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

[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 with rilzabrutinib 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 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).

[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 FEV1 (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 pre bronchodilator 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 the 400 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., oral delivery) 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-l-yl]piperdine-l-carbonyl]-4-methyl-4[4-(oxetan-3-yl)piperazin-l-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?sfvrsn=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 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-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 not require >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 FEV1.

[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 prior to 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 has asthma 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 02 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 02 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 AD ADSD AE AESI ANSD AQLQ(S) Asthma Control Questionnaire-5 Atopic dermatitis Asthma daytime symptom diary Adverse event Adverse event of special interest Asthma nighttime symptom diary Asthma Quality of Life Questionnaire with Standardized Activities ATC BD BDR BID BTK CI CS CSICF CYP DPI ECG EOT ETD FcyR FcsR FEF FVC HIV HR HRT ICS IgG4-RD IL ILC2 IMP IRT ITP ITT LABA LAR LOAC LOCF LS MCID Anatomical therapeutic chemical Bronchodilator Bronchodilator response Twice daily Bruton's tyrosine kinase Confidence interval Corticosteroid Core study informed consent form Cytochrome P450 Dry powder inhaler El ectrocardi ogram End of treatment Early treatment discontinuation Fc-gamma receptor Fc-epsilon receptor Forced expiratory flow Forced vital capacity Human immunodeficiency virus Hazard ratio Hormonal replacement therapy Inhaled corticosteroid Immunoglobin G4-related disease Interleukin Innate lymphoid cells type 2 Investigational medicinal product Interactive response technology Immune thrombocytopenia Intent-to-treat Long-acting P2 adrenergic agonist Legally authorized representative Loss of asthma control Last observation carried forward Least squared Minimal clinically important difference 19 MDI Metered dose inhaler Pg 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 reaction TB Tuberculosis TBI Tuberculosis infection TEAE Treatment-emergent adverse event TID Three times a day V Visit wAIHA Warm autoimmune hemolytic anemia Wk Week WOCBP Woman of childbearing potential WONCBP Woman of non-childbearing potential Example 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 skin testing 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 BID OR • 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) BID OR • Fluticasone (MDI formulation): o 2 inhalations of 125 pg (250 pig) BID or o 2 inhalations of 250 pig (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). Wk 4 / V 6 Wk 6 / V8 Wk 7 / V 9 Wk 8 / V 10 Wk 9 / V11 Fluticasone DPI Dose (pg) administered BID 250 100 50 0 0 500 250 100 50 0 Fluticasone MDI Dose (Pg) administered BID 220 110 44 0 0 440 220 110 44 0 250 125 50 0 0 500 250 125 50 0

[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 their 23 prescreening 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. Objectives Endpoints Primary Evaluate the effects of rilzabrutinib compared to placebo on reducing the incidence of “loss of asthma control” (LOAC) events Proportion of participants with an LOAC event during the treatment period, defined as any one of the following: (1) a 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on 2 consecutive days; (2) >6 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; (5) requiring hospitalization or emergency room visit for asthma exacerbation Secondary Evaluate the effects of rilzabrutinib compared to placebo on lung function as measured by FEV1 Pre-bronchodilator FEV1 change from baseline at EOT (key secondary endpoint) Post-bronchodilator FEV 1 change from baseline at EOT The absolute change in the percent predicted FEV1 from baseline to EOT (pre- and postbronchodilator) Assess the effects of rilzabrutinib on other elements of spirometric lung function Change from baseline in pre- and postbronchodilator FEV 1 and other lung function measurements (PEF, forced vital capacity (FVC), and forced expiratory flow (FEV) 2575%) at each spirometry endpoint Assess the effect of rilzabrutinib on patient reported outcomes 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 Assess the effects of rilzabrutinib on asthma symptoms Change from baseline at EOT and change from baseline at each week for Asthma Daytime Symptom Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD) scores. Assess the plasma pharmacokinetics (PK) of rilzabrutinib in participants with asthma Plasma PK concentrations of rilzabrutinib in participants with asthma Assess the safety of rilzabrutinib in participants with asthma Adverse events (AEs), vital signs, labs Assess the use of rilzabrutinib on bronchodilator therapy Change from baseline and at EOT and change from baseline at each week in numbers of inhalations / day of albuterol or levalbuterol for symptom relief Exploratory Assess the effect of rilzabrutinib based on baseline blood IgE levels Primary and secondary outcomes in subgroups of participants with baseline blood IgE levels of >100 or <100 IU / uL Assess the effects of rilzabrutinib on fraction of exhaled nitric oxide (FENO) Change in FENO from baseline to EOT Assess the effects of rilzabrutinib on allergic phenotype Skin prick test (SPT) to be administered in participants with documented previously positive allergy testing at baseline and EOT Assess the effects of rilzabrutinib on oscillatory lung mechanics Change from baseline in forced oscillatory technique (FOT) Assess the effects of rilzabrutinib on biomarkers in participants with asthma Patient Global Impression of Severity (PGIS) change from baseline to EOT and at each assessment time point Patient Global Impression of Change (PGIC) from baseline to EOT and at each assessment time point 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 425 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-sectional measurement properties ( / .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. Age Participants must have been from 18 to 70 years of age at the time of signing the informed consent Type of participant and disease characteristics A physician diagnosis of asthma for at least 12 months based on the Global Initiative for Asthma (GINA) 2019, 202, or 2021 Guidelines (Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, Updated 2019, Updated 2020, Updated 2021) Participants with existing treatment with 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 EABA as a second controller for at least 3 months with a stable dose >1 month prior to V 1. The lower limit of allowed ICS dose (500 pg of fluticasone propionate daily) corresponds to upper limit of medium dose defined by GINA guidelines. Patients receiving medium ICS dose <500 pg daily were not eligible. Participants with prebronchodilator FEV >40% of predicted normal at V 1 screening. Prebronchodilator FEV1 >50% of predicted normal at V 2 / baseline. Participants with reversibility of at least 12% and 200 mL in FEV1 15 to 30 minutes after administration of 2 to 4 puffs (200-400 pg) of albuterol / salbutamol or levalbuterol / levosalbutamol during screening or documented history of a reversibility test that met this criterion within 5 years prior to V 1 or documented positive response to methacholine challenge (a decrease in FEV 1 by 20% (PC20) of <8 mg / mL) within 5 years prior to V 1 / screening were considered acceptable to meet this inclusion criterion. Participants must have experienced, within 2 years prior to V 1, any of the following asthma exacerbation events at least once: (1) treatment with a systemic steroid (oral or parenteral) for worsening asthma; and (2) hospitalization or emergency medical care visit for worsening asthma. Weight Body mass index (BMI) >17.5 and <40 kg / m2 Sex, contraceptive / barrier method, and pregnancy testing requirements All contraceptive use by men and women should have been consistent with local regulations regarding the methods of contraception for those participating in clinical studies Male participants were eligible to participate if they agreed to the following during the study intervention period and for at least 13 weeks after the last administration of study intervention: • Refrain from donating or cryopreserving sperm; AND • (1) Abstain from heterosexual intercourse as their preferred and usual lifestyle (i.e., be abstinent on a long term and persistent basis) and agree to remain abstinent; OR (2) agree to use contraception / barrier1 Female participants were eligible to participate if they were not pregnant or breastfeeding, and one of the following conditions applied: • She was a woman of non-childbearing potential (WONCBP); OR • She was a woman of childbearing potential (WOCBP)2 and agreed to use a contraceptive method that is highly effective (with a failure rate of <1%), preferably with low user dependency, during the study intervention period (to be effective before starting the intervention) and for at least 4 weeks after the last administration of study 1 A 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. 2 A 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. intervention and agreed not to donate or cryopreserve eggs (ova, oocytes) for the purpose of reproduction during this period. Informed consent Capable of giving signed informed consent, which included compliance with the requirements listed in the informed consent form (ICF) and in this protocol. In countries where legal age of majority is above 18 years, a specific ICF must also have been signed by the participant’s legally authorized representative (LAR). COVID-19 vaccination Participants must have completed COVID-19 vaccination per current regional health authority recommendations prior to screening.

