min; Max 20.5; 40.1 21.8; 38.2 20.5; 40.1 19.6 ; 38.3 21.6; 38.7 19.6 ; 38.7BMI by category(kg / m2) [n (%)]Number 32 32 64 68 64 132<25 6(18.8) 8 (25.0) 14 (21.9) 22(32.4) 12(18.8) 34 (25.8)>25- <30 17 (53.1) 16 (50.0) 33 (51.6) 27 (39.7) 29 (45.3) 56 (42.4)>30 9(28.1) 8 (25.0) 17 (26.6) 19(27.9) 23 (35.9) 42 (31.8)Region [n (%)] Number 32 32 64 68 64 132Eastern Europe 4(12.5) 3 (9.4) 7(10.9) 45 (66.2) 43 (67.2) 88 (66.7)Latin America 25 (78.1) 25 (78.1) 50 (78.1) 19 (27.9) 19 (29.7) 38 (28.8)Western Countries 1(3.1) 2(6.3) 3(4.7) 2(2.9) 2(3.1) 4(3.0)Asia and Pacific 2(6.3) 2(6.3) 4(6.3) 2(2.9) 0 2(1.5)Region

[0212] Table 14. Asthma history characteristics at baseline (randomized population).400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo TIDRilzabrutinib AllBID 400 mg BID (N=64) (N=68) 400 mg TID (N=132)Age of onset of asthma (years)Number 32 32 64 68 64 132Mean(SD) 28.1 (16.6) 24.2(16.4) 26.1 (16.5) 28.5 (18.0) 28.7 (16.5) 28.6(17.2)Median 29.5 26.5 27.5 28.0 30.0 29.5Q1 ;Q3 15.0; 40.0 9.5 ; 36.0 11.5; 37.0 13.0; 44.5 13.5; 40.5 13.0; 41.5Min; Max 0 ; 65 0 ; 60 0 ; 65 0 ; 63 1 ; 61 0 ; 63Age of onset of asthma group 1(years) [n (%)]Number 32 32 64 68 64 132< 12 7(21.9) 9(28.1) 16 (25.0) 15 (22.1) 14(21.9) 29 (22.0)>12- <18 2(6.3) 5(15.6) 7(10.9) 5(7.4) 5(7.8) 10(7.6)>18- <40 15 (46.9) 14 (43.8) 29 (45.3) 28 (41.2) 27(42.2) 55 (41.7)>40 8 (25.0) 4(12.5) 12 (18.8) 20 (29.4) 18 (28.1) 38 (28.8)Age of onset of asthma group 2 (years) [n (%)]Number 32 32 64 68 64 132< 18 9(28.1) 14 (43.8) 23 (35.9) 20 (29.4) 19(29.7) 39 (29.5)400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo TIDRilzabrutinib AllBID 400 mg BID (N=64) (N=68) 400 mg TID (N=132)(N=32) (N=32) (N=64)> 18 23 (71.9) 18 (56.3) 41 (64.1) 48 (70.6) 45 (70.3) 93 (70.5)Time since first diagnosis of asthma (years)Number 32 32 64 68 64 132Mean(SD) 23.47 24.89(14.90) 24.18 20.93 (14.00)21.02(13.28)20.97 (13.61)(13.87) (14.30)Median 21.58 20.50 20.79 17.29 20.04 17.96Q1 ;Q3 12.63 ; 14.96 ; 34.92 13.71 ; 11.08; 32.21 9.67 ; 29.08 10.38 ; 30.0033.54 33.54Min; Max 1.3 ; 54.0 3.8 ; 56.5 1.3 ; 56.5 1.1 ; 55.8 1.8 ; 62.2 1.1 ; 62.2With history of atopic medical conditions [n (%)]Number 32 32 64 68 64 132Yes 17 (53.1) 20 (62.5) 37 (57.8) 24 (35.3) 21 (32.8) 45 (34.1)Ongoing 16 (50.0) 19 (59.4) 35 (54.7) 24 (35.3) 21 (32.8) 45 (34.1)Smoking history[n(%)] Number 32 32 64 68 64 132Former 8(25.0) 4(12.5) 12(18.8) 6(8.8) 6(9.4) 12(9.1)Never 24 (75.0) 28 (87.5) 52 (81.3) 62 (91.2) 58 (90.6) 120(90.9)Time since cessation (years)Number 8 4 12 6 6 12Mean(SD) 19.74 19.46(10.13) 19.65 21.82 (17.53)20.63 (11.86)21.22 (14.28)(15.64) (13.55)Median 21.21 20.67 21.21 17.25 20.63 20.63Q1 ;Q3 3.92; 32.17 12.29 ; 26.63 6.33 ; 31.21 9.33 ; 41.17 15.58 ; 25.42 9.33 ; 32.00Min; Max 0.8 ; 42.6 6.2 ; 30.3 0.8 ; 42.6 2.5 ; 43.4 2.9 ; 38.6 2.5 ; 43.4Pack-year Number 8 4 12 6 6 12Mean(SD) 1.402 4.500(1.291) 2.434 5.183 (2.669)3.092(2.288)4.138 (2.610)(1.139) (1.899)Median 1.300 4.500 2.400 4.500 3.000 4.000Q1 ;Q3 0.400; 3.500 ; 5.500 0.900; 4.000 ; 7.500 1.000 ; 4.6502.050 ; 5.7502.400 3.500Min; Max 0.01 ; 3.00 3.00 ; 6.00 0.01 ; 6.00 1.60; 9.00 0.40 ; 6.50 0.40 ; 9.00E-cigarette history [n (%)]Number 32 32 64 68 64 132Former 0 0 0 0 0 0Never 32 (100) 32 (100) 64 (100) 68 (100) 64 (100) 132(100)

[0213] Table 15. Asthma severity and control at baseline (randomized population).400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib AllBID 400 mg BID (N=64) TID 400 mg TID (N=132)ICS / LABA dose level [n (%)]Number 32 32 64 68 64 132High 29 (90.6) 27 (84.4) 56 (87.5) 33 (48.5) 35 (54.7) 68 (51.5)Medium 3 (9.4) 5 (15.6) 8 (12.5) 35 (51.5) 29 (45.3) 64 (48.5)ICS / LABA total dose (ug) Number 32 32 64 68 64 132Mean (SD) 953.1 953.1 (265.2) 953.1 742.6 773.4 (250.9) 757.6(148.1) (213.0) (251.7) (250.8)Median 1000.0 1000.0 1000.0 500.0 1000.0 1000.0QI ; Q3 1000.0 ; 1000.0 ; 1000.0 ; 500.0 ; 500.0 ; 1000.0 500.0 ;1000.0 1000.0 1000.0 1000.0 1000.0Min ; Max 500 ; 500 ; 2000 500 ; 500 ; 500 ; 1000 500 ;1000 2000 1000 1000LABA total daily dose(ug) Number 32 32 64 68 64 132Mean (SD) 98.4 (8.8) 100.0 (22.0) 99.2 97.8 96.1 (13.5) 97.0(16.6) (18.2) (16.1)Median 100.0 100.0 100.0 100.0 100.0 100.0Q1 ; Q3 100.0 ; 100.0 ; 100.0 100.0 ; 100.0 ; 100.0 ; 100.0 100.0 ;100.0 100.0 100.0 100.0Min ; Max 50 ; 100 50 ; 200 50 ; 200 50 ; 200 50 ; 100 50 ; 200Number of prescribed salbutamol / albuterol or levosalbutamol / levalbuterol(puffs)Number 19 23 42 53 47 100Mean (SD) 1.5 (0.5) 2.4 (2.3) 2.0 (1.8) 2.3 (2.9) 2.0 (1.8) 2.2 (2.4)Median 2.0 2.0 2.0 1.0 1.0 1.0Q1 ; Q3 1.0 ; 2.0 1.0 ; 2.0 1.0 ; 2.0 1.0 ; 2.0 1.0 ; 2.0 1.0 ; 2.0Min ; Max 1 ; 2 0 ; 8 0 ; 8 1 ; 20 1 ; 8 1 ; 20Time since last asthma exacerbation (months) Number 32 32 64 68 64 132Mean (SD) 6.94 7.69 (4.83) 7.31 8.51 9.64 (4.90) 9.06(3.73) (4.30) (4.55) (4.74)Median 6.00 7.00 6.00 8.00 9.00 8.00Q1 ; Q3 4.00 ; 4.00 ; 10.00 4.00 ; 6.00 ; 6.00 ; 12.50 6.00 ;8.50 9.00 11.00 11.50Min ; Max 2.0 ; 15.0 2.0 ; 23.0 2.0 ; 23.0 1.0 ; 24.0 2.0 ; 24.0 1.0 ; 24.0400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib AllBID 400 mg BID (N=64) TID 400 mg TID (N=132)Number of asthma exacerbations experienced 2 years before the screening visitNumber 32 32 64 68 64 132Mean(SD) 2.3 (1.5) 1.9 (1.0) 2.1 (1.2) 1.3 (0.7) 1.5 (0.8) 1.4 (0.7)Median 2.0 2.0 2.0 1.0 1.0 1.0Q1 ;Q3 1.0; 2.5 1.0; 2.5 1.0; 2.5 1.0 ; 1.5 1.0; 2.0 1.0; 2.0Min ; Max 1 ; 8 1 ; 5 1 ; 8 1 ; 6 1 ; 5 1 ; 6Number of asthma exacerbations experienced 2 years before the screening visit [n (%)] Number 32 32 64 68 64 1321 9 (28.1) 13 (40.6) 22 (34.4) 51 (75.0) 36 (56.3) 87 (65.9)2 15 (46.9) 11 (34.4) 26 (40.6) 16 (23.5) 23 (35.9) 39 (29.5)3 3 (9.4) 7(21.9) 10 (15.6) 0 4 (6.3) 4(3.0)>4 5(15.6) 1 (3.1) 6(9.4) 1 (1.5) 1 (1.6) 2(1.5)Number of asthma exacerbations experienced 1 year before the screening visit Number 32 32 64 68 64 132Mean(SD) 1.6 (0.9) 1.4 (0.8) 1.5 (0.8) 0.8 (0.6) 0.8 (0.8) 0.8 (0.7)Median 2.0 1.0 1.0 1.0 1.0 1.0Q1 ;Q3 1.0; 2.0 1.0; 2.0 1.0; 2.0 0.0 ; 1.0 0.0; 1.0 0.0 ; 1.0Min ; Max 0;4 0;3 0;4 0;3 0;4 0;4Number of asthma exacerbations experienced 1 year before the screening visit [n (%)] Number 32 32 64 68 64 1320 2(6.3) 2 (6.3) 4 (6.3) 19 (27.9) 23 (35.9) 42 (31.8)1 13 (40.6) 19 (59.4) 32 (50.0) 43 (63.2) 31 (48.4) 74 (56.1)2 13 (40.6) 8 (25.0) 21 (32.8) 5 (7.4) 9(14.1) 14 (10.6)3 3(9.4) 3 (9.4) 6(9.4) 1 (1.5) 0 1 (0.8)>4 1 (3.1) 0 1 (1.6) 0 1 (1.6) 1 (0.8)Number of asthma exacerbations experienced 1 year before the screening visit group 2 [n (%)]Number 32 32 64 68 64 1320 2(6.3) 2 (6.3) 4 (6.3) 19 (27.9) 23 (35.9) 42 (31.8)> 1 30(93.8) 30 (93.8) 60 (93.8) 49 (72.1) 41 (64.1) 90 (68.2)400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib AllBID 400 mg BID (N=64) TID 400 mg TID (N=132)Number of asthma exacerbations required hospitalization or emergency medical care within 2 years before the screening visit Number 32 32 64 68 64 132Mean(SD) 0.5 (1.3) 0.1 (0.3) 0.3 (1.0) 0.3 (0.6) 0.2 (0.5) 0.2 (0.5)Median 0.0 0.0 0.0 0.0 0.0 0.0Q1 ;Q3 0.0; 0.5 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0Min ; Max 0;7 0 ; 1 0;7 0;2 0;2 0;2Number of asthma exacerbations required hospitalization or emergency medical care within 2 years before the screening visit group [n (%)] Number 32 32 64 68 64 1320 24(75.0) 29 (90.6) 53 (82.8) 54 (79.4) 55 (85.9) 109(82.6)1 4(12.5) 3 (9.4) 7(10.9) 10(14.7) 6(9.4) 16(12.1)2 3 (9.4) 0 3 (4.7) 4(5.9) 3 (4.7) 7(5.3)3 0 0 0 0 0 0>4 1 (3.1) 0 1 (1.6) 0 0 0Number of asthma exacerbations required hospitalization or emergency medical care within 1 year before the screening visit Number 32 32 64 68 64 132Mean(SD) 0.3 (0.6) 0.1 (0.3) 0.2 (0.5) 0.2 (0.4) 0.1 (0.4) 0.2 (0.4)Median 0.0 0.0 0.0 0.0 0.0 0.0Q1 ;Q3 0.0; 0.0 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0Min ; Max 0;3 0 ; 1 0;3 0 ; 1 0;2 0;2Number of asthma exacerbations required hospitalization or emergency medical care within 1 year before the screening visit group [n (%)] Number 32 32 64 68 64 1320 26 (81.3) 29 (90.6) 55 (85.9) 55 (80.9) 58 (90.6) 113 (85.6)1 5(15.6) 3 (9.4) 8(12.5) 13 (19.1) 5 (7.8) 18(13.6)2 0 0 0 0 1 (1.6) 1 (0.8)3 1 (3.1) 0 1 (1.6) 0 0 0>4 0 0 0 0 0 0Pre-bronchodilator FEV 1 (L) Number 32 31 63 67 63 130400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib AllBID 400 mg BID (N=64) TID 400 mg TID (N=132)(N=32) (N=32) (N=68) (N=64)Mean(SD) 2.16 2.11 (0.67) 2.13 2.42 2.50(0.95) 2.46(0.77) (0.72) (0.90) (0.92)Median 2.10 1.94 2.02 2.15 2.36 2.20Q1 ;Q3 1.47; 1.59; 2.52 1.59; 1.77; 1.73; 3.10 1.75;2.50 2.52 2.98 3.03Min; Max 1.2; 3.9 1.0; 3.8 1.0; 3.9 1.0; 5.0 1.1; 5.3 1.0; 5.3Pre-bronchodilator FEV 1 percent predicted (%)Number 32 31 63 68 63 131Mean(SD) 71.7 66.4(10.4) 69.1 76.0 75.7(16.2) 75.9(12.7) (11.8) (16.7) (16.4)Median 72.5 64.0 68.0 74.5 78.0 77.0Q1 ;Q3 61.5; 58.0 ; 75.0 59.0; 62.5; 65.0 ; 85.0 64.0;79.5 78.0 87.0 86.0Min; Max 54; 115 50 ; 87 50; 115 50; 115 35 ; 118 35 ; 118Pre-bronchodilator FEV 1 percent predicted group(%) [n (%)]Number 32 31 63 68 63 131< 80 24 (75.0) 26 (83.9) 50 (79.4) 41 (60.3) 37 (58.7) 78 (59.5)> 80 8 (25.0) 5 (16.1) 13 (20.6) 27 (39.7) 26 (41.3) 53 (40.5)Post-bronchodilator FEV 1(L)Number 32 32 64 63 59 122Mean (SD) 2.39 2.40 (0.75) 2.40 2.60 2.66 (0.98) 2.63(0.77) (0.76) (0.91) (0.94)Median 2.30 2.21 2.26 2.35 2.51 2.42Q1 ;Q3 1.77; 1.96; 2.79 1.88; 1.94; 1.83; 3.27 1.91;2.86 2.85 3.03 3.08Min; Max 1.3; 4.3 1.2; 4.3 1.2; 4.3 1.1 ; 5.1 1.3; 5.3 1.1 ; 5.3Post-bronchodilator FEV 1 percent predicted (%)Number 32 32 64 67 62 129Mean(SD) 79.3 75.7(14.9) 77.5 82.0 81.9(14.9) 82.0(12.9) (13.9) (16.2) (15.5)Median 80.0 75.0 77.0 82.0 81.0 81.0Q1 ;Q3 70.5; 64.0 ; 85.5 67.5; 68.0; 71.0; 91.0 70.0;87.0 86.5 93.0 91.0Min; Max 53; 111 50 ; 126 50 ; 126 50; 117 51 ; 122 50 ; 122FEV 1 reversibility at screening (%)Number 30 32 62 67 64 131Mean(SD) 22.901 25.238 24.107 21.265 23.026 22.125(10.238) (12.189) (11.257) (14.469) (10.145) (12.527)Median 20.000 21.600 20.000 18.000 19.750 19.000400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib AllBID 400 mg BID (N=64) TID 400 mg TID (N=132)Q1 ;Q3 14.000; 15.500; 15.000; 14.000; 15.700; 15.000;29.000 35.500 30.600 26.000 28.825 27.000Min; Max 12.00; 10.00 ; 55.00 10.00; -1.00; 12.20 ; 55.00 -1.00;46.00 55.00 105.00 105.00FEV 1 reversibility (%) Number 30 29 59 60 56 116Mean(SD) 11.364 12.927(9.681) 12.132 7.142 7.932 7.523(13.206) (11.535) (8.179) (10.140) (9.146)Median 8.329 13.632 9.396 4.708 5.539 5.239Q1 ;Q3 4.079; 5.722; 18.199 4.977; 2.062; 1.105 ; 11.469 1.634;13.434 16.887 10.190 10.658Min; Max -2.84; -1.82; 33.42 -2.84; -4.56; -6.78 ; 53.68 -6.78 ;67.78 67.78 33.53 53.68Baseline FEV 1 reversibility group (%) [n (%)]Number 30 29 59 60 56 116< 12 21 (70.0) 14 (48.3) 35 (59.3) 48 (80.0) 43 (76.8) 91 (78.4)> 12 9(30.0) 15 (51.7) 24 (40.7) 12 (20.0) 13 (23.2) 25 (21.6)AM PEF (L / min) Number 32 32 64 68 63 131Mean(SD) 319.66 307.34 313.50 304.13 323.69 313.54(130.75) (123.27) (126.21) (121.76) (107.13) (114.94) Median 297.19 305.07 302.07 277.79 307.86 289.71Q1 ;Q3 214.29; 211.46; 211.46; 212.10; 245.14; 227.43 ;391.83 352.59 383.18 371.07 387.43 382.43Min; Max 148.6; 116.0; 611.1 116.0; 96.5 ; 144.8 ; 567.3 96.5 ;632.4 632.4 631.3 631.3PM PEF (L / min) Number 32 32 64 67 62 129Mean(SD) 322.39 320.15 321.27 308.20 330.75 319.04(127.71) (117.16) (121.57) (118.90) (104.19) (112.21) Median 298.29 317.78 306.91 283.43 319.36 306.29Q1 ;Q3 221.95 ; 220.92; 220.92; 218.33 ; 260.43 ; 234.29;387.43 378.00 378.93 380.57 409.43 383.71Min; Max 153.4; 135.6 ; 622.6 135.6; 99.7; 146.0 ; 557.6 99.7;651.6 651.6 596.2 596.2ACQ-5 score Number 32 32 64 68 64 132Mean(SD) 2.19 2.04(0.37) 2.12 2.18 2.24(0.48) 2.21(0.40) (0.38) (0.40) (0.44)Median 2.20 2.00 2.00 2.20 2.20 2.20Q1 ;Q3 2.00; 1.80; 2.20 1.80; 1.80; 2.00 ; 2.60 2.00;2.40 2.30 2.40 2.60Min; Max 1.4; 3.2 1.4; 2.8 1.4; 3.2 1.2; 3.2 1.4; 4.0 1.2; 4.0400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib AllBID 400 mg BID (N=64) TID 400 mg TID (N=132)ACQ-5 score group [n(%)] Number 32 32 64 68 64 132<2 15 (46.9) 19 (59.4) 34 (53.1) 29 (42.6) 24 (37.5) 53 (40.2)>2 17(53.1) 13 (40.6) 30 (46.9) 39 (57.4) 40 (62.5) 79 (59.8)AQLQ global score Number 31 32 63 67 62 129Mean(SD) 4.67 4.91 (1.04) 4.79 4.68 4.96(0.71) 4.82(1.07) (1.06) (0.83) (0.79)Median 4.69 5.19 4.88 4.56 4.94 4.81Q1 ;Q3 4.13; 4.31; 5.64 4.13; 4.00; 4.38 ; 5.44 4.22;5.59 5.59 5.41 5.41Min; Max 2.1 ; 6.2 2.4 ; 6.4 2.1; 6.4 2.8 ; 6.3 3.7 ; 6.6 2.8 ; 6.6PGIS score Number 31 32 63 67 62 129Mean(SD) 1.6 (0.5) 1.3 (0.6) 1.5 (0.6) 1.7 (0.6) 1.6 (0.6) 1.7 (0.6)Median 2.0 1.0 1.0 2.0 2.0 2.0Q1 ;Q3 1.0; 2.0 1.0; 2.0 1.0; 2.0 1.0; 2.0 1.0; 2.0 1.0; 2.0Min ; Max 1 ; 2 0;3 0;3 0;3 0;2 0;3Number of inhalations of salbutamol / albuterol or levosalbutamol / levalbuterol / 24 hours (puffs) Number 32 32 64 67 62 129Mean(SD) 2.52 1.57(1.98) 2.04 0.94 0.82(1.50) 0.88(3.02) (2.58) (2.13) (1.85)Median 1.29 0.62 0.85 0.00 0.00 0.00Q1 ;Q3 0.00; 0.00 ; 2.93 0.00; 0.00; 0.00; 1.00 0.00;4.71 4.00 1.14 1.00Min; Max 0.0 ; 12.3 0.0 ; 7.4 0.0 ; 12.30.0 ; 12.5 0.0 ; 7.3 0.0 ; 12.5

[0214] Table 16. Summary of baseline biomarkers (randomized population).400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib AllBID 400 mg BID (N=64) TID 400 mg TID (N=132)Blood eosinophils(109 / L)Number 32 32 64 68 64 132Mean(SD) 0.326 0.381 (0.334) 0.354 0.267 0.248 (0.215) 0.257(0.242) (0.290) (0.290) (0.256)Median 0.285 0.275 0.280 0.170 0.165 0.170Q1 ;Q3 0.160; 0.140; 0.495 0.150; 0.100; 0.100; 0.325 0.100;0.420 0.470 0.315 0.320Min; Max 0.02; 1.18 0.03 ; 1.59 0.02 ; 1.59 0.02 ; 1.51 0.04; 1.06 0.02; 1.51Blood eosinophils group [n (%)]Number 32 31 64 68 64 132<0.15 6(18.8) 8 (25.8) 14(21.9) 29 (42.6) 28 (43.8) 57(43.2)>0.15 -< 0.3 13 (40.6) 10 (31.3) 23 (35.9) 20 (29.4) 18 (28.1) 38 (28.8)>0.3 13 (40.6) 14 (43.8) 27(42.2) 19 (27.9) 18 (28.1) 37(28.0)FeNO (ppb) Number 31 32 63 64 62 126Mean(SD) 36.5 (34.4) 37.4(39.3) 37.0 (36.7) 24.4(22.2) 23.0(17.5) 23.7 (19.9)Median 26.0 27.0 26.0 17.5 17.0 17.5Q1 ;Q3 13.0; 46.0 18.5 ; 39.5 15.0 ; 42.0 11.5 ; 31.0 11.0; 32.0 11.0; 32.0Min; Max 8 ; 161 11 ; 231 8 ; 231 5 ; 147 5 ; 85 5 ; 147FeNO group 1 [n (%)] Number 31 32 63 64 62 126<25 15 (48.4) 12 (37.5) 27(42.9) 42 (65.6) 42 (67.7) 84(66.7)>25- <50 10 (32.3) 15 (46.9) 25 (39.7) 18 (28.1) 16 (25.8) 34 (27.0)> 50 6 (19.4) 5 (15.6) 11 (17.5) 4 (6.3) 4 (6.5) 8 (6.3)FeNO group 2 [n(%)]Number 31 32 63 64 62 126< 35 19 (61.3) 21 (65.6) 40 (63.5) 50 (78.1) 47 (75.8) 97 (77.0)>35 12 (38.7) 11 (34.4) 23 (36.5) 14 (21.9) 15 (24.2) 29(23.0)Total IgE (lU / mL) Number 32 32 64 68 64 132Mean(SD) 526.43 509.28 517.85 386.70 517.94 450.33(630.53) (815.43) (723.11) (724.05) (924.94) (826.98)Median 281.05 178.40 210.80 119.65 132.65 121.85Q1 ;Q3 88.70; 95.55 ; 682.20 93.30; 64.35 ; 40.00 ; 466.70 60.85 ;718.35 708.25 366.40 410.25Min; Max 10.9; 7.9 ; 4030.0 7.9; 2.9 ; 3630.0 0.2; 4015.0 0.2; 4015.02413.0 4030.0Total IgE level (lU / mL) [n (%)]400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib AllBID 400 mg BID (N=64) TID 400 mg TID (N=132)Number 32 32 64 68 64 132< 100 11 (34.4) 8 (25.0) 19 (29.7) 27 (39.7) 23 (35.9) 50 (37.9)> 100 21 (65.6) 24 (75.0) 45 (70.3) 41 (60.3) 41 (64.1) 82 (62.1)Total IgG (lU / mL)Number 32 32 64 68 64 132Mean (SD) 12.325 11.941 (2.805) 12.133 11.546 11.643 11.593(2.582) (2.681) (2.590) (2.601) (2.586)Median 12.210 11.645 12.020 10.985 11.385 11.205Q1 ; Q3 10.640 ; 9.705 ; 14.055 10.160 ; 9.630 ; 9.830 ; 13.120 9.650 ;13.490 13.615 12.920 13.100Min ; Max 6.90 ; 7.59 ; 17.90 6.90 ; 6.63 ; 19.75 6.28 ; 19.80 6.28 ; 19.8020.46 20.46Total IgA (lU / mL)Number 32 32 64 68 64 132Mean (SD) 2543.4 2785.9 2664.7 2510.1 2540.5 2524.8(1226.2) (1299.6) (1259.3) (1108.5) (1349.0) (1226.3)Median 2665.0 2440.0 2600.0 2190.0 2175.0 2190.0Q1 ; Q3 1570.0 ; 1785.0 ; 1695.0 ; 1585.0 ; 1650.0 ; 1640.0 ;3295.0 3525.0 3470.0 3340.0 2990.0 3240.0Min ; Max 360 ; 5640 890 ; 6690 360 ; 6690 730 ; 5100 930 ; 8950 730 ; 8950Total IgM (lU / mL)Number 32 32 64Mean (SD) 1.030 1.075 (0.579) 1.053 1.189 1.121 (0.718) 1.156(0.525) (0.549) (0.683) (0.698)Median 0.955 1.025 0.990 1.005 0.895 0.950Q1 ; Q3 0.645 ; 0.610 ; 1.365 0.610 ; 0.800 ; 0.670 ; 1.360 0.730 ;1.285 1.330 1.310 1.330Min ; Max 0.29 ; 2.40 0.26 ; 2.93 0.26 ; 2.93 0.25 ; 3.66 0.30 ; 3.88 0.25 ; 3.88

[0215] Table 17. Atopic comorbidity history (randomized population).400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo Rilzabrutinib All (N=132) n (%) BID 400 mg BID (N=64) TID (N=68) 400 mg TIDAny comorbidity historyNumber 32 32 64 68 64 132Yes 29 (90.6) 29 (90.6) 58 (90.6) 48 (70.6) 44 (68.8) 92 (69.7)Ongoing 29 (90.6) 28 (87.5) 57 (89.1) 48 (70.6) 44 (68.8) 92 (69.7) conditionAtopic diseases Number 32 32 64 68 64 132Yes 17 (53.1) 20 (62.5) 37 (57.8) 24 (35.3) 21 (32.8) 45 (34.1)400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo RilzabrutinibAll (N=132) n (%) BID 400 mg BID (N=64) TID (N=68) 400 mg TID(N=32) (N=32) (N=64)Ongoing 16 (50.0) 19 (59.4) 35 (54.7) 24 (35.3) 21 (32.8) 45 (34.1) conditionAtopy and type 2 diseasesNumber 32 32 64 68 64 132Yes 29(90.6) 29(90.6) 58 (90.6) 48 (70.6) 44 (68.8) 92(69.7)Ongoing 29(90.6) 28 (87.5) 57 (89.1) 48 (70.6) 44 (68.8) 92(69.7) conditionAtopic dermatitis historyNumber 32 32 64 68 64 132Yes 2(6.3) 2(6.3) 4(6.3) 2(2.9) 0 2(1.5)Ongoing 2(6.3) 2(6.3) 4(6.3) 2(2.9) 0 2(1.5) conditionAllergic conjunctivitis and allergic rhinitis historyNumber 32 32 64 68 64 132Yes 4(12.5) 3(9.4) 7(10.9) 2(2.9) 2(3.1) 4(3.0)Ongoing 4(12.5) 3(9.4) 7(10.9) 2(2.9) 2(3.1) 4(3.0) conditionAllergic conjunctivitis historyNumber 32 32 64 68 64 132Yes 4(12.5) 3(9.4) 7(10.9) 2(2.9) 2(3.1) 4(3.0)Ongoing 4(12.5) 3(9.4) 7(10.9) 2(2.9) 2(3.1) 4(3.0) conditionAllergic rhinitis historyNumber 32 32 64 68 64 132Yes 16 (50.0) 18 (56.3) 34 (53.1) 21 (30.9) 20 (31.3) 41 (31.1)Ongoing 15 (46.9) 17 (53.1) 32 (50.0) 21 (30.9) 20 (31.3) 41 (31.1) conditionChronic rhinosinusitis historyNumber 32 32 64 68 64 132Yes 6(18.8) 5(15.6) 11(17.2) 3(4.4) 4(6.3) 7(5.3)Ongoing 6(18.8) 5(15.6) 11(17.2) 3(4.4) 4(6.3) 7(5.3) condition400 mg BID cohort 400 mg TID cohortPlacebo Rilzabrutinib All Placebo RilzabrutinibAll (N=132) n (%) BID 400 mg BID (N=64) TID (N=68) 400 mg TIDNasal polyposis history Number 32 32 64 68 64 132Yes 1(3.1) 2(6.3) 3(4.7) 0 1(1.6) 1(0.8)Ongoing 1(3.1) 2(6.3) 3(4.7) 0 1(1.6) 1(0.8) conditionHypersensitivity to aspirin or otherNSAID Number 32 32 64 68 64 132Yes 2(6.3) 1(3.1) 3(4.7) 0 2(3.1) 2(1.5)Ongoing 2(6.3) 1(3.1) 3(4.7) 0 2(3.1) 2(1.5) conditionEosinophilic esophagitis history Number 32 32 64 68 64 132Yes 0 0 0 0 0 0Ongoing 0 0 0 0 0 0 conditionFood allergy history Number 32 32 64 68 64 132Yes 0 0 0 2(2.9) 1 (1.6) 3 (2.3)Ongoing 0 0 0 2(2.9) 1 (1.6) 3 (2.3) conditionHives history Number 32 32 64 68 64 132Yes 1(3.1) 2(6.3) 3(4.7) 0 1(1.6) 1(0.8)Ongoing 1(3.1) 2(6.3) 3(4.7) 0 0 0 conditionRubber sensitivityNumber 32 32 64 68 64 132Yes 1 (3.1) 0 1 (1.6) 0 0 0Ongoing 1 (3.1) 0 1 (1.6) 0 0 0 condition

[0216] Table 18. Prior medications for asthma - number of participants by predefined categories and standardized medication name (randomized population)400 mg BID cohort 400 mg TID cohortPredefined categories Placebo Rilzabrutinib All Placebo Rilzabrutinib AllStandardized BID 400 mg BID (N=64) TID 400 mg TID (N=132)Medication Name n (%) (N=32) (N=32) (N=68) (N=64)Any prior medications 32 32 (100) 64(100) 68 (100) 64 (100) 132 (100)(100)Pre-screening background 32 32 (100) 64(100) 68 (100) 64 (100) 132 (100) therapy (100)Salmeterol 15 9 (28.1) 24 (37.5) 10 (14.7) 8 (12.5) 18 (13.6)(46.9)Fluticasone 15 6 (18.8) 21 (32.8) 8 (11.8) 4 (6.3) 12 (9.1)(46.9)Fluticasone 5 (15.6) 11 (34.4) 16 (25.0) 26(38.2) 30 (46.9) 56 (42.4) propionate; salmeterol xinafoateFluticasone; salmeterol 4(12.5) 6(18.8) 10(15.6) 1 (1.5) 3(4.7) 4(3.0)Budesonide ;formoterol 4(12.5) 3(9.4) 7(10.9) 8(11.8) 8(12.5) 16(12.1) fumarateBeclometasone 2(6.3) 2(6.3) 4(6.3) 14(20.6) 7(10.9) 21 (15.9) dipropionate;formoterol fumarateBudesonide 2(6.3) 2(6.3) 4(6.3) 3(4.4) 2(3.1) 5 (3.8)Fluticasone propionate 1 (3.1) 3(9.4) 4(6.3) 3(4.4) 4(6.3) 7(5.3)Formoterol 2(6.3) 1 (3.1) 3 (4.7) 3(4.4) 1 (1.6) 4(3.0)Fluticasone 1 (3.1) 1 (3.1) 2(3.1) 1 (1.5) 3(4.7) 4(3.0) furoate;vilanterol trifenatateBeclometasone 0 0 0 2(2.9) 0 2 (1.5) dipropionate Beclometasone;formoterol 0 0 0 2(2.9) 2(3.1) 4 (3.0)Budesonide ;formoterol 0 0 0 2(2.9) 2(3.1) 4 (3.0)Formoterol fumarate 0 0 0 2(2.9) 0 2 (1.5)Glycopyrronium 0 0 0 1 (1.5) 0 1 (0.8) bromide;indacaterol acetate ;mometasone furoateSystemic steroids 3(9.4) 1 (3.1) 4(6.3) 3(4.4) 2(3.1) 5 (3.8)Meprednisone 1 (3.1) 1 (3.1) 2(3.1) 1 (1.5) 1 (1.6) 2(1.5)Prednisone 2(6.3) 0 2 (3.1) 2(2.9) 0 2 (1.5)Methylprednisolone 0 0 0 0 1 (1.6) 1 (0.8)Asthma reliever 29 31 (96.9) 60 (93.8) 66(97.1) 61 (95.3) 127(96.2)(90.6)Salbutamol 29 31 (96.9) 60 (93.8) 66(97.1) 60 (93.8) 126(95.5)(90.6)Salbutamol sulfate 0 0 0 0 1 (1.6) 1 (0.8)Antihistamines 3(9.4) 2(6.3) 5 (7.8) 1 (1.5) 0 1 (0.8)400 mg BID cohort 400 mg TID cohortPredefined categories Placebo Rilzabrutinib All Placebo Rilzabrutinib AllStandardized BID 400 mg BID (N=64) TID 400 mg TID (N=132)Medication Name n (%) (N=32) (N=32) (N=68) (N=64)Fexofenadine 1 (3.1) 1 (3.1) 2 (3.1) 0 0 0 hydrochlorideLevocetirizine 2 (6.3) 0 2 (3.1) 0 0 0Azelastine 0 1 (3.1) 1 (1.6) 0 0 0Desloratadine 0 1 (3.1) 1 (1.6) 0 0 0Levocetirizine 0 0 0 1 (1.5) 0 1 (0.8) dihydrochlorideMucolytics 0 2 (6.3) 2 (3.1) 0 0 0Carbocisteine 0 1 (3.1) 1 (1.6) 0 0 0Erdosteine 0 1 (3.1) 1 (1.6) 0 0 0Leukotriene receptor 1 (3.1) 1 (3.1) 2 (3.1) 0 2 (3.1) 2 (1.5) antagonists or leukotriene synthesis inhibitorsMontelukast sodium 1 (3.1) 1 (3.1) 2 (3.1) 0 0 0Azelastine 0 1 (3.1) 1 (1.6) 0 0 0Montelukast 0 0 0 0 2 (3.1) 2 (1.5)Anticholinergic 0 0 0 1 (1.5) 0 1 (0.8) bronchodilatorsIpratropium bromide 0 0 0 1 (1.5) 0 1 (0.8)Other 1 (3.1) 0 1 (1.6) 0 0 0Doxofylline 1 (3.1) 0 1 (1.6) 0 0 0Hedera helix extract 1 (3.1) 0 1 (1.6) 0 0 0

[0217] Table 19. Concomitant medications for asthma - number of participants by predefined categories and standardized medication name (randomized population).400 mg BID cohort 400 mg TID cohortPredefined categories Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400Standardized (N=32) 400 mg BID (N=68) mg TIDMedication Name n (%) (N=32) (N=64)Any concomitant 32 (100) 32 (100) 68 (100) 64 (100) medicationsController 32 (100) 32 (100) 68 (100) 64 (100)Fluticasone 32 (100) 32 (100) 68 (100) 64 (100)Salmeterol 32 (100) 32 (100) 68 (100) 64 (100)Formoterol 0 0 1 (1.5) 0Antibiotics 0 3 (9.4) 0 0Azithromycin 0 3 (9.4) 0 0Leukotriene receptor 0 0 0 0 antagonists or leukotriene synthesis inhibitors400 mg BID cohort 400 mg TID cohortPredefined categories Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400Standardized (N=32) 400 mg BID (N=68) mg TIDMedication Name n (%) (N=32) (N=64)Anticholinergic 0 0 1 (1.5) 0 bronchodilatorsIpratropium bromide 0 0 1 (L5) 0Antihistamines and 3 (9.4) 1 (3.1) 0 0 antiallergicsFexofenadine 1 (3.1) 1 (3.1) 0 0 hydrochlorideLevocetirizine 2 (6.3) 0 0 0Systemic steroid 4 (12.5) 5 (15.6) 2 (2.9) 1 (1.6)Prednisone 1 (3.1) 3 (9.4) 0 0Betamethasone 0 1 (3.1) 0 0 dipropionateMeprednisone 2 (6.3) 1 (3.1) 1 (1.5) 1 (1.6)Methylprednisolone 1 (3.1) 1 (3.1) 1 (1.5) 0Asthma reliever 29 (90.6) 31 (96.9) 65 (95.6) 60 (93.8)Salbutamol 29 (90.6) 31 (96.9) 65 (95.6) 59 (92.2)Salbutamol sulfate 0 0 0 1 (1.6)Mucolytics 0 2 (6.3) 0 0Carbocisteine 0 1 (3.1) 0 0Erdosteine 0 1 (3.1) 0 0Xanthines 0 0 1 (1.5) 0Theophylline 0 0 1 (1.5) 0PPI 0 0 0 0 n (%) = number and percentage of participants with at least one concomitant medication.LOAC

[0218] Treatment with rilzabrutinib yielded a numerical reduction in LOAC events relative to treatment with the placebo for patients in both the 400 mg BID and 400 mg TID cohorts (Figure 3 and Tables 20-28). Although 50% of placebo-treated patients in the 400 mg BID cohort experienced LOAC during the treatment period, only 37.5% of rilzabrutinib- treated patients in the 400 mg BID cohort experienced LOAC (Table 20). Similar results were observed for the 400 mg TID cohort, in which 29.4% of placebo-treated patients and 18.8% of rilzabrutinib-treated patients experienced LOAC (Table 20). This represents a relative risk reduction of 25% and 36%, for the 400 mg BID and 400 mg TID cohorts, respectively.