[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. Medical conditions History of serious infections requiring intravenous therapy with the potential for recurrence (as judged by the Site Investigator, with less than 4 weeks’ interval between resolution of serious infection and first dose of study drug, or currently active moderate-to-sever infection at screening (Grade 2 or higher). Chronic lung disease (for example, chronic obstructive pulmonary disease (COPD), or idiopathic pulmonary fibrosis (IPF)) which may impair lung function, or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts, for e.g., eosinophilic granulomatosis with polyangiitis. History of life-threatening asthma (i.e., severe exacerbation that requires intubation). Participants with any of the following events within the 4 weeks prior to their screening V 1 or during the screening period: (1) treatment with 1 or more systemic (oral and / or parenteral) steroid bursts for worsening asthma; and (2) hospitalization or emergency medical care visit for worsening asthma. Asthma Control Questionnaire 5-question version (ACQ-5) score <1.25 or >3.0 at V 2 / randomization. During the screening period, an ACQ-5 of up to <4 was acceptable. Current smoker or cessation of smoking within the 6 months prior to V 1. Previous smoker with a smoking history of >10 pack-years. Current or chronic history of liver disease. This included but was not limited to hepatitis virus infections, drug- or alcohol-related liver disease, non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson’s disease, a-1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis, or any other liver disease considered clinically significant by the Investigator. Symptomatic herpes zoster within 3 months prior to screening. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate rilzabrutinib / placebo absorption. Conditions that may have predisposed the participant to excessive bleeding: • A bleeding disorder or known platelet dysfunction at any time prior to the screening visit. • The participant had major surgery within 4 weeks prior to the screening visit, which could affect the participant’s safety or affect immune response (as judged by the Investigator) or had planned any elective major surgery during the study. • A history of significant bleeding event within 6 months prior to screening, according to the Investigator’s judgment such as, but not limited to, cerebral or gastrointestinal bleeding. History of solid organ transplant A history of malignancy of any type within 5 years before D 1, other than surgically excised non-melanoma skin cancers or in situ cervical cancers Was not up-to-date with recommended vaccinations per local guidelines. Prior / concomitant therapy Anti-immunoglobulin E (IgE) therapy (e.g., omalizumab (Xolair®) within 130 days prior to V 1 or any other biologic therapy (including anti-IL4 / 4R or IL-5 / 5R monoclonal antibodies (mAb) or systemic immunosuppressant (e.g., methotrexate) to treat inflammatory disease or autoimmune disease (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis) and other diseases, within 2 months or 5 half-lives prior to V 1, whichever is longer. Use of inhalers other than ICSs, LABAs, and short-acting beta agonists (no LAMAs or mucolytics) and leukotriene receptor antagonists (montelukast, zafirkulast) during the study period. Participants who had received bronchial thermoplasty within 2 years prior to V 1 or plan to begin therapy during the screening period or the randomized treatment period. Use of proton pump inhibitor drugs such as omeprazole and esomeprazole within 3 days of D 1 (it was acceptable to change patient to H2 receptor blocking drugs prior to D 1) Use of known systemic strong-to-moderate inducers3 or inhibitors4 of CYP3A within 14 days or 5 half-lives (whichever is longer) of study D 1 and until the end of the active treatment period. Five vaccine except Bacille Calmette Guerin vaccination within 28 days prior to D 1 or plans to receive one during the trial; Calmette Guerin vaccination within 12 months prior to screening. COVID-19 vaccine within 14 days prior to study D 1 Prior / concurrent clinical study experience Previous use of a BTK inhibitor Had received any investigational drug (or is currently using an investigational device) within the 30 days before D 1, or at least 5 times the respective elimination half-life time (whichever is longer). Diagnostic assessments Any of the following laboratory abnormalities at the screening visit (identified by the central laboratory): • Absolute neutrophil count <1.5 x 109 / L 3 Strong 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.. 4 Strong 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. • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 upper limit of normal (ULN) • Total bilirubin >1.5 ULN (isolated bilirubin >1.5 x ULN is acceptable if total bilirubin is fractionated and direct bilirubin <35%) • IgG <500 mg / dL • Abnormal international normalized ratio (INR) test and activated partial thromboplastin time (aPTT) judged by the Investigator to be clinically significant • A platelet count <150,000 / pL5 Positive for human immunodeficiency virus (HIV) at screening Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with positive DNA test result at screening or within 3 months prior to first administration of study intervention. Positive hepatitis C antibody test result at screening or within 3 months prior to starting study intervention6. Exclusion related to tuberculosis infection (TBI): • Active TBI or a history of incompletely treated TBI regardless of screening Quantiferon (QFT) result. • QFT positive patients (no active disease) are excluded from the study unless the following conditions were met: (1) patients with a history of prior documented completed chemoprophylaxis for latent TBI (e.g., acceptable treatments would be 9 months of isoniazid 300 mg oral daily or equivalent proven regimen per local guidelines) or treatment of active TBI who had obtained consultation with a specialist to rule out active TBI or treat active TBI; (2) consultation with and prior approval from the Sponsor were required in either of the aforementioned scenarios. Otherwise, a documented negative screening for TB via a negative QFT within 3 months prior to screening 5 A one-time retest value at screening may have been performed by the Investigator if abnormal laboratory test values are found. 6 Participants with positive hepatitis C antibody due to prior resolved disease could be enrolled, only if a confirmatory negative Hepatitis C RNA test was obtained. (and if required per local standard of care, a chest X-ray), was sufficient and no further screening with QFT was required; if clinically indicated, the test may have been repeated based on clinical judgment, borderline results, or clinical suspicion of TBI. • Clinically significant abnormality consistent with prior / active TBI based upon chest radiograph with at least posterior-anterior view (radiograph must have been taken within 12 weeks prior to screening visit or during the screening period). Additional lateral view was recommended but not required. • Suspected extrapulmonary TBI regardless of screening QFT result. • Patients at high risk of contracting TB, such as close contact with individuals with active or latent TBI. Electrocardiogram (ECG) findings of QT corrected for heart rate (QTc) >450 msec (males) or >470 msec (females), poorly controlled atrial fibrillation (i.e., symptomatic patients or a ventricular rate above 100 beats / min on ECG), or other clinically significant cardiovascular abnormalities. Active COVID-19 infection as documented by a positive COVID-19 molecular test 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. Intervention label Rilzabrutinib Placebo Intervention name Rilzabrutinib Placebo Type Drug Drug Dose formulation Tablets (modified-capsule shaped tablets) Tablets (modified-capsule shaped tablets) Unit dose strength(s) 400 mg Omg Dosage level(s) 400 mg (1 tablet) BID or TID 1 tablet BID or TID Route of administration Oral Oral Use Experimental Placebo IMP or NIMP IMP IMP Packaging and labeling Rilzabrutinib tablets were to be supplied in white plastic bottles with child-resistant induction-sealed caps. The bottles were to be labeled as required per country requirement Placebo tablets were to be supplied in white plastic bottles with child-resistant induction-sealed caps. The bottles were to be labeled as required per country requirement Current / former name(s) or alias(es) Rilzabrutinib Not applicable

[0138] Table 6. Arms and associated interventions. Arm name Rilzabrutinib 400 mg BID Placebo BID Rilzabrutinib 400 mg TID Placebo TID Associated interventions (intervention label(s)) Rilzabrutinib and ICS / LABA Placebo and ICS / LABA Rilzabrutinib and ICS / LABA Placebo and ICS / LABA

[0139] Participants were to continue their 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 (Figures 1-2 and Table 7).

[0140] Table 7. Background therapy. Intervention label ICS / LABA stabilization phase V2 Week 0 to V6 Week 4 ICS / LABA withdrawal phase V6 Week 4 to V10 Week 8 (Vil Week 9 in those tapering from high dose ICS) Intervention name Fluticasone / Salmeterol combination therapy Fluticasone monotherapy Type Drug Dose formulation Dry powder inhaler (DPI) or metered dose inhaler (MDI) Unit dose strength(s) DPI: 1 inhalation of 250 / 50 pg BID or 1 inhalation of 500 / 50 pg BID OR MDI: 2 inhalations of 115 / 21 pg BID or 2 inhalations 230 / 21 pg BID OR MDI: 2 inhalations of 125 / 25 pg BID or 2 inhalations of 250 / 25 pg BID DPI: 1 inhalation of 250 pg BID or 2 inhalations of 250 pg BID OR MDI: 2 inhalations of 110 pg BID or 2 inhalations of 220 pg BID OR MDI: 2 inhalations of 125 pg BID or 2 inhalations of 250 pg BID Dosage level(s) Route of administration Inhalation Use Background therapy IMP or NIMP NIMP Packaging and labelling Not applicable Current / former name(s) or alias(es) Not applicable

[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 substrates7 were 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. 7 Sensitive 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) 8 Live (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)) 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 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 Measures Spirometry

[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. The MCID 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, i.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 (i.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 / LABA 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. Population Description Screened All participants who signed the ICF. Randomized All participants from screened population who were allocated to a randomized intervention by IRT regardless of whether the intervention was received. Intent-to-treat (ITT) All randomized participants. Modified ITT (mITT) All participants from ITT population who received at least one dose of investigational product analyzed according to the treatment group allocated by randomization. Randomized participants for whom it was unclear whether they took the study medication were included in the mITT population. Safety All randomized participants who took at least 1 dose of study intervention. Participants were analyzed according to the intervention they actually received. Pharmacokinetic (PK) All randomized and treated participants (safety population) with at least one post-baseline PK sample with adequate documentation of dosing and sampling dates and times. Participants were analyzed according to the intervention they actually received.

[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 in Table 9 below.

[0196] Table 9. Summary of primary estimand for key secondary endpoints. Endpoint category (estimand) Estimands Endpoint Population Intercurrent event(s) handling strategy Population-level summary (analysis and missing data handling) Secondary o as measured FEV1. ijective: To evaluate the effects of rilzabrutinib compared to placebo on lung function by pre-BD Key secondary endpoint Prebronchodilator FEV1 change from baseline at EOT miTT Occurrence of LOAC. For LOAC with rescue medication, data collected after LOAC was to be set to missing, and missing data was to The missing values at after discontinuation of study intervention due to other reasons or after occurrence of LOAC without rescue be imputed with LOCF (hypothetical policy). For LOAC without rescue medication, all observed values after LOAC were to be included (treatment policy). If study intervention was discontinued due to lack of efficacy or AE related to asthma worsening, data were to be imputed with LOCF (hypothetical policy). If study intervention was discontinued for other reasons, all observed data after discontinuation of study intervention were to be included (treatment policy). If OCS were used without LOAC, data collected after start of OCS were to be set to missing and missing data were to be imputed with LOCF (hypothetical policy). medication were to be imputed using multiple imputation (MI). Mean difference of pre-BD FEV1 at EOT between intervention groups was to be estimated form analysis of covariance (ANCOVA). Statistical inference obtained from each imputed data was to be combined using Rubin's rule. Least squared (LS) means, differences in LS means, the corresponding 95% CI and p-value was to be presented. 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-value BID 400 mg BID (N=32) (N=32) vs. placebo (95% CI) TID 400 mg TID (N=68) (N=64) vs. placebo (95% CI) Primary endpoint Odds ratio incidence of LOAC 16      12 (37.5%) (50.0%) 0.570     0.2880 (0.202, 1.608) 20     12 (18.8%) (29.4%) 0.584     0.2083 (0.253, 1.349) Key secondary endpoint LS Mean change from baseline in prebronchodilator FEV1 (L) at Week 12 -0.08   -0.07 (0.08) (0.08) 0.01 (-    0.9466 0.17, 0.19) -0.04 -0.13 (0.05) (0.05) -0.09(-   0.1523 0.21,0.03) Patient 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. n (%) 400 mg BID cohort 400 mg TID cohort Placebo BID Rilzabrutinib 400 mg BID All BID Placebo TID Rilzabrutinib 400 mg TID All TID Randomized population 32(100) 32(100) 64 (100) 68 (100) 64 (100) 132 (100) Efficacy population Modified intent-to-treat (mITT) 32(100) 32(100) 64 (100) 68 (100) 64 (100) 132 (100) Safety population 32 32 64 68 64 132 Pharmacokinetic (PK) population 0 31 (96.9) 31 (48.4) 0 64 (100) 64 (48.5)