[0219] Subgroup analysis further supports the efficacy of rilzabrutinib treatment in both cohorts. In general, patients receiving 400 mg BID or 400 mg TID rilzabrutinib exhibited a numerical improvement in the incidence of LOAC events regardless of baseline demographic characteristics, disease characteristics, ICS / LABA dose level, biomarker levels, eosinophil count, and FeNO (ppb) (Tables 24-28).

[0220] Table 20. Primary analysis: incidence of LOAC (mITT population).400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400Number of participants with LOACNumber 32 32 68 64No 16 (50.0) 20 (62.5) 48 (70.6) 52 (81.3)Yes 16 (50.0) 12 (37.5) 20 (29.4) 12 (18.8)Crude RRR vs. 25.0 36.1 placeboOR vs. placebo 0.570 (0.202, 0.584 (0.253,(95% CI) 1.608) 1.349)P-value vs. 0.2880 0.2083 placeboRD vs. Placebo -0.123 (-0.361, -0.088 (-0.238,RRR vs. placebo 24.4 34.7(%) _LOAC: Loss of asthma control, OR: Odds ratio, RD: Risk difference, LATAM: Latin America, ROW: Rest of the world

[0221] Table 21. Critical or major protocol deviations potentially impact on the primary endpoint (randomized population).400 mg BID cohort 400 mg TID cohortDeviation category Placebo BID Rilzabrutinib Placebo TID RilzabrutinibDeviation term (N=32) 400 mg BID (N=68) 400 mg TIDAny critical or major protocol 2 (6.3) 1 (3.1) 2 (2.9) 3 (4.7) deviation with potential impact on the primary endpointInclusion / exclusion criteria 0 0 1 (L5) 1 (L6)400 mg BID cohort 400 mg TID cohortDeviation category Placebo BID Rilzabrutinib Placebo TID RilzabrutinibDeviation term (N=32) 400 mg BID (N=68) 400 mg TIDAsthma Control Questionnaire 0 0 1 (1.5) 05 -question version (ACQ-5) score of >4 during the screening period or <1.25 or >3.0 at V2.Participants with 0 0 0 1 (1.6) prebronchodilator FEV 1 > 40% of predicted normal at V 1.Prebronchodilator FEV 1 >=50% but <= 85% of predicted normal at V2.Concomitant medications / 2 (6.3) 1 (3.1) 1 (1.5) 2 (3.1) therapyNIMP administered but not as 2 (6.3) 1 (3.1) 1 (1.5) 2 (3.1) per protocol

[0222] Table 22. Summary of LOAC events (mITT population).400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TIDNumber of participants with LOAC Number 32 32 68 64No 16 (50.0) 20 (62.5) 48 (70.6) 52 (81.3)Yes 16 (50.0) 12 (37.5) 20 (29.4) 12 (18.8)Triggered by use of rescue 8 (25.0) 6 (18.8) 9 (13.2) 1 (1.6) medicationNumber of participants with 4 (12.5) 2 (6.3) 7 (10.3) 0>6 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol in a 24 hour period (compared with baseline) on 2 consecutive daysNumber of participants with 0 1 (3.1) 0 0 increase in ICS >4 times the last prescribed ICS dose (or>50% of the prescribed ICS dose at baseline if background therapy withdrawal completed)Number of participants 4 (12.5) 4 (12.5) 2 (2.9) 1 (1.6) requiring use of systemic (oral and / or parenteral) steroid treatmentNot triggered by use of rescue 8 (25.0) 6 (18.8) 10 (14.7) 10 (15.6) medication400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TIDNumber of participants with 8 (25.0) 6 (18.8) 10 (14.7) 10 (15.6)>30% reduction from baseline in AM PEF on 2 consecutive daysNumber of participants 0 0 0 0 requiring hospitalization or emergency room visitIntervention discontinuation 0 0 1 (1.5) 1 (1.6) due to lack of efficacy or anAE related to asthma worsening

[0223] Table 23. Supportive analysis: time to LOAC post-randomization (mITT population).400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400(N=32) mg BID (N=68) mg TID(N=32) (N=64)Number of 16 (50.0) 12 (37.5) 20 (29.4) 12 (18.8) participants with LOACNumber of 16 (50.0) 20 (62.5) 48 (70.6) 52 (81.3) participants censoredQI of time to LOAC 50.0 (14.0, 72.0) 55.0 (19.0, 84.0) 78.0 (52.0, NC) NC (44.0, NC)(days) (95% CI)Median time to 74.0 (64.0, NC) NC (73.0, NC) NC (87.0, NC) NC (NC, NC)LOAC (days) (95% ci)Q3 of time to LOAC NC (NC, NC) NC (NC, NC) NC (NC, NC) NC (NC, NC) (days) (95% CI)Probability ofLOAC (95% CI) atWeek 4 0.129 (0.041, 0.161 (0.059, 0.045 (0.012, 0.017 (0.001,0.270) 0.309) 0.115) 0.080)Week 9 0.330 (0.173, 0.265 (0.125, 0.168 (0.089, 0.156 (0.077,0.496) 0.429) 0.267) 0.261)Week 12 0.531 (0.341, 0.432 (0.243, 0.295 (0.189, 0.211 (0.117,0.689) 0.607) 0.408) 0.325)HR vs. Placebo 0.750 (0.352, 0.679 (0.327,(95% CI) 1.595) 1.408)P-value vs. placebo 0.4543 0.2980400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400P-value vs. placebo 0.3948 0.2794NE: Not able to estimate, LATAM: Latin America, ROW: Rest of the world

[0224] Table 24. Subgroup analysis: incidence of LOAC by demographics subgroups (mITT population).400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib (N=32) mg BID (N=68) 400 mg TIDAge group 1 (years)< 45Number 10 12 29 25LOAC 3 (30.0) 6 (50.0) 11 (37.9) 2 (8.0)OR vs. placebo 2.489 (0.342, 0. 142 (0.028,(95% CI) 18.129) 0.725)P-value vs. placebo 0.3680 0.0189RD vs. Placebo 0.184 (-0.266, -0.299 (-0.505, -(95% CI) 0.634) 0.093)> 45Number 22 20 39 39LOAC 13 (59.1) 6 (30.0) 9 (23.1) 10 (25.6)OR vs. placebo 0.266 (0.069, 1.023) 1.149 (0.408,(95% CI) 3.236)P-value vs. placebo 0.0540 0.7920RD vs. Placebo -0.295 (-0.583, - 0.026 (-0.165,(95% CI) 0.007) 0.216)Overall p-value for 0.0738 0.0298 interactionGenderMaleNumber 8 14 27 25LOAC 2 (25.0) 5 (35.7) 7 (25.9) 4 (16.0)OR vs. placebo 2.062 (0.173, 0.423 (0.091,(95% CI) 24.590) 1.966)P-value vs. placebo 0.5671 0.2721RD vs. Placebo 0.256 (-0.420, -0.111 (-0.461,(95% CI) 0.931) 0.238) femaleNumber 24 18 41 39LOAC 14 (58.3) 7 (38.9) 13 (31.7) 8 (20.5)OR vs. placebo 0.311 (0.076, 1.263) 0.640 (0.224,(95% CI) 1.828)P-value vs. placebo 0.1023 0.4042400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib(N=32) mg BID (N=68) 400 mg TID(N=32) (N=64)RD vs. Placebo -0.258 (-0.560, -0.084 (-0.291,(95% CI) 0.045) 0.123)Overall p-value for 0.1040 0.9230 interactionBaseline weight group(kg)< 60Number 4 3 12 2LOAC 4 (100) 0 3 (25.0) 1 (50.0)OR vs. placebo NC (NC, NC) 3.000 (0.140,(95% CI) 64.262)P-value vs. placebo NC 0.4823RD vs. Placebo NC (NC, NC) 0.250 (-0.485,(95% CI) 0.985)> 60 - < 90 Number 25 23 40 41LOAC 10 (40.0) 10 (43.5) 13 (32.5) 8 (19.5)OR vs. placebo 1.154 (0.366, 3.640) 0.503 (0.182,(95% CI) 1.392)P-value vs. placebo 0.8071 0.1860RD vs. Placebo 0.035 (-0.244, -0. 130 (-0.319,(95% CI) 0.314) 0.059)> 90Number 3 6 16 21LOAC 2 (66.7) 2 (33.3) 4 (25.0) 3 (14.3)OR vs. placebo 0.250 (0.013, 4.729) 0.500 (0.095,(95% CI) 2.645)P-value vs. placebo 0.3554 0.4147RD vs. Placebo -0.333 (-0.987, -0. 107 (-0.367,(95% CI) 0.320) 0.153)Overall p-value for 0.0116 0.4929 interactionBaseline BMI group(kg / m2)< 25 Number 6 8 22 12LOAC 4 (66.7) 3 (37.5) 8 (36.4) 3 (25.0)OR vs. placebo 0.300 (0.033, 2.763) 0.583 (0.121,(95% CI) 2.801)P-value vs. placebo 0.2879 0.5008RD vs. Placebo -0.292 (-0.796, -0. 114 (-0.431,(95% CI) 0.213) 0.203)> 25 - < 30400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib (N=32) mg BID (N=68) 400 mg TIDNumber 17 16 27 29LOAC 8 (47.1) 6 (37.5) 8 (29.6) 3 (10.3)OR vs. placebo 0.675 (0.168, 2.709) 0.274 (0.064,(95% CI) 1.172)P-value vs. placebo 0.5794 0.0807RD vs. Placebo -0.096 (-0.431, -0. 193 (-0.398,(95% CI) 0.240) 0.012)> 30Number 9 8 19 23LOAC 4 (44.4) 3 (37.5) 4 (21.1) 6 (26.1)OR vs. placebo 0.750 (0.107, 5.238) 1.324 (0.313,(95% CI) 5.604)P-value vs. placebo 0.7717 0.7034RD vs. Placebo -0.069 (-0.536, 0.050 (-0.206,(95% CI) 0.397) 0.307)P-value vs. placebo 0.7706 0.2506RegionEastern Europe Number 4 3 45 43LOAC 2 (50.0) 1 (33.3) 14 (31.1) 8 (18.6)OR vs. placebo 0.500 (0.023, 0.506 (0.187,(95% CI) 11.088) 1.368)P-value vs. placebo 0.6611 0.1794RD vs. Placebo -0.167 (-0.891, -0.125 (-0.303,(95% CI) 0.558) 0.053)Latin AmericaNumber 25 25 19 19LOAC 11 (44.0) 9 (36.0) 5 (26.3) 4 (21.1)OR vs. placebo 0.716 (0.230, 2.230) 0.747 (0.166,(95% CI) 3.357)P-value vs. placebo 0.5642 0.7032RD vs. Placebo -0.080 (-0.351, -0.053 (-0.322,(95% CI) 0.191) 0.217)Western CountriesNumber 1 2 2 2LOAC 1 (100) 0 1 (50.0) 0OR vs. placebo NC (NC, NC) NC (NC, NC)(95% CI)P-value vs. placebo NC NCRD vs. Placebo NC (NC, NC) NC (NC, NC)(95% CI)APACNumber 2 2 2 0LOAC 2 (100) 2 (100) 0 0400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib (N=32) mg BID (N=68) 400 mg TID(N=32) (N=64)OR vs. placebo NC (NC, NC) NC (NC, NC)(95% CI)P-value vs. placebo NC NCRD vs. Placebo NC (NC, NC) NC (NC, NC)(95% CI)Overall p-value for NC NC interactionLATAM: Latin America, ROW: Rest of the world

[0225] Table 25. Subgroup analysis: incidence of LOAC by disease and other characteristics subgroups (mITT population).400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400 (N=32) 400 mg BID (N=68) mg TIDAge at onset of asthma (years)< 12 Number 7 9 15 14LOAC 2 (28.6) 4 (44.4) 6 (40.0) 2 (14.3)OR vs. placebo (95% CI) 2.000 (0.244, 0.250 (0.041,16.362) 1.541)P-value vs. placebo 0.5180 0.1352RD vs. Placebo (95% CI) 0. 159 (-0.308, -0.257 (-0.565,0.625) 0.051)> 12 - < 18Number 2 5 5 5LOAC 1 (50.0) 1 (20.0) 1 (20.0) 0OR vs. placebo (95% CI) 0.250 (0.007, NC (NC, NC)8.560)P-value vs. placebo 0.4419 NCRD vs . Placebo (95 % CI) -0.300 (- 1.077, NC (NC, NC)0.477)> 18 - < 40Number 15 14 28 27LOAC 9 (60.0) 4 (28.6) 10 (35.7) 6 (22.2)OR vs. placebo (95% CI) 0.267 (0.056, 0.514 (0.156,1.260) 1.694)P-value vs. placebo 0.0953 0.2742RD vs. Placebo (95% CI) -0.314 (-0.657, -0. 135 (-0.372,0.028) 0.102)> 40 Number 8 4 20 18LOAC 4 (50.0) 3 (75.0) 3 (15.0) 4 (22.2)400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400 (N=32) 400 mg BID (N=68) mg TID(N=32) (N=64)OR vs. placebo (95% CI) 3.000 (0.211, 1.619 (0.309,42.624) 8.478)P-value vs. placebo 0.4171 0.5684RD vs. Placebo (95% CI) 0.250 (-0.298, 0.072 (-0.176,0.798) 0.320)Overall p-value for 0.1351 0.3189 interactionAge at onset of asthma (years)< 18Number 9 14 20 19LOAC 3 (33.3) 5 (35.7) 7 (35.0) 2 (10.5)OR vs. placebo (95% CI) 1.402 (0.206, 0.218 (0.039,9.530) 1.232)P-value vs. placebo 0.7295 0.0847RD vs. Placebo (95% CI) 0. 126 (-0.346, -0.245 (-0.495,0.597) 0.006)> 18 Number 23 18 48 45LOAC 13 (56.5) 7 (38.9) 13 (27.1) 10 (22.2)OR vs. placebo (95% CI) 0.323 (0.079, 0.769 (0.298,1.322) 1.986)P-value vs. placebo 0.1160 0.5876RD vs. Placebo (95% CI) -0.258 (-0.560, -0.049 (-0.223,0.045) 0.126)Overall p-value for 0.2794 0.1729 interactionNumber of asthma exacerbations within 2 years before screening visit 1Number 9 13 51 36LOAC 3 (33.3) 5 (38.5) 17 (33.3) 5 (13.9)OR vs. placebo (95% CI) 1.218 (0.176, 0.323 (0.106,8.423) 0.978)P-value vs. placebo 0.8416 0.0457RD vs. Placebo (95% CI) 0.059 (-0.390, -0.194 (-0.366, -0.508) 0.023)2 Number 15 11 16 23LOAC 9 (60.0) 4 (36.4) 3 (18.8) 7 (30.4)OR vs. placebo (95% CI) 0.471 (0.084, 1.896 (0.407,2.634) 8.824)P-value vs. placebo 0.3917 0.4149400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400(N=32) 400 mg BID (N=68) mg TID(N=32) (N=64)RD vs. Placebo (95% CI) -0.199 (-0.617, 0.117 (-0.151,0.219) 0.385)> 2Number 8 8 1 5LOAC 4 (50.0) 3 (37.5) 0 0OR vs. placebo (95% CI) 0.508 (0.044, NC (NC, NC)5.914)P-value vs. placebo 0.5890 NCRD vs. Placebo (95% CI) -0. 115 (-0.780, NC (NC, NC)0.551)Overall p-value for 0.8727 NC interactionAtopic medical conditionsYesNumber 17 20 24 21LOAC 8 (47.1) 8 (40.0) 6 (25.0) 4 (19.0)OR vs. placebo (95% CI) 0.681 (0.174, 0.821 (0.175,2.666) 3.846)P-value vs. placebo 0.5815 0.8026RD vs. Placebo (95% CI) -0.069 (-0.384, -0.031 (-0.320,0.246) 0.257)NoNumber 15 12 44 43LOAC 8 (53.3) 4 (33.3) 14 (31.8) 8 (18.6)OR vs. placebo (95% CI) 0.380 (0.065, 0.493 (0.180,2.206) 1.353)P-value vs. placebo 0.2809 0.1700RD vs. Placebo (95% CI) -0.204 (-0.557, -0.130 (-0.311,0.149) 0.051)Overall p-value for 0.6695 0.6159 interactionBackground ICS dose level at randomization (400 mg TID only)MediumNumber 35 29LOAC 14 (40.0) 6 (20.7)OR vs. placebo (95% CI) 0.421 (0.125,1.414)P-value vs. placebo 0.1615RD vs. placebo (95% CI) -0. 173 (-0.407,0.061)High400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400 (N=32) 400 mg BID (N=68) mg TIDNumber 33 35LOAC 6 (18.2) 6 (17.1)OR vs. placebo (95% CI) 0.911 (0.253,3.276)P-value vs. placebo 0.8867RD vs. placebo (95% CI) -0.011 (-0.218,0.195)Overall p-value for 0.3913 interactionSmoking historyFormer Number 8 4 6 6LOAC 4 (50.0) 3 (75.0) 3 (50.0) 2 (33.3)OR vs. placebo (95% CI) 3.000 (0.211, 0.500 (0.049,42.624) 5.154)P-value vs. placebo 0.4171 0.5603RD vs. Placebo (95% CI) 0.250 (-0.298, -0.167 (-0.717,0.798) 0.383)Never Number 24 28 62 58LOAC 12 (50.0) 9 (32.1) 17 (27.4) 10 (17.2)OR vs. placebo (95% CI) 0.474 (0. 154, 0.551 (0.229,1.461) 1.330)P-value vs. placebo 0.1936 0.1853RD vs. Placebo (95% CI) -0.179 (-0.443, -0. 102 (-0.249,0.086) 0.046)Overall p-value for 0.2175 0.7814 interactionBaseline pre-bronchodilatorFEV1 (L) (400 mg BID only)< Median (2.022) Number 14 17LOAC 7 (50.0) 7 (41.2)OR vs. placebo (95% CI) 0.700 (0. 168,2.910)P-value vs. placebo 0.6237RD vs. Placebo (95% CI) -0.088 (-0.439,0.263)P-value vs. placebo 0.6224> Median (2.022) Number 18 14LOAC 9 (50.0) 5 (35.7)OR vs. placebo (95% CI) 0.556 (0.133,2.325)400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400 (N=32) 400 mg BID (N=68) mg TIDP-value vs. placebo 0.4209RD vs. Placebo (95% CI) -0. 143 (-0.484,0.198)P-value vs. placebo 0.4117Overall p-value for 0.7743 interactionBaseline pre-bronchodilator percent predicted FEV 1 (%) (400 mg BID only)< Median (68)Number 12 17LOAC 6 (50.0) 7 (41.2)OR vs. placebo (95% CI) 0.700 (0. 158,3.099)P-value vs. placebo 0.6384RD vs. Placebo (95% CI) -0.088 (-0.455,0.279)P-value vs. placebo 0.6376> Median (68)Number 20 14LOAC 10 (50.0) 5 (35.7)OR vs. placebo (95% CI) 0.556 (0.137,2.256)P-value vs. placebo 0.4110RD vs. Placebo (95% CI) -0. 143 (-0.476,0.190)P-value vs. placebo 0.4007Overall p-value for 0.5557 interactionBaseline pre -bronchodilatorFEV1 (L) (400 mg TID only)< Median (2.1955)Number 36 29LOAC 10 (27.8) 7 (24.1)OR vs. placebo (95% CI) 0.827 (0.270,2.536)P-value vs. placebo 0.7401RD vs. placebo (95% CI) -0.036 (-0.250,0.177)> Median (2.1955)Number 31 34LOAC 10 (32.3) 5 (14.7)400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400(N=32) 400 mg BID (N=68) mg TIDOR vs. placebo (95% CI) 0.362 (0.108, 1.216)P-value vs. placebo 0.1003RD vs. placebo (95% CI) -0.176 (-0.379, 0.028)Overall p-value for 0.3196 interactionBaseline pre -bronchodilator percent predicted FEV 1 group 1 (%) (400 mg TID only)< Median (77)Number 36 29LOAC 9 (25.0) 4 (13.8)OR vs. placebo (95% CI) 0.452 (0.118,1.730)P-value vs. placebo 0.2464 RD vs. placebo (95% CI) -0.129 (-0.394,0.135)> Median (77)Number 32 34LOAC 11 (34.4) 8 (23.5)OR vs. placebo (95% CI) 0.599 (0.185, 1.937)P-value vs. placebo 0.3916RD vs. placebo (95% CI) -0.078 (-0.320, 0.165)Overall p-value for 0.6831 interactionBaseline pre -bronchodilator percent predicted FEV 1 group 2 (%) (400 mg TID only)< 80Number 41 37LOAC 10 (24.4) 7 (18.9)OR vs. placebo (95% CI) 0.736 (0.243, 2.229)P-value vs. placebo 0.5884RD vs. placebo (95% CI) -0.047 (-0.244, 0.149)> 80Number 27 26LOAC 10 (37.0) 5 (19.2)400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400(N=32) 400 mg BID (N=68) mg TIDOR vs. placebo (95% CI) 0.429 (0.112, 1.648)P-value vs. placebo 0.2176RD vs. placebo (95% CI) -0.139 (-0.406, 0.128)Overall p-value for 0.5675 interactionBaseline FEV 1 reversibility (%)< 12Number 21 14 48 43LOAC 10 (47.6) 5 (35.7) 14 (29.2) 9 (20.9)OR vs. placebo (95% CI) 0.611 (0.152, 0.643 (0.245, 2.450) 1.684)P-value vs. placebo 0.4870 0.3685RD vs. Placebo (95% CI) -0.119 (-0.449, -0.082 (-0.259, 0.211) 0.095)> 12Number 15 12 13LOAC 5 (55.6) 6 (40.0) 2 (16.7) 1 (7.7)OR vs. placebo (95% CI) 0.533 (0.100, 0.417 (0.033,2.839) 5.299)P-value vs. placebo 0.4612 0.4998RD vs. Placebo (95% CI) -0.156 (-0.564, -0.090 (-0.346, 0.253) 0.166)Overall p-value for 0.8792 0.7503 interactionBaseline ACQ-5 score< 2Number 15 19 29 24LOAC 7 (46.7) 7 (36.8) 7 (24.1) 6 (25.0)OR vs. placebo (95% CI) 0.651 (0.153, 1.162 (0.297,2.769) 4.543)P-value vs. placebo 0.5608 0.8289RD vs. Placebo (95% CI) -0.098 (-0.429, 0.025 (-0.209,0.233) 0.259)> 2Number 17 13 39 40LOAC 9 (52.9) 5 (38.5) 13 (33.3) 6 (15.0)OR vs. placebo (95% CI) 0.475 (0.090, 0.346 (0.113,2.502) 1.060)P-value vs. placebo 0.3800 0.0632RD vs. Placebo (95% CI) -0.125 (-0.473, -0.181 (-0.379,0.224) 0.018)400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400 (N=32) 400 mg BID (N=68) mg TIDOverall p-value for 0.7235 0.1501 interactionLATAM: Latin America, ROW: Rest of the world

[0226] Table 26. Subgroup analysis: incidence of LOAC by baseline ICS / LABA dose level subgroups (mITT population).Placebo BID Rilzabrutinib 400 mg BIDBackground ICS / LABA dose level at randomizationMediumNumber 3 5LOAC 2 (66.7) 1 (20.0)OR vs. placebo (95% CI) 0.125 (0.005, 3.225)P-value vs. placebo 0.2099RD vs. Placebo (95% CI) -0.467 (-1.105, 0.172)P-value vs. placebo 0.1519High Number 29 27LOAC 14 (48.3) 11 (40.7)OR vs. placebo (95% CI) 0.737 (0.256, 2.122)P-value vs. placebo 0.5713RD vs. Placebo (95% CI) -0.075 (-0.335, 0.184)P-value vs. placebo 0.5695Overall p-value for 0.3273 interactionLATAM: Latin America, ROW: Rest of the world

[0227] Table 27. Subgroup analysis: incidence of LOAC by baseline biomarker subgroups (mITT population).400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TIDBaseline IgE level (lU / mL)< 100Number 11 8 27 23LOAC 5 (45.5) 2 (25.0) 7 (25.9) 4 (17.4)OR vs. placebo (95% CI) 0.412 (0.053, 0.602 (0.151,3.217) 2.390)P-value vs. placebo 0.3977 0.4702400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)RD vs. Placebo (95% CI) -0.220 (-0.676, -0.085 (-0.312,0.236) 0.141)> 100Number 21 24 41 41LOAC 11 (52.4) 10 (41.7) 13 (31.7) 8 (19.5)OR vs. placebo (95% CI) 0.652 (0.192, 0.522 (0.189,2.222) 1.440)P-value vs. placebo 0.4946 0.2093RD vs. Placebo (95% CI) -0.092 (-0.376, -0.122 (-0.309,0.192) 0.065)Overall p-value for 0.6260 0.9272 interactionBaseline median IgE level(lU / mL) (400 mg BID only)< Median (210.8)Number 13 19LOAC 5 (38.5) 6 (31.6)OR vs. placebo (95% CI) 0.744 (0.161,3.434)P-value vs. placebo 0.7042RD vs. Placebo (95% CI) -0.053 (-0.393,0.286)P-value vs. placebo 0.7585> Median (210.8)Number 19 13LOAC 11 (57.9) 6 (46.2)OR vs. placebo (95% CI) 0.604 (0.136,2.679)P-value vs. placebo 0.5067RD vs. Placebo (95% CI) -0.124 (-0.482,0.233)P-value vs. placebo 0.4960Overall p-value for 0.9289 interactionBaseline median IgA level(lU / mL) (400 mg BID only)< Median (2600)Number 15 17LOAC 9 (60.0) 4 (23.5)OR vs. placebo (95% CI) 0.205 (0.045,0.942)P-value vs. placebo 0.0416RD vs. Placebo (95% CI) -0.365 (-0.684, -0.045)400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TIDP-value vs. placebo 0.0253> Median (2600)Number 17 15LOAC 7 (41.2) 8 (53.3)OR vs. placebo (95% CI) 1.633 (0.402,6.625)P-value vs. placebo 0.4927RD vs. Placebo (95% CI) 0.122 (-0.223,0.466)P-value vs. placebo 0.4888Overall p-value for 0.0553 interactionBaseline median IgE level (lU / mL) (400 mg TID only)< Median (121.85)Number 34 32LOAC 9 (26.5) 6 (18.8)OR vs. placebo (95% CI) 0.681 (0.209, 2.219)P-value vs. placebo 0.5236RD vs. placebo (95% CI) -0.070 (-0.274, 0.135)> Median (121.85)Number 34 32LOAC 11 (32.4) 6 (18.8)OR vs. placebo (95% CI) 0.510 (0.156, 1.672)P-value vs. placebo 0.2663 RD vs. placebo (95% CI) -0.122 (-0.356, 0.112)Overall p-value for 0.7981 interactionBaseline median IgA level (mg / L) (400 mg TID only)< Median (2190)Number 34 32LOAC 9 (26.5) 6 (18.8)OR vs. placebo (95% CI) 0.774 (0.217, 2.765)P-value vs. placebo 0.6933RD vs. placebo (95% CI) -0.011 (-0.239, 0.218)> Median (2190)400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TIDNumber 34 32LOAC 11 (32.4) 6 (18.8)OR vs. placebo (95% CI) 0.514 (0.160,1.646)P-value vs. placebo 0.2622RD vs. placebo (95% CI) -0.120 (-0.347,0.107)Overall p-value for 0.6801 interactionBaseline blood eosinophil level 1(10A9 / L)< 0.15 Number 6 8 29 28LOAC 3 (50.0) 2 (25.0) 8 (27.6) 6 (21.4)OR vs. placebo (95% CI) 0.527 (0.017, 0.716 (0.212,16.019) 2.415)P-value vs. placebo 0.7133 0.5900RD vs. Placebo (95% CI) -0.135 (-0.945, -0.062 (-0.284,0.675) 0.161)P-value vs. placebo 0.7433> 0.15 (400 mg BID only)Number 26 23LOAC 13 (50.0) 10 (43.5)OR vs. placebo (95% CI) 0.737 (0.221,2.453)P-value vs. placebo 0.6186RD vs. Placebo (95% CI) -0.077 (-0.361,0.207)P-value vs. placebo 0.5938Overall p-value for 0.4802 interaction> 0.15 - < 0.3 (400 mg TID only)Number 20 18LOAC 3 (15.0) 4 (22.2)OR vs. placebo (95% CI) 1.619 (0.309,8.478)P-value vs. placebo 0.5684RD vs. placebo (95% CI) 0.072 (-0.176,0.320)> 0.3 (400 mg TID only) Number 19 18LOAC 9 (47.4) 2 (11.1)400 mg BID cohort _ 400 mg TIP cohort _Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID_ (N=32) _ _ (N=64)OR vs. placebo (95% CI) 0.139 (0.025,0.779)P-value vs. placebo 0.0248RD vs. placebo (95% CI) -0.363 (-0.630, -0.095)Overall p-value for 0.1249 interactionBaseline blood eosinophil level 2(10A9 / L)< 0.3Number 19 17 49 46LOAC 10 (52.6) 5 (29.4) 11 (22.4) 10 (21.7)OR vs. placebo (95% CI) 0.231 (0.042, 1.019 (0.376,1.283) 2.763)P-value vs. placebo 0.0939 0.9711RD vs. Placebo (95% CI) -0.197 (-0.567, 0.047 (-0.153,0.174) 0.247)> 0.3Number 13 14 19 18LOAC 6 (46.2) 7 (50.0) 9 (47.4) 2 (11.1)OR vs. placebo (95% CI) 0.951 (0.192, 0.146 (0.025,4.710) 0.844)P-value vs. placebo 0.9511 0.0316RD vs. Placebo (95% CI) -0.013 (-0.398, -0.350 (-0.653, -0.372) 0.047)Overall p-value for 0.2298 0.0574 interactionBaseline FeNO level 1 (ppb)< 25Number 15 12 42 42LOAC 8 (53.3) 3 (25.0) 14 (33.3) 9 (21.4)OR vs. placebo (95% CI) 0.261 (0.044, 0.567 (0.208,1.567) 1.548)P-value vs. placebo 0.1420 0.2682RD vs. Placebo (95% CI) -0.227 (-0.621, -0.065 (-0.275,0.166) 0.145)> 25Number 16 20 22 20LOAC 8 (50.0) 9 (45.0) 4 (18.2) 3 (15.0)OR vs. placebo (95% CI) 0.946 (0.233, 0.798 (0.151,3.843) 4.218)P-value vs. placebo 0.9383 0.7903RD vs. Placebo (95% CI) -0.007 (-0.333, -0.053 (-0.313,0.320) 0.207)400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDOverall p-value for 0.2742 0.6308 interactionBaseline FeNO level 2 (ppb)< 35 Number 19 21 50 47LOAC 11 (57.9) 8 (38.1) 14 (28.0) 9 (19.1)OR vs. placebo (95% CI) 0.448 (0.126, 0.655 (0.246,1.589) 1.743)P-value vs. placebo 0.2136 0.3965RD vs. Placebo (95% CI) -0.198 (-0.502, -0.029 (-0.221,0.106) 0.162)> 35 Number 12 11 14 15LOAC 5 (41.7) 4 (36.4) 4 (28.6) 3 (20.0)OR vs. placebo (95% CI) 0.800 (0.149, 0.628 (0.108,4.297) 3.647)P-value vs. placebo 0.7947 0.6038RD vs. Placebo (95% CI) -0.053 (-0.451, -0.094 (-0.398,0.345) 0.210)Overall p-value for 0.1981 0.9120 interactionLATAM: Latin America, ROW: Rest of the world

[0228] Table 28. Subgroup analysis: incidence of LOAC in the baseline low EOS and low FeNO subgroup (mITT population).400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TIDBaseline blood eosinophil(10A9 / L) and FeNO (ppb)Low EOS (< 0.15) and lowFeNO (< 25) Number 4 3 23 21LOAC 3 (75.0) 0 8 (34.8) 4 (19.0)OR vs. placebo (95% CI) NC (NC, NC) 0.441 (0.110,1.765)P-value vs. placebo NC 0.2474RD vs. Placebo (95% CI) NC (NC, NC) -0.157 (-0.414,0.100)All others Number 27 28 41 41LOAC 13 (48.1) 12 (42.9) 10 (24.4) 8 (19.5)400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)OR vs. placebo (95% CI) 0.808 (0.279, 0.752 (0.263,2.338) 2.150)P-value vs. placebo 0.6938 0.5942RD vs. Placebo (95% CI) -0.053 (-0.316, -0.049 (-0.228,0.210) 0.130)P-value vs. placebo 0.69330.4970LATAM: Latin America, ROW: Rest of the worldFEV1

[0229] Rilzabrutinib treatment was not associated with an improvement in FEV1 values relative to treatment with the placebo (Figures 4-6 and Tables 29-38).

[0230] Table 29. Key secondary analysis: change from baseline in prebronchodilator FEV1 (L) at Week 12, reduced model (mITT population).400 mg BID cohort 400 mg TID cohortPre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400BaselineNumber 32 31Mean(SD) 2.16(0.77) 2.11 (0.67) 67 63Median 2.10 1.94 2.42(0.90) 2.50(0.95)Q1 ;Q3 1.47; 2.50 1.59; 2.52 2.15 2.36Min; Max 1.2; 3.9 1.0; 3.8 1.77; 2.98 1.73; 3.101.0; 5.0 1.1; 5.3Week 12Number 25 (16 / 9) 26 (21 / 5)(observed / LOCF imputed) Mean (SD) 2.00 (0.72) 2.02 (0.77) 55 (45 / 10) 49 (46 / 3)Median 1.82 1.88 2.47(0.90) 2.43 (0.83)Q1 ;Q3 1.44; 2.33 1.57; 2.57 2.39 2.39Min; Max 1.0; 3.6 0.6 ; 3.8 1.76; 3.10 1.86; 2.800.9; 5.0 1.1; 4.5Change from baselineNumber 25 (16 / 9) 25 (20 / 5) 54 (44 / 10) 48 (45 / 3)(observed / LOCF imputed)Mean(SD) -0.06 (0.22) -0.04(0.39) -0.06 (0.31) -0.15 (0.27)Median -0.06 -0.02 -0.07 -0.12Q1 ;Q3 -0.18; 0.10 -0.21 ; 0.12 -0.21 ; 0.06 -0.28 ; 0.05Min; Max -0.6 ; 0.3 -1.0 ; 0.7 -0.7 ; 1.2 -1.1 ; 0.4LS Mean (SE) -0.08 (0.08) -0.07(0.08) -0.04 (0.05) -0.13 (0.05)400 mg BID cohort 400 mg TID cohortPre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400FEV1(L) (N=32) mg BID (N=68) mg TID(N=32) (N=64)LS Mean Diff vs. 0.01 (-0.17, 0.19) placebo (95% CI)P-value vs. 0.9466 -0.09 (-0.21, 0.03) placeboLATAM: Latin America, ROW: Rest of the world

[0231] Table 30. Supplementary analysis (MMRM): change from baseline in pre-bronchodilator FEV1 (L) at EOT (Week 12; mITT population).400 mg BID cohort 400 mg TID cohortPre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400Baseline Number 32 31 67 63Mean(SD) 2.16(0.77) 2.11 (0.67) 2.42 (0.90) 2.50(0.95)Median 2.10 1.94 2.15 2.36Q1 ;Q3 1.47; 2.50 1.59; 2.52 1.77; 2.98 1.73; 3.10Min; Max 1.2; 3.9 1.0 ; 3.8 1.0; 5.0 1.1; 5.3Week 12 Number 16 21 45 46Mean(SD) 2.03 (0.69) 2.01 (0.83) 2.37 (0.83) 2.46(0.81)Median 1.78 1.88 2.22 2.40Q1 ;Q3 1.61; 2.40 1.57; 2.30 1.76; 2.82 1.89; 2.80Min; Max 1.0; 3.3 0.6 ; 3.8 0.9; 4.1 1.1; 4.5Change from baselineNumber 16 20 44 45Mean(SD) -0.03 (0.21) -0.02(0.41) -0.07 (0.34) -0.14 (0.27)Median -0.06 -0.04 -0.06 -0.09Q1 ;Q3 -0.16; 0.17 -0.22 ; 0.32 -0.27 ; 0.06 -0.28 ; 0.05Min; Max -0.4 ; 0.3 -1.0; 0.7 -0.7; 1.2 -1.1 ; 0.4LS Mean (SE) 0.00(0.08) -0.01 (0.08) -0.08 (0.05) -0.16 (0.05)LS Mean diff 0.00 (-0.21, 0.21) -0.08 (-0.21, 0.05) vs. placebo (95% CI) P-value vs. 0.9747 0.2225 placeboLATAM: Latin America, ROW: Rest of the world

[0232] Table 31. Summary of pre-bronchodilator FEV1 (L) over time (on-site conventional spirometry before LOAC and OCS use as observed; mITT population).Pre-bronchodilator FEV1 Placebo BID Rilzabrutinib 400 mg BIDBaselineNumber 32 31Mean(SD) 2.16(0.77) 2.11 (0.67)Median 2.10 1.94Q1 ;Q3 1.47; 2.50 1.59; 2.52Min; Max 1.2; 3.9 1.0; 3.8Week 2Number 28 27Mean (SD) 2.23 (0.77) 2.20 (0.68)Median 2.15 2.08Q1 ;Q3 1.68; 2.63 1.79; 2.64Min; Max 1.2; 4.0 1.0; 4.0Change from baselineNumber 28 26Mean (SD) 0.07 (0.29) 0.08 (0.29)Median 0.05 0.04Q1 ;Q3 -0.05 ; 0.18 -0.08 ; 0.22Min ; Max -0.7 ; 0.8 -0.6 ; 0.6Percent change from baselineNumber 28 26Mean (SD) 4.24 (15.23) 4.47 (12.91)Median 1.71 2.02Q1 ;Q3 -2.49; 9.97 -2.56; 11.40Min; Max -29.8; 45.4 -19.9 ; 38.3Week 4Number 24 25Mean (SD) 2.24 (0.75) 2.05 (0.62)Median 2.11 1.96Q1 ;Q3 1.73 ; 2.73 1.70; 2.36Min; Max 1.0; 3.9 1.0; 3.3Change from baselineNumber 24 25Mean (SD) 0.08 (0.29) 0.07 (0.24)Median 0.02 0.02Q1 ;Q3 -0.08; 0.19 -0.07; 0.17Min ; Max -0.4 ; 0.9 -0.3 ; 0.6Percent change from baselineNumber 24 25Mean(SD) 4.31 (16.19) 3.72(12.19)Median 0.51 0.55Q1 ;Q3 -5.00; 8.08 -4.02; 11.68Pre-bronchodilator FEV1 Placebo BID Rilzabrutinib 400 mg BID(L) (N=32) (N=32)Min ; Max -17.9 ; 54.0 -16.7 ; 30.7Week 6 Number 27 23Mean (SD) 2.08 (0.67) 2.24 (0.79)Median 2.19 2.01Q1 ;Q3 1.46; 2.53 1.56; 2.71Min; Max 1.0; 3.5 1.0; 3.9Change from baseline Number 27 22Mean (SD) 0.05 (0.33) 0.09 (0.39)Median 0.07 0.07Q1 ;Q3 -0.13 ; 0.18 -0.11 ; 0.25Min; Max -0.7 ; 0.9 -0.7; 1.2Percent change from baselineNumber 27 22Mean(SD) 3.38 (17.82) 3.99 (17.73)Median 2.56 3.66Q1 ;Q3 -5.05 ; 12.12 -4.84; 11.59Min; Max -35.5 ; 53.4 -27.7 ; 44.3Week 8 Number 24 20Mean(SD) 2.05 (0.68) 2.10 (0.85)Median 2.03 1.83Q1 ;Q3 1.49; 2.45 1.51 ; 2.51Min; Max 0.9 ; 3.6 0.9 ; 3.9Change from baselineNumber 24 19Mean(SD) 0.04(0.24) 0.08 (0.41)Median -0.01 0.11Q1 ;Q3 -0.12; 0.19 -0.07 ; 0.28Min; Max -0.3 ; 0.7 -1.1 ; 0.7Percent change from baselineNumber 24 19Mean(SD) 2.52 (14.71) 3.28 (18.63)Median -0.52 3.73Q1 ;Q3 -5.85 ; 7.52 -4.40 ; 17.61Min; Max -25.8; 41.1 -42.2 ; 27.5Week 10Number 21 17Mean (SD) 2.03 (0.75) 2.29 (0.76)Median 1.99 1.93Q1 ;Q3 1.57; 2.40 1.78 ; 2.57Min; Max 0.8 ; 3.8 1.6; 4.2Pre-bronchodilator FEV1 Placebo BID Rilzabrutinib 400 mg BIDChange from baselineNumber 21 16Mean (SD) 0.03 (0.29) 0.21 (0.29)Median -0.05 0.12Q1 ; Q3 -0.17 ; 0.23 -0.01 ; 0.42Min ; Max -0.4 ; 0.8 -0.2 ; 0.7Percent change from baselineNumber 21 16Mean (SD) 1.05 (15.30) 10.71 (16.43)Median -1.77 4.52Q1 ; Q3 -8.09 ; 13.55 -0.45 ; 24.37Min ; Max -28.7 ; 28.2 -11.9 ; 45.6Week 12Number 16 21Mean (SD) 2.03 (0.69) 2.01 (0.83)Median 1.78 1.88Q1 ; Q3 1.61 ; 2.40 1.57 ; 2.30Min ; Max 1.0 ; 3.3 0.6 ; 3.8Change from baselineNumber 16 20Mean (SD) -0.03 (0.21) -0.02 (0.41)Median -0.06 -0.04Q1 ; Q3 -0.16 ; 0.17 -0.22 ; 0.32Min ; Max -0.4 ; 0.3 -1.0 ; 0.7Percent change from baselineNumber 16 20Mean (SD) -0.55 (11.79) -2.63 (21.27)Median -2.60 -2.04Q1 ; Q3 -10.10 ; 9.07 -11.09 ; 12.57Min ; Max -18.0 ; 23.4 -54.6 ; 32.7Week 16Number 19 19Mean (SD) 2.21 (0.80) 2.30 (0.84)Median 2.09 2.01Q1 ; Q3 1.48 ; 2.66 1.80 ; 2.67Min ; Max 1.0 ; 3.8 0.9 ; 4.2Change from baselineNumber 19 18Mean (SD) 0.06 (0.29) 0.29 (0.37)Median 0.12 0.28Q1 ; Q3 -0.12 ; 0.28 -0.03 ; 0.44Min ; Max -0.7 ; 0.6 -0.3 ; 1.1Pre-bronchodilator FEV1 Placebo BID Rilzabrutinib 400 mg BIDPercent change from baselineNumber 19 18Mean(SD) 2.89 (15.39) 13.96 (17.98)Median 4.48 15.23Q1 ;Q3 -5.52; 9.15 -1.39; 22.70Min; Max -33.5 ; 34.5 -12.4 ; 57.3

[0233] Table 32. Summary of pre-bronchodilator FEV1 (L) over time (on-site conventional spirometry as observed; mITT population).Pre-bronchodilator FEV1 Placebo BID Rilzabrutinib 400 mg BIDBaselineNumber 32 31Mean(SD) 2.16(0.77) 2.11 (0.67)Median 2.10 1.94Q1 ;Q3 1.47; 2.50 1.59; 2.52Min; Max 1.2; 3.9 1.0; 3.8Week 2Number 29 27Mean (SD) 2.20 (0.77) 2.20 (0.68)Median 2.13 2.08Q1 ;Q3 1.66; 2.55 1.79; 2.64Min; Max 1.2; 4.0 1.0; 4.0Change from baselineNumber 29 26Mean (SD) 0.07 (0.29) 0.08 (0.29)Median 0.03 0.04Q1 ;Q3 -0.04; 0.17 -0.08 ; 0.22Min ; Max -0.7 ; 0.8 -0.6 ; 0.6Percent change from baselineNumber 29 26Mean(SD) 4.12(14.97) 4.47(12.91)Median 1.16 2.02Q1 ;Q3 -2.46; 8.38 -2.56; 11.40Min; Max -29.8; 45.4 -19.9 ; 38.3Week 4Number 25 25Mean (SD) 2.29 (0.79) 2.05 (0.62)Median 2.12 1.96Q1 ;Q3 1.79; 2.75 1.70; 2.36Min; Max 1.0; 3.9 1.0; 3.3Change from baselineNumber 25 25Pre-bronchodilator FEV1 Placebo BID Rilzabrutinib 400 mg BID(L) (N=32) (N=32)Mean (SD) 0.09 (0.28) 0.07 (0.24)Median 0.03 0.02Q1 ;Q3 -0.08; 0.19 -0.07; 0.17Min ; Max -0.4 ; 0.9 -0.3 ; 0.6Percent change from baselineNumber 25 25Mean(SD) 4.36 (15.85) 3.72 (12.19)Median 0.66 0.55Q1 ;Q3 -4.25 ; 7.82 -4.02; 11.68Min ; Max -17.9 ; 54.0 -16.7 ; 30.7Week 6 Number 29 24Mean (SD) 2.11 (0.70) 2.24 (0.78)Median 2.19 2.06Q1 ;Q3 1.51 ; 2.53 1.63 ; 2.64Min; Max 1.0; 3.5 1.0; 3.9Change from baseline Number 29 23Mean(SD) 0.07 (0.33) 0.10 (0.39)Median 0.07 0.07Q1 ;Q3 -0.06; 0.18 -0.11 ; 0.33Min; Max -0.7 ; 0.9 -0.7; 1.2Percent change from baselineNumber 29 23Mean(SD) 4.36 (18.18) 4.61 (17.58)Median 2.56 5.14Q1 ;Q3 -4.60; 12.12 -4.84 ; 13.93Min; Max -35.5 ; 53.4 -27.7 ; 44.3Week 8 Number 24 21Mean (SD) 2.05 (0.68) 2.08 (0.83)Median 2.03 1.86Q1 ;Q3 1.49; 2.45 1.52; 2.45Min; Max 0.9 ; 3.6 0.9 ; 3.9Change from baseline Number 24 20Mean (SD) 0.04 (0.24) 0.08 (0.40)Median -0.01 0.09Q1 ;Q3 -0.12; 0.19 -0.06 ; 0.25Min; Max -0.3 ; 0.7 -1.1 ; 0.7Percent change from baselineNumber 24 20Pre-bronchodilator FEV1 Placebo BID Rilzabrutinib 400 mg BID(L) (N=32) (N=32)Mean(SD) 2.52 (14.71) 3.30 (18.14)Median -0.52 3.64Q1 ;Q3 -5.85 ; 7.52 -4.06 ; 14.97Min; Max -25.8; 41.1 -42.2 ; 27.5Week 10 Number 24 17Mean(SD) 1.96(0.74) 2.29 (0.76)Median 1.97 1.93Q1 ;Q3 1.40; 2.33 1.78 ; 2.57Min; Max 0.8 ; 3.8 1.6; 4.2Change from baselineNumber 24 16Mean(SD) -0.02 (0.30) 0.21 (0.29)Median -0.10 0.12Q1 ;Q3 -0.18; 0.20 -0.01 ; 0.42Min ; Max -0.5 ; 0.8 -0.2 ; 0.7Percent change from baselineNumber 24 16Mean(SD) -1.48 (16.21) 10.71 (16.43)Median -5.47 4.52Q1 ;Q3 -9.15 ; 13.20 -0.45 ; 24.37Min; Max -30.1 ; 28.2 -11.9; 45.6Week 12 Number 19 23Mean(SD) 2.13(0.71) 1.97(0.81)Median 2.04 1.82Q1 ;Q3 1.67; 2.47 1.43 ; 2.30Min; Max 1.0; 3.5 0.6 ; 3.8Change from baseline Number 19 22Mean (SD) -0.04 (0.20) -0.03 (0.40)Median -0.08 -0.05Q1 ;Q3 -0.19; 0.14 -0.23 ; 0.31Min; Max -0.4 ; 0.3 -1.0 ; 0.7Percent change from baselineNumber 19 22Mean(SD) -1.25 (11.01) -3.27(20.46)Median -2.79 -2.70Q1 ;Q3 -8.91 ; 8.26 -11.12; 9.91Min; Max -18.0; 23.4 -54.6 ; 32.7Week 16 Number 19 19Mean(SD) 2.21 (0.80) 2.30 (0.84)Pre-bronchodilator FEV1 Placebo BID Rilzabrutinib 400 mg BIDMedian 2.09 2.01Q1 ;Q3 1.48; 2.66 1.80; 2.67Min; Max 1.0; 3.8 0.9 ; 4.2Change from baselineNumber 19 18Mean (SD) 0.06 (0.29) 0.29 (0.37)Median 0.12 0.28Q1 ;Q3 -0.12; 0.28 -0.03 ; 0.44Min; Max -0.7 ; 0.6 -0.3 ; 1.1Percent change from baselineNumber 19 18Mean(SD) 2.89 (15.39) 13.96 (17.98)Median 4.48 15.23Q1 ;Q3 -5.52; 9.15 -1.39; 22.70Min; Max -33.5 ; 34.5 -12.4 ; 57.3All data were summarized as observed.

[0234] Table 33. Change from baseline in pre-bronchodilator FEV1 (L) over time (mITT population).400 mg BID cohort 400 mg TID cohortPre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400BaselineNumber 32 31 67 63Mean(SD) 2.16(0.77) 2.11 (0.67) 2.42 (0.90) 2.50 (0.95)Median 2.10 1.94 2.15 2.36Q1 ;Q3 1.47; 2.50 1.59; 2.52 1.77; 2.98 1.73 ; 3.10Min; Max 1.2; 3.9 1.0 ; 3.8 1.0 ; 5.0 1.1 ; 5.3Week 2Number 29 (28 / 1) 27 (27 / 0) 64 (63 / 1) 56 (56 / 0)(observed / LOCF imputed)Mean (SD) 2.20 (0.77) 2.20 (0.68) 2.48 (0.94) 2.47 (0.80)Median 2.13 2.08 2.25 2.37Q1 ;Q3 1.66; 2.55 1.79; 2.64 1.75 ; 3.07 1.76; 3.06Min; Max 1.2; 4.0 1.0 ; 4.0 1.0 ; 5.2 1.1 ; 4.1Change from baselineNumber 29 (28 / 1) 26 (26 / 0) 63 (62 / 1) 55 (55 / 0)(observed / LOCF imputed)Mean(SD) 0.07(0.29) 0.08 (0.29) 0.01 (0.20) -0.04(0.25)Median 0.03 0.04 0.02 -0.02Q1 ;Q3 -0.04; 0.17 -0.08 ; 0.22 -0.12; 0.15 -0.17; 0.10400 mg BID cohort 400 mg TID cohortPre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400FEV1(L) (N=32) mg BID (N=68) mg TID(N=32) (N=64)Min ; Max -0.7 ; 0.8 -0.6 ; 0.6 -0.6 ; 0.6 -0.7 ; 0.7LS Mean (SE) 0.05 (0.06) 0.06(0.06) -0.01 (0.03) -0.05 (0.03)LS Mean Diff vs. 0.00 (-0.15, 0.15) -0.04 (-0.12, 0.04) placebo (95% CI) P-value vs. 0.9752 0.3401 placeboWeek 4 Number 26(24 / 2) 26(25 / 1) 56(55 / 1) 51 (51 / 0)(observed / LOCF imputed) Mean(SD) 2.25 (0.79) 2.07(0.62) 2.47 (0.92) 2.58 (0.86)Median 2.11 1.96 2.30 2.50Q1 ;Q3 1.66; 2.75 1.70; 2.56 1.75; 3.12 1.82; 3.14Min; Max 1.0; 3.9 1.0 ; 3.3 1.0 ; 5.3 1.2; 4.8Change from baselineNumber 26(24 / 2) 26(25 / 1) 55 (54 / 1) 51 (51 / 0)(observed / LOCF imputed) Mean (SD) 0.08 (0.28) 0.07 (0.24) -0.04 (0.30) 0.02 (0.22)Median 0.02 0.02 -0.05 -0.01Q1 ;Q3 -0.08; 0.18 -0.07; 0.17 -0.17; 0.13 -0.13; 0.13Min ; Max -0.4 ; 0.9 -0.3 ; 0.6 -0.9 ; 0.8 -0.5 ; 0.6LS Mean (SE) 0.09(0.05) 0.08 (0.05) -0.07(0.04) -0.01 (0.04)LS Mean Diff vs. -0.01 (-0.14, 0.12) 0.05 (-0.05, 0.15) placebo (95% CI) P-value vs. 0.8701 0.3010 placeboWeek 6 Number 29(27 / 2) 25 (23 / 2) 58 (56 / 2) 54 (52 / 2)(observed / LOCF imputed) Mean(SD) 2.10(0.72) 2.24(0.77) 2.35 (0.88) 2.52 (0.87)Median 2.19 2.01 2.23 2.37Q1 ;Q3 1.46; 2.53 1.70; 2.64 1.65; 2.97 1.84; 3.17Min; Max 1.0; 3.6 1.0 ; 3.9 1.0 ; 5.0 1.0; 4.8Change from baselineNumber 29(27 / 2) 24(22 / 2) 57(55 / 2) 53 (51 / 2)(observed / LOCF imputed) Mean(SD) 0.05 (0.32) 0.09(0.38) -0.08 (0.24) -0.07(0.34)Median 0.07 0.07 -0.05 -0.09Q1 ;Q3 -0.06; 0.18 -0.10; 0.22 -0.22 ; 0.08 -0.23 ; 0.08Min; Max -0.7 ; 0.9 -0.7 ; 1.2 -0.6 ; 0.4 -1.3 ; 0.9LS Mean (SE) -0.00 (0.08) -0.03 (0.08) -0.11 (0.04) -0.07(0.04)400 mg BID cohort 400 mg TID cohortPre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400FEV1(L) (N=32) mg BID (N=68) mg TID(N=32) (N=64)LS Mean Diff vs. -0.03 (-0.22, 0.17) 0.04 (-0.07, 0.15) placebo (95% CI) P-valuevs. 0.7797 0.4831 placeboWeek8 Number 27 (24 / 3) 24 (20 / 4) 56 (53 / 3) 45 (42 / 3)(observed / LOCF imputed) Mean(SD) 2.05 (0.74) 2.09(0.81) 2.36 (0.89) 2.41 (0.82)Median 2.00 1.83 2.23 2.38Q1 ;Q3 1.44; 2.48 1.51; 2.58 1.60; 3.03 1.81 ; 2.96Min; Max 0.9 ; 3.6 0.9 ; 3.9 0.7 ; 5.0 1.1 ; 4.3Change from baselineNumber 27(24 / 3) 23 (19 / 4) 55 (52 / 3) 44 (41 / 3)(observed / LOCF imputed) Mean(SD) 0.02(0.26) 0.04(0.41) -0.11 (0.22) -0.12(0.40)Median 0.00 0.05 -0.08 -0.10Q1 ;Q3 -0.12; 0.13 -0.09 ; 0.23 -0.26 ; 0.04 -0.21 ; 0.08Min; Max -0.6 ; 0.7 -1.1 ; 0.7 -0.6 ; 0.4 -2.3 ; 0.6LS Mean (SE) -0.03 (0.07) -0.00(0.07) -0.10(0.05) -0.07(0.05)LS Mean Diff vs. 0.02 (-0.14, 0.19) 0.03 (-0.10, 0.15) placebo (95% CI) P-value vs. 0.7849 0.6679 placeboWeek 10 Number 27(21 / 6) 21 (17 / 4) 54(50 / 4) 50 (47 / 3)(observed / LOCF imputed) Mean(SD) 2.02(0.77) 2.24(0.73) 2.32 (0.88) 2.53 (0.88)Median 1.99 1.93 2.15 2.50Q1 ;Q3 1.38; 2.40 1.76; 2.57 1.62; 2.98 1.78; 3.15Min; Max 0.8 ; 3.8 1.3 ; 4.2 0.9 ; 5.0 1.1 ; 4.4Change from baselineNumber 27(21 / 6) 20(16 / 4) 53 (49 / 4) 50 (47 / 3)(observed / LOCF imputed) Mean(SD) 0.00(0.28) 0.13 (0.33) -0.10(0.28) -0.10(0.27)Median -0.05 0.09 -0.07 -0.09Q1 ;Q3 -0.17; 0.18 -0.05 ; 0.36 -0.25 ; 0.05 -0.26 ; 0.09Min; Max -0.6 ; 0.8 -0.7 ; 0.7 -1.0; 0.6 -1.0 ; 0.4LS Mean (SE) -0.05 (0.08) 0.02(0.09) -0.10(0.04) -0.09(0.04)LS Mean Diff vs. 0.06 (-0.13, 0.26) 0.00 (-0.10, 0.11) placebo (95% CI)400 mg BID cohort 400 mg TID cohortPre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400P-value vs. 0.5282 0.9509 placeboWeek 12Number 25 (16 / 9) 26 (21 / 5) 55 (45 / 10) 49 (46 / 3)(observed / LOCF imputed) Mean (SD) 2.00 (0.72) 2.02 (0.77) 2.47 (0.90) 2.43 (0.83)Median 1.82 1.88 2.39 2.39Q1 ; Q3 1.44 ; 2.33 1.57 ; 2.57 1.76 ; 3.10 1.86 ; 2.80Min ; Max 1.0 ; 3.6 0.6 ; 3.8 0.9 ; 5.0 1.1 ; 4.5Change from baselineNumber 25 (16 / 9) 25 (20 / 5) 54 (44 / 10) 48 (45 / 3)(observed / LOCF imputed) Mean (SD) -0.06 (0.22) -0.04 (0.39) -0.06 (0.31) -0.15 (0.27)Median -0.06 -0.02 -0.07 -0.12Q1 ; Q3 -0.18 ; 0.10 -0.21 ; 0.12 -0.21 ; 0.06 -0.28 ; 0.05Min ; Max -0.6 ; 0.3 -1.0 ; 0.7 -0.7 ; 1.2 -1.1 ; 0.4LS Mean (SE) -0.08 (0.08) -0.07 (0.08) -0.04 (0.05) -0.13 (0.05)LS Mean Diff vs. 0.01 (-0.17, 0.19) -0.09 (-0.21, 0.03) placebo (95% CI) P-value vs. 0.9466 0.1523 placeboLATAM: Latin America, ROW: Rest of the world

[0235] Table 34. Subgroup analysis: change from baseline in pre-bronchodilatorFEV1 (L) at EOT (Week 12) by demographics subgroups (mITT population).400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDAge group 1 (years)< 45Number 8 9 26 22Mean (SD) -0.06 (0.21) -0.05 (0.52) -0.07 (0.24) -0.24 (0.34)LS Mean (SE) -0.01 (0.19) -0.13 (0.19) -0.06 (0.08) -0.24 (0.08)LS Mean Diff vs. placebo (95% -0.13 (-0.60, -0.18 (-0.38,CI) 0.35) 0.02)P-value vs. placebo 0.6056 0.0756> 45Number 17 16 28 26Mean (SD) -0.06 (0.23) -0.03 (0.32) -0.06 (0.38) -0.08 (0.17)LS Mean (SE) -0.16 (0.10) -0.14 (0.10) -0.03 (0.05) -0.04 (0.06)400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs. placebo (95% 0.02 (-0.19, -0.01 (-0.17,CI) 0.23) 0.14)P-value vs. placebo 0.8611 0.8854Overall p-value for interaction 0.9627 0.1988GenderMale Number 6 11 22 21Mean (SD) -0.12 (0.31) -0.08 (0.53) -0.07 (0.36) -0.16 (0.29)LS Mean (SE) -0.07 (0.19) -0.23 (0.19) -0.05 (0.08) -0.15 (0.08)LS Mean Diff vs. placebo (95% -0.16 (-0.72, -0.09 (-0.31,CI) 0.41) 0.12)P-value vs. placebo 0.5836 0.3923Female Number 19 14 32 27Mean (SD) -0.04 (0.18) -0.01 (0.26) -0.06 (0.28) -0.14 (0.25)LS Mean (SE) -0.03 (0.10) 0.00 (0.09) -0.02 (0.05) -0.11 (0.06)LS Mean Diff vs. placebo (95% 0.04 (-0.17, -0.09 (-0.24,CI) 0.24) 0.05)P-value vs. placebo 0.7294 0.2138Overall p-value for interaction 0.7567 0.9813Baseline weight group (kg) < 60Number 4 3 3 0Mean (SD) -0.10 (0.08) -0.02 (0.04) 0.11 (0.31) NC (NC)LS Mean (SE) NC (NC) NC (NC) NC (NC) NC (NC)LS Mean Diff vs . placebo (95 % NC (NC, NC) NC (NC, NC) ci) P-value vs. placebo NC NC> 60 - < 90 Number 18 18 29 28Mean (SD) -0.06 (0.25) -0.01 (0.43) -0.08 (0.37) -0.15 (0.31)LS Mean (SE) -0.12 (0.12) -0.09 (0.11) -0.05 (0.07) -0.13 (0.07)LS Mean Diff vs. placebo (95% 0.03 (-0.23, -0.07 (-0.25,CI) 0.28) 0.10)P-value vs. placebo 0.8258 0.4062> 90 Number 3 4 15 18Mean (SD) -0.00 (0.10) -0.17 (0.42) -0.15 (0.21) -0.17 (0.20)LS Mean (SE) 0.12 (0.23) -0.25 (0.37) -0.10 (0.06) -0.15 (0.06)LS Mean Diff vs. placebo (95% -0.37 (-1.14, -0.05 (-0.21,CI) 0.40) 0.11)P-value vs. placebo 0.3471 0.5184400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDOverall p-value for interaction 0.8383 0.9293Baseline BMI group (kg / m2) < 25Number 5 7 19 8Mean (SD) -0.10 (0.07) 0.02 (0.51) -0.04 (0.41) -0.21 (0.45)LS Mean (SE) -0.24 (0.33) -0.09 (0.32) -0.03 (0.10) -0.19 (0.15)LS Mean Diff vs. placebo (95% 0.15 (-0.48, -0.16 (-0.48,CI) 0.78) 0.16)P-value vs. placebo 0.6436 0.3337> 25 - < 30Number 14 12 20 25Mean (SD) -0.08 (0.25) -0.00 (0.36) -0.06 (0.27) -0.14 (0.23)LS Mean (SE) -0.12 (0.12) -0.06 (0.12) -0.06 (0.06) -0.11 (0.06)LS Mean Diff vs. placebo (95% 0.06 (-0.25, -0.05 (-0.22,CI) 0.37) 0.11)P-value vs. placebo 0.7084 0.5147> 30Number 6 6 15 15Mean (SD) 0.03 (0.23) -0.18 (0.33) -0.09 (0.25) -0.14 (0.22)LS Mean (SE) 0.09 (0.27) -0.04 (0.25) -0.04 (0.07) -0.11 (0.07)LS Mean Diff vs. placebo (95% -0.13 (-0.63, -0.07 (-0.27,CI) 0.37) 0.13)P-value vs. placebo 0.6158 0.5078Overall p-value for interaction 0.7816 0.6728RegionEastern Europe Number 4 1 38 32Mean (SD) -0.24 (0.31) -0.21 (NC) -0.10 (0.26) -0.18 (0.28)LS Mean (SE) NC (NC) NC (NC) -0.10 (0.05) -0.18 (0.05)LS Mean Diff vs. placebo (95% NC (NC, NC) -0.08 (-0.22,CI) 0.06)P-value vs. placebo NC 0.2618Latin America Number 19 21 14 14Mean (SD) -0.02 (0.19) -0.05 (0.39) 0.03 (0.44) -0.08 (0.27)LS Mean (SE) -0.06 (0.10) -0.07 (0.08) 0.04 (0.12) -0.08 (0.11)LS Mean Diff vs. placebo (95% -0.01 (-0.25, -0.12 (-0.37,CI) 0.22) 0.12)P-value vs. placebo 0.9056 0.3256Western CountriesNumber 1 2 1 2Mean (SD) -0.05 (NC) 0.24 (0.67) -0.14 (NC) -0.18 (0.06)LS Mean (SE) NC (NC) NC (NC) NC (NC) NC (NC)400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs . placebo (95 % NC (NC, NC) NC (NC, NC) ci)P-value vs. placebo NC NCAPACNumber 1 1 1 0Mean (SD) -0.07 (NC) -0.09 (NC) 0.02 (NC) NC (NC)LS Mean (SE) NC (NC) NC (NC) NC (NC) NC (NC)LS Mean Diff vs . placebo (95 % NC (NC, NC) NC (NC, NC) ci)P-value vs. placebo NC NCOverall p-value for interaction 0.8887 0.8187LATAM: Latin America, ROW: Rest of the world

[0236] Table 35. Subgroup analysis: change from baseline in pre-bronchodilatorFEV1 (L) at EOT (Week 12) by disease and other characteristics subgroups (mITT population).400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDAge at onset of asthma (years)< 12Number 7 8 12 11Mean (SD) -0.08 (0.21) 0.00 (0.48) -0.07 (0.25) -0.25 (0.38)LS Mean (SE) -0.06 (0.25) 0.12 (0.32) -0.05 (0.10) -0.34 (0.11)LS Mean Diff vs. placebo (95% 0.18 (-0.43, -0.28 (-0.58,CI) 0.80) 0.01)P-value vs. placebo 0.5568 0.0576> 12 - < 18Number 1 4 5 4Mean (SD) -0.01 (NC) 0.12 (0.29) 0.31 (0.56) -0.01 (0.38)LS Mean (SE) NC (NC) NC (NC) 0.45 (0.42) 0.05 (0.41)LS Mean Diff vs. placebo (95% NC (NC, NC) -0.40 (-1.36,CI) 0.57)P-value vs. placebo NC 0.4199> 18 - < 40Number 11 11 23 21Mean (SD) -0.06 (0.28) -0.08 (0.36) -0.13 (0.30) -0.17 (0.23)LS Mean (SE) -0.14 (0.13) -0.14 (0.13) -0.10 (0.06) -0.18 (0.07)LS Mean Diff vs. placebo (95% 0.00 (-0.29, -0.08 (-0.24,CI) 0.29) 0.09)P-value vs. placebo 0.9979 0.3506400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)> 40Number 6 2 14 12Mean (SD) -0.03 (0.12) -0.31 (0.55) -0.09 (0.19) -0.07 (0.14)LS Mean (SE) -0.07 (0.27) 0.00 (0.63) -0.05 (0.07) 0.01 (0.08)LS Mean Diff vs. placebo (95% 0.07 (-0.91, 0.06 (-0.13,CI) 1.05) 0.25)P-value vs. placebo 0.8887 0.5330Overall p-value for interaction 0.9178 0.2462Age at onset of asthma (years)< 18Number 8 12 17 15Mean (SD) -0.07 (0.19) 0.04 (0.41) 0.04 (0.39) -0.18 (0.38)LS Mean (SE) -0.09 (0.18) -0.00 (0.18) 0.02 (0.10) -0.25 (0.11)LS Mean Diff vs. placebo (95% 0.08 (-0.30, -0.27 (-0.55, -CI) 0.47) 0.00)P-value vs. placebo 0.6639 0.0498> 18Number 17 13 37 33Mean (SD) -0.05 (0.23) -0.11 (0.37) -0.11 (0.26) -0.14 (0.20)LS Mean (SE) -0.13 (0.11) -0.17 (0.11) -0.07 (0.05) -0.10 (0.05)LS Mean Diff vs. placebo (95% -0.03 (-0.27, -0.02 (-0.16,CI) 0.21) 0.11)P-value vs. placebo 0.7986 0.7110Overall p-value for interaction 0.4111 0.0777Number of asthma exacerbations within 2 years before screening visit1Number 5 10 40 31Mean (SD) -0.02 (0.19) 0.05 (0.51) -0.03 (0.30) -0.16 (0.29)LS Mean (SE) -0.03 (0.22) -0.08 (0.17) -0.01 (0.05) -0.14 (0.06)LS Mean Diff vs. placebo (95% -0.05 (-0.57, -0.13 (-0.27,CI) 0.47) 0.01)P-value vs. placebo 0.8488 0.06252Number 14 9 14 14Mean (SD) -0.07 (0.27) -0.06 (0.28) -0.17 (0.34) -0.16 (0.24)LS Mean (SE) -0.11 (0.12) -0.01 (0.16) -0.14 (0.09) -0.08 (0.09)LS Mean Diff vs. placebo (95% 0.10 (-0.22, 0.06 (-0.18,CI) 0.41) 0.30)P-value vs. placebo 0.5439 0.6174> 2Number 6 6 0 3Mean (SD) -0.05 (0.10) -0.15 (0.34) NC (NC) 0.01 (0.06)400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean (SE) -0.20 (0.18) -0.36 (0.14) NC (NC) NC (NC)LS Mean Diff vs. placebo (95% -0.16 (-0.52, NC (NC, NC)CI) 0.20)P-value vs. placebo 0.3826 NCOverall p-value for interaction 0.7653 0.4094Atopic medical conditionsYesNumber 15 16 16 16Mean (SD) 0.02 (0.18) 0.03 (0.25) -0.07 (0.25) -0.09 (0.25)LS Mean (SE) 0.05 (0.09) 0.02 (0.08) -0.07 (0.07) -0.12 (0.07)LS Mean Diff vs. placebo (95% -0.03 (-0.19, -0.04 (-0.23,CI) 0.12) 0.14)P-value vs. placebo 0.6793 0.6505NoNumber 10 9 38 32Mean (SD) -0.17 (0.23) -0.16 (0.56) -0.06 (0.34) -0.18 (0.28)LS Mean (SE) -0.25 (0.16) -0.15 (0.19) -0.04 (0.07) -0.15 (0.07)LS Mean Diff vs. placebo (95% 0.10 (-0.39, -0.11 (-0.26,CI) 0.60) 0.04)P-value vs. placebo 0.6862 0.1594Overall p-value for interaction 0.8948 0.6133Background ICS dose level at randomization (400 mg TID only)MediumNumber 29 21Mean (SD) -0.06 (0.26) -0.18 (0.28)LS Mean (SE) -0.05 (0.06) -0.15 (0.07)LS Mean Diff vs. placebo (95% -0.10 (-0.25,CI) 0.05)P-value vs. placebo 0.1837HighNumber 25 27Mean (SD) -0.07 (0.37) -0.13 (0.27)LS Mean (SE) -0.07 (0.07) -0.13 (0.07)LS Mean Diff vs. placebo (95% -0.07 (-0.25,CI) 0.11)P-value vs. placebo 0.4593Overall p-value for interaction 0.7498Smoking historyFormerNumber 7 4 3 3Mean (SD) -0.07 (0.28) -0.36 (0.39) -0.06 (0.09) -0.21 (0.28)400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean (SE) -0.36 (0.22) -0.57 (0.43) -0.07 (0.16) -0.12 (0.16)LS Mean Diff vs. placebo (95% -0.21 (-0.96, -0.05 (-0.46,CI) 0.55) 0.37)P-value vs. placebo 0.5908 0.8328NeverNumber 18 21 51 45Mean (SD) -0.05 (0.19) 0.02 (0.37) -0.06 (0.32) -0.15 (0.27)LS Mean (SE) -0.08 (0.11) -0.05 (0.10) -0.04 (0.05) -0.13 (0.05)LS Mean Diff vs. placebo (95% 0.03 (-0.18, -0.09 (-0.21,CI) 0.24) 0.04)P-value vs. placebo 0.7800 0.1745Overall p-value for interaction 0.1306 0.9511Baseline pre-bronchodilator FEV 1(L) (400 mg BID only)< Median (2.022)Number 12 13Mean (SD) -0.08 (0.25) -0.06 (0.27)LS Mean (SE) -0.12 (0.13) -0.08 (0.14)LS Mean Diff vs. placebo (95% 0.04 (-0.19,CI) 0.27)P-value vs. placebo 0.7330> Median (2.022)Number 13 12Mean (SD) -0.04 (0.19) -0.02 (0.50)LS Mean (SE) -0.07 (0.13) -0.09 (0.14)LS Mean Diff vs. placebo (95% -0.03 (-0.38,CI) 0.32)P-value vs. placebo 0.8705Overall p-value for interaction 0.8540Baseline pre-bronchodilator percent predicted FEV 1 (%) (400 mg BID only)< Median (68)Number 11 16Mean (SD) -0.08 (0.26) -0.05 (0.41)LS Mean (SE) -0.24 (0.16) -0.21 (0.16)LS Mean Diff vs. placebo (95% 0.03 (-0.27,CI) 0.34)P-value vs. placebo 0.8283> Median (68)Number 14 9Mean (SD) -0.04 (0.18) -0.02 (0.39)LS Mean (SE) -0.06 (0.13) -0.07 (0.13)400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs. placebo (95% -0.01 (-0.28,CI) 0.26)P-value vs. placebo 0.9404Overall p-value for interaction 0.7813Baseline pre -bronchodilator FEV1 (L) (400 mg TID only)< Median (2.1955)Number 24 18Mean (SD) 0.05 (0.35) -0.05 (0.23)LS Mean (SE) 0.05 (0.07) -0.03 (0.08)LS Mean Diff vs. placebo (95% -0.09 (-0.28,CI) 0.10)P-value vs. placebo 0.3726> Median (2.1955)Number 30 30Mean (SD) -0.15 (0.26) -0.21 (0.28)LS Mean (SE) -0.13 (0.06) -0.22 (0.06)LS Mean Diff vs. placebo (95% -0.09 (-0.24,CI) 0.07)P-value vs. placebo 0.2881Overall p-value for interaction 0.9725Baseline pre-bronchodilator percent predicted FEV 1 group 1 (%) (400 mg TID only)< Median (77)Number 28 21Mean (SD) -0.01 (0.37) -0.10 (0.25)LS Mean (SE) 0.01 (0.07) -0.03 (0.08)LS Mean Diff vs. placebo (95% -0.04 (-0.24,CI) 0.15)P-value vs. placebo 0.6453> Median (77)Number 26 27Mean (SD) -0.12 (0.24) -0.19 (0.28)LS Mean (SE) -0.09 (0.06) -0.21 (0.06)LS Mean Diff vs. placebo (95% -0.13 (-0.28,CI) 0.03)P-value vs. placebo 0.1033Overall p-value for interaction 0.4854Baseline pre-bronchodilator percent predicted FEV 1 group 2 (%) (400 mg TID only)400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)< 80Number 33 26Mean (SD) -0.03 (0.35) -0.13 (0.30)LS Mean (SE) -0.01 (0.06) -0.09 (0.07)LS Mean Diff vs. placebo (95% -0.08 (-0.25,CI) 0.08)P-value vs. placebo 0.3269> 80Number 21 22Mean (SD) -0.12 (0.25) -0.17 (0.24)LS Mean (SE) -0.09 (0.06) -0.20 (0.06)LS Mean Diff vs. placebo (95% -0.11 (-0.28,CI) 0.06)P-value vs. placebo 0.2034Overall p-value for interaction 0.8177Baseline FEV 1 reversibility (%)< 12Number 14 10 40 35Mean (SD) -0.16 (0.20) -0.24 (0.47) -0.06 (0.33) -0.18 (0.25)LS Mean (SE) -0.23 (0.10) -0.23 (0.12) -0.04 (0.05) -0.16 (0.05)LS Mean Diff vs. placebo (95% -0.00 (-0.26, -0.12 (-0.25,CI) 0.26) 0.02)P-value vs. placebo 0.9928 0.0828> 12Number 9 14 9 10Mean (SD) 0.04 (0.15) 0.08 (0.27) 0.01 (0.30) 0.00 (0.27)LS Mean (SE) 0.12 (0.12) 0.07 (0.11) 0.02 (0.13) -0.01 (0.12)LS Mean Diff vs. placebo (95% -0.05 (-0.26, -0.02 (-0.34,CI) 0.16) 0.29)P-value vs. placebo 0.6636 0.8822Overall p-value for interaction 0.4867 0.4422Baseline ACQ-5 score< 2Number 12 14 20 12Mean (SD) 0.00 (0.20) 0.00 (0.47) -0.20 (0.24) -0.10 (0.19)LS Mean (SE) -0.15 (0.16) -0.12 (0.13) -0.11 (0.06) -0.12 (0.08)LS Mean Diff vs. placebo (95% 0.04 (-0.28, -0.01 (-0.20,CI) 0.35) 0.19)P-value vs. placebo 0.8203 0.9587> 2Number 13 11 34 36Mean (SD) -0.11 (0.22) -0.09 (0.29) 0.01 (0.33) -0.17 (0.29)LS Mean (SE) -0.08 (0.10) -0.12 (0.12) 0.00 (0.06) -0.15 (0.06)400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs. placebo (95% -0.04 (-0.29, -0.16 (-0.31,CI) 0.20) 0.00)P-value vs. placebo 0.7321 0.0511Overall p-value for interaction 0.9187 0.2088LATAM: Latin America, ROW: Rest of the world

[0237] Table 36. Subgroup analysis: change from baseline in pre-bronchodilatorFEV1 (L) at EOT (Week 12) by baseline ICS / LABA dose level (mITT population).Pre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib 400 mg(N=32) BID(N=32)Background ICS / LABA dose level at randomizationMedium Number 2 2Mean (SD) -0.07 (0.00) 0.04 (0.47)LS Mean (SE) NC (NC) NC (NC)LS Mean Diff vs. placebo (95% CI) NC (NC, NC)P-value vs. placebo NCHigh Number 23 23Mean (SD) -0.06 (0.23) -0.05 (0.40)LS Mean (SE) -0.12 (0.09) -0.11 (0.09)LS Mean Diff vs. placebo (95% CI) 0.02 (-0.19, 0.23)P-value vs. placebo 0.8815Overall p-value for interaction 0.8062LATAM: Latin America, ROW: Rest of the world