[0210] Table 12. Participant disposition. 400 mg BID cohort 400 mg TID cohort Placebo Rilzabrutinib All Placebo Rilzabrutinib All n (%) BID (N=32) 400 mg BID (N=32) (N=64) TID (N=68) 400 mg TID (N=64) (N=132) Exposed but not randomized 0 0 0 0 0 0 Randomized and not exposed 0 0 0 0 0 0 Randomized and exposed 32(100) 32 (100) 64(100) 68(100) 64(100) 132(100) Still on study intervention or missing EOT page 0 0 0 0 0 0 400 mg BID cohort 400 mg TID cohort Placebo 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 study intervention 18 (56.3) 18 (56.3) 36 (56.3) 45 (66.2) 44 (68.8) 89 (67.4) period Did not complete the study intervention period 14(43.8) 14(43.8) 28 (43.8) 23 (33.8) 20 (31.3) 43 (32.6) Reason for permanent study intervention discontinuation Adverse 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-19 Not related to COVID-19 0 2 (6.3) 2(3.1) 1(1-5) 2(3.1) 3 (2.3) Lack of 0 0 0 1(1-5) 1(1-6) 2(1.5) efficacy Poor 1(3.1) 1(3.1) 2(3.1) 0 1(1-6) 1 (0.8) compliance to protocol Withdrawal by 0 1(3.1) 1(1-6) 1(1-5) 3 (4.7) 4(3.0) subject Loss 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 COVID-19 0 0 0 0 0 0 Not related to COVID-19 1(3.1) 2 (6.3) 3 (4.7) 1(1-5) 0 1 (0.8) Reason for study intervention withdrawal by subject Adverse event 0 1(3.1) 1(1.6) 0 2(3.1) 2(1.5) Study procedure 0 0 0 0 0 0 Inconvenience 0 0 0 0 0 0 of device use Other 0 0 0 0 0 0 Related to 0 0 0 0 0 0 COVID-19 Not related to COVID-19 0 0 0 0 0 0 400 mg BID cohort 400 mg TID cohort Placebo Rilzabrutinib All Placebo Rilzabrutinib All n (%) BID (N=32) 400 mg BID (N=32) (N=64) TID (N=68) 400 mg TID (N=64) (N=132) Completed the study period 31 (96.9) 30 (93.8) 61 (95.3) 67 (98.5) 60 (93.8) 127 (96.2) Did not complete the study period Reason for study discontinuation 1(3.1) 2 (6.3) 3 (4.7) 1(1-5) 4 (6.3) 5 (3.8) Adverse event 0 1(3.1) 1(1-6) 0 0 0 Related to COVID-19 0 0 0 0 0 0 Not related to COVID-19 0 1(3.1) 1(1-6) 0 0 0 Poor compliance to protocol 1(3.1) 0 1(1-6) 0 0 0 Withdrawal by subject 0 0 0 1(1.5) 4 (6.3) 5 (3.8) Site terminated by sponsor 0 0 0 0 0 0 Study terminated by sponsor 0 1(3.1) 1(1.6) 0 0 0 Other 0 0 0 0 0 0 Related to COVID-19 0 0 0 0 0 0 Not related to COVID-19 0 0 0 0 0 0 Status at last contact 32(100) 31 (96.9) 63 (98.4) 68(100) 64(100) 132(100) Alive 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 cohort Placebo Rilzabrutinib All Placebo Rilzabrutinib All BID 400 mg BID (N=64) TID 400 mg TID (N=132) (N=32)     (N=32) (N=68) (N=64) Age (years) Number Mean (SD) Median Min ; Max 32 50.8 (12.3) 53.5 28 ; 70 32 48.0(13.4) 51.5 21 ; 70 64 49.4(12.8) 52.0 21 ; 70 68 48.6 (13.7) 48.5 18 ; 70 64 48.8 (13.3) 50.0 18 ; 68 132 48.7(13.5) 50.0 18 ; 70 Age group 1 (years) [n (%)] Number <45 >45 32 10 (31.3) 22 (68.8) 32 12 (37.5) 20 (62.5) 64 22 (34.4) 42 (65.6) 68 29 (42.6) 39 (57.4) 64 25 (39.1) 39 (60.9) 132 54 (40.9) 78 (59.1) Age group 2 (years) [n (%)] Number <65 >65 32 28 (87.5) 4(12.5) 32 29 (90.6) 3 (9.4) 64 57 (89.1) 7(10.9) 68 57 (83.8) 11 (16.2) 64 56 (87.5) 8 (12.5) 132 113 (85.6) 19 (14.4) Sex [n (%)] Number Male Female 32 8 (25.0) 24 (75.0) 32 14 (43.8) 18 (56.3) 64 22 (34.4) 42 (65.6) 68 27 (39.7) 41 (60.3) 64 25 (39.1) 39 (60.9) 132 52 (39.4) 80 (60.6) Height (cm) Number Mean (SD) Median Min ; Max 32 164.9 (10.2) 165.0 148 ; 185 32 166.0 (8.8) 164.5 150 ; 184 64 165.4 (9.5) 165.0 148 ; 185 68 167.9 (11.8) 169.5 140 ; 194 64 169.5 (11.9) 169.0 146 ; 194 132 168.6(11.8) 169.0 140 ; 194 Weight (kg) Number Mean (SD) Median Min ; Max 32 77.0(13.1) 76.5 50 ; 117 32 78.0(15.2) 75.5 54 ; 126 64 77.5 (14.0) 76.0 50 ; 126 68 77.2 (14.1) 78.0 48 ; 104 64 83.2 (12.4) 83.7 54 ; 112 132 80.1 (13.6) 81.9 48 ; 112 Weight by category (kg) [n (%)] Number <60 > 60 - < 90 >90 32 4(12.5) 25 (78.1) 3 (9.4) 32 3 (9.4) 23 (71.9) 6(18.8) 64 7(10.9) 48 (75.0) 9(14.1) 68 12(17.6) 40 (58.8) 16(23.5) 64 2(3.1) 41 (64.1) 21 (32.8) 132 14 (10.6) 81 (61.4) 37 (28.0) BMI (kg / m2) Number Mean (SD) 32 28.39 (4.79) 32 28.18 (4.01) 64 28.29 (4.38) 55 68 27.46 (4.75) 64 29.08 (4.29) 132 28.24 (4.59) 400 mg BID cohort 400 mg TID cohort Placebo Rilzabrutinib All Placebo Rilzabrutinib All BID 400 mg BID (N=64) TID 400 mg TID (N=132) (N=32) (N=32) (N=68) (N=64) Median 27.60 27.75 27.65 26.75 28.90 27.55 Min ; Max 20.5 ; 40.1 21.8 ; 38.2 20.5 ; 40.1 19.6 ; 38.3 21.6 ; 38.7 19.6 ; 38.7 BMI 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 64 132 Eastern 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 TIP cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) All (N=64) Placebo TIDRilzabrutinib All (N=132) (N=68) 400 mg TID (N=64) Age of onset of asthma (years) Number 32 32 64 68 64 132 Mean (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 29.5 Q1;Q3 15.0 ; 40.0 9.5 ; 36.0 11.5 ; 37.0 13.0; 44.5 13.5 ; 40.5 13.0 ; 41.5 Min ; Max 0 ; 65 0 ; 60 0 ; 65 0 ; 63 1 ; 61 0 ; 63 Age 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 TIP cohort Placebo Rilzabrutinib All Placebo TIDRilzabrutinib All BID 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 64 132 Mean (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 17.96 Q1;Q3 12.63 ; 14.96 ; 34.92 13.71 ; 11.08 ; 32.21 9.67; 29.08 10.38 ; 30.00 33.54 33.54 Min ; Max 1.3 ; 54.0 3.8 ; 56.5 1.3 ; 56.5 1.1 ; 55.8 1.8 ; 62.2 1.1 ; 62.2 With history of atopic medical conditions [n (%)] Number 32 32 64 68 64 132 Yes 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 64 132 Former 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 12 Mean (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 20.63 Q1;Q3 3.92 ; 32.17 12.29 ; 26.63 6.33 ; 31.21 9.33 ; 41.17 15.58 ; 25.42 9.33 ; 32.00 Min ; Max 0.8 ; 42.6 6.2 ; 30.3 0.8 ; 42.6 2.5 ;43.4 2.9 ; 38.6 2.5 ;43.4 Pack-year Number 8 4 12 6 6 12 Mean (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 4.000 Q1;Q3 0.400 ; 3.500 ; 5.500 0.900 ; 4.000 ; 7.500 1.000 ; 4.650 2.050 ; 5.750 2.400 3.500 Min ; Max 0.01 ; 3.00 3.00 ; 6.00 0.01 ; 6.00 1.60 ; 9.00 0.40 ; 6.50 0.40 ; 9.00 E-cigarette history [n (%)] Number 32 32 64 68 64 132 Former 0 0 0 0 0 0 Never 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 cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) All (N=64) Placebo Rilzabrutinib All (N=132) TID (N=68) 400 mg TID (N=64) ICS / LABA dose level [n (%)] Number 32 32 64 68 64 132 High 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 64 132 Mean (SD) 953.1 (148.1) 953.1 (265.2) 953.1 (213.0) 742.6 (251.7) 773.4 (250.9) 757.6 (250.8) Median 1000.0 1000.0 1000.0 500.0 1000.0 1000.0 Q1;Q3 1000.0 ; 1000.0 1000.0 ; 1000.0 1000.0 ; 1000.0 500.0 ; 1000.0 500.0 ; 1000.0 500.0 ; 1000.0 Min ; Max 500 ; 1000 500 ; 2000 500 ; 2000 500 ; 1000 500 ; 1000 500 ; 1000 LABA total daily dose (ug) Number 32 32 64 68 64 132 Mean (SD) 98.4 (8.8) 100.0 (22.0) 99.2 (16.6) 97.8 (18.2) 96.1 (13.5) 97.0 (16.1) Median 100.0 100.0 100.0 100.0 100.0 100.0 Q1;Q3 100.0 ; 100.0 100.0 ; 100.0 100.0 ; 100.0 100.0 ; 100.0 100.0 ; 100.0 100.0 ; 100.0 Min ; Max 50 ; 100 50 ; 200 50 ; 200 50 ; 200 50 ; 100 50 ; 200 Number of prescribed salbutamol / albuterol or levosalbutamol / levalbuterol (puffs) Number 19 23 42 53 47 100 Mean (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 1.0 Q1;Q3 1.0 ; 2.0 1.0; 2.0 1.0; 2.0 1.0 ; 2.0 1.0; 2.0 1.0 ; 2.0 Min ; Max 1 ;2 0 ; 8 0 ; 8 1 ; 20 1; 8 1 ; 20 Time since last asthma exacerbation (months) Number 32 32 64 68 64 132 Mean (SD) 6.94 (3.73) 7.69 (4.83) 7.31 (4.30) 8.51 (4.55) 9.64 (4.90) 9.06 (4.74) Median 6.00 7.00 6.00 8.00 9.00 8.00 Q1;Q3 4.00 ; 8.50 4.00 ; 10.00 4.00 ; 9.00 6.00 ; 11.00 6.00 ; 12.50 6.00 ; 11.50 Min ; Max 2.0 ; 15.0 2.0 ; 23.0 2.0 ; 23.0 1.0 ; 24.0 2.0 ; 24.0 1.0 ; 24.0 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) All (N=64) Placebo Rilzabrutinib All (N=132) TID (N=68) 400 mg TID (N=64) Number of asthma exacerbations experienced 2 years before the screening visit Number 32 32 64 68 64 132 Mean (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 1.0 Q1;Q3 1.0 ; 2.5 1.0; 2.5 1.0; 2.5 1.0 ; 1.5 1.0; 2.0 1.0 ; 2.0 Min ; Max 1; 8 1; 5 1; 8 1; 6 1; 5 1; 6 Number of asthma exacerbations experienced 2 years before the screening visit [n (%)] Number 32 32 64 68 64 132 1 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 64 132 Mean (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 1.0 Q1;Q3 1.0 ; 2.0 1.0; 2.0 1.0; 2.0 0.0 ; 1.0 0.0 ; 1.0 0.0 ; 1.0 Min ; Max 0 ;4 0 ; 3 0 ; 4 0 ; 3 0;4 0;4 Number of asthma exacerbations experienced 1 year before the screening visit [n (%)] Number 32 32 64 68 64 132 0 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 (16) 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 64 132 0 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 cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) All (N=64) Placebo Rilzabrutinib All (N=132) TID (N=68) 400 mg TID (N=64) Number of asthma exacerbations required hospitalization or emergency medical care within 2 years before the screening visit Number 32 32 64 68 64 132 Mean (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 0.0 Q1;Q3 0.0 ; 0.5 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0 Min ; Max 0 ; 7 0 ; 1 0 ; 7 0;2 0;2 0;2 Number of asthma exacerbations required hospitalization or emergency medical care within 2 years before the screening visit group [n (%)] Number 32 32 64 68 64 132 0 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 0 Number of asthma exacerbations required hospitalization or emergency medical care within 1 year before the screening visit Number 32 32 64 68 64 132 Mean (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 0.0 Q1;Q3 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0 0.0 ; 0.0 Min ; Max 0 ; 3 0 ; 1 0 ; 3 0 ; 1 0;2 0;2 Number of asthma exacerbations required hospitalization or emergency medical care within 1 year before the screening visit group [n (%)] Number 32 32 64 68 64 132 0 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 0 Pre-bronchodilator FEV1 (L) Number 32 31 63 67 63 130 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) All (N=64) Placebo Rilzabrutinib All (N=132) TID (N=68) 400 mg TID (N=64) Mean (SD) 2.16 2.11 (0.67) 2.13 2.42 2.50(0.95) 2.46 Median (0.77) 2.10 1.94 (0.72) 2.02 (0.90) 2.15 2.36 (0.92) 2.20 Q1;Q3 1.47 ; 1.59; 2.52 1.59 ; 1.77 ; 1.73 ; 3.10 1.75 ; Min ; Max 2.50 1.2 ; 3.9 1.0 ; 3.8 2.52 1.0 ; 3.9 2.98 1.0 ; 5.0 1.1 ; 5.3 3.03 1.0 ; 5.3 Pre-bronchodilator FEV1 percent predicted (%) Number 32 31 63 68 63 131 Mean (SD) 71.7 66.4(10.4) 69.1 76.0 75.7(16.2) 75.9 Median (12.7) 72.5 64.0 (11.8) 68.0 (16.7) 74.5 78.0 (16.4) 77.0 Q1;Q3 61.5 ; 58.0 ; 75.0 59.0 ; 62.5 ; 65.0 ; 85.0 64.0 ; Min ; Max 79.5 54 ; 115 50 ; 87 78.0 50 ; 115 87.0 50 ; 115 35 ; 118 86.0 35 ; 118 Pre-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 59 122 Mean (SD) 2.39 2.40 (0.75) 2.40 2.60 2.66 (0.98) 2.63 Median (0.77) 2.30 2.21 (0.76) 2.26 (0.91) 2.35 2.51 (0.94) 2.42 Q1;Q3 1.77 ; 1.96; 2.79 1.88 ; 1.94 ; 1.83 ; 3.27 1.91 ; Min ; Max 2.86 1.3 ; 4.3 1.2; 4.3 2.85 1.2; 4.3 3.03 1.1 ; 5.1 1.3 ; 5.3 3.08 1.1 ; 5.3 Post-bronchodilator FEV 1 percent predicted (%) Number 32 32 64 67 62 129 Mean (SD) 79.3 75.7(14.9) 77.5 82.0 81.9(14.9) 82.0 Median (12.9) 80.0 75.0 (13.9) 77.0 (16.2) 82.0 81.0 (15.5) 81.0 Q1;Q3 70.5 ; 64.0 ; 85.5 67.5 ; 68.0 ; 71.0 ; 91.0 70.0 ; Min ; Max 87.0 53 ; 111 50 ; 126 86.5 50 ; 126 93.0 50 ; 117 51 ; 122 91.0 50 ; 122 FEV 1 reversibility at screening (%) Number 30 32 62 67 64 131 Mean (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 19.000 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) All (N=64) Placebo Rilzabrutinib All (N=132) TID (N=68) 400 mg TID (N=64) Q1;Q3 14.000 ; 15.500 ; 15.000 ; 14.000 ; 15.700 ; 15.000 ; 29.000 35.500 30.600 26.000 28.825 27.000 Min ; Max 12.00 ; 46.00 10.00 ; 55.00 10.00 ; 55.00 -1.00 ; 105.00 12.20 ; 55.00 -1.00 ; 105.00 FEV1 reversibility (%) Number 30 29 59 60 56 116 Mean (SD) 11.364 (13.206) 12.927 (9.681) 12.132 (11.535) 7.142 (8.179) 7.932 (10.140) 7.523 (9.146) Median 8.329 13.632 9.396 4.708 5.539 5.239 Q1;Q3 4.079 ; 13.434 5.722 ; 18.199 4.977 ; 16.887 2.062 ; 10.190 1.105 ; 11.469 1.634 ; 10.658 Min ; Max -2.84 ; 67.78 -1.82 ; 33.42 -2.84 ; 67.78 -4.56 ; 33.53 -6.78 ; 53.68 -6.78 ; 53.68 Baseline 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 63 131 Mean (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 297.19 305.07 302.07 277.79 307.86 289.71 Q1;Q3 214.29 ; 211.46 ; 211.46 ; 212.10 ; 245.14 ; 227.43 ; 391.83 352.59 383.18 371.07 387.43 382.43 Min ; Max 148.6 ; 632.4 116.0 ; 611.1 116.0 ; 632.4 96.5 ; 631.3 144.8 ; 567.3 96.5 ; 631.3 PM PEF (L / min) Number 32 32 64 67 62 129 Mean (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 298.29 317.78 306.91 283.43 319.36 306.29 Q1;Q3 221.95 ; 220.92 ; 220.92 ; 218.33 ; 260.43 ; 234.29 ; 387.43 378.00 378.93 380.57 409.43 383.71 Min; Max 153.4 ; 651.6 135.6; 622.6 135.6; 651.6 99.7; 596.2 146.0; 557.6 99.7; 596.2 ACQ-5 score Number 32 32 64 68 64 132 Mean (SD) 2.19 (0.40) 2.04 (0.37) 2.12 (0.38) 2.18 (0.40) 2.24 (0.48) 2.21 (0.44) Median 2.20 2.00 2.00 2.20 2.20 2.20 Q1;Q3 2.00 ; 2.40 1.80; 2.20 1.80 ; 2.30 1.80 ; 2.40 2.00; 2.60 2.00 ; 2.60 Min ; Max 1.4 ; 3.2 1.4; 2.8 1.4 ; 3.2 1.2 ; 3.2 1.4; 4.0 1.2 ; 4.0 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) All (N=64) Placebo Rilzabrutinib All (N=132) TID (N=68) 400 mg TID (N=64) 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 62 129 Mean (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 4.81 Q1;Q3 4.13 ; 4.31 ; 5.64 4.13 ; 4.00 ; 4.38 ; 5.44 4.22 ; 5.59 5.59 5.41 5.41 Min ; Max 2.1 ; 6.2 2.4 ; 6.4 2.1 ; 6.4 2.8 ; 6.3 3.7 ; 6.6 2.8 ; 6.6 PGIS score Number 31 32 63 67 62 129 Mean (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 2.0 Q1;Q3 1.0 ; 2.0 1.0; 2.0 1.0; 2.0 1.0 ; 2.0 1.0; 2.0 1.0 ; 2.0 Min ; Max 1 ;2 0 ; 3 0 ; 3 0 ; 3 0;2 0 ; 3 Number of inhalations of salbutamol / albuterol or levosalbutamol / levalbuterol / 24 hours (puffs) Number 32 32 64 67 62 129 Mean (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 0.00 Q1;Q3 0.00 ; 0.00; 2.93 0.00 ; 0.00 ; 0.00 ; 1.00 0.00 ; 4.71 4.00 1.14 1.00 Min ; Max 0.0 ; 12.3 0.0 ; 7.4 0.0 ; 12.3 0.0 ; 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 TIP cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) All (N=64) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) All (N=132) Blood eosinophils (109 / L) Number 32 32 64 68 64 132 Mean (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 0.170 Q1;Q3 0.160 ; 0.140 ; 0.495 0.150 ; 0.100 ; 0.100 ; 0.325 0.100 ; 0.420 0.470 0.315 0.320 Min ; Max 0.02 ; 1.18 0.03 ; 1.59 0.02 ; 1.59 0.02 ; 1.51 0.04 ; 1.06 0.02 ; 1.51 Blood 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 62 126 Mean (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 17.5 Q1;Q3 13.0 ; 46.0 18.5 ; 39.5 15.0 ; 42.0 11.5 ; 31.0 11.0 ; 32.0 11.0 ; 32.0 Min ; Max 8 ; 161 11 ; 231 8 ; 231 5 ; 147 5 ; 85 5 ; 147 FeNO 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 64 132 Mean (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 281.05 178.40 210.80 119.65 132.65 121.85 Q1;Q3 88.70 ; 95.55 ; 682.20 93.30 ; 64.35 ; 40.00 ; 466.70 60.85 ; 718.35 708.25 366.40 410.25 Min ; Max 10.9 ; 7.9 ; 4030.0 7.9 ; 2.9 ; 3630.0 0.2; 4015.0 0.2; 4015.0 2413.0 4030.0 Total IgE level (lU / mL) [n (%)] 400 mg BID cohort 400 mg TID cohort Placebo Rilzabrutinib All Placebo Rilzabrutinib All BID (N=32) 400 mg BID (N=32) (N=64) TID (N=68) 400 mg TID (N=64) (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 64 132 Mean (SD) 12.325 (2.582) 11.941 (2.805) 12.133 (2.681) 11.546 (2.590) 11.643 (2.601) 11.593 (2.586) Median 12.210 11.645 12.020 10.985 11.385 11.205 Q1;Q3 10.640 ; 13.490 9.705 ; 14.055 10.160 ; 13.615 9.630 ; 12.920 9.830 ; 13.120 9.650 ; 13.100 Min ; Max 6.90 ; 20.46 7.59 ; 17.90 6.90 ; 20.46 6.63 ; 19.75 6.28 ; 19.80 6.28 ; 19.80 Total IgA (lU / mL) Number 32 32 64 68 64 132 Mean (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 2190.0 Q1;Q3 1570.0 ; 1785.0 ; 1695.0 ; 1585.0 ; 1650.0 ; 1640.0 ; 3295.0 3525.0 3470.0 3340.0 2990.0 3240.0 Min ; Max 360 ; 5640 890 ; 6690 360 ; 6690 730 ; 5100 930 ; 8950 730 ; 8950 Total IgM (lU / mL) Number 32 32 64 Mean (SD) 1.030 (0.525) 1.075 (0.579) 1.053 (0.549) 1.189 (0.683) 1.121 (0.718) 1.156 (0.698) Median 0.955 1.025 0.990 1.005 0.895 0.950 Q1;Q3 0.645 ; 1.285 0.610 ; 1.365 0.610 ; 1.330 0.800 ; 1.310 0.670 ; 1.360 0.730 ; 1.330 Min ; 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 cohort n (%) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) All (N=64) Placebo Rilzabrutinib All (N=132) TID (N=68) 400 mg TID (N=64) Any comorbidity history Number Yes Ongoing condition 32 29 (90.6) 29 (90.6) 32 29 (90.6) 28 (87.5) 64 58 (90.6) 57 (89.1) 68 48 (70.6) 48 (70.6) 64 44 (68.8) 44 (68.8) 132 92 (69.7) 92 (69.7) Atopic diseases Number Yes 32 17(53.1) 32 20 (62.5) 64 37 (57.8) 68 24 (35.3) 64 21 (32.8) 132 45 (34.1) 400 mg BID cohort 400 mg TID cohort Placebo Rilzabrutinib All Placebo Rilzabrutinib All (N=132) n (%) BID (N=32) 400 mg BID (N=32) (N=64) TID (N=68) 400 mg TID (N=64) Ongoing condition Atopy and type 2 diseases 16(50.0) 19 (59.4) 35 (54.7) 24 (35.3) 21 (32.8) 45 (34.1) Number 32 32 64 68 64 132 Yes 29 (90.6) 29 (90.6) 58 (90.6) 48 (70.6) 44 (68.8) 92 (69.7) Ongoing condition Atopic dermatitis history 29 (90.6) 28 (87.5) 57 (89.1) 48 (70.6) 44 (68.8) 92 (69.7) Number 32 32 64 68 64 132 Yes 2 (6.3) 2 (6.3) 4 (6.3) 2 (2.9) 0 2(1.5) Ongoing condition Allergic conjunctivitis and allergic rhinitis history 2 (6.3) 2 (6.3) 4 (6.3) 2 (2.9) 0 2(1.5) Number 32 32 64 68 64 132 Yes 4 (12.5) 3 (9.4) 7(10.9) 2 (2.9) 2(3.1) 4(3.0) Ongoing condition Allergic conjunctivitis history 4 (12.5) 3 (9.4) 7(10.9) 2 (2.9) 2(3.1) 4(3.0) Number 32 32 64 68 64 132 Yes 4 (12.5) 3 (9.4) 7(10.9) 2 (2.9) 2(3.1) 4(3.0) Ongoing condition Allergic rhinitis history 4 (12.5) 3 (9.4) 7(10.9) 2 (2.9) 2(3.1) 4(3.0) Number 32 32 64 68 64 132 Yes 16(50.0) 18 (56.3) 34 (53.1) 21 (30.9) 20 (31.3) 41 (31.1) Ongoing condition Chronic rhinosinusitis history 15 (46.9) 17(53.1) 32 (50.0) 21 (30.9) 20 (31.3) 41 (31.1) Number 32 32 64 68 64 132 Yes 6 (18.8) 5 (15.6) 11 (17.2) 3 (4.4) 4 (6.3) 7(5.3) Ongoing condition 6 (18.8) 5 (15.6) 11 (17.2) 3 (4.4) 4 (6.3) 7(5.3) 400 mg BID cohort 400 mg TID cohort Placebo Rilzabrutinib All Placebo Rilzabrutinib All (N=132) n (%) BID 400 mg BID (N=64) TID (N=68) 400 mg TID (N=32) (N=32) (N=64) Nasal polyposis history Number 32 32 64 68 64 132 Yes 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) condition Hypersensitivity to aspirin or other NSAID Number 32 32 64 68 64 132 Yes 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) condition Eosinophilic esophagitis history Number 32 32 64 68 64 132 Yes 0 0 0 0 0 0 Ongoing 0 0 0 0 0 0 condition Food allergy history Number 32 32 64 68 64 132 Yes 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) condition Hives history Number 32 32 64 68 64 132 Yes 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 condition Rubber sensitivity Number 32 32 64 68 64 132 Yes 1(3.1) 0 1 (1.6) 0 0 0 Ongoing 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 cohort Predefined categories Placebo Rilzabrutinib All Placebo Rilzabrutinib All Standardized Medication Name n (%) BID (N=32) 400 mg BID (N=32) (N=64) TID (N=68) 400 mg TID (N=64) (N=132) Any prior medications 32 (100) 32 (100) 64(100) 68 (100) 64 (100) 132 (100) Pre-screening background therapy 32 (100) 32 (100) 64(100) 68 (100) 64 (100) 132 (100) Salmeterol 15 (46.9) 9 (28.1) 24 (37.5) 10(14.7) 8 (12.5) 18 (13.6) Fluticasone 15 (46.9) 6 (18.8) 21 (32.8) 8 (11.8) 4 (6.3) 12(9.1) Fluticasone propionate; salmeterol xinafoate 5 (15.6) 11 (34.4) 16 (25.0) 26 (38.2) 30 (46.9) 56 (42.4) Fluticasone; salmeterol 4 (12.5) 6 (18.8) 10 (15.6) 1(1-5) 3 (4.7) 4 (3.0) Budesonide;formoterol fumarate 4 (12.5) 3 (9.4) 7(10.9) 8 (11.8) 8 (12.5) 16 (12.1) Beclometasone dipropionate;formoterol fumarate 2 (6.3) 2 (6.3) 4 (6.3) 14 (20.6) 7(10.9) 21 (15.9) Budesonide 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 furoate;vilanterol trifenatate 1(3.1) 1(3.1) 2(3.1) 1(1-5) 3 (4.7) 4 (3.0) Beclometasone dipropionate 0 0 0 2 (2.9) 0 2(1.5) 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 bromide;indacaterol acetate ;mometasone furoate 0 0 0 1(1-5) 0 1 (0.8) Systemic 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 (90.6) 31 (96.9) 60 (93.8) 66 (97.1) 61 (95.3) 127 (96.2) Salbutamol 29 (90.6) 31 (96.9) 60 (93.8) 66 (97.1) 60 (93.8) 126 (95.5) 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 cohort Predefined categories Placebo Rilzabrutinib All Placebo Rilzabrutinib All Standardized 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 hydrochloride Levocetirizine 2 (6.3) 0 2(3.1) 0 0 0 Azelastine 0 1(3.1) 1 (1.6) 0 0 0 Desloratadine 0 1(3.1) 1 (1.6) 0 0 0 Levocetirizine 0 0 0 1(1.5) 0 1 (0.8) dihydrochloride Mucolytics 0 2 (6.3) 2(3.1) 0 0 0 Carbocisteine 0 1(3.1) 1 (1.6) 0 0 0 Erdosteine 0 1(3.1) 1 (1.6) 0 0 0 Leukotriene receptor 1(3.1) 1(3.1) 2(3.1) 0 2(3.1) 2(1.5) antagonists or leukotriene synthesis inhibitors Montelukast sodium 1(3.1) 1(3.1) 2(3.1) 0 0 0 Azelastine 0 1(3.1) 1 (1.6) 0 0 0 Montelukast 0 0 0 0 2(3.1) 2(1.5) Anticholinergic 0 0 0 1(1.5) 0 1 (0.8) bronchodilators Ipratropium bromide 0 0 0 1(1-5) 0 1 (0.8) Other 1(3.1) 0 1 (1.6) 0 0 0 Doxofylline 1(3.1) 0 1 (1.6) 0 0 0 Hedera 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 cohort Predefined categories Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400 Standardized (N=32) 400 mg BID (N=68) mg TID Medication Name n (%) (N=32) (N=64) Any concomitant medications 32(100) 32 (100) 68 (100) 64 (100) Controller 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) 0 Antibiotics 0 3 (9.4) 0 0 Azithromycin 0 3 (9.4) 0 0 Leukotriene receptor antagonists or leukotriene synthesis inhibitors 0 0 0 0 400 mg BID cohort 400 mg TIP cohort Predefined categories Standardized Medication Name n (%) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Anticholinergic 0 0 1(1-5) 0 bronchodilators Ipratropium bromide 0 0 1(1-5) 0 Antihistamines and 3 (9.4) 1(3.1) 0 0 antiallergics Fexofenadine 1(3.1) 1(3.1) 0 0 hydrochloride Levocetirizine 2 (6.3) 0 0 0 Systemic steroid 4(12.5) 5 (15.6) 2 (2.9) 1 (1.6) Prednisone 1(3.1) 3 (9.4) 0 0 Betamethasone 0 1(3.1) 0 0 dipropionate Meprednisone 2 (6.3) 1(3.1) 1(1-5) 1 (1.6) Methylprednisolone 1(3.1) 1(3.1) 1(1-5) 0 Asthma 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 0 Carbocisteine 0 1(3.1) 0 0 Erdosteine 0 1(3.1) 0 0 Xanthines 0 0 1(1-5) 0 Theophylline 0 0 1(1-5) 0 PPI 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 cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Number of participants with LOAC Number No Yes Crude RRR vs. placebo 32 16(50.0) 16(50.0) 32 20 (62.5) 12(37.5) 25.0 68 48 (70.6) 20 (29.4) 64 52 (81.3) 12 (18.8) 36.1 OR vs. placebo (95% CI) P-value vs. placebo 0.570 (0.202, 1.608) 0.2880 0.584 (0.253, 1.349) 0.2083 RD vs. Placebo (95% CI) -0.123 (-0.361, 0.115) -0.088 (-0.238, 0.061) RR vs. placebo (95% CI) 0.756 (0.433, 1.319) 0.653 (0.348, 1.226) 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 cohort Deviation category Deviation term n (%) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Any critical or major protocol deviation with potential impact on the primary endpoint 2 (6.3) 1(3.1) 2 (2.9) 3 (4.7) Inclusion / exclusion criteria 0 0 1(1-5) 1(1-6) 400 mg BID cohort 400 mg TID cohort Deviation category Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib Deviation term n (%) (N=32) 400 mg BID (N=32) (N=68) 400 mg TID (N=64) Asthma Control Questionnaire 5-question version (ACQ-5) score of >4 during the screening period or <1.25 or >3.0 at V2. 0 0 1(1-5) 0 Participants with prebronchodilator FEV1 > 40% of predicted normal at V1. Prebronchodilator FEV 1 >= 50% but <= 85% of predicted normal at V2. 0 0 0 1(1-6) Concomitant medications / 2 (6.3) 1(3.1) 1(1-5) 2(3.1) therapy NIMP 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 cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Number of participants with LOAC Number 32 32 68 64 No 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 medication 8 (25.0) 6(18.8) 9(13.2) 1(1-6) Number of participants with >6 additional reliever puffs of salbutamol / albuterol or 4(12.5) 2 (6.3) 7(10.3) 0 levosalbutamol / levalbuterol in a 24 hour period (compared with baseline) on 2 consecutive days Number of participants with increase in ICS >4 times the 0 1(3.1) 0 0 last prescribed ICS dose (or >50% of the prescribed ICS dose at baseline if background therapy withdrawal completed) Number of participants requiring use of systemic (oral and / or parenteral) steroid treatment 4(12.5) 4(12.5) 2 (2.9) 1(1-6) Not triggered by use of rescue 8 (25.0) 6(18.8) 10 (14.7) 10(15.6) medication 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Number of participants with >30% reduction from baseline in AM PEF on 2 consecutive days 8 (25.0) 6(18.8) 10 (14.7) 10(15.6) Number of participants requiring hospitalization or emergency room visit 0 0 0 0 Intervention discontinuation due to lack of efficacy or an AE related to asthma worsening 0 0 1(1-5) 1(1-6)