[0238] Table 37. Subgroup analysis: change from baseline in pre-bronchodilatorFEV1 (L) at EOT (Week 12) by baseline biomarker subgroups (mITT population).400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDBaseline IgE level (lU / mL)< 100Number 7 7 22 18Mean (SD) -0.10 (0.30) -0.09 (0.52) -0.08 (0.21) -0.20 (0.31)LS Mean (SE) -0.07 (0.27) -0.11 (0.26) 0.02 (0.12) -0.10 (0.13)LS Mean Diff vs. placebo (95% -0.03 (-0.56, -0.11 (-0.27,CI) 0.50) 0.05)P-value vs. placebo 0.8986 0.1765> 100400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDNumber 18 18 32 30Mean (SD) -0.04 (0.19) -0.02 (0.35) -0.05 (0.37) -0.12 (0.24)LS Mean (SE) -0.06 (0.20) -0.04 (0.18) -0.06 (0.09) -0.13 (0.09)LS Mean Diff vs. placebo (95% 0.02 (-0.20, -0.07 (-0.24,CI) 0.23) 0.10)P-value vs. placebo 0.8821 0.4002Overall p-value for interaction 0.5502 0.6890Baseline median IgE level (lU / mL)(400 mg BID only)< Median (210.8)Number 8 17Mean (SD) -0.11 (0.28) -0.02 (0.37)LS Mean (SE) -0.13 (0.15) -0.11 (0.13)LS Mean Diff vs. placebo (95% 0.01 (-0.34,CI) 0.37)P-value vs. placebo 0.9444> Median (210.8)Number 17 8Mean (SD) -0.03 (0.19) -0.08 (0.45)LS Mean (SE -0.04 (0.11) -0.02 (0.14)LS Mean Diff vs. placebo (95% 0.01 (-0.29,CI) 0.31)P-value vs. placebo 0.9284Overall p-value for interaction 0.8938Baseline median IgE level(lU / mL) (400 mg TID only)< Median (121.85)Number 28 24Mean (SD) -0.10 (0.23) -0.17 (0.29)LS Mean (SE) -0.08 (0.07) -0.16 (0.07)LS Mean Diff vs. placebo (95% -0.08 (-0.23,CI) 0.07)P-value vs. placebo 0.3135> Median (121.85)Number 26 24Mean (SD) -0.03 (0.39) -0.13 (0.25)LS Mean (SE) -0.22 (0.22) -0.33 (0.23)LS Mean Diff vs. placebo (95% -0.11 (-0.30,CI) 0.07)P-value vs. placebo 0.2365Overall p-value for interaction 0.8457I l l400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDBaseline median IgA level (mg / L)(400 mg TID only)< Median (2190)Number 29 21Mean (SD) -0.04 (0.23) -0.12 (0.26)LS Mean (SE) -0.03 (0.06) -0.12 (0.07)LS Mean Diff vs. placebo (95% -0.09 (-0.25,CI) 0.07)P-value vs. placebo 0.2572> Median (2190)Number 25 27Mean (SD) -0.09 (0.39) -0.17 (0.28)LS Mean (SE) -0.06 (0.07) -0.15 (0.07)LS Mean Diff vs. placebo (95% -0.09 (-0.27,CI) 0.09)P-value vs. placebo 0.3176Overall p-value for interaction 0.9795Baseline blood eosinophil level 1(10A9 / L)< 0.15Number 5 8 22 22Mean (SD) 0.03 (0.18) -0.10 (0.49) -0.15 (0.27) -0.17 (0.32)LS Mean (SE) -0.04 (0.26) -0.08 (0.16) -0.13 (0.07) -0.17 (0.07)LS Mean Diff vs. placebo (95% -0.04 (-0.65, -0.05 (-0.23,CI) 0.57) 0.14)P-value vs. placebo 0.8932 0.6211> 0.15 (400 mg BID only)Number 20 17Mean (SD) -0.08 (0.22) -0.01 (0.35)LS Mean (SE) -0.10 (0.10) -0.03 (0.11)LS Mean Diff vs. placebo (95% 0.07 (-0.15,CI) 0.28)P-value vs. placebo 0.5498Overall p-value for interaction 0.3640Baseline blood eosinophil level 2(10A9 / L) (400 mg BID only)< 0.3Number 14 14Mean (SD) -0.01 (0.25) -0.10 (0.42)LS Mean (SE) -0.08 (0.11) -0.15 (0.12)LS Mean Diff vs. placebo (95% -0.07 (-0.35,CI) 0.20)P-value vs. placebo 0.6075400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID> 0.3Number 11 11Mean (SD) -0.11 (0.16) 0.04 (0.36)LS Mean (SE) -0.07 (0.17) 0.00 (0.14)LS Mean Diff vs. placebo (95% 0.07 (-0.21,CI) 0.35)P-value vs. placebo 0.6310Overall p-value for interaction 0.2578Baseline blood eosinophil level 1(10A9 / L) (400 mg TID only)< 0.15Number 22 22Mean (SD) -0.15 (0.27) -0.17 (0.32)LS Mean (SE) -0.13 (0.07) -0.17 (0.07)LS Mean Diff vs. placebo (95% -0.05 (-0.23,CI) 0.14)P-value vs. placebo 0.6211> 0.15 - < 0.3Number 18 13Mean (SD) -0.04 (0.25) -0.10 (0.16)LS Mean (SE) -0.00 (0.08) -0.04 (0.09)LS Mean Diff vs. placebo (95% -0.04 (-0.24,CI) 0.17)P-value vs. placebo 0.7282> 0.3Number 14 13Mean (SD) 0.04 (0.42) -0.16 (0.27)LS Mean (SE) 0.04 (0.12) -0.16 (0.11)LS Mean Diff vs. placebo (95% -0.20 (-0.45,CI) 0.05)P-value vs. placebo 0.1159Overall p-value for interaction 0.5643Baseline blood eosinophil level 2(10A9 / L) (400 mg TID only)< 0.3Number 40 35Mean (SD) -0.10 (0.27) -0.15 (0.27)LS Mean (SE) -0.08 (0.05) -0.13 (0.05)LS Mean Diff vs. placebo (95% -0.05 (-0.19,CI) 0.09)P-value vs. placebo 0.4664> 0.3Number 14 13400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDMean (SD) 0.04 (0.42) -0.16 (0.27)LS Mean (SE) 0.04 (0.12) -0.16 (0.11)LS Mean Diff vs. placebo (95% -0.20 (-0.45,CI) 0.05)P-value vs. placebo 0.1159Overall p-value for interaction 0.3072Baseline FeNO level 1 (ppb)< 25 Number 11 9 31 32Mean (SD) -0.04 (0.26) -0.12 (0.51) -0.06 (0.25) -0.19 (0.28)LS Mean (SE) -0.18 (0.15) -0.16 (0.14) -0.04 (0.05) -0.16 (0.05)LS Mean Diff vs. placebo (95% 0.03 (-0.32, -0.12 (-0.26,CI) 0.37) 0.02)P-value vs. placebo 0.8792 0.0953> 25 Number 14 16 19 14Mean (SD) -0.07 (0.19) 0.01 (0.32) -0.06 (0.41) -0.09 (0.25)LS Mean (SE) 0.01 (0.11) -0.00 (0.11) -0.04 (0.10) -0.09 (0.11)LS Mean Diff vs. placebo (95% -0.01 (-0.23, -0.04 (-0.32,CI) 0.22) 0.23)P-value vs. placebo 0.9359 0.7523Overall p-value for interaction 0.6767 0.5841Baseline FeNO level 2 (ppb) < 35Number 14 17 38 36Mean (SD) -0.03 (0.25) -0.10 (0.43) -0.09 (0.27) -0.18 (0.27)LS Mean (SE) -0.15 (0.13) -0.19 (0.11) -0.06 (0.05) -0.14 (0.05)LS Mean Diff vs. placebo (95% -0.04 (-0.30, -0.09 (-0.22,CI) 0.21) 0.04)P-value vs. placebo 0.7398 0.1794> 35 Number 11 8 12 10Mean (SD) -0.09 (0.17) 0.08 (0.29) 0.02 (0.44) -0.07 (0.27)LS Mean (SE) -0.01 (0.12) 0.05 (0.14) 0.04 (0.17) -0.07 (0.16)LS Mean Diff vs. placebo (95% 0.06 (-0.26, -0.12 (-0.49,CI) 0.38) 0.26)P-value vs. placebo 0.7100 0.5388Overall p-value for interaction 0.2631 0.8679LATAM: Latin America, ROW: Rest of the world

[0239] Table 38. Subgroup analysis: change from baseline in pre-bronchodilatorFEV1 (L) at EOT (Week 12) in the baseline low EOS and low FeNO subgroup (mITT population).400 mg BID cohort 400 mg TID cohortPre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDBaseline blood eosinophil (10A9 / L) and FeNO (ppb)Low EOS (< 0.15) and low FeNO(< 25)Number 3 3 16 16Mean (SD) 0.02 (0.17) -0.17 (0.85) -0.08 (0.23) -0.24 (0.35)LS Mean (SE) NC (NC) NC (NC) -0.06 (0.07) -0.20 (0.07)LS Mean Diff vs. placebo (95% NC (NC, NC) -0.14 (-0.33,CI) 0.06)P-value vs. placebo NC 0.1770All othersNumber 22 22 34 30Mean (SD) -0.07 (0.22) -0.02 (0.32) -0.05 (0.35) -0.11 (0.22)LS Mean (SE) -0.08 (0.09) -0.05 (0.09) -0.02 (0.06) -0.09 (0.06)LS Mean Diff vs. placebo (95% 0.03 (-0.16, -0.07 (-0.23,CI) 0.21) 0.09)P-value vs. placebo 0.7753 0.3909Overall p-value for interaction 0.3586 0.6290FLATAM: Latin America, ROW: Rest of the worldBronchodilator Therapy

[0240] When used in combination with ICS / LABA, treatment with 400 mg BID rilzabrutinib led to a reduction in the number of inhalations / day relative to treatment with the placebo (Figures 7-8 and Tables 39-40A).

[0241] An analysis was performed on the number of participants with >2, >3, >4, and >5 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol compared with baseline on 2 consecutive days during the treatment period, to assess increase in reliever medication during 12-week treatment period. In both cohorts, number of participants with >2 to 5 additional reliever puffs compared to baseline was lower in the rilzabrutinib arms compared to the placebo arms (Table 40B).

[0242] Table 39. Change from baseline in inhalations / day of albuterol or levalbuterol for symptom relief over time (mITT population).Albuterol or levalbuterol for Placebo BID Rilzabrutinib 400 mg BID symptom relief (N=32) (N=32)Baseline Number 32 32Mean (SD) 2.52 (3.02) 1.57 (1.98)Median 1.29 0.62Q1 ; Q3 0.00 ; 4.71 0.00 ; 2.93Min ; Max 0.0 ; 12.3 0.0 ; 7.4Week 1Number (observed / LOCF 32 (32 / 0) 32 (32 / 0) imputed) Mean (SD) 2.02 (2.56) 1.15 (1.78)Median 0.59 0.21Q1 ; Q3 0.00 ; 3.50 0.00 ; 1.93Min ; Max 0.0 ; 10.3 0.0 ; 7.4Change from baselineNumber (observed / LOCF 32 (32 / 0) 32 (32 / 0) imputed) Mean (SD) -0.50 (1.03) -0.41 (1.03)Median 0.00 0.00QI ; Q3 -0.69 ; 0.00 -0.62 ; 0.00Min ; Max -3.5 ; 0.7 -5.3 ; 1.0LS Mean (SE) -0.23 (0.20) -0.39 (0.19)LS Mean Diff vs. placebo (95% -0.16 (-0.64, 0.32) ci)P-value vs. placebo 0.5052Week 2Number (observed / LOCF 32 (31 / 1) 31 (31 / 0) imputed) Mean (SD) 1.91 (2.63) 0.94 (1.76)Median 0.37 0.14Q1 ; Q3 0.00 ; 3.21 0.00 ; 0.80Min ; Max 0.0 ; 9.5 0.0 ; 7.4Change from baselineNumber (observed / LOCF 32 (31 / 1) 31 (31 / 0) imputed) Mean (SD) -0.61 (1.34) -0.68 (1.24)Median 0.00 0.00Q1 ; Q3 -1.50 ; 0.00 -1.14 ; 0.00Min ; Max -4.0 ; 2.9 -5.3 ; 0.3LS Mean (SE) -0.31 (0.27) -0.61 (0.26)LS Mean Diff vs. placebo (95% -0.31 (-0.91, 0.30) ci)P-value vs. placebo 0.3228Week 3Albuterol or levalbuterol for Placebo BID Rilzabrutinib 400 mg BID symptom relief (N=32) (N=32)Number (observed / LOCF 31 (30 / 1) 31 (31 / 0) imputed) Mean(SD) 1.96(2.75) 0.79 (1.48)Median 0.29 0.00Q1 ;Q3 0.00; 4.00 0.00 ; 0.67Min; Max 0.0 ; 9.0 0.0 ; 5.3Change from baselineNumber (observed / LOCF 31 (30 / 1) 31 (31 / 0) imputed) Mean(SD) -0.24(1.98) -0.83 (1.48)Median 0.00 0.00Q1 ;Q3 -0.67; 0.00 -1.33 ; 0.00Min; Max -5.4 ; 6.3 -5.0; 1.3LS Mean (SE) 0.32 (0.37) -0.49 (0.35)LS Mean Diff vs. placebo (95% -0.81 (-1.64, 0.01) ci)P-value vs. placebo 0.0539Week 4Number (observed / LOCF 31 (29 / 2) 30 (29 / 1) imputed) Mean(SD) 1.92(2.71) 0.86 (1.72)Median 0.29 0.00Q1 ;Q3 0.00; 3.43 0.00 ; 0.50Min ; Max 0.0 ; 9.0 0.0 ; 6.0Change from baseline Number (observed / LOCF 31 (29 / 2) 30 (29 / 1) imputed) Mean(SD) -0.28(2.14) -0.81 (1.41)Median 0.00 -0.29Q1 ;Q3 -1.29; 0.00 -1.71 ; 0.00Min; Max -5.4 ; 6.3 -5.5 ; 2.0LS Mean (SE) 0.31 (0.37) -0.51 (0.36)LS Mean Diff vs. placebo (95% -0.82 (-1.67, 0.03) ci) P-value vs. placebo 0.0573Week 5Number (observed / LOCF 30(28 / 2) 31 (29 / 2) imputed)Mean(SD) 1.89 (2.65) 1.11 (1.80)Median 0.25 0.00Q1 ;Q3 0.00; 4.00 0.00 ; 2.50Min; Max 0.0 ; 9.0 0.0 ; 5.7Change from baseline Number (observed / LOCF 30(28 / 2) 31 (29 / 2) imputed) Mean(SD) -0.39(1.97) -0.51 (1.14)Median 0.00 0.00Albuterol or levalbuterol for Placebo BID Rilzabrutinib 400 mg BID symptom relief (N=32) (N=32)Q1 ;Q3 -1.29; 0.00 -0.83 ; 0.00Min; Max -4.9 ; 6.3 -3.5 ; 1.0LS Mean (SE) 0.13 (0.33) -0.20 (0.32)LS Mean Diff vs. placebo (95% -0.33 (-1.08, 0.41) ci) P-value vs. placebo 0.3824Week 6Number (observed / LOCF 30(28 / 2) 31 (29 / 2) imputed) Mean(SD) 2.13 (2.77) 1.00 (1.92)Median 1.14 0.00Q1 ;Q3 0.00; 3.14 0.00 ; 0.50Min ; Max 0.0 ; 9.0 0.0 ; 7.3Change from baselineNumber (observed / LOCF 30(28 / 2) 31 (29 / 2) imputed)Mean(SD) -0.15 (1.94) -0.61 (1.44)Median 0.00 0.00Q1 ;Q3 -0.83 ; 0.00 -1.00; 0.05Min; Max -4.9 ; 6.3 -5.0; 1.3LS Mean (SE) 0.39 (0.36) -0.40 (0.35)LS Mean Diff vs. placebo (95% -0.79 (-1.61, 0.03) ci)P-value vs. placebo 0.0589Week 7Number (observed / LOCF 30(27 / 3) 31 (29 / 2) imputed) Mean(SD) 1.64(2.52) 1.61 (3.82)Median 0.57 0.00Q1 ;Q3 0.00; 2.00 0.00 ; 0.86Min ; Max 0.0 ; 9.0 0.0 ; 19.4Change from baselineNumber (observed / LOCF 30(27 / 3) 31 (29 / 2) imputed) Mean(SD) -0.63 (2.16) -0.00 (3.35)Median -0.05 0.00Q1 ;Q3 -1.43 ; 0.00 -1.00; 0.00Min ; Max -4.9 ; 6.3 -4.3 ; 16.8LS Mean (SE) -0.28 (0.67) -0.07 (0.64)LS Mean Diff vs. placebo (95% 0.21 (-1.27, 1.70) ci) P-value vs. placebo 0.7812Week 8Number (observed / LOCF 30 (27 / 3) 30 (27 / 3) imputed) Mean(SD) 1.59 (2.52) 1.66 (3.98)Median 0.21 0.00Albuterol or levalbuterol for Placebo BID Rilzabrutinib 400 mg BID symptom relief (N=32) (N=32)Q1 ;Q3 0.00; 3.00 0.00 ; 1.14Min ; Max 0.0 ; 9.0 0.0 ; 19.4Change from baselineNumber (observed / LOCF 30 (27 / 3) 30 (27 / 3) imputed)Mean(SD) -0.68 (2.34) -0.01 (3.76)Median 0.00 0.00Q1 ;Q3 -1.86; 0.00 -1.00; 0.00Min; Max -5.9 ; 6.3 -5.5 ; 16.8LS Mean (SE) -0.36 (0.71) -0.08 (0.68)LS Mean Diff vs. placebo (95% 0.28 (-1.32, 1.87) ci)P-value vs. placebo 0.7344Week 9Number (observed / LOCF 30 (27 / 3) 29 (25 / 4) imputed) Mean(SD) 1.70 (2.55) 1.66 (3.98)Median 0.29 0.00Q1 ;Q3 0.00; 2.29 0.00 ; 1.00Min ; Max 0.0 ; 9.0 0.0 ; 19.4Change from baselineNumber (observed / LOCF 30 (27 / 3) 29 (25 / 4) imputed)Mean(SD) -0.57(2.40) -0.07(3.96)Median 0.00 -0.29Q1 ;Q3 -1.86; 0.00 -1.14; 0.00Min; Max -5.9 ; 6.3 -5.5 ; 16.8LS Mean (SE) -0.10(0.69) -0.11 (0.66)LS Mean Diff vs. placebo (95% -0.01 (-1.58, 1.56) ci) P-value vs. placebo 0.9891Week 10Number (observed / LOCF 29 (25 / 4) 29 (25 / 4) imputed) Mean(SD) 1.90(2.72) 1.49 (3.98)Median 0.00 0.00Q1 ;Q3 0.00; 3.29 0.00 ; 0.57Min ; Max 0.0 ; 9.0 0.0 ; 19.4Change from baselineNumber (observed / LOCF 29 (25 / 4) 29 (25 / 4) imputed) Mean(SD) -0.25 (2.97) -0.23 (3.88)Median 0.00 -0.29Q1 ;Q3 -1.86; 0.33 -1.86; 0.00Min; Max -6.9 ; 6.3 -5.5 ; 16.8LS Mean (SE) -0.13 (0.73) -0.68 (0.70)Albuterol or levalbuterol for Placebo BID Rilzabrutinib 400 mg BID symptom relief (N=32) (N=32)LS Mean Diffvs. placebo (95% -0.55 (-2.20, 1.11) ci)P-value vs. placebo 0.5185Week 11Number (observed / LOCF 30 (24 / 6) 27 (23 / 4) imputed) Mean(SD) 2.37(3.30) 1.61 (4.24)Median 0.33 0.00Q1 ;Q3 0.00; 5.00 0.00 ; 0.67Min; Max 0.0; 11.0 0.0 ; 19.4Change from baselineNumber (observed / LOCF 30 (24 / 6) 27 (23 / 4) imputed) Mean(SD) 0.09 (3.30) -0.10 (3.99)Median 0.00 -0.40Q1 ;Q3 -1.71 ; 0.50 -1.43 ; 0.00Min; Max -6.5 ; 7.2 -5.5 ; 16.8LS Mean (SE) 0.28 (0.82) -0.29 (0.79)LS Mean Diffvs. placebo (95% -0.57 (-2.39, 1.25) ci) P-value vs. placebo 0.5406Week 12Number (observed / LOCF 28 (19 / 9) 26 (21 / 5) imputed) Mean(SD) 2.57(3.34) 1.97 (4.32)Median 1.14 0.00Q1 ;Q3 0.00; 4.60 0.00 ; 2.00Min; Max 0.0; 11.0 0.0 ; 19.4Change from baselineNumber (observed / LOCF 28 (19 / 9) 26 (21 / 5) imputed) Mean(SD) 0.16 (3.31) 0.26 (3.85)Median 0.00 -0.19Q1 ;Q3 -2.41 ; 1.00 -1.00; 0.00Min; Max -5.3 ; 7.2 -4.3 ; 16.8LS Mean (SE) 0.19 (0.77) 0.07 (0.76)LS Mean Diffvs. placebo (95% -0.12 (-1.90, 1.66) ci)P-value vs. placebo 0.8932LATAM: Latin America, ROW: Rest of the world

[0243] Table 40A. Change from baseline in inhalations / day of albuterol or levalbuterol for symptom relief over time, reduced model (mITT population).Albuterol or levalbuterol for symptom relief Placebo BID Rilzabrutinib 400 mgBaselineNumber 32 32Mean (SD) 2.52 (3.02) 1.57 (1.98)Median 1.29 0.62Q1 ; Q3 0.00 ; 4.71 0.00 ; 2.93Min ; Max 0.0 ; 12.3 0.0 ; 7.4Week 1Number (observed / LOCF imputed) 32 (32 / 0) 32 (32 / 0)Mean (SD) 2.02 (2.56) 1.15 (1.78)Median 0.59 0.21Q1 ; Q3 0.00 ; 3.50 0.00 ; 1.93Min ; Max 0.0 ; 10.3 0.0 ; 7.4Change from baselineNumber (observed / LOCF imputed) 32 (32 / 0) 32 (32 / 0)Mean (SD) -0.50 (1.03) -0.41 (1.03)Median 0.00 0.00QI ; Q3 -0.69 ; 0.00 -0.62 ; 0.00Min ; Max -3.5 ; 0.7 -5.3 ; 1.0LS Mean (SE) -0.34 (0.18) -0.44 (0.19)LS Mean Diff vs. placebo (95% CI) -0.10 (-0.56, 0.36)P-value vs. placebo 0.6691Week 2Number (observed / LOCF imputed) 32 (31 / 1) 31 (31 / 0)Mean (SD) 1.91 (2.63) 0.94 (1.76)Median 0.37 0.14Q1 ; Q3 0.00 ; 3.21 0.00 ; 0.80Min ; Max 0.0 ; 9.5 0.0 ; 7.4Change from baselineNumber (observed / LOCF imputed) 32 (31 / 1) 31 (31 / 0)Mean (SD) -0.61 (1.34) -0.68 (1.24)Median 0.00 0.00Q1 ; Q3 -1.50 ; 0.00 -1.14 ; 0.00Min ; Max -4.0 ; 2.9 -5.3 ; 0.3LS Mean (SE) -0.42 (0.23) -0.67 (0.24)LS Mean Diff vs. placebo (95% CI) -0.25 (-0.82, 0.32)P-value vs. placebo 0.3848Week 3Number (observed / LOCF imputed) 31 (30 / 1) 31 (31 / 0)Mean (SD) 1.96 (2.75) 0.79 (1.48)Median 0.29 0.00Q1 ; Q3 0.00 ; 4.00 0.00 ; 0.67Min ; Max 0.0 ; 9.0 0.0 ; 5.3Albuterol or levalbuterol for symptom relief Placebo BID Rilzabrutinib 400 mgChange from baselineNumber (observed / LOCF imputed) 31 (30 / 1) 31 (31 / 0)Mean (SD) -0.24 (1.98) -0.83 (1.48)Median 0.00 0.00Q1 ; Q3 -0.67 ; 0.00 -1.33 ; 0.00Min ; Max -5.4 ; 6.3 -5.0 ; 1.3LS Mean (SE) 0.11 (0.32) -0.59 (0.34)LS Mean Diff vs. placebo (95% CI) -0.70 (-1.49, 0.09)P-value vs. placebo 0.0826Week 4Number (observed / LOCF imputed) 31 (29 / 2) 30 (29 / 1)Mean (SD) 1.92 (2.71) 0.86 (1.72)Median 0.29 0.00Q1 ; Q3 0.00 ; 3.43 0.00 ; 0.50Min ; Max 0.0 ; 9.0 0.0 ; 6.0Change from baselineNumber (observed / LOCF imputed) 31 (29 / 2) 30 (29 / 1)Mean (SD) -0.28 (2.14) -0.81 (1.41)Median 0.00 -0.29Q1 ; Q3 -1.29 ; 0.00 -1.71 ; 0.00Min ; Max -5.4 ; 6.3 -5.5 ; 2.0LS Mean (SE) -0.01 (0.33) -0.65 (0.35)LS Mean Diff vs. placebo (95% CI) -0.64 (-1.46, 0.18)P-value vs. placebo 0.1245Week 5Number (observed / LOCF imputed) 30 (28 / 2) 31 (29 / 2)Mean (SD) 1.89 (2.65) 1.11 (1.80)Median 0.25 0.00Q1 ; Q3 0.00 ; 4.00 0.00 ; 2.50Min ; Max 0.0 ; 9.0 0.0 ; 5.7Change from baselineNumber (observed / LOCF imputed) 30 (28 / 2) 31 (29 / 2)Mean (SD) -0.39 (1.97) -0.51 (1.14)Median 0.00 0.00Q1 ; Q3 -1.29 ; 0.00 -0.83 ; 0.00Min ; Max -4.9 ; 6.3 -3.5 ; 1.0LS Mean (SE) -0.11 (0.30) -0.35 (0.32)LS Mean Diff vs. placebo (95% CI) -0.23 (-0.97, 0.50)P-value vs. placebo 0.5339Week 6Number (observed / LOCF imputed) 30 (28 / 2) 31 (29 / 2)Mean (SD) 2.13 (2.77) 1.00 (1.92)Median 1.14 0.00Q1 ; Q3 0.00 ; 3.14 0.00 ; 0.50Min ; Max 0.0 ; 9.0 0.0 ; 7.3Albuterol or levalbuterol for symptom relief Placebo BID Rilzabrutinib 400 mgChange from baselineNumber (observed / LOCF imputed) 30 (28 / 2) 31 (29 / 2)Mean (SD) -0.15 (1.94) -0.61 (1.44)Median 0.00 0.00Q1 ; Q3 -0.83 ; 0.00 -1.00 ; 0.05Min ; Max -4.9 ; 6.3 -5.0 ; 1.3LS Mean (SE) -0.03 (0.34) -0.60 (0.35)LS Mean Diff vs. placebo (95% CI) -0.57 (-1.40, 0.25)P-value vs. placebo 0.1706Week ?Number (observed / LOCF imputed) 30 (27 / 3) 31 (29 / 2)Mean (SD) 1.64 (2.52) 1.61 (3.82)Median 0.57 0.00Q1 ; Q3 0.00 ; 2.00 0.00 ; 0.86Min ; Max 0.0 ; 9.0 0.0 ; 19.4Change from baselineNumber (observed / LOCF imputed) 30 (27 / 3) 31 (29 / 2)Mean (SD) -0.63 (2.16) -0.00 (3.35)Median -0.05 0.00Q1 ; Q3 -1.43 ; 0.00 -1.00 ; 0.00Min ; Max -4.9 ; 6.3 -4.3 ; 16.8LS Mean (SE) -0.59 (0.59) -0.14 (0.62)LS Mean Diff vs. placebo (95% CI) 0.45 (-0.98, 1.87)P-value vs. placebo 0.5396Week 8Number (observed / LOCF imputed) 30 (27 / 3) 30 (27 / 3)Mean (SD) 1.59 (2.52) 1.66 (3.98)Median 0.21 0.00Q1 ; Q3 0.00 ; 3.00 0.00 ; 1.14Min ; Max 0.0 ; 9.0 0.0 ; 19.4Change from baselineNumber (observed / LOCF imputed) 30 (27 / 3) 30 (27 / 3)Mean (SD) -0.68 (2.34) -0.01 (3.76)Median 0.00 0.00Q1 ; Q3 -1.86 ; 0.00 -1.00 ; 0.00Min ; Max -5.9 ; 6.3 -5.5 ; 16.8LS Mean (SE) -0.56 (0.62) -0.07 (0.65)LS Mean Diff vs. placebo (95% CI) 0.49 (-1.03, 2.00)P-value vs. placebo 0.5291Week 9Number (observed / LOCF imputed) 30 (27 / 3) 29 (25 / 4)Mean (SD) 1.70 (2.55) 1.66 (3.98)Median 0.29 0.00Q1 ; Q3 0.00 ; 2.29 0.00 ; 1.00Min ; Max 0.0 ; 9.0 0.0 ; 19.4Albuterol or levalbuterol for symptom relief Placebo BID Rilzabrutinib 400 mgChange from baselineNumber (observed / LOCF imputed) 30 (27 / 3) 29 (25 / 4)Mean (SD) -0.57 (2.40) -0.07 (3.96)Median 0.00 -0.29Q1 ; Q3 -1.86 ; 0.00 -1.14 ; 0.00Min ; Max -5.9 ; 6.3 -5.5 ; 16.8LS Mean (SE) -0.48 (0.61) -0.23 (0.64)LS Mean Diff vs. placebo (95% CI) 0.24 (-1.27, 1.76)P-value vs. placebo 0.7514Week 10Number (observed / LOCF imputed) 29 (25 / 4) 29 (25 / 4)Mean (SD) 1.90 (2.72) 1.49 (3.98)Median 0.00 0.00Q1 ; Q3 0.00 ; 3.29 0.00 ; 0.57Min ; Max 0.0 ; 9.0 0.0 ; 19.4Change from baselineNumber (observed / LOCF imputed) 29 (25 / 4) 29 (25 / 4)Mean (SD) -0.25 (2.97) -0.23 (3.88)Median 0.00 -0.29Q1 ; Q3 -1.86 ; 0.33 -1.86 ; 0.00Min ; Max -6.9 ; 6.3 -5.5 ; 16.8LS Mean (SE) -0.45 (0.64) -0.77 (0.68)LS Mean Diff vs. placebo (95% CI) -0.33 (-1.91, 1.25)P-value vs. placebo 0.6832Week 11Number (observed / LOCF imputed) 30 (24 / 6) 27 (23 / 4)Mean (SD) 2.37 (3.30) 1.61 (4.24)Median 0.33 0.00Q1 ; Q3 0.00 ; 5.00 0.00 ; 0.67Min ; Max 0.0 ; 11.0 0.0 ; 19.4Change from baselineNumber (observed / LOCF imputed) 30 (24 / 6) 27 (23 / 4)Mean (SD) 0.09 (3.30) -0.10 (3.99)Median 0.00 -0.40Q1 ; Q3 -1.71 ; 0.50 -1.43 ; 0.00Min ; Max -6.5 ; 7.2 -5.5 ; 16.8LS Mean (SE) -0.01 (0.71) -0.36 (0.75)LS Mean Diff vs. placebo (95% CI) -0.36 (-2.08, 1.37)P-value vs. placebo 0.6865Week 12Number (observed / LOCF imputed) 28 (19 / 9) 26 (21 / 5)Mean (SD) 2.57 (3.34) 1.97 (4.32)Median 1.14 0.00Q1 ; Q3 0.00 ; 4.60 0.00 ; 2.00Min ; Max 0.0 ; 11.0 0.0 ; 19.4Albuterol or levalbuterol for symptom relief Placebo BID Rilzabrutinib 400 mgChange from baselineNumber (observed / LOCF imputed) 28 (19 / 9) 26 (21 / 5)Mean (SD) 0.16 (3.31) 0.26 (3.85)Median 0.00 -0.19Q1 ; Q3 -2.41 ; 1.00 -1.00 ; 0.00Min ; Max -5.3 ; 7.2 -4.3 ; 16.8LS Mean (SE) 0.06 (0.68) -0.01 (0.72)LS Mean Diff vs. placebo (95% CI) -0.07 (-1.75, 1.60)P-value vs. placebo 0.9303LATAM: Latin America, ROW: Rest of the worldTable 40B. Number of participants requiring >2, >3, >4, or >5 reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterolBID cohort TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400mg BID (N=68) 400m TID(N=32) (N=64)Number of participants 11 (34.4) 6 (18.8) 24 (35.3) 11 (17.2) with > 2 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol compared with baseline on 2 consecutive days during the treatment periodNumber of participants 7 (21.9) 3 (9.4) 16 (23.5) 4 (6.3) with > 3 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol compared with baseline on 2 consecutive days during the treatment periodNumber of participants 6 (18.8) 2 (6.3) 12 (17.6) 3 (4.7) with > 4 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol compared with baseline on 2 consecutive days during the treatment period,BID cohort TIP cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400mg BID (N=68) 400m g TID(N=32) (N=64)Number of participants 4 (12.5) 2 (6.3) 10 (14.7) 1 (1.6) with > 5 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol compared with baseline on 2 consecutive days during the treatment periodACQ-5

[0244] In both the 400 mg BID and 400 mg TID rilzabrutinib cohorts, patients experienced significant and clinically meaningful changes in ACQ-5 relative to patients who received the placebo (Figures 9-15) and Tables 41-50). The 400 mg BID rilzabrutinib cohort and placebo cohort exhibited LS mean (SE) values of -0.70 and -0.12 (p=0.0184), respectively, at Week 12 (Table 41). Meanwhile, the 400 mg TID rilzabrutinib cohort and placebo cohort exhibited LS mean (SE) values of -0.85 and -0.31 (p=0.0013), respectively, at Week 12 (Table 41). The overall ACQ-5 reduction observed in both of the rilzabrutinib cohorts therefore exceeded the minimal clinically important (MCID) difference of -0.5.

[0245] Consistent with this, a significant percentage of rilzabrutinib-treated patients also achieved ACQ-5 reductions in excess of -0.5. 67.9% of rilzabrutinib-treated patients in the 400 mg BID cohort showed ACQ-5 score reductions of at least -0.05 from baseline at Week 12. Meanwhile, only 35.7% of placebo-treated patients had equivalent reductions in ACQ-5 scores (p=0.0100) (Table 43). Meanwhile, 63.3% of patients in the 400 mg TID cohort showed ACQ-5 score reductions of at least -0.05 from baseline at Week 12, as compared to 40.0% of patients in the placebo group (p=0.0297) (Table 43). Additionally, at Week 12, 40.6% and 15.6% of rilzabrutinib-treated patients in the 400 mg BID and 400 mg TID cohorts, respectively, achieved an ACQ-5 below 0.75, while only 9.4% and 13.2% of placebo-treated patients in the 400 mg BID and 400 mg TID cohorts, respectively, achieved a similar reduction in score (p=0.0092 for the 400 mg BID cohort and 0.6286 for the 400 mg TID cohort) (Table 44).

[0246] Patients treated with rilzabrutinib also experienced a rapid decrease in ACQ-5. Significant (p<0.05) differences between rilzabrutinib- and placebo-treated patients in thetwo cohorts were observed as early as Week 2 and were largely sustained over the course of the treatment period. Moreover, in the 400 mg TID rilzabrutinib cohort, the difference between rilzabrutinib- and placebo-treated patients continued to increase throughout the treatment period.

[0247] Additionally, 34.4% of rilzabrutinib-treated patients in the 400 mg BID cohort achieved an ACQ-5 score below 0.75 as early as Week 4, as compared to 6.3% of placebo- treated patients in the 400 mg BID cohort (p=0.0133) (Table 44). Similarly, 17.2% of rilzabrutinib-treated patients in the 400 mg TID cohort achieved an ACQ-5 score below 0.75 by Week 4, as compared to 7.4% of placebo-treated patients in the 400 mg TID cohort (p=0.0919) (Table 44).

[0248] Rilzabrutinib was efficacious across patients with different baseline demographics, disease characteristics, with or without exacerbations in the previous year, ICS / LABA dose levels, biomarker levels, eosinophil counts, orFeNO (ppb) (Tables 46-50).