[0223] Table 23. Supportive analysis: time to LOAC post-randomization (mITT population). 400 mg BID cohort 400 mg TIP cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Number of participants with LOAC 16 (50.0) 12(37.5) 20 (29.4) 12 (18.8) Number of participants censored 16 (50.0) 20 (62.5) 48 (70.6) 52 (81.3) Q1 of time to LOAC (days) (95% CI) 50.0(14.0, 72.0) 55.0 (19.0, 84.0) 78.0(52.0, NC) NC (44.0, NC) Median time to LOAC (days) (95% ci) 74.0 (64.0, NC) NC (73.0, NC) NC (87.0, NC) NC (NC, NC) Q3 of time to LOAC (days) (95% CI) Probability of LOAC (95% CI) at NC (NC, NC) NC (NC, NC) NC (NC, NC) NC (NC, NC) Week 4 0.129 (0.041, 0.270) 0.161 (0.059, 0.309) 0.045 (0.012, 0.115) 0.017 (0.001, 0.080) Week 9 0.330 (0.173, 0.496) 0.265 (0.125, 0.429) 0.168 (0.089, 0.267) 0.156 (0.077, 0.261) Week 12 HR vs. Placebo (95% CI) P-value vs. placebo 0.531 (0.341, 0.689) 0.432 (0.243, 0.607) 0.750 (0.352, 1.595) 0.4543 73 0.295 (0.189, 0.408) 0.211 (0.117, 0.325) 0.679 (0.327, 1.408) 0.2980 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) P-value vs. placebo 0.3948 0.2794 NE: 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 TIP cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Age group 1 (years) <45 Number 10 12 29 25 LOAC 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 0.0189 RD vs. Placebo 0.184 (-0.266, -0.299 (-0.505, - (95% CI) 0.634) 0.093) >45 Number 22 20 39 39 LOAC 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 0.7920 RD vs. Placebo -0.295 (-0.583, - 0.026 (-0.165, (95% CI) 0.007) 0.216) Overall p-value for 0.0738 0.0298 interaction Gender Male Number 8 14 27 25 LOAC 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 0.2721 RD vs. Placebo 0.256 (-0.420, -0.111 (-0.461, (95% CI) 0.931) 0.238) Female Number 24 18 41 39 LOAC 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 0.4042 400 mg BID cohort_____________400 mg TIP cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (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 interaction Baseline weight group (kg) <60 Number 4 3 12 2 LOAC 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 0.4823 RD vs. Placebo NC (NC, NC) 0.250 (-0.485, (95% CI) 0.985) > 60 -< 90 Number 25 23 40 41 LOAC 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 0.1860 RD vs. Placebo 0.035 (-0.244, -0.130(-0.319, (95% CI) 0.314) 0.059) >90 Number 3 6 16 21 LOAC 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 0.4147 RD vs. Placebo -0.333 (-0.987, -0.107 (-0.367, (95% CI) 0.320) 0.153) Overall p-value for 0.0116 0.4929 interaction Baseline BMI group (kg / m2) <25 Number 6 8 22 12 LOAC 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 0.5008 RD vs. Placebo -0.292 (-0.796, -0.114(-0.431, (95% CI) 0.213) 0.203) >25 - < 30 400 mg BID cohort_____________400 mg TIP cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Number 17 16 27 29 LOAC 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 0.0807 RD vs. Placebo -0.096 (-0.431, -0.193 (-0.398, (95% CI) 0.240) 0.012) >30 Number 9 8 19 23 LOAC 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 0.7034 RD vs. Placebo -0.069 (-0.536, 0.050 (-0.206, (95% CI) 0.397) 0.307) P-value vs. placebo 0.7706 0.2506 Region Eastern Europe Number 4 3 45 43 LOAC 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 0.1794 RD vs. Placebo -0.167 (-0.891, -0.125 (-0.303, (95% CI) 0.558) 0.053) Latin America Number 25 25 19 19 LOAC 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 0.7032 RD vs. Placebo -0.080 (-0.351, -0.053 (-0.322, (95% CI) 0.191) 0.217) Western Countries Number 1 2 2 2 LOAC 1 (100) 0 1 (50.0) 0 OR vs. placebo NC (NC, NC) NC (NC, NC) (95% CI) P-value vs. placebo NC NC RD vs. Placebo NC (NC, NC) NC (NC, NC) (95% CI) APAC Number 2 2 2 0 LOAC 2(100) 2(100) 0 0 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) OR vs. placebo NC (NC, NC) NC (NC, NC) (95% CI) P-value vs. placebo NC NC RD vs. Placebo NC (NC, NC) NC (NC, NC) (95% CI) Overall p-value for NC NC interaction LATAM: Latin America, ROW: Rest of the world