[0249] Table 41. Change from baseline in ACQ-5 over time (mITT population).400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDBaselineNumber 32 3268 64Mean(SD) 2.19 (0.40) 2.04 (0.37) 2.18(0.40) 2.24(0.48)Median 2.20 2.00220 220Q1 ;Q3 2.00; 2.40 1.80; 2.20 1.80; 2.40 2.00;2.60Min; Max 1.4; 3.2 1.4; 2.8 l-2;3-2i-4;4.oWeek 2Number 30 (29 / 1) 30 (30 / 0) 63(62 / 1) 61 (61 / 0)(observed / LOCF imputed)Mean(SD) 1.91 (0.74) 1.30 (0.64) 2.00(0.69) 1.87(0.88)Median 1.80 1.20200 220Q1 ;Q3 1.60; 2.20 0.80 ; 1.80 1.60; 2.40 1.20; 2.60Min; Max 0.4 ; 3.8 0.4 ; 2.6 °-4-3-40.0;3.4Change from baselineNumber 30 (29 / 1) 30 (30 / 0) 63(62 / 1) 61 (61 / 0)(observed / LOCF imputed)Mean(SD) -0.25 (0.78) -0.74 (0.62) -0.17(0.62) -0.37(0.79)Median -0.20 -1.00 o.oo -0.20400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDQ1 ;Q3 -0.80; 0.00 -1.20 ; -0.20 -0.60 ;0.20 -0.80;0.20Min; Max -1.8 ; 1.6 -1.8 ; 0.4 -1.8; 1.6 -2.0; 1.2LS Mean (SE) -0.20(0.14) -0.74(0.15) -0.19(0.09) -0.47 (O.iO)LS Mean Diff -0.54 (-0.89, - -O-27(-0.53, -0.02) vs. placebo 0.19)(95% CI)P-value vs. 0.0026 0.0335 placeboWeek 4Number 30 (28 / 2) 31 (30 / 1) 62(61 / 1) 59(59 / 0)(observed / LOCF imputed)Mean(SD) 1.77 (0.82) 1.10 (0.78) 1.93(0.84) 1.66(0.86)Median 1.80 1.00200 180Q1 ;Q3 1.20; 2.20 0.40 ; 1.80 i.40;2.60 1.00 ; 2.40Min; Max 0.0 ; 3.4 0.0 ; 2.600; 4.0 0.0 ; 3.4Change from baselineNumber 30 (28 / 2) 31 (30 / 1) 62(61 / 1) 59(59 / 0)(observed / LOCF imputed)Mean(SD) -0.40 (0.96) -0.94 (0.64) -0.23(0.79) -0.57(0.77)Median -0.30 -0.80 -°-20-°-40Q1 ;Q3 -0.80; 0.20 -1.60; -0.40 -0.60 ;0.20 -i.00;0.00Min; Max -2.6; 1.6 -2.0 ; 0.4 -2.2; 2.0 -2.4; 1.0LS Mean (SE) -0.29 (0.16) -0.84 (0.17) -0.29(0.10) -0.66(0.11)LS Mean Diff -0.55 (-0.95, - -°-37(-0-64, -0.09) vs. placebo 0.14)(95% CI)P-value vs. 0.0085 0.0088 placeboWeek 6Number 28 (26 / 2) 30 (28 / 2) 60(58 / 2) 57(56 / 1)(observed / LOCF imputed)Mean(SD) 1.91 (0.92) 1.10 (0.80) 1.79(0.80) 1.68(0.92)Median 2.00 1.00160 200Q1 ;Q3 1.20; 2.50 0.40 ; 1.60 1.20 ; 2.20 0.80;2.40Min; Max 0.4 ; 4.0 0.0 ; 3.2 0.0 ; 3.200; 3.2Change from baseline400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDNumber 28 (26 / 2) 30 (28 / 2) 60(58 / 2) 57(56 / 1)(observed / LOCF imputed) Mean(SD) -0.26 (0.99) -0.97 (0.74) -0.38(0.75) -0.57(0.83)Median -0.10 -1.20 -040-°-0Q1 ;Q3 -1.00; 0.40 -1.60 ; -0.60 -i.oo;o.2o -i.oo;o.ooMin; Max -2.4; 1.4 -1.8 ; 1.0 -2.0; 0.8 -2.8; 1.2LS Mean (SE) -0.16 (0.18) -0.89 (0.19) -0.30(0.12) -0.62(0.12)LSMeanDiff -0.72 (-1.16, - -0.32 (-0.62, -o.oi) vs. placebo 0.28)(95% CI)P-value vs. 0.0013 0.0412 placeboWeek8Number 30 (27 / 3 ) 28 (24 / 4) 63(60 / 3) 52(49 / 3)(observed / LOCF imputed)Mean(SD) 1.61 (0.97) 1.12 (0.90) 1.95(0.99) 1.54(0.77)Median 1.80 0.80 1-80 1.80Q1 ;Q3 0.80; 2.20 0.60 ; 1.40 1.20 ; 2.40 1.00 ; 2.00Min; Max 0.0 ; 4.0 0.0 ; 3.6 0.0 ; 5.2 0.0 ; 3.2Change from baselineNumber 30 (27 / 3 ) 28 (24 / 4) 63(60 / 3) 52(49 / 3)(observed / LOCF imputed)Mean(SD) -0.56 (1.04) -0.91 (0.80) -0.19(0.94) -0.72(0.73)Median -0.40 -1.20 -0-40 -0.60Q1 ;Q3 -1.20; 0.00 -1.40 ; -0.80 -i.00;0.40 -1.20 ; -0.20Min ; Max -3.2; 1.4 -2.2; 1.0 -2.0;3.0 -2.6;l.oLS Mean (SE) -0.40 (0.19) -0.80 (0.22) -0.29 (O.ii) -0.75 (0.12)LS Mean Diff -0.40 (-0.87, -046 (-0.76, -0.17) vs. placebo 0.07)(95% CI)P-value vs. 0.0968 0.0023 placeboWeek 10Number 28 (22 / 6) 27 (23 / 4) 55(51 / 4) 56(53 / 3)(observed / LOCF imputed)Mean(SD) 1.73 (1.03) 1.15 (0.90) 1.80(1.02) 1.49(0.84)Median 1.70 1.00180 160400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDQ1 ;Q3 0.90; 2.50 0.40 ; 1.60 i.00;2.60 o.9o;2.ooMin; Max 0.0 ; 4.0 0.0 ; 3.2 o.o;4.o o.o;3.2Change from baselineNumber 28 (22 / 6) 27 (23 / 4) 55(51 / 4) 56(53 / 3)(observed / LOCF imputed)Mean(SD) -0.42 (1.11) -0.92 (0.89) -0.33(0.90) -0.75(0.81)Median -0.40 -1.00 -0-40 -0.70Q1 ;Q3 -1.20; 0.40 -1.60; -0.40 -i.oo;o.4o -1.40; -0.20Min; Max -2.6; 1.6 -2.4; 1.0 -2.2; 1.4 -2.6; 1.2LS Mean (SE) -0.15(0.18) -0.73 (0.19) -0.33(0.13) -0.84(0.13)LSMeanDiff -0.59 (-1.03, - -0.51 (-0.84,-0.18) vs. placebo 0.14)(95% CI)P-value vs. 0.0095 0.0022 placeboWeek 12Number 28 (19 / 9) 28 (23 / 5) 60(50 / 10) 49(46 / 3)(observed / LOCF imputed)Mean(SD) 1.83 (0.98) 1.16 (0.94) 1.93(1.12) 1.46(0.75)Median 2.00 1.00180 160Q1 ;Q3 1.10; 2.20 0.40 ; 2.00 1.1O;2.5O 1.00;2.00Min; Max 0.0 ; 4.0 0.0 ; 3.200; 5.4 0.0 ; 3.2Change from baselineNumber 28 (19 / 9) 28 (23 / 5) 60(50 / 10) 49(46 / 3)(observed / LOCF imputed)Mean(SD) -0.34 (1.02) -0.89 (0.93) -0.22 (1.03) -0.82 (0.72)Median -0.10 -1.30 -°.4° -0.80Q1 ;Q3 -1.00; 0.10 -1.60; -0.20 -1.00;0.40 -1.40; -0.20Min ; Max -3.0; 1.6 -2.4; 1.0 -1.8;3.2 -2.2;0.4LS Mean (SE) -0.12 (0.20) -0.70 (0.22) -0.31(0.12) -0.85 (0.13)LS Mean Diff -0.59 (-1.07, - -°-54 (-0.86, -0.21) vs. placebo 0.10)(95% CI)P-value vs. 0.0184 0.0013 placeboLATAM: Latin America, ROW: Rest of the world

[0250] Table 42. Summary of ACQ-5 over time (mITT population).400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Mean scoreBaseline Number 32 32 68 64Mean(SD) 2.19 (0.40) 2.04(0.37) 2.18 (0.40) 2.24(0.48)Median 2.20 2.00 2.20 2.20Q1 ;Q3 2.00; 2.40 1.80; 2.20 1.80; 2.40 2.00 ; 2.60Min; Max 1.4; 3.2 1.4; 2.8 1.2; 3.2 1.4; 4.0Week 2Number (observed / LOCF 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) imputed) Mean(SD) 1.91 (0.74) 1.30(0.64) 2.00(0.69) 1.87(0.88)Median 1.80 1.20 2.00 2.20Q1 ;Q3 1.60; 2.20 0.80; 1.80 1.60; 2.40 1.20; 2.60Min; Max 0.4 ; 3.8 0.4 ; 2.6 0.4 ; 3.4 0.0 ; 3.4Change from baseline Number (observed / LOCF 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) imputed) Mean(SD) -0.25 (0.78) -0.74 (0.62) -0.17 (0.62) -0.37 (0.79)Median -0.20 -1.00 0.00 -0.20Q1 ;Q3 -0.80; 0.00 -1.20; -0.20 -0.60 ; 0.20 -0.80 ; 0.20Min; Max -1.8 ; 1.6 -1.8; 0.4 -1.8 ; 1.6 -2.0 ; 1.2LS Mean (SE) -0.20(0.14) -0.74 (0.15) -0.19 (0.09) -0.47 (0.10)LS Mean Diff vs. placebo -0.54 (-0.89, - -0.27 (-0.53, -(95% CI) 0.19) 0.02)P-value vs. placebo 0.0026 0.0335Week 4Number (observed / LOCF 30 (28 / 2) 31 (30 / 1) 62 (61 / 1) 59 (59 / 0) imputed) Mean(SD) 1.77 (0.82) 1.10(0.78) 1.93 (0.84) 1.66(0.86)Median 1.80 1.00 2.00 1.80Q1 ;Q3 1.20; 2.20 0.40; 1.80 1.40; 2.60 1.00; 2.40Min; Max 0.0 ; 3.4 0.0 ; 2.6 0.0 ; 4.0 0.0 ; 3.4Change from baseline Number (observed / LOCF 30 (28 / 2) 31 (30 / 1) 62 (61 / 1) 59 (59 / 0) imputed) Mean (SD) -0.40 (0.96) -0.94 (0.64) -0.23 (0.79) -0.57 (0.77)Median -0.30 -0.80 -0.20 -0.40Q1 ;Q3 -0.80; 0.20 -1.60; -0.40 -0.60 ; 0.20 -1.00; 0.00400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Min; Max -2.6; 1.6 -2.0 ; 0.4 -2.2 ; 2.0 -2.4 ; 1.0LS Mean (SE) -0.29(0.16) -0.84 (0.17) -0.29 (0.10) -0.66 (0.11)LS Mean Diff vs. placebo -0.55 (-0.95, - -0.37 (-0.64, -(95% CI) 0.14) 0.09)P-value vs. placebo 0.0085 0.0088Week 6Number (observed / LOCF 28 (26 / 2) 30 (28 / 2) 60(58 / 2) 57(56 / 1) imputed) Mean(SD) 1.91 (0.92) 1.10(0.80) 1.79(0.80) 1.68 (0.92)Median 2.00 1.00 1.60 2.00Q1 ;Q3 1.20; 2.50 0.40; 1.60 1.20; 2.20 0.80 ; 2.40Min; Max 0.4 ; 4.0 0.0 ; 3.2 0.0 ; 3.2 0.0 ; 3.2Change from baseline Number (observed / LOCF 28 (26 / 2) 30 (28 / 2) 60(58 / 2) 57(56 / 1) imputed) Mean(SD) -0.26(0.99) -0.97 (0.74) -0.38 (0.75) -0.57 (0.83)Median -0.10 -1.20 -0.40 -0.60Q1 ;Q3 -1.00; 0.40 -1.60; -0.60 -1.00; 0.20 -1.00; 0.00Min; Max -2.4; 1.4 -1.8 ; 1.0 -2.0 ; 0.8 -2.8 ; 1.2LS Mean (SE) -0.16(0.18) -0.89 (0.19) -0.30 (0.12) -0.62 (0.12)LS Mean Diff vs. placebo -0.72 (-1.16, - -0.32 (-0.62, -(95% CI) 0.28) 0.01)P-value vs. placebo 0.0013 0.0412Week 8Number (observed / LOCF 30 (27 / 3) 28 (24 / 4) 63 (60 / 3) 52(49 / 3) imputed) Mean(SD) 1.61 (0.97) 1.12(0.90) 1.95 (0.99) 1.54(0.77)Median 1.80 0.80 1.80 1.80Q1 ;Q3 0.80; 2.20 0.60; 1.40 1.20; 2.40 1.00; 2.00Min; Max 0.0 ; 4.0 0.0 ; 3.6 0.0 ; 5.2 0.0 ; 3.2Change from baseline Number (observed / LOCF 30 (27 / 3) 28 (24 / 4) 63 (60 / 3) 52(49 / 3) imputed) Mean(SD) -0.56(1.04) -0.91 (0.80) -0.19 (0.94) -0.72 (0.73)Median -0.40 -1.20 -0.40 -0.60Q1 ;Q3 -1.20; 0.00 -1.40; -0.80 -1.00; 0.40 -1.20; -0.20Min; Max -3.2; 1.4 -2.2 ; 1.0 -2.0 ; 3.0 -2.6 ; 1.0LS Mean (SE) -0.40(0.19) -0.80 (0.22) -0.29 (0.11) -0.75 (0.12)LS Mean Diff vs. placebo -0.40 (-0.87, -0.46 (-0.76, -(95% CI) 0.07) 0.17)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)P-value vs. placebo 0.0968 0.0023Week 10 Number (observed / LOCF 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) imputed) Mean(SD) 1.73 (1.03) 1.15 (0.90) 1.80(1.02) 1.49(0.84)Median 1.70 1.00 1.80 1.60Q1 ;Q3 0.90; 2.50 0.40; 1.60 1.00; 2.60 0.90 ; 2.00Min; Max 0.0 ; 4.0 0.0 ; 3.2 0.0 ; 4.0 0.0 ; 3.2Change from baseline Number (observed / LOCF 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) imputed) Mean(SD) -0.42(1.11) -0.92 (0.89) -0.33 (0.90) -0.75 (0.81)Median -0.40 -1.00 -0.40 -0.70Q1 ;Q3 -1.20; 0.40 -1.60; -0.40 -1.00; 0.40 -1.40; -0.20Min; Max -2.6; 1.6 -2.4 ; 1.0 -2.2 ; 1.4 -2.6 ; 1.2LS Mean (SE) -0.15 (0.18) -0.73 (0.19) -0.33 (0.13) -0.84 (0.13)LS MeanDiffvs. placebo -0.59 (-1.03, - -0.51 (-0.84, -(95% CI) 0.14) 0.18)P-value vs. placebo 0.0095 0.0022Week 12Number (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49(46 / 3) imputed) Mean(SD) 1.83 (0.98) 1.16(0.94) 1.93 (1.12) 1.46(0.75)Median 2.00 1.00 1.80 1.60Q1 ;Q3 1.10; 2.20 0.40 ; 2.00 1.10; 2.50 1.00; 2.00Min; Max 0.0 ; 4.0 0.0 ; 3.2 0.0 ; 5.4 0.0 ; 3.2Change from baseline Number (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49(46 / 3) imputed) Mean(SD) -0.34(1.02) -0.89 (0.93) -0.22 (1.03) -0.82 (0.72)Median -0.10 -1.30 -0.40 -0.80Q1 ;Q3 -1.00; 0.10 -1.60; -0.20 -1.00; 0.40 -1.40; -0.20Min; Max -3.0; 1.6 -2.4 ; 1.0 -1.8 ; 3.2 -2.2 ; 0.4LS Mean (SE) -0.12(0.20) -0.70 (0.22) -0.31 (0.12) -0.85 (0.13)LS Mean Diff vs. placebo -0.59 (-1.07, - -0.54 (-0.86, -(95% CI) 0.10) 0.21)P-value vs. placebo 0.0184 0.0013Frequency of awakening by asthma400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)BaselineNumber 32 32 68 64Mean(SD) 1.91 (0.64) 1.63 (0.66) 1.91 (0.69) 1.89(0.72)Median 2.00 2.00 2.00 2.00Q1 ;Q3 2.00; 2.00 1.00; 2.00 2.00 ; 2.00 2.00 ; 2.00Min; Max 0.0 ; 3.0 0.0 ; 3.0 0.0 ; 3.0 0.0 ; 4.0Week 2Number (observed / LOCF 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) imputed)Mean(SD) 1.70 (1.12) 1.03 (0.81) 1.67(1.05) 1.72(1.05)Median 2.00 1.00 2.00 2.00Q1 ;Q3 1.00; 2.00 0.00 ; 2.00 1.00; 2.00 1.00; 2.00Min; Max 0.0 ; 4.0 0.0 ; 2.0 0.0 ; 5.0 0.0 ; 4.0Change from baselineNumber (observed / LOCF 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) imputed)Mean(SD) -0.17(1.15) -0.57 (0.82) -0.24 (1.07) -0.18 (1.09)Median 0.00 -0.50 0.00 0.00Q1 ;Q3 -1.00; 0.00 -1.00; 0.00 -1.00; 0.00 -1.00; 0.00Min; Max -3.0; 2.0 -2.0 ; 1.0 -3.0; 2.0 -2.0 ; 2.0LS Mean (SE) -0.06(0.20) -0.58 (0.21) -0.19 (0.14) -0.23 (0.14)LS Mean Diff vs. placebo -0.53 (-1.01, - -0.03 (-0.39,(95% CI) 0.04) 0.32)P-value vs. placebo 0.0349 0.8553Week 4Number (observed / LOCF 30 (28 / 2) 31 (30 / 1) 62 (61 / 1) 59 (59 / 0) imputed)Mean(SD) 1.40 (1.04) 0.90(0.98) 1.65 (1.03) 1.39(0.93)Median 2.00 1.00 2.00 2.00Q1 ;Q3 0.00; 2.00 0.00 ; 2.00 1.00; 2.00 1.00; 2.00Min; Max 0.0 ; 3.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 3.0Change from baselineNumber (observed / LOCF 30 (28 / 2) 31 (30 / 1) 62 (61 / 1) 59 (59 / 0) imputed)Mean(SD) -0.47(1.04) -0.71 (1.07) -0.24 (1.10) -0.51 (1.06)Median 0.00 -1.00 0.00 0.00Q1 ;Q3 -1.00; 0.00 -2.00 ; 0.00 -1.00; 0.00 -1.00; 0.00Min; Max -3.0; 1.0 -2.0 ; 2.0 -3.0 ; 3.0 -2.0 ; 2.0LS Mean (SE) -0.39(0.21) -0.76 (0.22) -0.23 (0.14) -0.52 (0.14)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs. placebo -0.36 (-0.88, -0.29 (-0.64,(95% CI) 0.15) 0.07)P-value vs. placebo 0.1702 0.1165Week 6Number (observed / LOCF 28 (26 / 2) 30 (28 / 2) 60(58 / 2) 57(56 / 1) imputed)Mean(SD) 1.46 (0.96) 0.93 (0.83) 1.50(1.10) 1.56(0.91)Median 2.00 1.00 1.00 2.00Q1 ;Q3 1.00; 2.00 0.00; 1.00 1.00; 2.00 1.00; 2.00Min; Max 0.0 ; 3.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 4.0Change from baselineNumber (observed / LOCF 28 (26 / 2) 30 (28 / 2) 60(58 / 2) 57(56 / 1) imputed)Mean(SD) -0.39(0.96) -0.67 (0.88) -0.40 (1.06) -0.33 (0.87)Median 0.00 -1.00 0.00 0.00Q1 ;Q3 -1.00; 0.00 -1.00; 0.00 -1.00; 0.00 -1.00; 0.00Min; Max -3.0; 1.0 -2.0 ; 1.0 -3.0; 2.0 -2.0 ; 1.0LS Mean (SE) -0.30(0.18) -0.70 (0.19) -0.31 (0.14) -0.39 (0.14)LS Mean Diff vs. placebo -0.40 (-0.85, -0.08 (-0.42,(95% CI) 0.05) 0.27)P-value vs. placebo 0.0792 0.6678Week 8Number (observed / LOCF 30 (27 / 3) 28 (24 / 4) 63 (60 / 3) 52(49 / 3) imputed)Mean(SD) 1.23 (0.97) 0.93 (1.05) 1.70(1.16) 1.46(0.87)Median 1.00 1.00 2.00 1.50Q1 ;Q3 0.00; 2.00 0.00; 1.50 1.00; 3.00 1.00; 2.00Min; Max 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 5.0 0.0 ; 4.0Change from baselineNumber (observed / LOCF 30 (27 / 3) 28 (24 / 4) 63 (60 / 3) 52(49 / 3) imputed)Mean(SD) -0.63 (0.93) -0.64 (1.10) -0.16 (1.12) -0.42 (1.02)Median -0.50 -1.00 0.00 0.00Q1 ;Q3 -1.00; 0.00 -1.50; 0.00 -1.00; 1.00 -1.00; 0.00Min; Max -3.0; 1.0 -2.0 ; 2.0 -3.0 ; 3.0 -3.0; 2.0LS Mean (SE) -0.47(0.21) -0.64 (0.23) -0.20 (0.14) -0.47 (0.15)LS Mean Diff vs. placebo -0.17 (-0.69, -0.28 (-0.64,(95% CI) 0.35) 0.09)P-value vs. placebo 0.5311 0.1389400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Week 10 Number (observed / LOCF 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) imputed) Mean(SD) 1.29 (1.05) 0.89 (0.89) 1.45 (1.05) 1.32 (1.11)Median 1.00 1.00 1.00 1.00Q1 ;Q3 0.00; 2.00 0.00; 1.00 1.00; 2.00 1.00; 2.00Min; Max 0.0 ; 3.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 5.0Change from baseline Number (observed / LOCF 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) imputed) Mean(SD) -0.57(1.10) -0.67 (1.07) -0.42 (1.08) -0.55 (1.14)Median 0.00 -1.00 0.00 -1.00Q1 ;Q3 -1.00; 0.00 -1.00; 0.00 -1.00; 0.00 -1.00; 0.00Min; Max -3.0; 1.0 -3.0 ; 1.0 -3.0; 2.0 -2.0 ; 3.0LS Mean (SE) -0.26(0.20) -0.65 (0.21) -0.44 (0.15) -0.68 (0.15)LS Mean Diff vs. placebo -0.38 (-0.88, -0.24 (-0.62,(95% CI) 0.11) 0.14)P-value vs. placebo 0.1272 0.2171Week 12 Number (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49(46 / 3) imputed) Mean(SD) 1.39 (1.10) 0.89 (1.07) 1.63 (1.16) 1.31 (0.89)Median 1.00 1.00 2.00 1.00Q1 ;Q3 0.50; 2.00 0.00; 1.50 1.00; 2.00 1.00; 2.00Min; Max 0.0 ; 4.0 0.0 ; 4.0 0.0 ; 5.0 0.0 ; 3.0Change from baseline Number (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49(46 / 3) imputed) Mean(SD) -0.46(1.00) -0.71 (1.24) -0.23 (1.17) -0.61 (1.02)Median 0.00 -1.00 0.00 -1.00Q1 ;Q3 -1.00; 0.00 -1.50; 0.00 -1.00; 0.50 -1.00; 0.00Min; Max -2.0 ; 2.0 -3.0; 2.0 -3.0 ; 3.0 -3.0 ; 1.0LS Mean (SE) -0.21 (0.23) -0.60 (0.25) -0.27 (0.14) -0.63 (0.15)LS Mean Diff vs. placebo -0.39 (-0.95, -0.36 (-0.73,(95% CI) 0.18) 0.01)P-value vs. placebo 0.1778 0.0598Asthma symptoms when woke upBaseline Number 32 32 68 64Mean(SD) 2.25 (0.62) 2.16(0.51) 2.34(0.61) 2.52(0.67)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Median 2.00 2.00 2.00 3.00Q1 ;Q3 2.00; 3.00 2.00 ; 2.00 2.00 ; 3.00 2.00 ; 3.00Min; Max 1.0; 4.0 1.0; 3.0 1.0; 4.0 1.0; 4.0Week 2Number (observed / LOCF 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) imputed) Mean(SD) 1.90 (0.88) 1.60 (0.81) 2.11 (0.76) 1.93 (1.05)Median 2.00 2.00 2.00 2.00Q1 ;Q3 1.00; 2.00 1.00; 2.00 2.00 ; 3.00 1.00 ; 3.00Min; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 3.0 0.0 ; 3.0Change from baselineNumber (observed / LOCF 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) imputed) Mean(SD) -0.33 (0.92) -0.57 (1.01) -0.21 (0.79) -0.57 (1.09)Median 0.00 -1.00 0.00 0.00Q1 ;Q3 -1.00; 0.00 -1.00; 0.00 -1.00; 0.00 -1.00; 0.00Min; Max -2.0; 1.0 -3.0 ; 1.0 -2.0 ; 2.0 -3.0 ; 1.0LS Mean (SE) -0.28 (0.18) -0.57 (0.19) -0.33 (0.11) -0.66 (0.12)LS Mean Diff vs. placebo -0.28 (-0.72, -0.33 (-0.63, -(95% CI) 0.15) 0.03)P-value vs. placebo 0.2021 0.0333Week 4Number (observed / LOCF 30 (28 / 2) 31 (30 / 1) 62 (61 / 1) 59 (59 / 0) imputed) Mean(SD) 1.77 (1.14) 1.13 (0.92) 2.08 (0.89) 1.83 (1.10)Median 2.00 1.00 2.00 2.00Q1 ;Q3 1.00; 3.00 0.00 ; 2.00 2.00 ; 3.00 1.00 ; 3.00Min; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 4.0Change from baselineNumber (observed / LOCF 30 (28 / 2) 31 (30 / 1) 62 (61 / 1) 59 (59 / 0) imputed) Mean(SD) -0.47(1.41) -1.03 (1.05) -0.24 (0.97) -0.66 (1.08)Median 0.00 -1.00 0.00 0.00Q1 ;Q3 -1.00; 0.00 -2.00 ; 0.00 -1.00; 0.00 -2.00 ; 0.00Min; Max -3.0 ; 3.0 -3.0 ; 1.0 -3.0; 2.0 -3.0 ; 1.0LS Mean (SE) -0.16(0.20) -0.71 (0.22) -0.44 (0.12) -0.81 (0.12)LS Mean Diff vs. placebo -0.55 (-1.05, - -0.37 (-0.69, -(95% CI) 0.05) 0.05)P-value vs. placebo 0.0324 0.0252400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Week 6Number (observed / LOCF 28 (26 / 2) 30 (28 / 2) 60(58 / 2) 57(56 / 1) imputed) Mean(SD) 2.00 (1.02) 1.30(0.95) 1.92(0.89) 1.86(1.04)Median 2.00 1.00 2.00 2.00Q1 ;Q3 1.00; 3.00 1.00; 2.00 1.00; 3.00 1.00 ; 3.00Min; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 3.0Change from baselineNumber (observed / LOCF 28 (26 / 2) 30 (28 / 2) 60(58 / 2) 57(56 / 1) imputed)Mean(SD) -0.25 (1.14) -0.87 (1.04) -0.45 (0.91) -0.61 (0.98)Median 0.00 -1.00 0.00 -1.00Q1 ;Q3 -1.00; 1.00 -2.00 ; 0.00 -1.00; 0.00 -1.00; 0.00Min; Max -2.0 ; 2.0 -3.0 ; 1.0 -3.0 ; 1.0 -3.0 ; 1.0LS Mean (SE) -0.12(0.20) -0.76 (0.22) -0.44 (0.13) -0.73 (0.13)LS Mean Diff vs. placebo -0.64 (-1.13, - -0.29 (-0.62,(95% CI) 0.15) 0.05)P-value vs. placebo 0.0107 0.0947Week 8Number (observed / LOCF 30 (27 / 3) 28 (24 / 4) 63 (60 / 3) 52(49 / 3) imputed) Mean(SD) 1.60 (1.10) 1.25 (1.11) 2.00(1.03) 1.73 (0.95)Median 2.00 1.00 2.00 2.00Q1 ;Q3 1.00; 2.00 1.00; 2.00 1.00; 3.00 1.00; 2.50Min; Max 0.0 ; 4.0 0.0 ; 5.0 0.0 ; 5.0 0.0 ; 3.0Change from baselineNumber (observed / LOCF 30 (27 / 3) 28 (24 / 4) 63 (60 / 3) 52(49 / 3) imputed) Mean(SD) -0.63 (1.33) -0.96 (1.00) -0.30 (1.07) -0.83 (1.00)Median -1.00 -1.00 0.00 -1.00Q1 ;Q3 -1.00; 0.00 -2.00 ; 0.00 -1.00; 0.00 -2.00 ; 0.00Min; Max -3.0; 2.0 -3.0; 2.0 -3.0 ; 3.0 -3.0 ; 1.0LS Mean (SE) -0.40(0.23) -0.71 (0.26) -0.48 (0.13) -0.82 (0.14)LS Mean Diff vs. placebo -0.32 (-0.87, -0.34 (-0.69,(95% CI) 0.24) 0.01)P-value vs. placebo 0.2646 0.0540Week 10Number (observed / LOCF 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) imputed) Mean(SD) 1.79 (1.32) 1.30(0.99) 1.93 (1.00) 1.64(1.02)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Median 2.00 1.00 2.00 2.00Q1 ;Q3 1.00; 3.00 1.00; 2.00 1.00; 3.00 1.00; 2.00Min; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 3.0Change from baseline Number (observed / LOCF 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) imputed) Mean(SD) -0.43 (1.37) -0.89 (0.97) -0.35 (0.87) -0.86 (1.02)Median 0.00 -1.00 0.00 -1.00Q1 ;Q3 -1.50; 0.50 -2.00 ; 0.00 -1.00; 0.00 -2.00 ; 0.00Min; Max -3.0; 2.0 -2.0 ; 1.0 -2.0 ; 1.0 -3.0 ; 1.0LS Mean (SE) -0.15 (0.22) -0.63 (0.24) -0.46 (0.13) -0.95 (0.13)LS Mean Diff vs. placebo -0.47 (-1.02, -0.49 (-0.83, -(95% CI) 0.07) 0.15)P-value vs. placebo 0.0874 0.0050Week 12 Number (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49(46 / 3) imputed) Mean(SD) 2.00 (1.15) 1.25 (1.08) 2.00(1.25) 1.67(0.97)Median 2.00 1.00 2.00 2.00Q1 ;Q3 1.00; 3.00 0.00 ; 2.00 1.00; 3.00 1.00; 2.00Min; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 6.0 0.0 ; 3.0Change from baseline Number (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49(46 / 3) imputed) Mean(SD) -0.18 (1.25) -0.89 (1.10) -0.32 (1.24) -0.84 (0.99)Median 0.00 -1.00 0.00 -1.00Q1 ;Q3 -1.00; 1.00 -2.00 ; 0.00 -1.00; 0.00 -1.00; 0.00Min; Max -3.0; 2.0 -3.0 ; 1.0 -3.0; 4.0 -3.0 ; 1.0LS Mean (SE) 0.03 (0.25) -0.66 (0.28) -0.49 (0.15) -0.89 (0.15)LS Mean Diff vs. placebo -0.70 (-1.28, - -0.40 (-0.79, -(95% CI) 0.11) 0.00)P-value vs. placebo 0.0192 0.0494Limitation activities by asthmaBaseline Number 32 32 68 64Mean(SD) 2.34 (0.87) 2.06(0.56) 2.13 (0.64) 2.17(0.52)Median 2.00 2.00 2.00 2.00Q1 ;Q3 2.00; 3.00 2.00 ; 2.00 2.00 ; 3.00 2.00 ; 2.00Min; Max 0.0 ; 4.0 1.0; 3.0 1.0; 3.0 1.0; 4.0400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Week 2Number (observed / LOCF 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) imputed)Mean (SD) 1.93 (0.98) 1.27 (0.94) 2.03 (0.98) 1.75 (0.99)Median 2.00 1.00 2.00 2.00Q1 ; Q3 1.00 ; 3.00 1.00 ; 2.00 2.00 ; 3.00 1.00 ; 3.00Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 3.0Change from baselineNumber (observed / LOCF 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) imputed)Mean (SD) -0.37 (1.16) -0.80 (1.03) -0.13 (0.89) -0.39 (1.04)Median 0.00 -1.00 0.00 0.00Q1 ; Q3 -1.00 ; 0.00 -2.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00Min ; Max -3.0 ; 3.0 -2.0 ; 2.0 -2.0 ; 2.0 -3.0 ; 2.0LS Mean (SE) -0.31 (0.20) -0.90 (0.22) -0.11 (0.13) -0.48 (0.13)LS Mean Diff vs. placebo -0.59 (-1.08, - -0.37 (-0.71, -(95% CI) 0.09) 0.03)P-value vs. placebo 0.0203 0.0323Week 4Number (observed / LOCF 30 (28 / 2) 31 (30 / 1) 62 (61 / 1) 59 (59 / 0) imputed)Mean (SD) 1.93 (1.01) 0.94 (1.00) 1.95 (1.00) 1.56 (0.95)Median 2.00 1.00 2.00 2.00Q1 ; Q3 1.00 ; 3.00 0.00 ; 2.00 2.00 ; 2.00 1.00 ; 2.00Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 3.0Change from baselineNumber (observed / LOCF 30 (28 / 2) 31 (30 / 1) 62 (61 / 1) 59 (59 / 0) imputed)Mean (SD) -0.37 (1.27) -1.13 (0.96) -0.16 (0.96) -0.58 (1.05)Median 0.00 -1.00 0.00 0.00Q1 ; Q3 -1.00 ; 0.00 -2.00 ; 0.00 -1.00 ; 1.00 -1.00 ; 0.00Min ; Max -3.0 ; 2.0 -3.0 ; 1.0 -2.0 ; 2.0 -3.0 ; 1.0LS Mean (SE) -0.27 (0.21) -1.15 (0.22) -0.23 (0.13) -0.70 (0.13)LS Mean Diff vs. placebo -0.88 (-1.40, - -0.47 (-0.80, -(95% CI) 0.37) 0.13)P-value vs. placebo 0.0007 0.0064Week 6Number (observed / LOCF 28 (26 / 2) 30 (28 / 2) 60 (58 / 2) 57 (56 / 1) imputed)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Mean(SD) 2.04 (1.17) 0.97(1.07) 1.82(1.03) 1.46(1.05)Median 2.00 1.00 2.00 1.00Q1 ;Q3 1.00; 3.00 0.00 ; 2.00 1.00; 2.00 1.00; 2.00Min; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 4.0Change from baseline Number (observed / LOCF 28 (26 / 2) 30 (28 / 2) 60(58 / 2) 57(56 / 1) imputed) Mean(SD) -0.29(1.08) -1.13 (1.04) -0.32 (1.08) -0.72 (1.15)Median 0.00 -1.00 0.00 -1.00Q1 ;Q3 -1.00; 0.50 -2.00 ; 0.00 -1.00; 1.00 -2.00 ; 0.00Min; Max -3.0; 1.0 -3.0 ; 1.0 -3.0; 2.0 -3.0; 2.0LS Mean (SE) -0.07(0.22) -0.95 (0.23) -0.25 (0.15) -0.76 (0.15)LS Mean Diff vs. placebo -0.89 (-1.42, - -0.51 (-0.89, -(95% CI) 0.35) 0.13)P-value vs. placebo 0.0012 0.0090Week 8Number (observed / LOCF 30 (27 / 3) 28 (24 / 4) 63 (60 / 3) 52(49 / 3) imputed) Mean(SD) 1.73 (1.17) 1.00 (0.98) 1.94 (1.15) 1.31 (0.88)Median 2.00 1.00 2.00 1.00Q1 ;Q3 1.00; 3.00 0.00; 1.50 1.00; 2.00 1.00; 2.00Min; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 5.0 0.0 ; 3.0Change from baseline Number (observed / LOCF 30 (27 / 3) 28 (24 / 4) 63 (60 / 3) 52(49 / 3) imputed) Mean(SD) -0.60(1.28) -1.07 (1.09) -0.16 (1.21) -0.87 (0.95)Median 0.00 -1.00 0.00 -1.00Q1 ;Q3 -2.00; 0.00 -2.00 ; 0.00 -1.00; 1.00 -1.00; 0.00Min; Max -3.0; 1.0 -3.0 ; 1.0 -3.0; 4.0 -3.0 ; 1.0LS Mean (SE) -0.30(0.21) -0.85 (0.25) -0.27 (0.14) -0.91 (0.14)LS Mean Diff vs. placebo -0.55 (-1.08, - -0.64 (-1.00, -(95% CI) 0.02) 0.28)P-value vs. placebo 0.0432 0.0005Week 10Number (observed / LOCF 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) imputed) Mean(SD) 1.79 (1.45) 1.11 (1.19) 1.76(1.14) 1.36(0.98)Median 1.50 1.00 2.00 1.00Q1 ;Q3 1.00; 3.00 0.00 ; 2.00 1.00; 3.00 1.00; 2.00Min; Max 0.0 ; 5.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 3.0400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Change from baselineNumber (observed / LOCF 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) imputed)Mean (SD) -0.54 (1.48) -0.96 (1.16) -0.35 (1.11) -0.80 (1.05)Median 0.00 -1.00 0.00 -1.00Q1 ; Q3 -2.00 ; 0.50 -2.00 ; 0.00 -1.00 ; 1.00 -1.00 ; 0.00Min ; Max -3.0 ; 3.0 -2.0 ; 1.0 -2.0 ; 2.0 -3.0 ; 1.0LS Mean (SE) -0.10 (0.24) -0.67 (0.26) -0.34 (0.15) -0.91 (0.15)LS Mean Diff vs. placebo -0.58 (-1.17, -0.57 (-0.96, -(95% CI) 0.02) 0.19)P-value vs. placebo 0.0570 0.0035Week 12Number (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49 (46 / 3) imputed)Mean (SD) 1.93 (1.27) 1.18 (1.12) 1.78 (1.12) 1.20 (0.96)Median 2.00 1.00 2.00 1.00Q1 ; Q3 1.00 ; 3.00 0.00 ; 2.00 1.00 ; 3.00 0.00 ; 2.00Min ; Max 0.0 ; 5.0 0.0 ; 3.0 0.0 ; 5.0 0.0 ; 4.0Change from baselineNumber (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49 (46 / 3) imputed)Mean (SD) -0.39 (1.31) -0.89 (1.03) -0.30 (1.25) -0.98 (1.03)Median 0.00 -1.00 0.00 -1.00Q1 ; Q3 -1.00 ; 0.50 -2.00 ; 0.00 -1.00 ; 1.00 -2.00 ; 0.00Min ; Max -3.0 ; 3.0 -2.0 ; 1.0 -3.0 ; 4.0 -3.0 ; 2.0LS Mean (SE) -0.08 (0.23) -0.67 (0.25) -0.42 (0.14) -1.02 (0.15)LS Mean Diff vs. placebo -0.58 (-1.13, - -0.60 (-0.97, -(95% CI) 0.03) 0.22)P-value vs. placebo 0.0391 0.0020Shortness of breath experiencedBaselineNumber 32 32 68 64Mean (SD) 2.50 (0.62) 2.31 (0.69) 2.37 (0.62) 2.41 (0.71)Median 2.00 2.00 2.00 2.00Q1 ; Q3 2.00 ; 3.00 2.00 ; 3.00 2.00 ; 3.00 2.00 ; 3.00Min ; Max 2.0 ; 4.0 1.0 ; 4.0 1.0 ; 4.0 0.0 ; 4.0Week 2Number (observed / LOCF 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) imputed)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Mean(SD) 2.23 (0.90) 1.60(0.77) 2.29(0.87) 2.05 (1.07)Median 2.00 1.50 2.00 2.00Q1 ;Q3 2.00; 3.00 1.00; 2.00 2.00 ; 3.00 1.00 ; 3.00Min; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 4.0Change from baseline Number (observed / LOCF 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) imputed) Mean(SD) -0.23 (0.94) -0.70 (0.84) -0.06 (0.90) -0.38 (1.11)Median 0.00 -1.00 0.00 0.00Q1 ;Q3 -1.00; 0.00 -1.00; 0.00 -1.00; 0.00 -1.00; 0.00Min; Max -2.0 ; 2.0 -2.0 ; 1.0 -3.0; 2.0 -3.0; 2.0LS Mean (SE) -0.12(0.17) -0.66 (0.18) -0.09 (0.13) -0.44 (0.13)LS Mean Diff vs. placebo -0.55 (-0.96, - -0.35 (-0.68, -(95% CI) 0.13) 0.01)P-value vs. placebo 0.0099 0.0409Week 4Number (observed / LOCF 30 (28 / 2) 31 (30 / 1) 62 (61 / 1) 59 (59 / 0) imputed) Mean(SD) 2.13 (1.04) 1.29(0.94) 2.11 (1.09) 1.73 (1.05)Median 2.00 1.00 2.00 2.00Q1 ;Q3 2.00; 3.00 1.00; 2.00 2.00 ; 3.00 1.00 ; 3.00Min; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 5.0 0.0 ; 3.0Change from baseline Number (observed / LOCF 30 (28 / 2) 31 (30 / 1) 62 (61 / 1) 59 (59 / 0) imputed) Mean(SD) -0.33 (1.21) -1.03 (0.87) -0.24 (1.07) -0.66 (1.06)Median 0.00 -1.00 0.00 -1.00Q1 ;Q3 -1.00; 0.00 -2.00 ; 0.00 -1.00; 0.00 -1.00; 0.00Min; Max -3.0; 2.0 -3.0 ; 0.0 -3.0 ; 3.0 -3.0 ; 1.0LS Mean (SE) -0.17(0.20) -0.88 (0.21) -0.27 (0.14) -0.73 (0.15)LS Mean Diff vs. placebo -0.71 (-1.21, - -0.47 (-0.84, -(95% CI) 0.21) 0.09)P-value vs. placebo 0.0053 0.0147Week 6Number (observed / LOCF 28 (26 / 2) 30 (28 / 2) 60(58 / 2) 57(56 / 1) imputed) Mean(SD) 2.32 (1.16) 1.33 (1.03) 2.05 (0.89) 1.81 (1.09)Median 2.00 1.00 2.00 2.00Q1 ;Q3 1.50; 3.00 1.00; 2.00 2.00 ; 3.00 1.00 ; 3.00Min; Max 0.0 ; 5.0 0.0 ; 4.0 0.0 ; 4.0 0.0 ; 4.0400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Change from baselineNumber (observed / LOCF 28 (26 / 2) 30 (28 / 2) 60 (58 / 2) 57 (56 / 1) imputed)Mean (SD) -0.14 (1.27) -1.03 (1.03) -0.30 (0.83) -0.61 (1.18)Median 0.00 -1.00 0.00 0.00Q1 ; Q3 -1.00 ; 1.00 -2.00 ; -1.00 -1.00 ; 0.00 -1.00 ; 0.00Min ; Max -3.0 ; 2.0 -3.0 ; 2.0 -3.0 ; 1.0 -4.0 ; 2.0LS Mean (SE) -0.00 (0.24) -0.90 (0.25) -0.25 (0.14) -0.64 (0.14)LS Mean Diff vs. placebo -0.90 (-1.47, - -0.39 (-0.74, -(95% CI) 0.33) 0.04)P-value vs. placebo 0.0019 0.0310Week 8Number (observed / LOCF 30 (27 / 3) 28 (24 / 4) 63 (60 / 3) 52 (49 / 3) imputed)Mean (SD) 1.80 (1.06) 1.32 (1.19) 2.16 (1.25) 1.63 (1.01)Median 2.00 1.00 2.00 2.00Q1 ; Q3 1.00 ; 3.00 1.00 ; 2.00 1.00 ; 3.00 1.00 ; 2.00Min ; Max 0.0 ; 4.0 0.0 ; 5.0 0.0 ; 6.0 0.0 ; 3.0Change from baselineNumber (observed / LOCF 30 (27 / 3) 28 (24 / 4) 63 (60 / 3) 52 (49 / 3) imputed)Mean (SD) -0.67 (1.21) -0.93 (1.25) -0.21 (1.12) -0.77 (1.08)Median 0.00 -1.00 0.00 -1.00Q1 ; Q3 -1.00 ; 0.00 -2.00 ; -1.00 -1.00 ; 0.00 -1.00 ; 0.00Min ; Max -4.0 ; 1.0 -3.0 ; 3.0 -2.0 ; 3.0 -3.0 ; 1.0LS Mean (SE) -0.44 (0.24) -0.83 (0.27) -0.29 (0.14) -0.87 (0.15)LS Mean Diff vs. placebo -0.39 (-0.97, -0.58 (-0.96, -(95% CI) 0.19) 0.20)P-value vs. placebo 0.1848 0.0026Week 10Number (observed / LOCF 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) imputed)Mean (SD) 1.86 (1.18) 1.26 (1.10) 2.02 (1.28) 1.63 (0.98)Median 2.00 1.00 2.00 2.00Q1 ; Q3 1.00 ; 3.00 0.00 ; 2.00 1.00 ; 3.00 1.00 ; 2.00Min ; Max 0.0 ; 4.0 0.0 ; 4.0 0.0 ; 5.0 0.0 ; 3.0Change from baselineNumber (observed / LOCF 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) imputed)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Mean(SD) -0.57(1.37) -1.15 (1.17) -0.31 (1.22) -0.79 (1.16)Median 0.00 -1.00 0.00 -1.00Q1 ;Q3 -2.00; 0.50 -2.00 ; 0.00 -1.00; 1.00 -1.00; 0.00Min; Max -4.0; 1.0 -3.0; 2.0 -3.0; 2.0 -3.0; 2.0LS Mean (SE) -0.19(0.21) -0.74 (0.23) -0.24 (0.16) -0.81 (0.17)LS Mean Diff vs. placebo -0.54 (-1.07, - -0.57 (-0.99, -(95% CI) 0.01) 0.15)P-value vs. placebo 0.0442 0.0080Week 12 Number (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49(46 / 3) imputed) Mean(SD) 1.96 (0.96) 1.29(1.05) 2.17(1.33) 1.63 (0.97)Median 2.00 1.00 2.00 2.00Q1 ;Q3 1.00; 3.00 0.50 ; 2.00 1.00; 3.00 1.00; 2.00Min; Max 0.0 ; 4.0 0.0 ; 4.0 0.0 ; 6.0 0.0 ; 3.0Change from baseline Number (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49(46 / 3) imputed) Mean(SD) -0.50(1.17) -1.07 (1.18) -0.22 (1.22) -0.86 (1.02)Median 0.00 -1.00 0.00 -1.00Q1 ;Q3 -1.00; 0.00 -2.00; -1.00 -1.00; 1.00 -2.00 ; 0.00Min; Max -4.0; 1.0 -3.0; 2.0 -3.0 ; 3.0 -3.0 ; 1.0LS Mean (SE) -0.20(0.21) -0.87 (0.23) -0.25 (0.15) -0.84 (0.15)LS Mean Diff vs. placebo -0.66 (-1.18, - -0.59 (-0.99, -(95% CI) 0.15) 0.19)P-value vs. placebo 0.0116 0.0039WheezeBaselineNumber 32 32 68 64Mean(SD) 1.97 (0.82) 2.06(0.72) 2.13 (0.83) 2.23 (0.79)Median 2.00 2.00 2.00 2.00Q1 ;Q3 1.00; 2.00 2.00 ; 2.00 2.00 ; 3.00 2.00 ; 3.00Min; Max 1.0; 4.0 1.0; 4.0 0.0 ; 5.0 1.0; 4.0Week 2 Number (observed / LOCF 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) imputed) Mean(SD) 1.80 (1.19) 1.00 (0.87) 1.90 (0.93) 1.89 (1.05)Median 2.00 1.00 2.00 2.00Q1 ;Q3 1.00; 2.00 0.00 ; 2.00 1.00; 3.00 1.00 ; 3.00400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Min; Max 0.0 ; 6.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 5.0Change from baseline Number (observed / LOCF 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) imputed) Mean(SD) -0.17(1.05) -1.07 (0.94) -0.21 (1.09) -0.34 (1.00)Median 0.00 -1.00 0.00 0.00Q1 ;Q3 -1.00; 0.00 -2.00 ; 0.00 -1.00; 0.00 -1.00; 0.00Min; Max -2.0 ; 3.0 -3.0 ; 1.0 -4.0 ; 2.0 -2.0 ; 3.0LS Mean (SE) -0.25 (0.19) -1.08 (0.20) -0.29 (0.12) -0.44 (0.12)LS Mean Diff vs. placebo -0.83 (-1.29, - -0.15 (-0.47,(95% CI) 0.36) 0.17)P-value vs. placebo 0.0005 0.3687Week 4Number (observed / LOCF 30 (28 / 2) 31 (30 / 1) 62 (61 / 1) 59 (59 / 0) imputed) Mean(SD) 1.60 (1.04) 1.26(1.12) 1.84(1.09) 1.81 (1.12)Median 1.50 1.00 2.00 2.00Q1 ;Q3 1.00; 2.00 0.00 ; 2.00 1.00; 3.00 1.00 ; 3.00Min; Max 0.0 ; 4.0 0.0 ; 5.0 0.0 ; 4.0 0.0 ; 5.0Change from baselineNumber (observed / LOCF 30 (28 / 2) 31 (30 / 1) 62 (61 / 1) 59 (59 / 0) imputed) Mean(SD) -0.37(1.10) -0.81 (1.01) -0.26 (1.23) -0.42 (1.02)Median 0.00 -1.00 0.00 0.00Q1 ;Q3 -1.00; 0.00 -1.00; 0.00 -1.00; 0.00 -1.00; 0.00Min; Max -3.0; 2.0 -3.0; 2.0 -5.0; 2.0 -2.0 ; 3.0LS Mean (SE) -0.45 (0.21) -0.83 (0.22) -0.43 (0.14) -0.50 (0.14)LS Mean Diff vs. placebo -0.38 (-0.89, -0.07 (-0.44,(95% CI) 0.14) 0.30)P-value vs. placebo 0.1498 0.7130Week 6Number (observed / LOCF 28 (26 / 2) 30 (28 / 2) 60(58 / 2) 57(56 / 1) imputed) Mean(SD) 1.75 (1.46) 0.97(0.93) 1.67(1.13) 1.70(1.05)Median 2.00 1.00 2.00 2.00Q1 ;Q3 1.00; 2.00 0.00 ; 2.00 1.00; 2.00 1.00; 2.00Min; Max 0.0 ; 6.0 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 4.0Change from baseline400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Number (observed / LOCF 28 (26 / 2) 30 (28 / 2) 60(58 / 2) 57(56 / 1) imputed) Mean(SD) -0.21 (1.55) -1.13 (1.04) -0.45 (1.21) -0.58 (0.96)Median 0.00 -1.00 0.00 -1.00Q1 ;Q3 -1.00; 0.00 -2.00 ; 0.00 -1.00; 0.00 -1.00; 0.00Min; Max -3.0 ; 3.0 -3.0 ; 1.0 -5.0; 2.0 -3.0; 2.0LS Mean (SE) -0.27(0.24) -1.08 (0.26) -0.45 (0.14) -0.61 (0.14)LS Mean Diff vs. placebo -0.81 (-1.40, - -0.16 (-0.52,(95% CI) 0.22) 0.20)P-value vs. placebo 0.0076 0.3907Week 8Number (observed / LOCF 30 (27 / 3) 28 (24 / 4) 63 (60 / 3) 52(49 / 3) imputed) Mean(SD) 1.70 (1.44) 1.11 (1.07) 1.94(1.32) 1.58 (0.98)Median 2.00 1.00 2.00 2.00Q1 ;Q3 1.00; 2.00 0.00 ; 2.00 1.00; 3.00 1.00; 2.00Min; Max 0.0 ; 5.0 0.0 ; 3.0 0.0 ; 5.0 0.0 ; 4.0Change from baselineNumber (observed / LOCF 30 (27 / 3) 28 (24 / 4) 63 (60 / 3) 52(49 / 3) imputed) Mean(SD) -0.27(1.44) -0.96 (1.07) -0.13 (1.41) -0.69 (0.98)Median 0.00 -1.00 0.00 -1.00Q1 ;Q3 -1.00; 0.00 -2.00 ; 0.00 -1.00; 1.00 -1.00; 0.00Min; Max -4.0 ; 3.0 -3.0 ; 1.0 -5.0 ; 3.0 -3.0 ; 1.0LS Mean (SE) -0.32(0.25) -0.99 (0.27) -0.31 (0.15) -0.69 (0.16)LS Mean Diff vs. placebo -0.67 (-1.27, - -0.37 (-0.77,(95% CI) 0.06) 0.03)P-value vs. placebo 0.0315 0.0669Week 10Number (observed / LOCF 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) imputed) Mean(SD) 1.93 (1.27) 1.19 (0.96) 1.85 (1.38) 1.52 (1.03)Median 2.00 1.00 2.00 1.00Q1 ;Q3 1.00; 2.50 0.00 ; 2.00 1.00; 3.00 1.00; 2.00Min; Max 0.0 ; 5.0 0.0 ; 3.0 0.0 ; 5.0 0.0 ; 4.0Change from baselineNumber (observed / LOCF 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) imputed) Mean(SD) 0.00 (1.44) -0.93 (1.14) -0.25 (1.49) -0.73 (1.12)Median 0.00 -1.00 0.00 -1.00400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Q1 ; Q3 -1.00 ; 1.00 -2.00 ; 0.00 -1.00 ; 1.00 -1.00 ; 0.00Min ; Max -3.0 ; 2.0 -4.0 ; 1.0 -5.0 ; 3.0 -3.0 ; 2.0LS Mean (SE) -0.00 (0.21) -0.83 (0.23) -0.36 (0.16) -0.79 (0.17)LS Mean Diff vs. placebo -0.82 (-1.35, - -0.43 (-0.85, -(95% CI) 0.30) 0.01)P-value vs. placebo 0.0021 0.0450Week 12 Number (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49 (46 / 3) imputed) Mean (SD) 1.86 (1.35) 1.21 (1.10) 2.05 (1.53) 1.49 (0.84)Median 2.00 1.00 2.00 2.00Q1 ; Q3 1.00 ; 2.00 0.00 ; 2.00 1.00 ; 3.50 1.00 ; 2.00Min ; Max 0.0 ; 5.0 0.0 ; 3.0 0.0 ; 5.0 0.0 ; 3.0Change from baseline Number (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49 (46 / 3) imputed) Mean (SD) -0.14 (1.58) -0.86 (1.11) -0.05 (1.41) -0.80 (1.00)Median 0.00 -1.00 0.00 -1.00Q1 ; Q3 -1.00 ; 1.00 -2.00 ; 0.00 -1.00 ; 1.00 -1.00 ; 0.00Min ; Max -4.0 ; 2.0 -2.0 ; 1.0 -3.0 ; 3.0 -3.0 ; 1.0LS Mean (SE) -0.03 (0.25) -0.63 (0.28) -0.22 (0.16) -0.80 (0.17)LS Mean Diff vs. placebo -0.60 (-1.21, -0.58 (-1.00, -(95% CI) 0.00) 0.15)P-value vs. placebo 0.0500 0.0078ACQ-5: Asthma control questionnaire, 5-question version, LOAC: Loss of asthma control, LOCF: Last observation carried forward, LATAM: Latin America, EASTEU: Eastern Europe, ROW: Rest of the world

[0251] Table 43. Responder analysis for change from baseline in ACQ-5 score atWeek 12 (mITT population).400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TIDWeek 12Number (observed / LOCF 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49 (46 / 3) imputed)Responder (observed / LOCF 10 (35.7) (9 / 1) 19 (67.9) (17 / 2) 24 (40.0) (23 / 1) 31 (63.3) (31 / 0) imputed)Non-responder 18 (64.3) (10 / 8) 9 (32.1) (6 / 3) 36 (60.0) (27 / 9) 18 (36.7) (15 / 3)(observed / LOCF imputed)400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Responder (including 11.5 (35.9) 21.2 (66.1) 26.8 (39.4) 38.3 (59.8) multiply imputed)OR vs. placebo (95% CI) 5.18 (1.48, 2.38 (1.09, 5.18)18.15)P-value vs. placebo 0.0100 0.0297LATAM: Latin America, ROW: Rest of the world

[0252] Table 44. Responder analysis for ACQ-5 score less than 0.75 over time(mITT population)._ BID cohort _ TIP cohort _ Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID_ _ (N=32) _ (N=64)Baseline Number (observed / NR imputed) 32 (32 / 0) 32 (32 / 0) 68 (68 / 0) 64 (64 / 0)Responder (observed) 0 0 0 0Non-responder (observed / NR 32 (100) (32 / 0) 32 (100) (32 / 0) 68 (100) (68 / 0) 64 (100) (64 / 0) imputed)Week 2Number (observed / LOCF 32 (29 / 1 / 2) 32 (30 / 0 / 2) 68 (62 / 1 / 5) 64 (61 / 0 / 3) imputed / NR imputed) Responder (observed / LOCF 1 (3.1) (1 / 0) 6 (18.8) (6 / 0) 4 (5.9) (4 / 0) 10 (15.6) (10 / 0) imputed)Non-responder (observed / LOCF 31 (96.9) 26 (81.3) 64 (94.1) 54 (84.4) imputed / NR imputed) (28 / 1 / 2) (24 / 0 / 2) (58 / 1 / 5) (51 / 0 / 3) OR vs. placebo (95% CI) 5.66 (0.61, 3.39 (0.95,52.11) 12.05)P-value vs. placebo 0.1262 0.0590Week 4Number (observed / LOCF 32 (28 / 2 / 2) 32 (30 / 1 / 1) 68 (61 / 1 / 6) 64 (59 / 0 / 5) imputed / NR imputed) Responder (observed / LOCF 2 (6.3) (2 / 0) 11 (34.4) 5 (7.4) (5 / 0) 10 (15.6) (10 / 0) imputed) (H / 0)Non-responder (observed / LOCF 30 (93.8) 21 (65.6) 63 (92.6) 54 (84.4) imputed / NR imputed) (26 / 2 / 2) (19 / 1 / 1) (56 / 1 / 6) (49 / 0 / 5) OR vs. placebo (95% CI) 8.34 (1.55, 2.78 (0.82, 44.69) 9.38)P-value vs. placebo 0.0133 0.1003Week 6Number (observed / LOCF 32 (26 / 2 / 4) 32 (28 / 2 / 2) 68 (58 / 2 / 8) 64 (56 / 1 / 7) imputed / NR imputed) Responder (observed / LOCF 3 (9.4) (3 / 0) 11 (34.4) 5 (7.4) (5 / 0) 11 (17.2) (11 / 0) imputed) (H / 0)Non-responder (observed / LOCF 29 (90.6) 21 (65.6) 63 (92.6) 53 (82.8) imputed / NR imputed) (23 / 2 / 4) (17 / 2 / 2) (53 / 2 / 8) (45 / 1 / 7)BID cohort TID cohortPlacebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)OR vs. placebo (95% CI) 4.74 (1.12, 3.22 (0.96,20.02) 10.79)P-value vs. placebo 0.0344 0.0575Week 8Number (observed / LOCF 32 (27 / 3 / 2) 32 (24 / 4 / 4) 68 (60 / 3 / 5) 64 (49 / 3 / 12) imputed / NR imputed)Responder (observed / LOCF 6 (18.8) (6 / 0) 9 (28.1) (9 / 0) 4 (5.9) (4 / 0) 9 (14.1) (9 / 0) imputed)Non-responder (observed / LOCF 26 (81.3) 23 (71.9) 64 (94.1) 55 (85.9) imputed / NR imputed) (21 / 3 / 2) (15 / 4 / 4) (56 / 3 / 5) (40 / 3 / 12)OR vs. placebo (95% CI) 1.51 (0.45, 3.03 (0.83,5.09) 11.04)P-value vs. placebo 0.5033 0.0919Week 10Number (observed / LOCF 32 (22 / 6 / 4) 32 (23 / 4 / 5) 68 (51 / 4 / 13) 64 (53 / 3 / 8) imputed / NR imputed)Responder (observed / LOCF 5 (15.6) (5 / 0) 11 (34.4) 7 (10.3) (7 / 0) 12 (18.8) (12 / 0) imputed) (11 / 0)Non-responder (observed / LOCF 27 (84.4) 21 (65.6) 61 (89.7) 52 (81.3) imputed / NR imputed) (17 / 6 / 4) (12 / 4 / 5) (44 / 4 / 13) (41 / 3 / 8)OR vs. placebo (95% CI) 3.58 (0.95, 2.45 (0.80,13.55) 7.47)P-value vs. placebo 0.0599 0.1146Week 12Number (observed / LOCF 32 (19 / 9 / 4) 32 (23 / 5 / 4) 68 (50 / 10 / 8) 64 (46 / 3 / 15) imputed / NR imputed)Responder (observed / LOCF 3 (9.4) (3 / 0) 13 (40.6) 9 (13.2) (9 / 0) 10 (15.6) (10 / 0) imputed) (12 / 1)Non-responder (observed / LOCF 29 (90.6) 19 (59.4) 59 (86.8) 54 (84.4) imputed / NR imputed) (16 / 9 / 4) (11 / 4 / 4) (41 / 10 / 8) (36 / 3 / 15)OR vs. placebo (95% CI) 6.79 (1.61, 1.29 (0.46,28.67) 3.64)P-value vs. placebo 0.0092 0.6286LATAM: Latin America, ROW: Rest of the world, NR: non-responder

[0253] Table 45. Number and proportion of participants remained as ACQ-5 less than 0.75 responders since Week 4 over time (mITT population).Placebo BID Rilzabrutinib 400 mg(N=32) BID_ (N=32)Week 4Number (observed / LOCF imputed / NR imputed) 32 (28 / 2 / 2) 32 (30 / 1 / 1)Responder (observed / LOCF imputed) 2 (6.3) (2 / 0) 11 (34.4) (11 / 0)Placebo BID Rilzabrutinib 400 mg(N=32) BID(N=32)Non-responder (observed / LOCF imputed / NR 30 (93.8) (26 / 2 / 2) 21 (65.6) (19 / 1 / 1) imputed)Week 6Number (observed / LOCF imputed) 2 (2 / 0) 11 (10 / 0)Responder (observed / LOCF imputed) 1 (50.0) (1 / 0) 7 (63.6) (7 / 0)OR vs. placebo (95% CI) 0.81 (0.01, 126.85)P-value vs. placebo 0.9356Week 8Number (observed / LOCF imputed) 2 (2 / 0) 11 (10 / 1)Responder (observed / LOCF imputed) 1 (50.0) (1 / 0) 5 (45.5) (5 / 0)OR vs. placebo (95% CI) 0.26 (0.00, 28.99)P-value vs. placebo 0.5729Week 10Number (observed / LOCF imputed) 2 (2 / 0) 11 (8 / 1)Responder (observed / LOCF imputed) 1 (50.0) (1 / 0) 4 (36.4) (4 / 0)OR vs. placebo (95% CI) 0. 12 (0.00, 16.67)P-value vs. placebo 0.3991Week 12Number (observed / LOCF imputed) 2 (1 / 1) 11 (8 / 2)Responder (observed / LOCF imputed) 0 3 (27.3) (2 / 1)OR vs. placebo (95% CI) NC (NC, NC)P-value vs. placebo NCLATAM: Latin America, ROW: Rest of the world, NR: non-responder

[0254] Table 46. Subgroup analysis: change from baseline in ACQ-5 score atEOT (Week 12) by demographics subgroups (mITT population).400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDAge group 1 (years)< 45Number 10 9 28 23Mean (SD) -0.70 (0.91) -0.49 (0.94) -0.05 (1.02) -0.84 (0.62)LS Mean (SE) -0.70 (0.31) -0.68 (0.34) -0.25 (0.17) -0.95 (0.17)LS Mean Diff vs. placebo (95% 0.02 (-0.76, -0.70 (-1.15, -CI) 0.79) 0.25)P-value vs. placebo 0.9616 0.0024> 45Number 18 19 32 26Mean (SD) -0.13 (1.05) -1.07 (0.88) -0.38 (1.04) -0.79 (0.81)LS Mean (SE) 0.14 (0.23) -0.78 (0.25) -0.35 (0.17) -0.79 (0.18)LS Mean Diff vs. placebo (95% -0.92 (-1.50, - -0.43 (-0.90,CI) 0.35) 0.03)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDP-value vs. placebo 0.0016 0.0643Overall p-value for interaction 0.0568 0.5311GenderMaleNumber 7 12 26 22Mean (SD) -0.31 (0.98) -1.08 (0.79) -0.22 (0.82) -0.65 (0.65)LS Mean (SE) -0.32 (0.36) -0.82 (0.42) -0.31 (0.17) -0.64 (0.17)LS Mean Diff vs. placebo (95% -0.50 (-1.67, -0.34 (-0.78,CI) 0.67) 0.11)P-value vs. placebo 0.4019 0.1396FemaleNumber 21 16 34 27Mean (SD) -0.34 (1.06) -0.74 (1.02) -0.22 (1.18) -0.96 (0.76)LS Mean (SE) -0.02 (0.27) -0.58 (0.27) -0.31 (0.17) -0.96 (0.18)LS Mean Diffvs. placebo (95% -0.56 (-1.19, -0.65 (-1.11, -CI) 0.06) 0.19)P-value vs. placebo 0.0747 0.0056Overall p-value for interaction 0.9599 0.3680Baseline weight group (kg)< 60Number 4 3 10 2Mean (SD) 0.35 (0.47) -1.13 (0.83) -0.54 (1.12) -1.90 (0.42)LS Mean (SE) 0.32 (0.47) -1.71 (0.99) -0.18 (0.41) -1.72 (0.80)LS Mean Diffvs. placebo (95% -2.03 (-5.03, -1.54 (-3.28,CI) 0.98) 0.21)P-value vs. placebo 0.1010 0.0847> 60 - < 90Number 21 20 35 29Mean (SD) -0.52 (1.00) -0.80 (0.89) -0.15 (1.07) -0.74 (0.68)LS Mean (SE) -0.27 (0.25) -0.63 (0.25) -0.25 (0.16) -0.80 (0.17)LS Mean Diffvs. placebo (95% -0.35 (-0.93, -0.54 (-0.97, -CI) 0.22) 0.11)P-value vs. placebo 0.2295 0.0130> 90Number 3 5 15 18Mean (SD) 0.07 (1.50) -1.08 (1.25) -0.17 (0.91) -0.81 (0.74)LS Mean (SE) -0.68 (0.45) -1.96 (0.57) -0.34 (0.23) -0.86 (0.19)LS Mean Diffvs. placebo (95% -1.27 (-2.46, - -0.51 (-1.08,CI) 0.09) 0.05)P-value vs. placebo 0.0353 0.0737Overall p-value for interaction 0.4298 0.4325400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDBaseline BMI group (kg / m2)< 25Number 6 8 20 8Mean (SD) 0.00 (0.79) -0.90 (0.81) -0.33 (1.02) -1.03 (0.82)LS Mean (SE) 0.65 (0.54) 0.03 (0.68) -0.40 (0.25) -1.06 (0.37)LS Mean Diff vs. placebo (95% -0.61 (-1.75, -0.66 (-1.45,CI) 0.53) 0.14)P-value vs. placebo 0.2545 0.1043> 25 - < 30Number 15 13 23 26Mean (SD) -0.53 (1.16) -0.69 (0.94) -0.22 (0.98) -0.86 (0.73)LS Mean (SE) -0.40 (0.29) -0.67 (0.33) -0.42 (0.18) -1.01 (0.17)LS Mean Diffvs. placebo (95% -0.27 (-1.10, -0.59 (-1.04, -CI) 0.56) 0.14)P-value vs. placebo 0.5253 0.0101> 30Number 7 7 17 15Mean (SD) -0.20 (0.92) -1.23 (1.06) -0.11 (1.16) -0.63 (0.65)LS Mean (SE) 0.50 (0.37) -0.67 (0.37) -0.13 (0.24) -0.66 (0.23)LS Mean Diffvs. placebo (95% -1.17 (-1.91, - -0.53 (-1.17,CI) 0.42) 0.11)P-value vs. placebo 0.0021 0.1017Overall p-value for interaction 0.3782 0.9246RegionEastern Europe Number 4 1 43 32Mean (SD) -0.05 (1.17) 1.00 (NC) -0.04 (0.88) -0.72 (0.66)LS Mean (SE) -0.48 (0.69) 0.40 (0.94) -0.06 (0.13) -0.59 (0.14)LS Mean Diffvs. placebo (95% 0.88 (-1.58, -0.53 (-0.90, -CI) 3.35) 0.15)P-value vs. placebo 0.4823 0.0059Latin AmericaNumber 22 24 15 15Mean (SD) -0.54 (0.91) -1.02 (0.85) -0.93 (0.81) -0.87 (0.77)LS Mean (SE) -0.54 (0.21) -1.12 (0.20) -0.91 (0.26) -1.04 (0.25)LS Mean Diffvs. placebo (95% -0.58 (-1.11, - -0.14 (-0.70,CI) 0.05) 0.43)P-value vs. placebo 0.0315 0.6394Western CountriesNumber 1 2 1 2Mean (SD) 1.60 (NC) -0.60 (1.41) 3.20 (NC) -2.00 (0.00)LS Mean (SE) NC (NC) NC (NC) NC (NC) NC (NC)LS Mean Diff vs . placebo (95 % NC (NC, NC) NC (NC, NC)CI)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDP-value vs. placebo NC NCAPACNumber 1 1 1 0Mean (SD) 1.00 (NC) -0.20 (NC) -0.80 (NC) NC (NC)LS Mean (SE) NC (NC) NC (NC) NC (NC) NC (NC)LS Mean Diff vs . placebo (95 % NC (NC, NC) NC (NC, NC) ci)P-value vs. placebo NC NCOverall p-value for interaction 0.6608 0.0007LATAM: Latin America, ROW: Rest of the world

[0255] Table 47. Subgroup analysis: change from baseline in ACQ-5 score atEOT (Week 12) by disease and other characteristics subgroups (mITT population).400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDAge at onset of asthma (years)< 12 Number 7 8 14 12Mean (SD) -0.49 (0.80) -0.68 (1.13) 0.09 (0.93) -0.58 (0.67)LS Mean (SE) -0.70 (0.42) -0.71 (0.55) -0.02 (0.22) -0.63 (0.24)LS Mean Diff vs. placebo (95% -0.01 (-1.21, -0.61 (-1.24,CI) 1.18) 0.02)P-value vs. placebo 0.9822 0.0595> 12 - < 18Number 2 4 5 5Mean (SD) -0.40 (0.57) -1.30 (0.20) -0.76 (1.18) -1.04 (0.65)LS Mean (SE) -0.14 (0.88) -0.96 (0.54) -1.10 (0.84) -1.08 (0.64)LS Mean Diff vs. placebo (95% -0.82 (-3.23, 0.01 (-1.86,CI) 1.59) 1.89)P-value vs. placebo 0.2812 0.9849> 18 - < 40Number 13 13 24 20Mean (SD) -0.25 (1.06) -0.97 (0.98) -0.11 (1.24) -0.87 (0.69)LS Mean (SE) 0.15 (0.27) -0.71 (0.27) -0.20 (0.23) -0.77 (0.24)LS Mean Diff vs. placebo (95% -0.85 (-1.52, - -0.57 (-1.15,CI) 0.19) 0.01)P-value vs. placebo 0.0119 0.0537> 40Number 6 3 17 12Mean (SD) -0.33 (1.44) -0.53 (0.81) -0.48 (0.64) -0.87 (0.86)LS Mean (SE) -0.08 (0.49) -0.87 (0.83) -0.39 (0.20) -0.90 (0.22)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs. placebo (95% -0.78 (-2.44, -0.51 (-1.06,CI) 0.88) 0.03)P-value vs. placebo 0.3555 0.0660Overall p-value for interaction 0.5580 0.8917Age at onset of asthma (years)< 18 Number 9 12 19 17Mean (SD) -0.47 (0.72) -0.88 (0.96) -0.14 (1.04) -0.72 (0.68)LS Mean (SE) -0.67 (0.34) -0.91 (0.39) -0.22 (0.20) -0.66 (0.21)LS Mean Diff vs. placebo (95% -0.24 (-1.08, -0.44 (-0.99,CI) 0.59) 0.12)P-value vs. placebo 0.5658 0.1215> 18 Number 19 16 41 32Mean (SD) -0.27 (1.15) -0.89 (0.94) -0.26 (1.04) -0.87 (0.75)LS Mean (SE) 0.05 (0.23) -0.70 (0.26) -0.30 (0.15) -0.84 (0.17)LS Mean Diff vs. placebo (95% -0.76 (-1.35, - -0.54 (-0.94, -CI) 0.16) 0.14)P-value vs. placebo 0.0136 0.0089Overall p-value for interaction 0.4014 0.8634Number of asthma exacerbations within 2 years before screening visit 1Number 8 10 45 31Mean (SD) -0.63 (0.92) -1.06 (1.05) -0.23 (0.99) -0.95 (0.74)LS Mean (SE) -0.37 (0.37) -1.12 (0.35) -0.39 (0.15) -1.04 (0.16)LS Mean Diff vs. placebo (95% -0.76 (-1.61, -0.66 (-1.07, -CI) 0.09) 0.25)P-value vs. placebo 0.0811 0.00162 Number 14 10 15 15Mean (SD) -0.39 (1.18) -0.88 (0.97) -0.21 (1.20) -0.64 (0.69)LS Mean (SE) 0.13 (0.33) -0.11 (0.48) -0.26 (0.26) -0.70 (0.24)LS Mean Diff vs. placebo (95% -0.23 (-1.17, -0.45 (-1.07,CI) 0.70) 0.17)P-value vs. placebo 0.6244 0.1584> 2 Number 6 8 0 3Mean (SD) 0.17 (0.61) -0.68 (0.78) NC (NC) -0.33 (0.31)LS Mean (SE) 0.18 (0.30) -0.53 (0.25) NC (NC) NC (NC)LS Mean Diff vs. placebo (95% -0.70 (-1.38, - NC (NC, NC)CI) 0.03)P-value vs. placebo 0.0417 NC400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDOverall p-value for interaction 0.8549 0.4193Atopic medical conditionsYes Number 16 19 19 16Mean (SD) -0.75 (1.04) -0.89 (0.92) -0.38 (0.97) -0.80 (0.83)LS Mean (SE) -0.41 (0.29) -0.71 (0.28) -0.23 (0.21) -0.79 (0.24)LS Mean Diff vs. placebo (95% -0.30 (-0.92, -0.56 (-1.15,CI) 0.32) 0.03)P-value vs. placebo 0.3393 0.0640NoNumber 12 9 41 33Mean (SD) 0.22 (0.71) -0.87 (1.00) -0.15 (1.06) -0.82 (0.67)LS Mean (SE) 0.27 (0.28) -0.69 (0.33) -0.36 (0.17) -0.87 (0.17)LS Mean Diffvs. placebo (95% -0.96 (-1.71, - -0.51 (-0.92, -CI) 0.21) 0.10)P-value vs. placebo 0.0118 0.0149Overall p-value for interaction 0.1288 0.8698Background ICS dose level at randomization (400 mg TID only)MediumNumber 32 19Mean (SD) -0.11 (0.96) -0.72 (0.72)LS Mean (SE) -0.29 (0.19) -0.76 (0.20)LS Mean Diff vs. placebo (95% -0.46 (-0.93,CI) 0.00)P-value vs. placebo 0.0518High Number 28 30Mean (SD) -0.36 (1.11) -0.88 (0.73)LS Mean (SE) -0.32 (0.18) -0.92 (0.18)LS Mean Diff vs. placebo (95% -0.60 (-1.08, -CI) 0.11)P-value vs. placebo 0.0167Overall p-value for interaction 0.6694Smoking historyLormerNumber 7 4 3 3Mean (SD) -0.03 (0.88) -1.20 (1.07) 0.33 (0.42) 0.07 (0.42)LS Mean (SE) 0.75 (0.48) -0.50 (0.62) 0.27 (0.44) -0.56 (0.47)LS Mean Diffvs. placebo (95% -1.25 (-2.44, - -0.83 (-1.97,CI) 0.06) 0.31)P-value vs. placebo 0.0396 0.1522400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDNeverNumber 21 24 57 46Mean (SD) -0.44 (1.07) -0.83 (0.92) -0.25 (1.05) -0.87 (0.70)LS Mean (SE) -0.25 (0.23) -0.69 (0.23) -0.40 (0.13) -0.92 (0.13)LS Mean Diff vs. placebo (95% -0.44 (-0.98, -0.52 (-0.86, -CI) 0.10) 0.18)P-value vs. placebo 0.1102 0.0025Overall p-value for interaction 0.2052 0.7507Baseline pre-bronchodilator FEV 1(L) (400 mg BID only)< Median (2.022)Number 13 15Mean (SD) -0.31 (1.08) -0.88 (0.81)LS Mean (SE) 0.04 (0.28) -0.42 (0.30)LS Mean Diff vs. placebo (95% -0.45 (-1.09,CI) 0.19)P-value vs. placebo 0.1647> Median (2.022)Number 15 12Mean (SD) -0.36 (1.01) -0.83 (1.11)LS Mean (SE) -0.24 (0.29) -0.89 (0.34)LS Mean Diff vs. placebo (95% -0.66 (-1.46,CI) 0.14)P-value vs. placebo 0.1073Overall p-value for interaction 0.7510Baseline pre-bronchodilator percent predicted FEV 1 (%) (400 mg BID only)< Median (68)Number 12 16Mean (SD) -0.32 (1.13) -0.98 (0.85)LS Mean (SE) 0.27 (0.32) -0.23 (0.32)LS Mean Diff vs. placebo (95% -0.50 (-1.15, CI) 0.16)P-value vs. placebo 0.1359> Median (68)Number 16 11Mean (SD) -0.35 (0.97) -0.69 (1.07)LS Mean (SE) -0.26 (0.25) -0.79 (0.33)LS Mean Diff vs. placebo (95% -0.53 (-1.28,CI) 0.22)P-value vs. placebo 0.1642400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDOverall p-value for interaction 0.9232Baseline pre-bronchodilator FEV 1 (L) (400 mg TID only)< Median (2.1955)Number 28 19Mean (SD) -0.24 (1.11) -0.91 (0.74)LS Mean (SE) -0.23 (0.18) -0.89 (0.21)LS Mean Diff vs. placebo (95% -0.66 (-1.18, -CI) 0.15)P-value vs. placebo 0.0120> Median (2.1955)Number 31 29Mean (SD) -0.21 (0.99) -0.76 (0.72)LS Mean (SE) -0.39 (0.17) -0.83 (0.16)LS Mean Diff vs. placebo (95% -0.44 (-0.88, -CI) 0.01)P-value vs. placebo 0.0467Overall p-value for interaction 0.4527Baseline pre-bronchodilator percent predicted FEV 1 group 1 (%) (400 mg TID only)< Median (77)Number 31 21Mean (SD) -0.14 (1.04) -0.72 (0.70)LS Mean (SE) -0.23 (0.18) -0.74 (0.22)LS Mean Diff vs. placebo (95% -0.52 (-1.01, -CI) 0.03)P-value vs. placebo 0.0393> Median (77)Number 29 27Mean (SD) -0.32 (1.03) -0.89 (0.75)LS Mean (SE) -0.38 (0.17) -0.90 (0.16)LS Mean Diff vs. placebo (95% -0.52 (-0.98, -CI) 0.05)P-value vs. placebo 0.0286Overall p-value for interaction 0.9797Baseline pre-bronchodilator percent predicted FEV 1 group 2 (%) (400 mg TID only)< 80Number 36 26Mean (SD) -0.13 (1.03) -0.75 (0.73)LS Mean (SE) -0.21 (0.17) -0.75 (0.19)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDLS Mean Diff vs. placebo (95% -0.54 (-0.98, -CI) 0.10)P-value vs. placebo 0.0165> 80Number 24 22Mean (SD) -0.36 (1.04) -0.89 (0.73)LS Mean (SE) -0.38 (0.18) -0.95 (0.19)LS Mean Diff vs. placebo (95% -0.57 (-1.08, -CI) 0.06)P-value vs. placebo 0.0295Overall p-value for interaction 0.9237Baseline FEV 1 reversibility (%)< 12Number 17 12 43 33Mean (SD) -0.14 (0.82) -0.65 (0.88) -0.33 (1.11) -0.79 (0.75)LS Mean (SE) -0.15 (0.23) -0.61 (0.28) -0.41 (0.15) -0.85 (0.17)LS Mean Diff vs. placebo (95% -0.46 (-1.10, -0.45 (-0.87, -CI) 0.18) 0.03)P-value vs. placebo 0.1609 0.0375> 12Number 9 14 10 10Mean (SD) -0.31 (1.06) -1.03 (1.01) -0.20 (0.72) -0.94 (0.68)LS Mean (SE) 0.12 (0.33) -0.29 (0.35) -0.22 (0.30) -0.85 (0.32)LS Mean Diff vs. placebo (95% -0.41 (-1.10, -0.63 (-1.36,CI) 0.28) 0.10)P-value vs. placebo 0.2413 0.0907Overall p-value for interaction 0.9399 0.6991Baseline ACQ-5 score< 2Number 13 16 25 14Mean (SD) -0.15 (0.83) -0.76 (0.96) -0.29 (0.80) -0.91 (0.89)LS Mean (SE) 0.12 (0.28) -0.60 (0.27) -0.27 (0.18) -0.81 (0.21)LS Mean Diff vs. placebo (95% -0.72 (-1.32, - -0.54 (-1.06, -CI) 0.12) 0.02)P-value vs. placebo 0.0197 0.0426> 2Number 15 12 35 35Mean (SD) -0.49 (1.17) -1.05 (0.89) -0.18 (1.18) -0.78 (0.65)LS Mean (SE) -0.20 (0.34) -0.78 (0.39) -0.34 (0.17) -0.89 (0.17)LS Mean Diff vs. placebo (95% -0.58 (-1.39, -0.55 (-0.98, -CI) 0.23) 0.12)P-value vs. placebo 0.1633 0.0118400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDOverall p-value for interaction 0.8615 0.9369LATAM: Latin America, ROW: Rest of the world