[0225] Table 25. Subgroup analysis: incidence of LOAC by disease and other characteristics subgroups (mlTT population). 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Age at onset of asthma (years) < 12 Number 7 9 15 14 LOAC 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 0.1352 RD vs. Placebo (95% CI) 0.159 (-0.308, -0.257 (-0.565, 0.625) 0.051) > 12-< 18 Number 2 5 5 5 LOAC 1 (50.0) 1 (20.0) 1 (20.0) 0 OR vs. placebo (95% CI) 0.250 (0.007, NC (NC, NC) 8.560) P-value vs. placebo 0.4419 NC RD vs. Placebo (95% CI) -0.300 (-1.077, NC (NC, NC) 0.477) > 18 -<40 Number 15 14 28 27 LOAC 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 0.2742 RD vs. Placebo (95% CI) -0.314 (-0.657, -0.135 (-0.372, 0.028) 0.102) >40 Number 8 4 20 18 LOAC 4 (50.0) 3 (75.0) 3 (15.0) 4 (22.2) 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) Overall p-value for interaction Age at onset of asthma (years) < 18 3.000 (0.211, 42.624) 0.4171 0.250 (-0.298, 0.798) 0.1351 1.619(0.309, 8.478) 0.5684 0.072 (-0.176, 0.320) 0.3189 Number 9 14 20 19 LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) > 18 3 (33.3) 5 (35.7) 1.402 (0.206, 9.530) 0.7295 0.126 (-0.346, 0.597) 7(35.0) 2 (10.5) 0.218 (0.039, 1.232) 0.0847 -0.245 (-0.495, 0.006) Number 23 18 48 45 LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) Overall p-value for interaction Number of asthma exacerbations within 2 years before screening visit 1 13 (56.5) 7(38.9) 0.323 (0.079, 1.322) 0.1160 -0.258 (-0.560, 0.045) 0.2794 13 (27.1) 10 (22.2) 0.769 (0.298, 1.986) 0.5876 -0.049 (-0.223, 0.126) 0.1729 Number 9 13 51 36 LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) 2 3 (33.3) 5 (38.5) 1.218 (0.176, 8.423) 0.8416 0.059 (-0.390, 0.508) 17 (33.3) 5 (13.9) 0.323 (0.106, 0.978) 0.0457 -0.194 (-0.366, -0.023) Number 15 11 16 23 LOAC OR vs. placebo (95% CI) P-value vs. placebo 9 (60.0) 4 (36.4) 0.471 (0.084, 2.634) 0.3917 3 (18.8) 7 (30.4) 1.896 (0.407, 8.824) 0.4149 400 mg BID cohort 400 mg TID cohort Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400 (N=32)     400 mg BID (N=68)       mg TID (N=32) (N=64) RD vs. Placebo (95? / oCI) -0.199 (-0.617, 0.219) 0.117 (-0.151, 0.385) >2 Number LOAC OR vs. placebo (95? P-value vs. placebo RD vs. Placebo (95? A CI) / oCI) 8 4 (50.0) 8 3 (37.5) 0.508 (0.044, 5.914) 0.5890 -0.115 (-0.780, 0.551) 1 0 5 0 NC (NC, NC) NC NC (NC, NC) Overall p-value for interaction 0.8727 NC Atopic medical conditions Yes Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) 17 8 (47.1) 20 8 (40.0) 0.681 (0.174, 2.666) 0.5815 -0.069 (-0.384, 0.246) 24 6(25.0) 21 4 (19.0) 0.821 (0.175, 3.846) 0.8026 -0.031 (-0.320, 0.257) No Number LOAC OR vs. placebo (95? P-value vs. placebo RD vs. Placebo (95? A CI) / oCI) 15 8 (53.3) 12 4(33.3) 0.380 (0.065, 2.206) 0.2809 -0.204 (-0.557, 0.149) 44 14 (31.8) 43 8 (18.6) 0.493 (0.180, 1.353) 0.1700 -0.130(-0.311, 0.051) Overall p-value for interaction 0.6695 0.6159 Background ICS dose level at randomization (400 mg TID only) Medium Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. placebo (95% CI) 35 14 (40.0) 29 6 (20.7) 0.421 (0.125, 1.414) 0.1615 -0.173 (-0.407, 0.061) High 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Number 33 35 LOAC 6(18.2) 6(17.1) OR vs. placebo (95% CI) 0.911 (0.253, 3.276) P-value vs. placebo 0.8867 RD vs. placebo (95% CI) -0.011 (-0.218, 0.195) Overall p-value for 0.3913 interaction Smoking history Former Number 8 4 6 6 LOAC 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 0.5603 RD vs. Placebo (95% CI) 0.250 (-0.298, -0.167 (-0.717, 0.798) 0.383) Never Number 24 28 62 58 LOAC 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 0.1853 RD vs. Placebo (95% CI) -0.179 (-0.443, -0.102 (-0.249, 0.086) 0.046) Overall p-value for 0.2175 0.7814 interaction Baseline pre-bronchodilator FEV1 (L) (400 mg BID only) < Median (2.022) Number 14 17 LOAC 7 (50.0) 7(41.2) OR vs. placebo (95% CI) 0.700 (0.168, 2.910) P-value vs. placebo 0.6237 RD vs. Placebo (95% CI) -0.088 (-0.439, 0.263) P-value vs. placebo 0.6224 > Median (2.022) Number 18 14 LOAC 9 (50.0) 5 (35.7) OR vs. placebo (95% CI) 0.556 (0.133, 2.325) 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) P-value vs. placebo RD vs. Placebo (95% CI) P-value vs. placebo 0.4209 -0.143 (-0.484, 0.198) 0.4117 Overall p-value for interaction 0.7743 Baseline pre-bronchodilator percent predicted FEV1 (%) (400 mg BID only) < Median (68) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) P-value vs. placebo 12 6 (50.0) 17 7(41.2) 0.700 (0.158, 3.099) 0.6384 -0.088 (-0.455, 0.279) 0.6376 > Median (68) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) P-value vs. placebo 20 10 (50.0) 14 5 (35.7) 0.556 (0.137, 2.256) 0.4110 -0.143 (-0.476, 0.190) 0.4007 Overall p-value for interaction 0.5557 Baseline pre-bronchodilator FEV1 (L)(400 mg TID only) < Median (2.1955) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. placebo (95% CI) 36 10 (27.8) 29 7(24.1) 0.827 (0.270, 2.536) 0.7401 -0.036 (-0.250, 0.177) > Median (2.1955) Number LOAC 31 10 (32.3) 34 5 (14.7) 400 mg BID cohort 400 mg TID cohort Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400 (N=32)     400 mg BID (N=68)       mg TID (N=32) (N=64) OR vs. placebo (95% CI) P-value vs. placebo RD vs. placebo (95% CI) 0.362 (0.108, 1.216) 0.1003 -0.176 (-0.379, 0.028) Overall p-value for interaction 0.3196 Baseline pre-bronchodilator percent predicted FEV1 group 1 (%) (400 mg TID only) < Median (77) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. placebo (95% CI) 36 9(25.0) 29 4 (13.8) 0.452 (0.118, 1.730) 0.2464 -0.129 (-0.394, 0.135) > Median (77) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. placebo (95% CI) 32 11 (34.4) 34 8 (23.5) 0.599 (0.185, 1.937) 0.3916 -0.078 (-0.320, 0.165) Overall p-value for interaction 0.6831 Baseline pre-bronchodilator percent predicted FEV 1 group 2 (%) (400 mg TID only) < 80 Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. placebo (95% CI) 41 10 (24.4) 37 7 (18.9) 0.736 (0.243, 2.229) 0.5884 -0.047 (-0.244, 0.149) > 80 Number LOAC 27 10 (37.0) 26 5 (19.2) 400 mg BID cohort 400 mg TID cohort Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib 400 (N=32)     400 mg BID (N=68)       mg TID (N=32) (N=64) OR vs. placebo (95% CI) 0.429 (0.112, 1.648) P-value vs. placebo 0.2176 RD vs. placebo (95% CI) -0.139(-0.406, 0.128) 0.5675 Overall p-value for interaction Baseline FEV1 reversibility (%) < 12 Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) 21 10 (47.6) 14 5 (35.7) 0.611 (0.152, 2.450) 0.4870 -0.119 (-0.449, 0.211) 48 14 (29.2) 43 9 (20.9) 0.643 (0.245, 1.684) 0.3685 -0.082 (-0.259, 0.095) > 12 Number 9 15 12 13 LOAC 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 0.4998 RD vs. Placebo (95% CI) -0.156 (-0.564, -0.090 (-0.346, 0.253) 0.166) Overall p-value for 0.8792 0.7503 interaction Baseline ACQ-5 score <2 Number 15 19 29 24 LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) 7 (46.7) 7(36.8) 0.651 (0.153, 2.769) 0.5608 -0.098 (-0.429, 0.233) 7(24.1) 6 (25.0) 1.162 (0.297, 4.543) 0.8289 0.025 (-0.209, 0.259) >2 Number 17 13 39 40 LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) 9 (52.9) 5 (38.5) 0.475 (0.090, 2.502) 0.3800 -0.125 (-0.473, 0.224) 13 (33.3) 6 (15.0) 0.346 (0.113, 1.060) 0.0632 -0.181 (-0.379, 0.018) 400 mg BID cohort 400 mg TID cohort Placebo BID Rilzabrutinib (N=32)     400 mg BID (N=32) Placebo TID Rilzabrutinib 400 (N=68)       mg TID (N=64) Overall p-value for interaction 0.7235 0.1501 LATAM: Latin America, ROW: Rest of the world