[0256] Table 48. Subgroup analysis: change from baseline in ACQ-5 score at EOT (Week 12) by baseline ICS / LABA dose level (mITT population).ACQ-5 Placebo BID Rilzabrutinib 400 mg(N=32) BID(N=32)Background ICS / LABA dose level at randomizationMediumNumber 3 3Mean (SD) 0.00 (1.00) -1.07 (0.70)LS Mean (SE) 0.02 (0.94) -0.79 (0.75)LS Mean Diff vs. placebo (95% CI) -0.80 (-2.49, 0.88)P-value vs. placebo 0.3496HighNumber 25 25Mean (SD) -0.38 (1.04) -0.86 (0.96)LS Mean (SE) -0.12 (0.22) -0.70 (0.23)LS Mean Diff vs. placebo (95% CI) -0.57 (-1.12, -0.03)P-value vs. placebo 0.0372Overall p-value for interaction 0.9013LATAM: Latin America, ROW: Rest of the world

[0257] Table 49. Subgroup analysis: change from baseline in ACQ-5 score atEOT (Week 12) by baseline biomarker subgroups (mITT population).400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDBaseline IgE level (lU / mL)< 100Number 8 7 24 18Mean (SD) -0.50 (1.22) -0.83 (0.76) -0.20 (0.93) -0.93 (0.66)LS Mean (SE) -0.35 (0.50) -0.63 (0.50) -0.40 (0.37) -1.08 (0.40)LS Mean Diff vs. placebo (95% -0.28 (-1.44, -0.67 (-1.19, -CI) 0.88) 0.16)P-value vs. placebo 0.6362 0.0107> 100Number 20 21 36 31Mean (SD) -0.27 (0.96) -0.90 (1.00) -0.24 (1.11) -0.75 (0.76)LS Mean (SE) -0.24 (0.51) -0.83 (0.48) -0.18 (0.22) -0.64 (0.24)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs. placebo (95% -0.59 (-1.14, - -0.46 (-0.89, -CI) 0.04) 0.03)P-value vs. placebo 0.0358 0.0366Overall p-value for interaction 0.8951 0.5332Baseline median IgE level (lU / mL)(400 mg BID only)< Median (210.8)Number 10 18Mean (SD) -0.44 (1.09) -0.76 (0.94)LS Mean (SE) -0. 14 (0.33) -0.60 (0.26)LS Mean Diff vs. placebo (95% -0.46 (-1.24,CI) 0.32)P-value vs. placebo 0.2488> Median (210.8)Number 18 10Mean (SD) -0.28 (1.01) -1.12 (0.90)LS Mean (SE) -0.08 (0.24) -0.87 (0.36)LS Mean Diff vs. placebo (95% -0.79 (-1.49, -CI) 0.08)P-value vs. placebo 0.0282Overall p-value for interaction 0.5416Baseline median IgE level(lU / mL) (400 mg TID only)< Median (121.85)Number 30 23Mean (SD) 0.01 (1.11) -0.95 (0.63)LS Mean (SE) 0.02 (0.23) -0.79 (0.23)LS Mean Diff vs. placebo (95% -0.81 (-1.30, -CI) 0.32)P-value vs. placebo 0.0011> Median (121.85)Number 30 26Mean (SD) -0.46 (0.91) -0.70 (0.79)LS Mean (SE) -0.71 (0.43) -0.99 (0.46)LS Mean Diff vs. placebo (95% -0.27 (-0.71,CI) 0.16)P-value vs. placebo 0.2121Overall p-value for interaction 0.0955Baseline median IgA level (mg / L)(400 mg TID only)< Median (2190)Number 32 23400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDMean (SD) -0.06 (1.02) -0.86 (0.68)LS Mean (SE) -0.23 (0.17) -0.90 (0.19)LS Mean Diff vs. placebo (95% -0.67 (-1.14, -CI) 0.19)P-value vs. placebo 0.0060> Median (2190)Number 28 26Mean (SD) -0.41 (1.03) -0.78 (0.77)LS Mean (SE) -0.38 (0.18) -0.80 (0.18)LS Mean Diff vs. placebo (95% -0.41 (-0.89,CI) 0.07)P-value vs. placebo 0.0925Overall p-value for interaction 0.4742Baseline blood eosinophil level 1(10A9 / L) (400 mg BID only)< 0.15Number 6 8Mean (SD) -0.80 (1.40) -0.50 (0.99)LS Mean (SE) -0.34 (0.65) -0.57 (0.45)LS Mean Diff vs. placebo (95% -0.23 (-2.01,CI) 1.56)P-value vs. placebo 0.7785> 0.15Number 22 20Mean (SD) -0.21 (0.90) -1.04 (0.88)LS Mean (SE) -0.07 (0.21) -0.85 (0.26)LS Mean Diff vs. placebo (95% -0.78 (-1.31, -CI) 0.24)P-value vs. placebo 0.0044Overall p-value for interaction 0.1355Baseline blood eosinophil level 2(10A9 / L) (400 mg BID only)< 0.3Number 17 16Mean (SD) -0.52 (1.21) -1.04 (0.92)LS Mean (SE) -0.13 (0.24) -0.81 (0.27)LS Mean Diff vs. placebo (95% -0.68 (-1.33, -CI) 0.03)P-value vs. placebo 0.0399> 0.3Number 11 12Mean (SD) -0.05 (0.57) -0.68 (0.94)LS Mean (SE) -0.16 (0.35) -0.72 (0.35)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs. placebo (95% -0.55 (-1.22,CI) 0.12)P-value vs. placebo 0. 1049Overall p-value for interaction 0.8601Baseline blood eosinophil level 1 ( 10A9 / L) (400 mg TID only) < 0.15Number 27 21Mean (SD) -0.38 (0.84) -0.85 (0.80)LS Mean (SE) -0.49 (0.16) -0.84 (0.17)LS Mean Diff vs. placebo (95% -0.35 (-0.79,CI) 0.09)P-value vs. placebo 0.1217> 0.15 - < 0.3Number 18 13Mean (SD) -0.02 (1.32) -0.78 (0.66)LS Mean (SE) 0.03 (0.27) -0.81 (0.29)LS Mean Diff vs. placebo (95% -0.83 (-1.55, -CI) 0.12)P-value vs. placebo 0.0229> 0.3Number 15 15Mean (SD) -0.19 (0.98) -0.80 (0.70)LS Mean (SE) -0.26 (0.30) -0.91 (0.27)LS Mean Diff vs. placebo (95% -0.65 (-1.29, -CI) 0.01)P-value vs. placebo 0.0451Overall p-value for interaction 0.5667Baseline blood eosinophil level 2 (10A9 / L) (400 mg TID only) < 0.3Number 45 34Mean (SD) -0.24 (1.06) -0.82 (0.74)LS Mean (SE) -0.34 (0.15) -0.86 (0.15)LS Mean Diff vs. placebo (95% -0.52 (-0.92, -CI) 0.12)P-value vs. placebo 0.0104> 0.3Number 15 15Mean (SD) -0.19 (0.98) -0.80 (0.70)LS Mean (SE) -0.26 (0.30) -0.91 (0.27)LS Mean Diff vs. placebo (95% -0.65 (-1.29, - CI) 0.01)400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDP-value vs. placebo 0.0451Overall p-value for interaction 0.7504Baseline FeNO level 1 (ppb)< 25Number 14 11 37 30Mean (SD) -0.39 (1.12) -1.02 (0.80) -0.26 (0.97) -0.84 (0.71)LS Mean (SE) -0.01 (0.32) -0.81 (0.32) -0.43 (0.15) -0.93 (0.15)LS Mean Diff vs. placebo (95% -0.80 (-1.53, - -0.51 (-0.89, -CI) 0.06) 0.12)P-value vs. placebo 0.0344 0.0101> 25Number 14 17 19 17Mean (SD) -0.29 (0.95) -0.80 (1.02) -0.31 (1.18) -0.84 (0.78)LS Mean (SE) -0.15 (0.26) -0.62 (0.30) -0.29 (0.27) -0.82 (0.26)LS Mean Diffvs. placebo (95% -0.47 (-1.15, -0.53 (-1.19,CI) 0.22) 0.13)P-value vs. placebo 0.1826 0.1127Overall p-value for interaction 0.5887 0.9211Baseline FeNO level 2 (ppb)< 35Number 17 20 44 35Mean (SD) -0.36 (1.05) -0.91 (0.86) -0.25 (1.08) -0.81 (0.72)LS Mean (SE) 0.11 (0.27) -0.64 (0.24) -0.36 (0.15) -0.85 (0.15)LS Mean Diffvs. placebo (95% -0.75 (-1.32, - -0.49 (-0.89, -CI) 0.19) 0.10)P-value vs. placebo 0.0089 0.0141> 35Number 11 8 12 12Mean (SD) -0.29 (1.02) -0.83 (1.15) -0.37 (0.90) -0.92 (0.77)LS Mean (SE) -0.26 (0.32) -0.67 (0.46) -0.38 (0.36) -0.89 (0.32)LS Mean Diffvs. placebo (95% -0.41 (-1.47, -0.51 (-1.24,CI) 0.66) 0.23)P-value vs. placebo 0.4551 0.1744Overall p-value for interaction 0.4819 0.8970LATAM: Latin America, ROW: Rest of the world

[0258] Table 50. Subgroup analysis: change from baseline in ACQ-5 score atEOT (Week 12) in the baseline low EOS and low FeNO subgroup (mlTT population).400 mg BID cohort 400 mg TID cohortACQ-5 Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDBaseline blood eosinophil (10A9 / L) and FeNO (ppb)Low EOS (< 0.15) and low FeNO(< 25)Number 4 3 21 14Mean (SD) -0.50 (1.70) -0.60 (1.00) -0.30 (0.86) -1.04 (0.80)LS Mean (SE) 0.83 (1.42) -1.61 (1.12) -0.41 (0.18) -1.02 (0.21)LS Mean Diffvs. placebo (95% -2.44 (-11.51, -0.61 (-1.13, -CI) 6.64) 0.09)P-value vs. placebo 0.3675 0.0214All othersNumber 24 25 35 33Mean (SD) -0.31 (0.92) -0.92 (0.94) -0.27 (1.14) -0.75 (0.68)LS Mean (SE) -0.09 (0.20) -0.68 (0.23) -0.26 (0.17) -0.76 (0.17)LS Mean Diffvs. placebo (95% -0.59 (-1.08, - -0.50 (-0.95, -CI) 0.11) 0.06)P-value vs. placebo 0.0172 0.0267Overall p-value for interaction 0.9709 0.8721LATAM: Latin America, ROW: Rest of the worldAQLQ and AQLQ(S)

[0259] Rilzabrutinib treatment led to significant improvements in AQLQ and AQLQ(S) (Figure 16 and Tables 51-57). Notably, 51.7% of participants in the 400 mg rilzabrutinib BID cohort and 54.7% of participants in the 400 mg rilzabrutinib TID cohort — but only 34.5% of participants in the placebo BID cohort and 40.3% of participants in the placebo TID cohort — achieved a response, defined as an improvement of at least 0.5 from baseline at Week 12 (p=0.0281 and p=0.0456, respectively). Clinically important results were observed as early as Week 4 and sustained through Week 12 (Tables 51 and 52).

[0260] Table 51. Responder analysis for change from baseline in AQLQ global score at Week 12 (mITT population).400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib 400 Placebo Rilzabrutinib(N=32) mg BID TID 400 mg TIDWeek 12 Number (observed / LOCF 29 (20 / 9) 29 (24 / 5) 62 (52 / 10) 53 (50 / 3) imputed)400 mg BID cohort 400 mg TID cohortPlacebo BID Rilzabrutinib 400 Placebo Rilzabrutinib(N=32) mg BID TID 400 mg TID(N=32) (N=68) (N=64)Responder 10 (34.5) (7 / 3) 15 (51.7) (14 / 1) 25 (40.3) 29 (54.7) (28 / 1)(observed / LOCF imputed) (24 / 1)Non-responder 19 (65.5) (13 / 6) 14 (48.3) (10 / 4) 37 (59.7) 24 (45.3) (22 / 2)(observed / LOCF imputed) (28 / 9)Responder (including 10.6 (33.0) 16.6 (51.7) 26.9 (39.6) 32.9 (51.4) multiply imputed)OR vs. placebo (95% CI) 4.89 (1.19, 20.17) 2.23 (1.02, 4.89)P-value vs. placebo 0.0281 0.0456LATAM: Latin America, ROW: Rest of the world

[0261] Table 52. Change from baseline in AQLQ(S) over time (mITT population).400 mg BID cohort 400 mg TID cohortAQLQ(S) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDGlobal scoreBaseline Number 31 32 67 62Mean (SD) 4.67 (1.07) 4.91 (1.04) 4.68 (0.83) 4.96 (0.71)Median 4.69 5.19 4.56 4.94Q1 ; Q3 4.13 ; 5.59 4.31 ; 5.64 4.00 ; 5.41 4.38 ; 5.44Min ; Max 2.1 ; 6.2 2.4 ; 6.4 2.8 ; 6.3 3.7 ; 6.6Week 4Number (observed / LOCF 30 (28 / 2) 31 (30 / 1) 65 (64 / 1) 61 (61 / 0) imputed)Mean (SD) 4.67 (1.17) 5.63 (0.82) 4.90 (0.91) 5.16 (0.97)Median 4.69 5.69 4.84 5.03Q1 ; Q3 4.03 ; 5.50 5.34 ; 6.28 4.22 ; 5.59 4.44 ; 6.03Min ; Max 1.9 ; 6.7 3.1 ; 6.7 2.2 ; 6.7 2.5 ; 6.9Change from baselineNumber (observed / LOCF 29 (27 / 2) 31 (30 / 1) 65 (64 / 1) 60 (60 / 0) imputed)Mean (SD) -0.03 (1.35) 0.73 (0.93) 0.19 (0.72) 0.19 (0.89)Median 0.00 0.69 0.28 0.13Q1 ; Q3 -0.50 ; 0.63 0.09 ; 1.09 -0.19 ; 0.59 -0.25 ; 0.67Min ; Max -3.7 ; 2.2 -0.8 ; 3.2 -1.9 ; 1.7 -2.2 ; 2.7LS Mean (SE) -0.04 (0.21) 0.80 (0.21) 0.24 (0.10) 0.33 (0.11)LS Mean Diff vs. placebo 0.84 (0.34, 0.09 (-0.18,(95% CI) 1.34) 0.36)P-value vs. placebo 0.0010 0.4929Week 8400 mg BID cohort 400 mg TID cohortAQLQ(S) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Number (observed / LOCF 31 (28 / 3) 31 (27 / 4) 65 (62 / 3) 59 (56 / 3) imputed) Mean(SD) 4.94 (1.14) 5.79 (0.75) 5.02 (0.98) 5.27(0.88)Median 5.06 5.88 5.13 5.06Q1 ;Q3 3.88 ; 6.00 5.53 ; 6.28 4.06; 5.81 4.59; 6.16Min; Max 2.8 ; 6.8 4.0 ; 7.0 2.6 ; 7.0 3.5 ; 6.9Change from baselineNumber (observed / LOCF 30 (27 / 3) 31 (27 / 4) 65 (62 / 3) 58 (55 / 3) imputed)Mean(SD) 0.22 (1.06) 0.90 (0.85) 0.30 (0.86) 0.29(0.74)Median 0.33 0.63 0.34 0.34Q1 ;Q3 -0.19; 0.88 0.22; 1.31 -0.25 ; 1.00 -0.09 ; 0.75Min; Max -3.0; 1.9 -0.4 ; 2.8 -1.6; 2.6 -1.3 ; 2.0LS Mean (SE) 0.13 (0.16) 0.92 (0.17) 0.32 (0.10) 0.42(0.11)LS Mean Diff vs. placebo 0.79 (0.39, 0.10 (-0.18,(95% CI) 1.20) 0.37)P-value vs. placebo 0.0001 0.4993Week 12Number (observed / LOCF 30(21 / 9) 29 (24 / 5) 62(52 / 10) 54(51 / 3) imputed) Mean(SD) 4.99 (1.17) 5.75 (0.84) 4.99 (1.06) 5.41 (0.88)Median 5.05 5.72 5.06 5.23Q1 ;Q3 3.88 ; 5.97 5.41 ; 6.34 4.13 ; 5.88 4.91 ; 6.13Min; Max 2.9 ; 7.0 4.0 ; 7.0 1.4; 6.7 3.1 ; 7.0Change from baselineNumber (observed / LOCF 29(20 / 9) 29 (24 / 5) 62(52 / 10) 53 (50 / 3) imputed)Mean(SD) 0.29 (1.15) 0.84 (0.99) 0.26 (0.90) 0.46(0.86)Median 0.22 0.69 0.30 0.53Q1 ;Q3 -0.13 ; 1.25 0.16; 1.38 -0.41 ; 0.78 0.00; 1.00Min; Max -2.5 ; 2.3 -0.7; 3.1 -1.7; 3.1 -1.9; 2.6LS Mean (SE) 0.10 (0.18) 0.82 (0.20) 0.28 (0.12) 0.57(0.12)LS Mean Diff vs. placebo 0.72 (0.25, 0.29 (-0.01,(95% CI) 1.18) 0.60)P-value vs. placebo 0.0025 0.0620Symptoms scoreBaseline Number 31 32 67 62Mean(SD) 4.59 (1.05) 5.05 (1.05) 4.70 (0.80) 4.97(0.73)Median 4.75 5.21 4.75 4.83Q1 ;Q3 4.25 ; 5.25 4.42 ; 5.83 4.08 ; 5.33 4.33 ; 5.42Min; Max 1.7 ; 6.0 2.6 ; 6.6 3.0 ; 6.8 3.8 ; 6.6Week 4Number (observed / LOCF 30(28 / 2) 31 (30 / 1) 65 (64 / 1) 61 (61 / 0) imputed)400 mg BID cohort 400 mg TID cohortAQLQ(S) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Mean(SD) 4.82 (1.09) 5.83 (0.72) 4.92 (0.90) 5.19(1.00)Median 4.88 6.00 4.92 5.08Q1 ;Q3 4.00; 5.50 5.50 ; 6.33 4.42 ; 5.58 4.42 ; 6.00Min; Max 1.8 ; 6.8 3.7 ; 6.7 2.2 ; 6.6 2.4 ; 7.0Change from baselineNumber (observed / LOCF 29(27 / 2) 31 (30 / 1) 65 (64 / 1) 60(60 / 0) imputed)Mean(SD) 0.15 (1.27) 0.80 (0.90) 0.19 (0.77) 0.22(0.98)Median 0.08 0.75 0.25 0.25Q1 ;Q3 -0.25 ; 0.75 0.08 ; 1.25 -0.25 ; 0.67 -0.29 ; 0.67Min; Max -3.2; 2.4 -0.8 ; 3.3 -1.8 ; 1.7 -2.3 ; 2.8LS Mean (SE) 0.06 (0.18) 0.92 (0.19) 0.22 (0.11) 0.38 (0.11)LS Mean Diff vs. placebo 0.86(0.41, 0.15 (-0.14,(95% CI) 1.32) 0.44)P-value vs. placebo 0.0002 0.3018Week 8Number (observed / LOCF 31 (28 / 3) 31 (27 / 4) 65 (62 / 3) 59 (56 / 3) imputed)Mean(SD) 5.05 (1.06) 5.93 (0.79) 5.02 (1.03) 5.29 (0.84)Median 5.08 6.00 5.25 5.17Q1 ;Q3 4.25 ; 5.83 5.67 ; 6.50 4.17; 5.75 4.58 ; 6.08Min; Max 2.3 ; 6.9 3.5 ; 6.9 2.6 ; 7.0 3.7 ; 7.0Change from baselineNumber (observed / LOCF 30 (27 / 3) 31 (27 / 4) 65 (62 / 3) 58 (55 / 3) imputed)Mean(SD) 0.38 (1.06) 0.91 (0.94) 0.29 (0.96) 0.29(0.77)Median 0.13 0.83 0.17 0.38Q1 ;Q3 -0.08; 0.83 0.25 ; 1.25 -0.42 ; 1.08 -0.08 ; 0.75Min; Max -1.8; 2.6 -0.6 ; 3.0 -1.6; 2.3 -1.8 ; 2.0LS Mean (SE) 0.23 (0.17) 0.99 (0.18) 0.31 (0.11) 0.44(0.12)LS Mean Diff vs. placebo 0.76 (0.35, 0.13 (-0.16,(95% CI) 1.18) 0.43)P-value vs. placebo 0.0003 0.3792Week 12Number (observed / LOCF 30(21 / 9) 29 (24 / 5) 62(52 / 10) 54(51 / 3) imputed)Mean(SD) 5.13 (1.05) 5.87 (0.85) 4.97 (1.19) 5.41 (0.83)Median 5.08 5.92 5.00 5.25Q1 ;Q3 4.67; 5.83 5.50 ; 6.50 4.42 ; 5.92 4.83 ; 6.08Min; Max 3.0 ; 7.0 3.8 ; 7.0 1.0; 6.8 3.7 ; 7.0Change from baselineNumber (observed / LOCF 29(20 / 9) 29 (24 / 5) 62(52 / 10) 53 (50 / 3) imputed)Mean(SD) 0.47 (1.07) 0.87 (1.12) 0.21 (1.08) 0.44(0.92)Median 0.33 0.83 0.08 0.58400 mg BID cohort 400 mg TID cohortAQLQ(S) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Q1 ;Q3 -0.08; 1.17 0.08 ; 1.58 -0.58 ; 0.92 0.00 ; 0.92Min; Max -1.8; 2.6 -1.3 ; 3.3 -2.3 ; 3.2 -2.0 ; 2.8LS Mean (SE) 0.17 (0.18) 0.84 (0.19) 0.26 (0.13) 0.59(0.14)LS Mean Diff vs. placebo 0.67 (0.22, 0.34 (-0.01,(95% CI) 1.11) 0.68)P-value vs. placebo 0.0032 0.0542Activity limitation scoreBaseline Number 31 32 67 62Mean(SD) 4.74 (1.13) 4.78 (1.12) 4.70 (0.83) 4.99(0.78)Median 4.73 5.00 4.64 4.91Q1 ;Q3 4.09; 5.73 4.09 ; 5.55 4.00 ; 5.36 4.45 ; 5.45Min; Max 2.4 ; 6.6 1.9; 6.5 3.0 ; 6.6 3.4 ; 6.7Week 4Number (observed / LOCF 30(28 / 2) 31 (30 / 1) 65 (64 / 1) 61 (61 / 0) imputed)Mean(SD) 4.70 (1.24) 5.48 (0.88) 4.93 (0.97) 5.15 (0.95)Median 4.68 5.55 5.00 5.18Q1 ;Q3 4.00; 5.45 5.09; 6.18 4.27 ; 5.64 4.45 ; 6.00Min; Max 2.5 ; 7.0 3.2 ; 7.0 2.5 ; 6.7 2.6 ; 6.9Change from baselineNumber (observed / LOCF 29(27 / 2) 31 (30 / 1) 65 (64 / 1) 60(60 / 0) imputed)Mean(SD) -0.07(1.21) 0.73 (0.98) 0.20 (0.80) 0.16(0.89)Median 0.00 0.55 0.27 0.09Q1 ;Q3 -0.64; 0.55 0.00 ; 1.18 -0.18; 0.64 -0.41 ; 0.59Min; Max -3.2; 2.1 -1.1; 3.0 -2.2; 1.9 -2.0 ; 2.9LS Mean (SE) -0.03 (0.20) 0.72 (0.21) 0.26 (0.10) 0.34(0.11)LS Mean Diff vs. placebo 0.75 (0.26, 0.08 (-0.20,(95% CI) 1.24) 0.35)P-value vs. placebo 0.0029 0.5846Week 8Number (observed / LOCF 31 (28 / 3) 31 (27 / 4) 65 (62 / 3) 59 (56 / 3) imputed)Mean(SD) 4.96 (1.22) 5.72 (0.81) 5.05 (0.94) 5.28 (0.90)Median 5.09 5.91 5.09 5.27Q1 ;Q3 3.91 ; 6.27 5.09; 6.18 4.18; 5.82 4.64 ; 6.00Min; Max 2.6 ; 6.9 3.9 ; 7.0 3.0 ; 7.0 3.5 ; 6.9Change from baselineNumber (observed / LOCF 30 (27 / 3) 31 (27 / 4) 65 (62 / 3) 58 (55 / 3) imputed)Mean(SD) 0.17 (0.97) 0.96 (0.92) 0.30 (0.86) 0.29(0.83)Median 0.18 0.82 0.36 0.36Q1 ;Q3 -0.18; 0.73 0.18 ; 1.55 -0.18; 0.91 -0.27 ; 0.91Min; Max -3.1 ; 1.5 -0.4 ; 2.8 -1.8; 2.9 -1.4; 2.2400 mg BID cohort 400 mg TID cohortAQLQ(S) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean (SE) 0.09 (0.17) 0.89 (0.17) 0.32 (0.11) 0.42(0.11)LS Mean Diff vs. placebo 0.80 (0.39, 0.10 (-0.18,(95% CI) 1.21) 0.38)P-value vs. placebo 0.0001 0.4877Week 12Number (observed / LOCF 30(21 / 9) 29 (24 / 5) 62(52 / 10) 54(51 / 3) imputed) Mean(SD) 4.90 (1.31) 5.66 (0.96) 5.03 (1.00) 5.45 (0.86)Median 4.95 5.82 4.95 5.36Q1 ;Q3 3.82; 6.00 5.18 ; 6.36 4.18 ; 5.82 4.91 ; 6.18Min; Max 2.7 ; 7.0 3.8 ; 7.0 2.1 ; 6.6 3.1 ; 7.0Change from baselineNumber (observed / LOCF 29(20 / 9) 29 (24 / 5) 62(52 / 10) 53 (50 / 3) imputed) Mean(SD) 0.14 (1.14) 0.85 (0.96) 0.29 (0.82) 0.50(0.86)Median 0.00 0.45 0.27 0.55Q1 ;Q3 -0.18; 0.91 0.18 ; 1.27 -0.27 ; 0.91 -0.18; 1.09Min; Max -3.0; 2.3 -0.7 ; 2.9 -1.8; 2.8 -1.3 ; 2.8LS Mean (SE) -0.01 (0.20) 0.77 (0.22) 0.31 (0.11) 0.62(0.11)LS Mean Diff vs. placebo 0.78 (0.28, 0.31 (0.02, 0.60)(95% CI) 1.28)P-value vs. placebo 0.0023 0.0339Emotional function scoreBaselineNumber 31 32 67 62Mean(SD) 4.70 (1.71) 5.21 (1.26) 4.87 (1.14) 5.15 (1.14)Median 5.40 5.30 4.80 5.20Q1 ;Q3 3.80; 5.80 4.10; 6.50 4.20 ; 5.60 4.40 ; 6.00Min; Max 1.2 ; 7.0 2.0 ; 7.0 1.8 ; 6.8 1.2; 7.0Week 4Number (observed / LOCF 30(28 / 2) 31 (30 / 1) 65 (64 / 1) 61 (61 / 0) imputed) Mean(SD) 4.51 (1.71) 5.85 (1.36) 5.02 (1.12) 5.37 (1.23)Median 4.70 6.40 5.00 5.40Q1 ;Q3 3.60; 5.80 5.00 ; 7.00 4.40 ; 5.80 4.80 ; 6.40Min; Max 1.0 ; 7.0 1.6; 7.0 2.0 ; 7.0 1.2; 7.0Change from baselineNumber (observed / LOCF 29(27 / 2) 31 (30 / 1) 65 (64 / 1) 60(60 / 0) imputed) Mean(SD) -0.23 (1.80) 0.61 (1.24) 0.10 (0.99) 0.22(1.08)Median 0.20 0.40 0.20 0.20Q1 ;Q3 -0.60; 0.60 -0.40 ; 1.60 -0.40 ; 0.80 -0.40 ; 0.80Min; Max -5.2; 2.8 -2.4 ; 3.0 -2.4 ; 3.0 -2.6 ; 2.8LS Mean (SE) -0.25 (0.29) 0.77 (0.31) 0.14 (0.13) 0.35 (0.13)400 mg BID cohort 400 mg TID cohortAQLQ(S) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs. placebo 1.02 (0.30, 0.21 (-0.12,(95% CI) 1.74) 0.54)P-value vs. placebo 0.0058 0.2202Week 8Number (observed / LOCF 31 (28 / 3) 31 (27 / 4) 65 (62 / 3) 59 (56 / 3) imputed)Mean (SD) 4.92 (1.63) 6.12 (1.01) 5.25 (1.21) 5.52 (1.11)Median 5.20 6.20 5.60 5.40QI ; Q3 3.40 ; 6.20 5.80 ; 7.00 4.40 ; 6.20 4.80 ; 6.60Min ; Max 1.0 ; 7.0 2.8 ; 7.0 2.0 ; 7.0 1.2 ; 7.0Change from baselineNumber (observed / LOCF 30 (27 / 3) 31 (27 / 4) 65 (62 / 3) 58 (55 / 3) imputed)Mean (SD) 0.15 (1.34) 0.87 (1.17) 0.33 (1.09) 0.37 (0.87)Median 0.20 0.60 0.20 0.40Q1 ; Q3 -0.40 ; 1.00 0.00 ; 1.40 -0.60 ; 1.20 0.00 ; 0.80Min ; Max -3.8 ; 2.2 -1.2 ; 4.2 -1.8 ; 3.0 -1.8 ; 2.6LS Mean (SE) 0.08 (0.23) 1.06 (0.24) 0.38 (0.12) 0.51 (0.13)LS Mean Diff vs. placebo 0.98 (0.42, 0.13 (-0.20,(95% CI) 1.54) 0.45)P-value vs. placebo 0.0006 0.4378Week 12Number (observed / LOCF 30 (21 / 9) 29 (24 / 5) 62 (52 / 10) 54 (51 / 3) imputed) Mean (SD) 5.14 (1.55) 5.96 (1.16) 5.12 (1.42) 5.57 (1.28)Median 5.40 6.20 5.10 5.60QI ; Q3 4.00 ; 6.20 5.20 ; 7.00 4.40 ; 6.40 5.20 ; 6.60Min ; Max 1.0 ; 7.0 3.2 ; 7.0 1.0 ; 7.0 1.2 ; 7.0Change from baselineNumber (observed / LOCF 29 (20 / 9) 29 (24 / 5) 62 (52 / 10) 53 (50 / 3) imputed)Mean (SD) 0.37 (1.62) 0.72 (1.14) 0.19 (1.20) 0.43 (1.04)Median 0.40 0.40 0.20 0.40Q1 ; Q3 0.00 ; 1.20 0.00 ; 1.40 -0.40 ; 1.00 0.00 ; 1.00Min ; Max -3.8 ; 4.8 -0.8 ; 3.4 -3.8 ; 3.4 -2.4 ; 2.8LS Mean (SE) 0.23 (0.24) 0.97 (0.27) 0.21 (0.15) 0.53 (0.16)LS Mean Diff vs. placebo 0.74 (0.12, 0.32 (-0.08,(95% CI) 1.36) 0.72)P-value vs. placebo 0.0195 0.1134Environmental stimuli scoreBaselineNumber 31 32 67 62Mean (SD) 4.62 (1.46) 4.43 (1.64) 4.31 (1.16) 4.64 (1.06)Median 4.75 4.75 4.25 4.75Q1 ; Q3 3.75 ; 5.75 3.63 ; 5.75 3.50 ; 5.25 4.00 ; 5.25400 mg BID cohort 400 mg TID cohortAQLQ(S) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDMin; Max 1.8 ; 7.0 1.0; 7.0 1.0; 7.0 1.0; 7.0Week 4Number (observed / LOCF 30(28 / 2) 31 (30 / 1) 65 (64 / 1) 61 (61 / 0) imputed)Mean(SD) 4.37 (1.62) 5.13 (1.26) 4.62 (1.25) 4.78 (1.20)Median 4.88 5.25 4.75 4.75Q1 ;Q3 3.00; 5.75 4.25 ; 6.00 3.75 ; 5.50 4.00 ; 5.75Min; Max 1.3 ; 6.5 2.0 ; 7.0 1.0; 7.0 1.8; 7.0Change from baselineNumber (observed / LOCF 29(27 / 2) 31 (30 / 1) 65 (64 / 1) 60(60 / 0) imputed)Mean(SD) -0.22(2.04) 0.67 (1.52) 0.28 (0.97) 0.12(1.09)Median 0.00 0.50 0.00 0.25Q1 ;Q3 -0.50; 1.25 -0.75 ; 1.75 -0.25 ; 0.75 -0.50 ; 0.63Min; Max -5.8; 2.5 -2.3 ; 4.8 -2.5 ; 2.8 -2.5 ; 2.3LS Mean (SE) -0.15 (0.30) 0.60 (0.31) 0.33 (0.12) 0.30 (0.13)LS Mean Diff vs. placebo 0.76 (0.02, -0.03 (-0.37,(95% CI) 1.49) 0.30)P-value vs. placebo 0.0432 0.8468Week 8Number (observed / LOCF 31 (28 / 3) 31 (27 / 4) 65 (62 / 3) 59 (56 / 3) imputed)Mean(SD) 4.60 (1.53) 5.19 (1.24) 4.66 (1.34) 4.90(1.29)Median 5.25 5.25 5.00 4.75Q1 ;Q3 3.75 ; 5.75 4.50 ; 6.00 3.75 ; 5.75 4.00 ; 6.00Min; Max 1.3 ; 6.8 2.0 ; 7.0 1.0; 7.0 2.0 ; 7.0Change from baselineNumber (observed / LOCF 30 (27 / 3) 31 (27 / 4) 65 (62 / 3) 58 (55 / 3) imputed)Mean(SD) 0.01 (1.65) 0.73 (1.57) 0.33 (1.21) 0.24 (1.15)Median 0.25 0.50 0.00 0.25QI ; Q3 -0.50 ; 1.25 -0.25 ; 1.25 -0.25 ; 1.00 -0.50 ; 1.00Min; Max -5.8; 2.0 -1.8; 4.8 -2.8 ; 3.8 -2.8 ; 2.8LS Mean (SE) -0.02(0.27) 0.66 (0.28) 0.29 (0.15) 0.36(0.16)LS Mean Diff vs. placebo 0.68 (0.03, 0.06 (-0.34,(95% CI) 1.33) 0.47)P-value vs. placebo 0.0394 0.7524Week 12Number (observed / LOCF 30(21 / 9) 29 (24 / 5) 62(52 / 10) 54(51 / 3) imputed) Mean(SD) 4.66 (1.66) 5.34 (1.20) 4.76 (1.35) 5.08 (1.27)Median 4.88 5.25 5.00 5.00Q1 ;Q3 3.75 ; 6.00 5.00 ; 6.25 3.75 ; 5.75 4.50 ; 5.75Min; Max 1.0 ; 7.0 2.0 ; 7.0 1.0; 7.0 1.0; 7.0400 mg BID cohort 400 mg TID cohortAQLQ(S) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDChange from baselineNumber (observed / LOCF 29 (20 / 9) 29 (24 / 5) 62 (52 / 10) 53 (50 / 3) imputed)Mean (SD) 0.09 (1.71) 0.87 (1.65) 0.40 (1.10) 0.46 (1.18)Median 0.25 0.50 0.25 0.50Q1 ; Q3 -0.50 ; 1.25 0.00 ; 1.75 -0.25 ; 1.00 0.00 ; 1.25Min ; Max -5.5 ; 2.3 -2.0 ; 5.3 -2.0 ; 3.0 -3.3 ; 2.5LS Mean (SE) -0.08 (0.28) 0.70 (0.31) 0.37 (0.15) 0.54 (0.16)LS Mean Diff vs. placebo 0.78 (0.06, 0.17 (-0.23,(95% CI) 1.49) 0.57)P-value vs. placebo 0.0331 0.4016

[0262] Table 53. Subgroup analysis: change from baseline in AQLQ global score at EOT (Week 12) by demographics subgroups (mITT population).400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDAge group 1 (years)< 45 Number 10 10 29 23Mean (SD) 0.80 (0.76) 0.62 (0.82) 0.12 (1.03) 0.53 (0.64)LS Mean (SE) 0.66 (0.23) 0.86 (0.26) 0.26 (0.16) 0.69 (0.17)LS Mean Diff vs. placebo (95% 0.20 (-0.36, 0.43 (0.00,CI) 0.76) 0.85)P-value vs. placebo 0.4823 0.0494> 45Number 19 19 33 30Mean (SD) 0.03 (1.25) 0.95 (1.07) 0.37 (0.76) 0.41 (1.01)LS Mean (SE) -0.16 (0.22) 0.89 (0.25) 0.32 (0.16) 0.47 (0.18)LS Mean Diff vs. placebo (95% 1.04 (0.47, 0.15 (-0.29,CI) 1.62) 0.59)P-value vs. placebo 0.0004 0.5139Overall p-value for interaction 0.0607 0.5248GenderMaleNumber 7 13 27 23Mean (SD) 0.31 (0.58) 0.97 (0.88) 0.17 (0.82) 0.40 (0.92)LS Mean (SE) 0.32 (0.28) 0.73 (0.30) 0.26 (0.17) 0.41 (0.18)LS Mean Diffvs. placebo (95% 0.41 (-0.46, 0.15 (-0.31,CI) 1.28) 0.60)P-value vs. placebo 0.3547 0.5238FemaleNumber 22 16 35 30400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Mean (SD) 0.29 (1.30) 0.74 (1.09) 0.32 (0.96) 0.51 (0.83)LS Mean (SE) 0.02 (0.27) 0.74 (0.27) 0.33 (0.16) 0.66 (0.17)LS Mean Diffvs. placebo (95% 0.73 (0.11, 0.32 (-0.11,CI) 1.35) 0.75)P-value vs. placebo 0.0220 0.1394Overall p-value for interaction 0.6030 0.5902Baseline weight group (kg) < 60Number 4 3 10 2Mean (SD) -0.12 (1.31) 0.95 (1.45) 0.58 (0.79) 0.78 (0.40)LS Mean (SE) -0.81 (0.11) 0.82 (0.16) 0.67 (0.29) 0.59 (0.63)LS Mean Diffvs. placebo (95% 1.63 (0.98, -0.08 (-1.53,CI) 2.28) 1.37)P-value vs. placebo 0.0084 0.9112> 60 - < 90 Number 22 20 37 32Mean (SD) 0.26 (1.17) 0.87 (0.91) 0.23 (0.98) 0.56 (0.86)LS Mean (SE) 0.06 (0.22) 0.77 (0.24) 0.25 (0.16) 0.66 (0.17)LS Mean Diffvs. placebo (95% 0.70 (0.17, 0.41 (-0.02,CI) 1.23) 0.84)P-value vs. placebo 0.0092 0.0612> 90Number 3 6 15 19Mean (SD) 1.09 (0.62) 0.70 (1.21) 0.11 (0.73) 0.26 (0.89)LS Mean (SE) 1.06 (0.70) 0.80 (1.03) 0.15 (0.21) 0.32 (0.18)LS Mean Diffvs. placebo (95% -0.26 (-3.62, 0.17 (-0.34,CI) 3.10) 0.68)P-value vs. placebo 0.8398 0.5090Overall p-value for interaction 0.4319 0.7466Baseline BMI group (kg / m2)< 25Number 6 8 20 8Mean (SD) 0.09 (1.08) 1.12 (0.99) 0.24 (0.88) 0.65 (0.74)LS Mean (SE) -0.45 (0.56) 0.55 (0.62) 0.42 (0.19) 0.98 (0.29)LS Mean Diffvs. placebo (95% 1.00 (-0.23, 0.56 (-0.07,CI) 2.22) 1.18)P-value vs. placebo 0.0991 0.0813> 25 - < 30Number 15 13 25 26Mean (SD) 0.13 (1.24) 0.61 (0.73) 0.25 (1.05) 0.75 (0.71)LS Mean (SE) 0.02 (0.25) 0.69 (0.29) 0.48 (0.16) 0.96 (0.16)LS Mean Diffvs. placebo (95% 0.67 (-0.05, 0.47 (0.07,CI) 1.39) 0.87)400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDP-value vs. placebo 0.0679 0.0210> 30 Number 8 8 17 19Mean (SD) 0.75 (1.03) 0.93 (1.36) 0.28 (0.70) 0.00 (0.94)LS Mean (SE) 0.56 (0.46) 1.30 (0.45) 0.20 (0.21) 0.19 (0.20)LS Mean Diff vs. placebo (95% 0.73 (-0.21, -0.01 (-0.58,CI) 1.68) 0.56)P-value vs. placebo 0.1287 0.9701Overall p-value for interaction 0.9298 0.3404Region Eastern EuropeNumber 4 2 44 35Mean (SD) -0.04 (0.34) -0.19 (0.66) 0.08 (0.91) 0.46 (0.68)LS Mean (SE) -0.03 (0.30) 0.04 (0.53) 0.06 (0.11) 0.48 (0.12)LS Mean Diffvs. placebo (95% 0.08 (-1.12, 0.43 (0.10,CI) 1.28) 0.76)P-value vs. placebo 0.9007 0.0111Latin America Number 22 24 16 16Mean (SD) 0.35 (1.29) 0.98 (0.96) 0.83 (0.51) 0.44 (1.22)LS Mean (SE) 0.30 (0.20) 1.16 (0.20) 0.74 (0.28) 0.52 (0.28)LS Mean Diffvs. placebo (95% 0.87 (0.36, -0.22 (-0.83,CI) 1.38) 0.39)P-value vs. placebo 0.0009 0.4745Western Countries Number 1 2 1 2Mean (SD) 1.25 (NC) 0.44 (1.64) -1.44 (NC) 0.78 (0.75)LS Mean (SE) NC (NC) NC (NC) NC (NC) NC (NC)LS Mean Diff vs . placebo (95 % NC (NC, NC) NC (NC, NC) ci) P-value vs. placebo NC NCAPAC Number 2 1 1 0Mean (SD) -0.11 (0.60) 0.22 (NC) 0.72 (NC) NC (NC)LS Mean (SE) NC (NC) NC (NC) NC (NC) NC (NC)LS Mean Diff vs . placebo (95 % NC (NC, NC) NC (NC, NC) ci) P-value vs. placebo NC NCOverall p-value for interaction 0.4777 0.0019LATAM: Latin America, ROW: Rest of the world