[0226] Table 26. Subgroup analysis: incidence of LOAC by baseline ICS / LABA dose level subgroups (mlTT population). Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Background ICS / LABA dose level at randomization Medium Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) P-value vs. placebo 3 2 (66.7) 5 1 (20.0) 0.125 (0.005, 3.225) 0.2099 -0.467 (-1.105, 0.172) 0.1519 High Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) P-value vs. placebo 29 14 (48.3) 27 11 (40.7) 0.737(0.256,2.122) 0.5713 -0.075 (-0.335, 0.184) 0.5695 Overall p-value for interaction 0.3273 LATAM: Latin America, ROW: Rest of the world

[0227] Table 27. Subgroup analysis: incidence of LOAC by baseline biomarker subgroups (mlTT population). 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Baseline IgE level (lU / mL) < 100 Number LOAC OR vs. placebo (95% CI) P-value vs. placebo 11 5 (45.5) 8 2(25.0) 0.412 (0.053, 3.217) 0.3977 84 27 7 (25.9) 23 4(17.4) 0.602 (0.151, 2.390) 0.4702 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) RD vs. Placebo (95% ci) -0.220 (-0.676, 0.236) -0.085 (-0.312, 0.141) > 100 Number LOAC OR vs. placebo (95% P-value vs. placebo RD vs. Placebo (95% ci) CI) 21 11 (52.4) 24 10 (41.7) 0.652 (0.192, 2.222) 0.4946 -0.092 (-0.376, 0.192) 41 13 (31.7) 41 8 (19.5) 0.522 (0.189, 1.440) 0.2093 -0.122 (-0.309, 0.065) Overall p-value for interaction 0.6260 0.9272 Baseline median IgE level (lU / mL) (400 mg BID only) < Median (210.8) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) P-value vs. placebo 13 5 (38.5) 19 6(31.6) 0.744 (0.161, 3.434) 0.7042 -0.053 (-0.393, 0.286) 0.7585 > Median (210.8) Number LOAC OR vs. placebo (95% P-value vs. placebo RD vs. Placebo (95% P-value vs. placebo CI) CI) 19 11 (57.9) 13 6 (46.2) 0.604 (0.136, 2.679) 0.5067 -0.124 (-0.482, 0.233) 0.4960 Overall p-value for interaction 0.9289 Baseline median IgA level (lU / mL) (400 mg BID only) < Median (2600) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) 15 9 (60.0) 17 4(23.5) 0.205 (0.045, 0.942) 0.0416 -0.365 (-0.684, -0.045) 400 mg BID cohort 400 mg TID cohort Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32)     400 mg BID (N=68)     400 mg TID (N=32) (N=64) P-value vs. placebo 0.0253 > Median (2600) Number 17 15 LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) P-value vs. placebo Overall p-value for interaction Baseline median IgE level (lU / mL) (400 mg TID only) < Median (121.85) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. placebo (95% CI) > Median (121.85) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. placebo (95% CI) Overall p-value for interaction Baseline median IgA level (mg / L) (400 mg TID only) < Median (2190) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. placebo (95% CI) > Median (2190) 7(41.2)        8(53.3) 1.633 (0.402, 6.625) 0.4927 0.122 (-0.223, 0.466) 0.4888 0.0553 34            32 9(26.5)        6(18.8) 0.681 (0.209, 2.219) 0.5236 -0.070 (-0.274, 0.135) 34            32 11(32.4)       6(18.8) 0.510 (0.156, 1.672) 0.2663 -0.122 (-0.356, 0.112) 0.7981 34            32 9(26.5)        6(18.8) 0.774 (0.217, 2.765) 0.6933 -0.011 (-0.239, 0.218) 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. placebo (95% CI) 34 11 (32.4) 32 6(18.8) 0.514 (0.160, 1.646) 0.2622 -0.120 (-0.347, 0.107) Overall p-value for interaction 0.6801 Baseline blood eosinophil level 1 (10A9 / L) <0.15 Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) P-value vs. placebo 6 3 (50.0) 8 2(25.0) 0.527 (0.017, 16.019) 0.7133 -0.135 (-0.945, 0.675) 0.7433 29 8 (27.6) 28 6(21.4) 0.716 (0.212, 2.415) 0.5900 -0.062 (-0.284, 0.161) >0.15 (400 mg BID only) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) P-value vs. placebo 26 13 (50.0) 23 10 (43.5) 0.737 (0.221, 2.453) 0.6186 -0.077 (-0.361, 0.207) 0.5938 Overall p-value for interaction 0.4802 >0.15 -<0.3 (400 mg TID only) Number LOAC OR vs. placebo (95% CI) P-value vs. placebo RD vs. placebo (95% CI) 20 3 (15.0) 18 4 (22.2) 1.619 (0.309, 8.478) 0.5684 0.072 (-0.176, 0.320) > 0.3 (400 mg TID only) Number LOAC 19 9 (47.4) 18 2(11.1) 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) OR vs. placebo (95% CI) 0.139 (0.025, 0.779) P-value vs. placebo 0.0248 RD vs. placebo (95% CI) -0.363 (-0.630, - 0.095) Overall p-value for 0.1249 interaction Baseline blood eosinophil level 2 (10A9 / L) <0.3 Number 19 17 49 46 LOAC 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 0.9711 RD vs. Placebo (95% CI) -0.197 (-0.567, 0.047 (-0.153, 0.174) 0.247) >0.3 Number 13 14 19 18 LOAC 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 0.0316 RD vs. Placebo (95% CI) -0.013 (-0.398, -0.350 (-0.653, - 0.372) 0.047) Overall p-value for 0.2298 0.0574 interaction Baseline FeNO level 1 (ppb) <25 Number 15 12 42 42 LOAC 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 0.2682 RD vs. Placebo (95% CI) -0.227 (-0.621, -0.065 (-0.275, 0.166) 0.145) >25 Number 16 20 22 20 LOAC 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 0.7903 RD vs. Placebo (95% CI) -0.007 (-0.333, -0.053 (-0.313, 0.320) 0.207) 400 mg BID cohort 400 mg TID cohort Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32)     400 mg BID (N=68)     400 mg TID (N=32) (N=64) Overall p-value for interaction 0.2742 0.6308 Baseline FeNO level 2 (ppb) <35 Number 19              21 50            47 LOAC 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 0.3965 RD vs. Placebo (95% CI) -0.198 (-0.502, -0.029 (-0.221, 0.106) 0.162) >35 Number 12               11 14              15 LOAC 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 0.6038 RD vs. Placebo (95% CI) -0.053 (-0.451, -0.094 (-0.398, 0.345) 0.210) Overall p-value for 0.1981 0.9120 interaction LATAM: Latin America, ROW: Rest of the world

[0228] Table 28. Subgroup analysis: incidence of LOAC in the baseline low EOS and low FeNO subgroup (mlTT population). 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Baseline blood eosinophil (10A9 / L) and FeNO (ppb) Low EOS (< 0.15) and low FeNO (< 25) Number 4 3 23 21 LOAC 3 (75.0) 0 8 (34.8) 4(19.0) OR vs. placebo (95% CI) P-value vs. placebo RD vs. Placebo (95% CI) All others Number 27 NC (NC, NC) NC NC (NC, NC) 28 41 0.441 (0.110, 1.765) 0.2474 -0.157 (-0.414, 0.100) 41 LOAC 13 (48.1) 12 (42.9) 10 (24.4) 8 (19.5) 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (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 0.5942 RD vs. Placebo (95% CI) -0.053 (-0.316, -0.049 (-0.228, 0.210) 0.130) P-value vs. placebo 0.6933 0.4970 LATAM: Latin America, ROW: Rest of the world FEV1