[0263] Table 54. Subgroup analysis: change from baseline in AQLQ global score at EOT (Week 12) by disease and other characteristics subgroups (mITT population).400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Age at onset of asthma (years)< 12Number 7 8 14 12Mean (SD) 0.58 (0.91) 0.89 (0.71) -0.04 (0.87) 0.51 (0.94)LS Mean (SE) 0.61 (0.29) 0.95 (0.38) 0.03 (0.23) 0.49 (0.26)LS Mean Diff vs. placebo (95% 0.34 (-0.43, 0.46 (-0.19,CI) 1.11) 1.12)P-value vs. placebo 0.3884 0.1645> 12 - < 18Number 2 5 5 5Mean (SD) 0.44 (0.57) 0.91 (1.28) 0.34 (0.67) 0.53 (1.61)LS Mean (SE) -3.05 (5.06) -0.56 (2.39) 0.77 (0.98) 0.40 (0.73)LS Mean Diff vs. placebo (95% 2.49 (-9.16, -0.37 (-2.70,CI) 14.14) 1.96)P-value vs. placebo 0.4551 0.7001> 18 - < 40Number 14 13 26 22Mean (SD) 0.51 (1.05) 0.86 (1.12) 0.13 (0.95) 0.34 (0.74)LS Mean (SE) 0.20 (0.30) 0.77 (0.31) 0.23 (0.18) 0.48 (0.19)LS Mean Diff vs. placebo (95% 0.57 (-0.18, 0.25 (-0.23,CI) 1.32) 0.72)P-value vs. placebo 0.1339 0.3043> 40Number 6 3 17 14Mean (SD) -0.59 (1.53) 0.48 (0.97) 0.67 (0.81) 0.60 (0.71)LS Mean (SE) -0.70 (0.46) 0.23 (0.73) 0.41 (0.22) 0.71 (0.25)LS Mean Diff vs. placebo (95% 0.93 (-0.59, 0.29 (-0.34,CI) 2.46) 0.92)P-value vs. placebo 0.2299 0.3596Overall p-value for interaction 0.8090 0.8443Age at onset of asthma (years)< 18Number 9 13 19 17Mean (SD) 0.55 (0.81) 0.90 (0.92) 0.06 (0.82) 0.52 (1.12)LS Mean (SE) 0.60 (0.23) 1.03 (0.23) 0.15 (0.22) 0.45 (0.23)LS Mean Diff vs. placebo (95% 0.43 (-0.08, 0.31 (-0.27,CI) 0.95) 0.89)P-value vs. placebo 0.0978 0.2994> 18Number 20 16 43 36400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Mean (SD) 0.18 (1.28) 0.79 (1.07) 0.34 (0.93) 0.44 (0.73)LS Mean (SE) -0.07 (0.25) 0.68 (0.29) 0.34 (0.14) 0.57 (0.15)LS Mean Diff vs. placebo (95% 0.75 (0.08, 0.24 (-0. 14,CI) 1.43) 0.61)P-value vs. placebo 0.0286 0.2154Overall p-value for interaction 0.5227 0.7855Number of asthma exacerbations within 2 years before screening visit 1Number 9 11 47 31Mean (SD) 0.84 (0.91) 1.05 (0.99) 0.30 (0.86) 0.57 (0.88)LS Mean (SE) 0.42 (0.34) 1.16 (0.37) 0.39 (0.13) 0.68 (0.16)LS Mean Diff vs. placebo (95% 0.75 (-0.16, 0.29 (-0.08,CI) 1.65) 0.66)P-value vs. placebo 0.1070 0.12482 Number 13 10 15 19Mean (SD) 0.35 (0.98) 0.76 (0.86) 0.12 (1.01) 0.34 (0.89)LS Mean (SE) 0.15 (0.27) 0.76 (0.37) 0.14 (0.24) 0.41 (0.22)LS Mean Diffvs. placebo (95% 0.61 (-0.11, 0.27 (-0.33,CI) 1.33) 0.87)P-value vs. placebo 0.0972 0.3775> 2Number 7 8 0 3Mean (SD) -0.51 (1.41) 0.66 (1.20) NC (NC) 0.14 (0.53)LS Mean (SE) -0.64 (0.36) 0.54 (0.33) NC (NC) NC (NC)LS Mean Diff vs . placebo (95 % 1. 18 (0.30, NC (NC, NC)CI) 2.07)P-value vs. placebo 0.0089 NCOverall p-value for interaction 0.4656 0.2099Atopic medical conditionsYes Number 16 20 20 18Mean (SD) 0.28 (1.35) 0.81 (0.98) 0.52 (0.92) 0.48 (0.84)LS Mean (SE) 0.14 (0.28) 0.66 (0.26) 0.43 (0.21) 0.56 (0.23)LS Mean Diffvs. placebo (95% 0.52 (-0.09, 0.13 (-0.45,CI) 1.13) 0.71)P-value vs. placebo 0.0945 0.6600NoNumber 13 9 42 35Mean (SD) 0.31 (0.91) 0.91 (1.06) 0.13 (0.87) 0.46 (0.89)LS Mean (SE) -0.10 (0.27) 0.99 (0.32) 0.27 (0.16) 0.64 (0.16)400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs. placebo (95% 1.08 (0.29, 0.37 (0.00,CI) 1.87) 0.73)P-value vs. placebo 0.0074 0.0477Overall p-value for interaction 0.2340 0.6262Background ICS dose level at randomization (400 mg TID only)MediumNumber 34 22Mean (SD) 0.15 (0.85) 0.41 (0.73)LS Mean (SE) 0.23 (0.17) 0.53 (0.19)LS Mean Diff vs. placebo (95% 0.31 (-0. 11,CI) 0.72)P-value vs. placebo 0. 1446HighNumber 28 31Mean (SD) 0.38 (0.95) 0.50 (0.96)LS Mean (SE) 0.33 (0.18) 0.59 (0.19)LS Mean Diff vs. placebo (95% 0.26 (-0.22,CI) 0.74)P-value vs. placebo 0.2872Overall p-value for interaction 0.8865Smoking historyLormerNumber 7 4 4 4Mean (SD) 0.43 (1.52) 0.73 (1.45) 0.23 (0.26) -0.55 (1.82)LS Mean (SE) -0.16 (0.46) 1.74 (0.68) -0.09 (0.79) -0.11 (0.84)LS Mean Diff vs. placebo (95% 1.89 (0.62, -0.02 (-1.90,CI) 3.16) 1.86)P-value vs. placebo 0.0035 0.9823NeverNumber 22 25 58 49Mean (SD) 0.25 (1.05) 0.86 (0.94) 0.26 (0.93) 0.55 (0.71)LS Mean (SE) 0.09 (0.21) 0.74 (0.21) 0.34 (0.11) 0.68 (0.12)LS Mean Diff vs. placebo (95% 0.65 (0.15, 0.34 (0.04,CI) 1.15) 0.63)P-value vs. placebo 0.0106 0.0266Overall p-value for interaction 0.5532 0.5469Baseline pre-bronchodilator LEV 1(L) (400 mg BID only)< Median (2.022)Number 13 15Mean (SD) 0.04 (1.27) 0.89 (0.98)400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean (SE) -0.30 (0.26) 0.59 (0.28)LS Mean Diff vs. placebo (95% 0.89 (0.28,CI) 1.51)P-value vs. placebo 0.0046> Median (2.022)Number 16 13Mean (SD) 0.50 (1.04) 0.74 (1.06)LS Mean (SE) 0.40 (0.26) 0.94 (0.29)LS Mean Diff vs. placebo (95% 0.54 (-0. 14,CI) 1.21)P-value vs. placebo 0. 1187Overall p-value for interaction 0.3692Baseline pre-bronchodilator percent predicted FEV 1 (%) (400 mg BID only)< Median (68)Number 11 16Mean (SD) 0.24 (1.11) 1.00 (1.01)LS Mean (SE) -0.22 (0.30) 0.69 (0.30)LS Mean Diff vs. placebo (95% 0.92 (0.29,CI) 1.55)P-value vs. placebo 0.0044> Median (68)Number 18 12Mean (SD) 0.32 (1.21) 0.58 (0.98)LS Mean (SE) 0.20 (0.25) 0.67 (0.31)LS Mean Diff vs. placebo (95% 0.47 (-0.26,CI) 1.20)P-value vs. placebo 0.2058Overall p-value for interaction 0.3643Baseline pre -bronchodilator FEV1(L) (400 mg TID only)< Median (2.1955)Number 30 23Mean (SD) 0.26 (0.84) 0.48 (0.93)LS Mean (SE) 0.25 (0.17) 0.53 (0.20)LS Mean Diff vs. placebo (95% 0.28 (-0.19,CI) 0.76)P-value vs. placebo 0.2414> Median (2.1955)Number 31 29Mean (SD) 0.22 (0.96) 0.47 (0.84)LS Mean (SE) 0.32 (0.16) 0.59 (0.16)400 mg BID cohort 400 mg TIP cohortAQLQ global score Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs. placebo (95% 0.27 (-0.15,CI) 0.69)P-value vs. placebo 0.2026Overall p-value for interaction 0.7803Baseline pre-bronchodilator percent predicted FEV 1 group 1 (%) (400 mg TID only)< Median (77)Number 32 23Mean (SD) 0.05 (0.87) 0.49 (0.92)LS Mean (SE) 0.13 (0.18) 0.55 (0.21)LS Mean Diff vs. placebo (95% 0.42 (-0.05,CI) 0.88)P-value vs. placebo 0.0787> Median (77)Number 30 29Mean (SD) 0.48 (0.89) 0.47 (0.84)LS Mean (SE) 0.43 (0.16) 0.60 (0.16)LS Mean Diff vs. placebo (95% 0.16 (-0.26,CI) 0.58)P-value vs. placebo 0.4566Overall p-value for interaction 0.2958Baseline pre-bronchodilator percent predicted FEV 1 group 2 (%) (400 mg TID only)< 80Number 37 30Mean (SD) 0.10 (0.82) 0.41 (0.94)LS Mean (SE) 0.16 (0.16) 0.50 (0.18)LS Mean Diff vs. placebo (95% 0.35 (-0.06,CI) 0.76)P-value vs. placebo 0.0977> 80Number 25 22Mean (SD) 0.49 (0.97) 0.57 (0.77)LS Mean (SE) 0.43 (0.17) 0.70 (0.18)LS Mean Diff vs. placebo (95% 0.27 (-0.20,CI) 0.74)P-value vs. placebo 0.2629Overall p-value for interaction 0.5797Baseline FEV 1 reversibility (%)< 12400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Number 19 13 45 36Mean (SD) 0.11 (1.26) 0.61 (0.72) 0.33 (0.86) 0.42 (0.85)LS Mean (SE) -0.03 (0.23) 0.71 (0.28) 0.36 (0.13) 0.48 (0.15)LS Mean Diff vs. placebo (95% 0.73 (0.07, 0.12 (-0.24,CI) 1.40) 0.48)P-value vs. placebo 0.0303 0.5068> 12Number 9 14 10 10Mean (SD) 0.57 (0.88) 0.97 (1.23) 0.39 (0.79) 0.56 (0.72)LS Mean (SE) 0.47 (0.33) 0.76 (0.33) 0.30 (0.32) 0.63 (0.41)LS Mean Diff vs. placebo (95% 0.29 (-0.39, 0.32 (-0.63,CI) 0.97) 1.28)P-value vs. placebo 0.4038 0.5035Overall p-value for interaction 0.3793 0.3913Baseline ACQ-5 score< 2Number 14 17 26 18Mean (SD) 0.47 (0.92) 0.50 (0.80) 0.46 (0.94) 0.53 (1.02)LS Mean (SE) 0.17 (0.27) 0.60 (0.24) 0.35 (0.19) 0.64 (0.22)LS Mean Diff vs. placebo (95% 0.43 (-0.16, 0.29 (-0.26,CI) 1.02) 0.85)P-value vs. placebo 0.1568 0.2966> 2Number 15 12 36 35Mean (SD) 0.13 (1.35) 1.32 (1.06) 0.11 (0.85) 0.43 (0.78)LS Mean (SE) 0.10 (0.33) 1.05 (0.40) 0.22 (0.14) 0.60 (0.15)LS Mean Diff vs. placebo (95% 0.95 (0.11, 0.38 (0.01,CI) 1.79) 0.75)P-value vs. placebo 0.0267 0.0447Overall p-value for interaction 0.3060 0.6263LATAM: Latin America, ROW: Rest of the world

[0264] Table 55. Subgroup analysis: change from baseline in AQLQ global score at EOT (Week 12) by baseline ICS / LABA dose level (mITT population).AQLQ global score Placebo BID Rilzabrutinib 400 mg(N=32) BID(N=32)Background ICS / LABA dose level at randomizationMediumNumber 3 4Mean (SD) 0.02 (0.48) 1.07 (0.57)LS Mean (SE) -0.08 (0.50) 0.84 (0.50)LS Mean Diff vs. placebo (95% CI) 0.93 (0.72, 1.13)AQLQ global score Placebo BID Rilzabrutinib 400 mg(N=32) BID(N=32)P-value vs. placebo 0.0007HighNumber 26 25Mean (SD) 0.32 (1.21) 0.80 (1.04)LS Mean (SE) 0.10 (0.20) 0.83 (0.22)LS Mean Diff vs. placebo (95% CI) 0.73 (0.21, 1.24)P-value vs. placebo 0.0057Overall p-value for interaction 0.8629LATAM: Latin America, ROW: Rest of the world

[0265] Table 56. Subgroup analysis: change from baseline in AQLQ global score at EOT (Week 12) by baseline biomarker subgroups (mITT population).400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDBaseline IgE level (lU / mL)< 100Number 10 7 24 18Mean (SD) 0.00 (1.71) 1.01 (1.21) 0.13 (0.98) 0.55 (0.59)LS Mean (SE) -0.25 (0.58) 0.64 (0.61) 0.23 (0.30) 0.69 (0.36)LS Mean Diff vs. placebo (95% 0.90 (-0.36, 0.46 (0.01,CI) 2.16) 0.91)P-value vs. placebo 0.1622 0.0448> 100Number 19 22 38 35Mean (SD) 0.45 (0.74) 0.78 (0.94) 0.34 (0.85) 0.42 (0.98)LS Mean (SE) 0.15 (0.41) 0.74 (0.39) 0.32 (0.22) 0.49 (0.23)LS Mean Diff vs. placebo (95% 0.59 (0.14, 0.16 (-0.25,CI) 1.04) 0.58)P-value vs. placebo 0.0095 0.4392Overall p-value for interaction 0.6080 0.4953Baseline median IgE level (lU / mL)(400 mg BID only)< Median (210.8)Number 12 18Mean (SD) -0.03 (1.56) 0.73 (0.89)LS Mean (SE) -0.34 (0.34) 0.68 (0.27)LS Mean Diff vs. placebo (95% 1.03 (0.21,CI) 1.84)P-value vs. placebo 0.0141> Median (210.8)Number 17 11400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)Mean (SD) 0.52 (0.72) 1.01 (1.15)LS Mean (SE) 0.26 (0.20) 0.94 (0.26)LS Mean Diff vs. placebo (95% 0.67 (0.12,CI) 1.22)P-value vs. placebo 0.0161Overall p-value for interaction 0.7770Baseline median IgE level(lU / mL) (400 mg TID only)< Median (121.85)Number 31 25Mean (SD) 0.03 (1.00) 0.64 (0.61)LS Mean (SE) 0.10 (0.19) 0.71 (0.20)LS Mean Diff vs. placebo (95% 0.60 (0.19,CI) 1.02)P-value vs. placebo 0.0044> Median (121.85)Number 31 28Mean (SD) 0.48 (0.73) 0.31 (1.03)LS Mean (SE) 0.76 (0.45) 0.74 (0.48)LS Mean Diff vs. placebo (95% -0.02 (-0.48,CI) 0.44)P-value vs. placebo 0.9314Overall p-value for interaction 0.0564Baseline median IgA level (mg / L)(400 mg TID only)< Median (2190)Number 33 26Mean (SD) 0.14 (0.93) 0.69 (0.74)LS Mean (SE) 0.27 (0.16) 0.77 (0.17)LS Mean Diff vs. placebo (95% 0.50 (0.09,CI) 0.92)P-value vs. placebo 0.0162> Median (2190)Number 29 27Mean (SD) 0.39 (0.85) 0.25 (0.94)LS Mean (SE) 0.33 (0.17) 0.41 (0.18)LS Mean Diff vs. placebo (95% 0.08 (-0.39,CI) 0.55)P-value vs. placebo 0.7400Overall p-value for interaction 0.1785Baseline blood eosinophil level 1 ( 10A9 / L) (400 mg BID only)400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID< 0.15Number 5 8Mean (SD) -0.01 (1.38) 0.82 (1.24)LS Mean (SE) 0.07 (0.59) 0.69 (0.40)LS Mean Diff vs. placebo (95% 0.62 (-0.95,CI) 2.19)P-value vs. placebo 0.3897> 0.15Number 24 21Mean (SD) 0.36 (1.12) 0.85 (0.91)LS Mean (SE) 0.14 (0.20) 0.83 (0.26)LS Mean Diff vs. placebo (95% 0.69 (0.15,CI) 1.23)P-value vs. placebo 0.0128Overall p-value for interaction 0.9910Baseline blood eosinophil level 2(10A9 / L) (400 mg BID only)< 0.3Number 17 16Mean (SD) 0.33 (1.18) 0.90 (1.18)LS Mean (SE) 0. 10 (0.26) 0.89 (0.29)LS Mean Diff vs. placebo (95% 0.79 (0.09,CI) 1.49)P-value vs. placebo 0.0267> 0.3Number 12 13Mean (SD) 0.23 (1.16) 0.77 (0.73)LS Mean (SE) -0. 11 (0.32) 0.56 (0.30)LS Mean Diff vs. placebo (95% 0.67 (0.10,CI) 1.25)P-value vs. placebo 0.0221Overall p-value for interaction 0.9184Baseline blood eosinophil level 1(10A9 / L) (400 mg TID only)< 0.15Number 28 21Mean (SD) 0.40 (0.76) 0.41 (0.58)LS Mean (SE) 0.47 (0.13) 0.54 (0.15)LS Mean Diff vs. placebo (95% 0.07 (-0.29,CI) 0.44)P-value vs. placebo 0.6928> 0.15 - < 0.3Number 19 15400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDMean (SD) 0.16 (1.13) 0.43 (0.93)LS Mean (SE) 0.07 (0.27) 0.39 (0.29)LS Mean Diff vs. placebo (95% 0.32 (-0.36,CI) 1.01)P-value vs. placebo 0.3579> 0.3Number 15 17Mean (SD) 0.12 (0.83) 0.57 (1.11)LS Mean (SE) 0.02 (0.31) 0.72 (0.28)LS Mean Diff vs. placebo (95% 0.70 (0.04,CI) 1.36)P-value vs. placebo 0.0378Overall p-value for interaction 0.3666Baseline blood eosinophil level 2(10A9 / L) (400 mg TID only)< 0.3Number 47 36Mean (SD) 0.30 (0.92) 0.42 (0.73)LS Mean (SE) 0.33 (0.13) 0.50 (0.14)LS Mean Diff vs. placebo (95% 0.17 (-0.18,CI) 0.52)P-value vs. placebo 0.3450> 0.3Number 15 17Mean (SD) 0.12 (0.83) 0.57 (1.11)LS Mean (SE) 0.02 (0.31) 0.72 (0.28)LS Mean Diff vs. placebo (95% 0.70 (0.04,CI) 1.36)P-value vs. placebo 0.0378Overall p-value for interaction 0.2659Baseline LeNO level 1 (ppb)< 25Number 13 12 39 32Mean (SD) 0.41 (1.26) 0.92 (0.93) 0.33 (0.91) 0.40 (0.88)LS Mean (SE) 0.18 (0.28) 1.16 (0.28) 0.38 (0.14) 0.53 (0.16)LS Mean Diffvs. placebo (95% 0.98 (0.31, 0.15 (-0.24,CI) 1.66) 0.54)P-value vs. placebo 0.0044 0.4375> 25Number 16 17 19 19Mean (SD) 0.20 (1.10) 0.78 (1.05) 0.29 (0.80) 0.61 (0.86)LS Mean (SE) 0.08 (0.25) 0.59 (0.29) 0.26 (0.22) 0.70 (0.22)400 mg BID cohort 400 mg TID cohortAQLQ global score Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs. placebo (95% 0.51 (-0.15, 0.44 (-0. 12,CI) 1.17) 1.00)P-value vs. placebo 0.1276 0.1229Overall p-value for interaction 0.4272 0.2955Baseline FeNO level 2 (ppb)< 35Number 17 21 46 37Mean (SD) 0.40 (1.25) 0.74 (0.99) 0.28 (0.91) 0.41 (0.84)LS Mean (SE) 0.01 (0.25) 0.85 (0.23) 0.30 (0.13) 0.48 (0.15)LS Mean Diffvs. placebo (95% 0.84 (0.28, 0.18 (-0.19,CI) 1.40) 0.54)P-value vs. placebo 0.0032 0.3422> 35Number 12 8 12 14Mean (SD) 0.15 (1.03) 1.09 (1.01) 0.47 (0.70) 0.65 (0.97)LS Mean (SE) 0.08 (0.30) 0.85 (0.40) 0.23 (0.34) 0.68 (0.30)LS Mean Diffvs. placebo (95% 0.77 (-0.16, 0.45 (-0.24,CI) 1.70) 1.14)P-value vs. placebo 0.1046 0.2020Overall p-value for interaction 0.8943 0.5672AQLQ(S): Asthma quality of life questionnaire with standardized activities, LOAC: Loss of asthma control, LOCF: Last observation carried forward, LATAM: Latin America, ROW: Rest of the world

[0266] Table 57. Subgroup analysis: change from baseline in AQLQ global score at EOT (Week 12) in the baseline low EOS and low FeNO subgroup (mlTT population).400 mg BID 400 mg TIDAQLQ global score Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TIDBaseline blood eosinophil (10A9 / L) and FeNO (ppb)Low EOS (< 0.15) and low FeNO(< 25)Number 3 3 22 14Mean (SD) -0.49 (1.63) 0.71 (1.25) 0.41 (0.72) 0.41 (0.64)LS Mean (SE) -1.16 (0.91) 1.28 (0.65) 0.45 (0.15) 0.55 (0.19)LS Mean Diffvs. placebo (95% 2.45 (-13.85, 0.10 (-0.36,CI) 18.75) 0.56)P-value vs. placebo 0.3072 0.6810All othersNumber 26 26 36 37Mean (SD) 0.38 (1.09) 0.85 (0.99) 0.26 (0.95) 0.51 (0.95)LS Mean (SE) 0.16 (0.19) 0.77 (0.22) 0.21 (0.17) 0.56 (0.16)400 mg BID 400 mg TIDAQLQ global score Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib(N=32) 400 mg BID (N=68) 400 mg TID(N=32) (N=64)LS Mean Diff vs. placebo (95% 0.61 (0.13, 0.35 (-0.07,CI) 1.09) 0.77)P-value vs. placebo 0.0135 0.1044Overall '-value for interaction 0.1818 0.4365LATAM: Latin America, ROW: Rest of the worldSafety

[0267] Rilzabrutinib was generally safe, with no evidence of new safety concerns (Table 58). Participants receiving 400 mg BID or 400 mg TID rilzabrutinib experienced fewer TEAEs than patients receiving the placebo, further attesting to the safety of rilzabrutinib.

[0268] Table 58. Overview of adverse event profile: treatment-emergent adverse events (safety population).400 mg BID cohort 400 mg TID cohort Combined n (%) Placebo Rilzabrutinib Placebo Rilzabrutinib Placebo RilzabrutinibBID 400 mg BID TID 400 mg TID (N=100) (N=96)(N=32) (N=32) (N=68) (N=64)Participants 20 (62.5) 14 (43.8) 18 (26.5) 26 (40.6) 38 (38.0) 40 (41.7) with any TEAEParticipants 0 0 0 1 (1.6) 0 1 (1.0) with any severe TEAEParticipants 0 2 (6.3) 0 0 0 2 (2.1) with any treatment emergent SAEParticipants 0 0 0 0 0 0 with any TEAE leading to deathParticipants 2 (6.3) 4 (12.5) 3 (4.4) 7 (10.9) 5 (5.0) 11 (11.5) with any TEAE leading to permanent study intervention discontinuationParticipants 2 (6.3) 1 (3.1) 4 (5.9) 3 (4.7) 6 (6.0) 4 (4.2) with any treatment emergent AESIParticipants 1 (3.1) 5 (15.6) 7 (10.3) 10 (15.6) 8 (8.0) 15 (15.6) with any TEAE related to IMP400 mg BID cohort 400 mg TID cohort Combined n (%) Placebo Rilzabrutinib Placebo Rilzabrutinib Placebo RilzabrutinibBID 400 mg BID TID 400 mg TID (N=100) (N=96)(N=32) (N=32) (N=68) (N=64)TEAE: Treatment-emergent adverse event, SAE: Serious adverse event, AESE Adverse event of special interest, IMP: Investigational medicinal product n (%) = number and percentage of participants with at least one TEAEChange from baseline at EOT and change from baseline at each week for Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD) scores

[0269] In both cohorts, patients treated with rilzabrutinib showed an improvement in ADSD and ANSD symptom score as indicated by a reduction from baseline in ADSD and ANSD symptom score at Week 12 relative to patients treated with the placebo. The improvement has been observed across all ADSD and ANSD components, including difficulty breathing, wheezing, shortness of breath, chest tightness, chest pain, and cough.

[0270] Patients in the rilzabrutinib 400 mg BID arm exhibited a reduction in daytime and nighttime asthma symptom score as measured by change from baseline at Week 12 (LS mean ADSD: -0.27, LS mean ANSD: -0.35) that was greater than that observed in patients in the placebo BID arm (LS mean ADSD: 0.12, ANSD: 0.33); the LS mean difference versus placebo was -0.39 [95% CI: -1.03, 0.26, nominal p-value=0.2377] for ADSD symptom score and -0.68 [95% CI: -1.33, -0.03, nominal p-value=0.0390] for ANSD symptom score. The improvement has been observed across all ADSD and ANSD components.

[0271] Patients in the rilzabrutinib 400 mg TID arm also exhibited a reduction in daytime and nighttime asthma symptom score as measured by change from baseline at Week 12 (LS mean ADSD: -0.43, LS mean ANSD: -0.48) that was greater than that observed in patients in the placebo TID arm (LS mean ADSD: 0.08, ANSD: 0.06), the LS mean difference versus placebo was -0.50 [95% CI: -1.15, 0.14, nominal p-value=0.1276] for ADSD symptom score and -0.54 [95% CI: -1.13, 0.06, nominal p-value=0.0758] for ANSD symptom score. The improvement has been observed across all ADSD and ANSD components.Embodiments:Non-limiting embodiments of the disclosure include:1. A method of treating asthma in a human patient in need thereof, comprising administering to the human patient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan- 3-yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof. The method of Embodiment 1, wherein the human patient has mild asthma. The method of Embodiment 1, wherein the human patient has moderate-to-severe asthma. The method of Embodiment 1 or 3, wherein the human patient has moderate asthma. The method of Embodiment 1 or 3, wherein the human patient has severe asthma. The method of any one of Embodiments 1-5, wherein the human patient has asthma that is not well controlled. The method of any one of the preceding Embodiments, wherein the human patient has asthma that is not well controlled for one or more symptoms. The method of Embodiment 7, wherein the one or more symptoms is selected from frequency of awakening by asthma, asthma symptoms when woke up, limitation of activities by asthma, shortness of breath, and wheeze. The method of any one of the preceding Embodiments, wherein the human patient is receiving treatment with step 3, 4, or 5 of the Global Initiative for Asthma (GINA). The method of any one of the preceding Embodiments, wherein the human patient has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA). The method of any one of the preceding Embodiments, wherein the human patient is withdrawn from ICS / LABA therapy. The method of any one of the preceding Embodiments, wherein the human patient does not experience a >30% reduction from baseline in morning peak expiratory flow (PEF) on at least 2 consecutive days. The method of any one of the preceding Embodiments, wherein the human patient does not experience a >30% reduction fro...

Claims

What is claimed is:

1. A method of treating asthma in a human patient in need thereof, comprising administering to the human patient in need thereof a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan- 3-yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof.

2. The method of claim 1, wherein the human patient has mild asthma.

3. The method of claim 1, wherein the human patient has moderate-to-severe asthma.

4. The method of claim 1 or 3, wherein the human patient has moderate asthma.

5. The method of claim 1 or 3, wherein the human patient has severe asthma.

6. The method of any one of claims 1-5, wherein the human patient has asthma that is not well controlled.

7. The method of any one of the preceding claims, wherein the human patient has asthma that is not well controlled for one or more symptoms.

8. The method of claim 7, wherein the one or more symptoms is selected from frequency of awakening by asthma, asthma symptoms when woke up, limitation of activities by asthma, shortness of breath, and wheeze.

9. The method of any one of the preceding claims, wherein the human patient is receiving treatment with step 3, 4, or 5 of the Global Initiative for Asthma (GINA).

10. The method of any one of the preceding claims, wherein the human patient has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).

11. The method of any one of the preceding claims, wherein the human patient is withdrawn from ICS / LABA therapy.

12. The method of any one of the preceding claims, wherein the human patient does not experience a >30% reduction from baseline in morning peak expiratory flow (PEF) on at least 2 consecutive days.

13. The method of any one of the preceding claims, wherein the human patient does not experience a >30% reduction from baseline in morning PEF.

14. The method of any one of the preceding claims, wherein the human patient does not require >6 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol within a 24-hour period for two consecutive 24-hour periods.

15. The method of any one of the preceding claims, wherein the human patient does not require >6 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol within a 24-hour period.

16. The method of any one of the preceding claims, wherein the human patient does not require an increase in ICS >4 times the last prescribed ICS dose.

17. The method of any one of the preceding claims, wherein the human patient does not require an increase in ICS >50% of the last prescribed ICS dose.

18. The method of any one of the preceding claims, wherein the human patient does not require the use of systemic steroid treatment, optionally wherein the systemic steroid treatment comprises oral or parenteral treatment.

19. The method of any one of the preceding claims, wherein the human patient does not require hospitalization or an emergency room visit for asthma exacerbation.

20. The method of any one of the preceding claims, wherein the human patient achieves an increase in pre-bronchodilator FEV1 relative to baseline pre-bronchodilator FEV1.

21. The method of any one of the preceding claims, wherein the human patient achieves an increase in the percent predicted pre-bronchodilator FEV1 prior to baseline prebronchodilator FEV 1.

22. The method of any one of the preceding claims, wherein the human patient achieves a reduction in Asthma Control Questionnaire-5 (ACQ-5) score relative to a baseline ACQ-5 score.

23. The method of any one of the preceding claims, wherein the human patient achieves a reduction in ACQ-5 of >0.5 relative to baseline ACQ-5.

24. The method of any one of the preceding claims, wherein the human patient achieves an ACQ-5 score of <0.75.

25. The method of any one of the preceding claims, wherein the human patient achieves an increase in Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ(S)) relative to baseline AQLQ(S).

26. The method of any one of the preceding claims, wherein the human patient achieves a reduction in asthma daytime symptom diary (ADSD) relative to baseline ADSD.

27. The method of any one of the preceding claims, wherein the human patient achieves a reduction in asthma nighttime symptom diary (ANSD) relative to baseline ANSD.

28. The method of any one of claims 1-10 or 12-27, wherein the human patient achieves a reduction in inhalations / day of albuterol or levalbuterol for symptom relief relative to baseline inhalations / day.

29. The method of any one of claims 1-10 or 12-28, wherein the human patient achieves a reduction in inhalations / day of albuterol or levalbuterol for symptom relief relative tobaseline inhalations / day, further wherein the patient receives concomitant treatment with ICS and / or LABA.

30. The method of any one of the preceding claims, wherein the human patient achieves a reduction in Patient Global Impression of Severity (PGIS) relative to baseline PGIS.

31. The method of any one of the preceding claims, wherein the human patient achieves an improvement in Patient Global Impression of Change (PGIC).

32. The method of any one of the preceding claims, wherein the human patient has had asthma for at least 12 months.

33. The method of any one of the preceding claims, wherein the human patient is being treated with a moderate to high dose of ICS therapy in combination with LABA.

34. The method of claim 33, wherein the ICS is fluticasone propionate and the human patient is being treated with >250 pg of fluticasone propionate BID or comparable ICS daily dosage to a maximum of 2000 pg / day of fluticasone propionate or clinically comparable ICS.

35. The method of claim 33 or 34, wherein the human patient has received treatment with the ICS for at least 3 months.

36. The method of any one of the preceding claims, wherein the human patient has a baseline reversibility of at least 12% and 200 mL in FEV1 15 to 30 minutes after administration of 200-400 pg of albuterol / salbutamol or levalbuterol / levosalbutamol.

37. The method of any one of the preceding claims, wherein the human patient has a history reversibility of at least 12% and 200 mL in FEV1 15 to 30 minutes after administration of 200-400 pg of albuterol / salbutamol or levalbuterol / levosalbutamol within the 5 years prior to initiation rilzabrutinib treatment.

38. The method of any one of the preceding claims, wherein the human patient has a history of positive response to methacholine challenge within the 5 years prior to initiation rilzabrutinib treatment.

39. The method of any one of the preceding claims, wherein the human patient has a history of one or more of the following within the 2 years prior to initiation of rilzabrutinib treatment: a. treatment with a systemic steroid for worsening asthma, optionally wherein the systemic steroid treatment comprises oral or parenteral treatment; and b. hospitalization or an emergency room visit for asthma exacerbation.

40. The method of any one of the preceding claims, wherein the treatment period is at least 12 weeks.

41. The method of any one of the preceding claims, wherein the at least one compound consists of at least one compound chosen from the (E) isomer of rilzabrutinib and pharmaceutically acceptable salts thereof.

42. The method of any one of claims 1-40, wherein the at least one compound consists of at least one compound chosen from the (Z) isomer of rilzabrutinib and pharmaceutically acceptable salts thereof.

43. The method of any one of claims 1-40, wherein the at least one compound consists of a mixture of (E) and (Z) isomers of rilzabrutinib or a pharmaceutically acceptable salt of the foregoing.

44. The method of any one of claims 1-43, comprising administering rilzabrutinib to the human patient twice a day.

45. The method of any one of claims 1-44, comprising administering to the human patient46. The method of any one of claims 1-43, comprising administering rilzabrutinib to the human patient three times a day.

47. The method of any one of claims 1-43 or 46, comprising administering to the human patient 400 mg of rilzabrutinib three times a day.

48. The method of any one of claims 1-41 or 44-47 wherein the at least one compound is the (E) isomer of rilzabrutinib.

49. The method of any one of claims 1-40, 42, or 44-47, wherein the at least one compound is the (Z) isomer of rilzabrutinib.

50. The method of any one of claims 1-40 or 43-47, wherein the at least one compound consists of a mixture of (E) and (Z) isomers of rilzabrutinib.

51. The method of any one of the preceding claims, wherein the at least one compound is orally administered to the human patient.

52. The method of any one of the preceding claims, wherein the at least one compound is administered to the human patient in the form of at least one tablet.

53. The method of any one of the preceding claims, wherein the at least one compound is administered with water.

54. The method of any one of claims 1-40 and 51-53, wherein the at least one compound is rilzabrutinib.

55. A method of treating asthma in a human patient in need thereof, comprising administering to the human patient a therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan- 3-yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptablesalts thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).

56. Use of a therapeutically effective amount of at least one compound chosen from (R)- 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for treating asthma in a human patient in need thereof.

57. Use of a therapeutically effective amount of at least one compound chosen from (R)- 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for treating asthma in a human patient in need thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).

58. Use of a therapeutically effective amount of at least one compound chosen from (R)- 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating asthma in a human patient in need thereof.

59. Use of a therapeutically effective amount of at least one compound chosen from (R)- 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3 -yl)piperazin- 1 -yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating asthma in a human patient in need thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).

60. A therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for use in treating asthma in a human patient in need thereof.

61. A therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for use in treating asthma in a human patient in need thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long- acting P2 adrenergic agonist (LABA).

62. A therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for use in the manufacture of a medicament for treating asthma in a human patient in need thereof.

63. A therapeutically effective amount of at least one compound chosen from (R)-2-[3-[4- amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l- carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile (rilzabrutinib) and pharmaceutically acceptable salts thereof for use in the manufacture of a medicament for treating asthma in a human patient in need thereof, wherein the human patient in need thereof has asthma that is not well controlled by treatment with an inhaled corticosteroid (ICS) and / or a long-acting P2 adrenergic agonist (LABA).

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