[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 pre bronchodilator FEV1 (L) at Week 12, reduced model (mITT population). 400 mg BID cohort 400 mg TID cohort Pre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400 FEV1 (L) (N=32) mg BID (N=68) mg TID (N=32) (N=64) Baseline Number 32 31 Mean (SD) 2.16(0.77) 2.11 (0.67) 67 63 Median 2.10 1.94 2.42 (0.90) 2.50(0.95) Q1;Q3 1.47; 2.50 1.59 ; 2.52 2.15 2.36 Min ; Max 1.2 ; 3.9 1.0 ; 3.8 1.77; 2.98 1.73 ; 3.10 1.0 ; 5.0 1.1 ; 5.3 Week 12 Number 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 2.39 Min ; Max 1.0 ; 3.6 0.6 ; 3.8 1.76 ; 3.10 1.86; 2.80 0.9 ; 5.0 1.1 ; 4.5 Change from baseline Number 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 -0.12 Q1;Q3 -0.18 ; 0.10 -0.21 ; 0.12 -0.21 ; 0.06 -0.28 ; 0.05 Min ; Max -0.6 ; 0.3 -1.0 ; 0.7 -0.7 ; 1.2 -1.1 ; 0.4 LS 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 cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo 0.01 (-0.17, 0.19) 0.9466 -0.09 (-0.21, 0.03) LATAM: 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 cohort Pre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400 FEV1 (L) (N=32) mg BID (N=68) mg TID (N=32) (N=64) Baseline Number 32 31 67 63 Mean (SD) 2.16(0.77) 2.11 (0.67) 2.42 (0.90) 2.50(0.95) Median 2.10 1.94 2.15 2.36 Q1;Q3 1.47; 2.50 1.59 ; 2.52 1.77 ; 2.98 1.73 ; 3.10 Min ; Max 1.2 ; 3.9 1.0 ; 3.8 1.0 ; 5.0 1.1 ; 5.3 Week 12 Number 16 21 45 46 Mean (SD) 2.03 (0.69) 2.01 (0.83) 2.37 (0.83) 2.46 (0.81) Median 1.78 1.88 2.22 2.40 Q1;Q3 1.61 ; 2.40 1.57 ; 2.30 1.76 ; 2.82 1.89; 2.80 Min ; Max 1.0 ; 3.3 0.6 ; 3.8 0.9 ; 4.1 1.1 ; 4.5 Change from baseline Number 16 20 44 45 Mean (SD) -0.03 (0.21) -0.02 (0.41) -0.07 (0.34) -0.14 (0.27) Median -0.06 -0.04 -0.06 -0.09 Q1;Q3 -0.16 ; 0.17 -0.22 ; 0.32 -0.27 ; 0.06 -0.28 ; 0.05 Min ; Max -0.4 ; 0.3 -1.0 ; 0.7 -0.7 ; 1.2 -1.1 ; 0.4 LS 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. placebo 0.9747 0.2225 LATAM: 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 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Baseline Number 32 31 Mean (SD) 2.16(0.77) 2.11 (0.67) Median 2.10 1.94 Q1;Q3 1.47; 2.50 1.59 ; 2.52 Min; Max 1.2; 3.9 1.0; 3.8 Week 2 Number 28 27 Mean (SD) 2.23 (0.77) 2.20 (0.68) Median 2.15 2.08 Q1;Q3 1.68 ; 2.63 1.79 ; 2.64 Min ; Max 1.2; 4.0 1.0 ; 4.0 Change from baseline Number 28 26 Mean (SD) 0.07 (0.29) 0.08 (0.29) Median 0.05 0.04 Q1;Q3 -0.05 ; 0.18 -0.08 ; 0.22 Min ; Max -0.7 ; 0.8 -0.6 ; 0.6 Percent change from baseline Number 28 26 Mean (SD) 4.24 (15.23) 4.47 (12.91) Median 1.71 2.02 Q1;Q3 -2.49 ; 9.97 -2.56 ; 11.40 Min ; Max -29.8 ; 45.4 -19.9 ; 38.3 Week 4 Number 24 25 Mean (SD) 2.24 (0.75) 2.05 (0.62) Median 2.11 1.96 Q1;Q3 1.73 ; 2.73 1.70 ; 2.36 Min ; Max 1.0 ; 3.9 1.0 ; 3.3 Change from baseline Number 24 25 Mean (SD) 0.08 (0.29) 0.07 (0.24) Median 0.02 0.02 Q1;Q3 -0.08 ; 0.19 -0.07 ; 0.17 Min ; Max -0.4 ; 0.9 -0.3 ; 0.6 Percent change from baseline Number 24 25 Mean (SD) 4.31 (16.19) 3.72 (12.19) Median 0.51 0.55 Q1;Q3 -5.00 ; 8.08 -4.02 ; 11.68 92 Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Min ; Max -17.9 ; 54.0 -16.7 ; 30.7 Week 6 Number 27 23 Mean (SD) 2.08 (0.67) 2.24 (0.79) Median 2.19 2.01 Q1;Q3 1.46; 2.53 1.56 ; 2.71 Min ; Max 1.0 ; 3.5 1.0 ; 3.9 Change from baseline Number 27 22 Mean (SD) 0.05 (0.33) 0.09 (0.39) Median 0.07 0.07 Q1;Q3 -0.13 ; 0.18 -0.11 ; 0.25 Min ; Max -0.7 ; 0.9 -0.7 ; 1.2 Percent change from baseline Number 27 22 Mean (SD) 3.38 (17.82) 3.99 (17.73) Median 2.56 3.66 Q1;Q3 -5.05 ; 12.12 -4.84 ; 11.59 Min ; Max -35.5 ; 53.4 -27.7 ; 44.3 Week 8 Number 24 20 Mean (SD) 2.05 (0.68) 2.10 (0.85) Median 2.03 1.83 Q1;Q3 1.49; 2.45 1.51 ; 2.51 Min ; Max 0.9 ; 3.6 0.9 ; 3.9 Change from baseline Number 24 19 Mean (SD) 0.04 (0.24) 0.08 (0.41) Median -0.01 0.11 Q1;Q3 -0.12 ; 0.19 -0.07 ; 0.28 Min ; Max -0.3 ; 0.7 -1.1 ; 0.7 Percent change from baseline Number 24 19 Mean (SD) 2.52(14.71) 3.28 (18.63) Median -0.52 3.73 Q1;Q3 -5.85 ; 7.52 -4.40 ; 17.61 Min ; Max -25.8 ; 41.1 -42.2 ; 27.5 Week 10 Number 21 17 Mean (SD) 2.03 (0.75) 2.29 (0.76) Median 1.99 1.93 Q1;Q3 1.57; 2.40 1.78 ; 2.57 Min ; Max 0.8 ; 3.8 1.6 ; 4.2 Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Change from baseline Number 21 16 Mean (SD) 0.03 (0.29) 0.21 (0.29) Median -0.05 0.12 Q1;Q3 -0.17 ; 0.23 -0.01 ; 0.42 Min ; Max -0.4 ; 0.8 -0.2 ; 0.7 Percent change from baseline Number 21 16 Mean (SD) 1.05 (15.30) 10.71 (16.43) Median -1.77 4.52 Q1;Q3 -8.09 ; 13.55 -0.45 ; 24.37 Min ; Max -28.7; 28.2 -11.9 ; 45.6 Week 12 Number 16 21 Mean (SD) 2.03 (0.69) 2.01 (0.83) Median 1.78 1.88 Q1;Q3 1.61 ; 2.40 1.57 ; 2.30 Min ; Max 1.0 ; 3.3 0.6 ; 3.8 Change from baseline Number 16 20 Mean (SD) -0.03 (0.21) -0.02 (0.41) Median -0.06 -0.04 Q1;Q3 -0.16 ; 0.17 -0.22 ; 0.32 Min ; Max -0.4 ; 0.3 -1.0 ; 0.7 Percent change from baseline Number 16 20 Mean (SD) -0.55 (11.79) -2.63 (21.27) Median -2.60 -2.04 Q1;Q3 -10.10 ; 9.07 -11.09 ; 12.57 Min ; Max -18.0; 23.4 -54.6 ; 32.7 Week 16 Number 19 19 Mean (SD) 2.21 (0.80) 2.30 (0.84) Median 2.09 2.01 Q1;Q3 1.48 ; 2.66 1.80 ; 2.67 Min ; Max 1.0 ; 3.8 0.9 ; 4.2 Change from baseline Number 19 18 Mean (SD) 0.06 (0.29) 0.29 (0.37) Median 0.12 0.28 Q1;Q3 -0.12 ; 0.28 -0.03 ; 0.44 Min ; Max -0.7 ; 0.6 -0.3 ; 1.1 Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Percent change from baseline Number 19 18 Mean (SD) 2.89 (15.39) 13.96 (17.98) Median 4.48 15.23 Q1;Q3 -5.52 ; 9.15 -1.39; 22.70 Min ; 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 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Baseline Number 32 31 Mean (SD) 2.16(0.77) 2.11 (0.67) Median 2.10 1.94 Q1;Q3 1.47; 2.50 1.59 ; 2.52 Min ; Max 1.2 ; 3.9 1.0 ; 3.8 Week 2 Number 29 27 Mean (SD) 2.20 (0.77) 2.20 (0.68) Median 2.13 2.08 Q1;Q3 1.66; 2.55 1.79 ; 2.64 Min ; Max 1.2; 4.0 1.0 ; 4.0 Change from baseline Number 29 26 Mean (SD) 0.07 (0.29) 0.08 (0.29) Median 0.03 0.04 Q1;Q3 -0.04 ; 0.17 -0.08 ; 0.22 Min ; Max -0.7 ; 0.8 -0.6 ; 0.6 Percent change from baseline Number 29 26 Mean (SD) 4.12 (14.97) 4.47 (12.91) Median 1.16 2.02 Q1;Q3 -2.46 ; 8.38 -2.56 ; 11.40 Min; Max -29.8 ; 45.4 -19.9; 38.3 Week 4 Number 25 25 Mean (SD) 2.29 (0.79) 2.05 (0.62) Median 2.12 1.96 Q1;Q3 1.79; 2.75 1.70 ; 2.36 Min ; Max 1.0 ; 3.9 1.0 ; 3.3 Change from baseline Number 25 25 Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Mean (SD) 0.09 (0.28) 0.07 (0.24) Median 0.03 0.02 Q1;Q3 -0.08 ; 0.19 -0.07 ; 0.17 Min ; Max -0.4 ; 0.9 -0.3 ; 0.6 Percent change from baseline Number 25 25 Mean (SD) 4.36 (15.85) 3.72(12.19) Median 0.66 0.55 Q1;Q3 -4.25 ; 7.82 -4.02 ; 11.68 Min ; Max -17.9 ; 54.0 -16.7 ; 30.7 Week 6 Number 29 24 Mean (SD) 2.11 (0.70) 2.24 (0.78) Median 2.19 2.06 Q1;Q3 1.51 ; 2.53 1.63 ; 2.64 Min ; Max 1.0 ; 3.5 1.0 ; 3.9 Change from baseline Number 29 23 Mean (SD) 0.07 (0.33) 0.10 (0.39) Median 0.07 0.07 Q1;Q3 -0.06 ; 0.18 -0.11 ; 0.33 Min ; Max -0.7 ; 0.9 -0.7 ; 1.2 Percent change from baseline Number 29 23 Mean (SD) 4.36 (18.18) 4.61 (17.58) Median 2.56 5.14 Q1;Q3 -4.60 ; 12.12 -4.84 ; 13.93 Min ; Max -35.5 ; 53.4 -27.7 ; 44.3 Week 8 Number 24 21 Mean (SD) 2.05 (0.68) 2.08 (0.83) Median 2.03 1.86 Q1;Q3 1.49; 2.45 1.52 ; 2.45 Min ; Max 0.9 ; 3.6 0.9 ; 3.9 Change from baseline Number 24 20 Mean (SD) 0.04 (0.24) 0.08 (0.40) Median -0.01 0.09 Q1;Q3 -0.12 ; 0.19 -0.06 ; 0.25 Min ; Max -0.3 ; 0.7 -1.1 ; 0.7 Percent change from baseline Number 24 20 Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Mean (SD) 2.52 (14.71) 3.30 (18.14) Median -0.52 3.64 Q1;Q3 -5.85 ; 7.52 -4.06 ; 14.97 Min ; Max -25.8 ; 41.1 -42.2 ; 27.5 Week 10 Number 24 17 Mean (SD) 1.96 (0.74) 2.29 (0.76) Median 1.97 1.93 Q1;Q3 1.40; 2.33 1.78 ; 2.57 Min ; Max 0.8 ; 3.8 1.6 ; 4.2 Change from baseline Number 24 16 Mean (SD) -0.02 (0.30) 0.21 (0.29) Median -0.10 0.12 Q1;Q3 -0.18 ; 0.20 -0.01 ; 0.42 Min ; Max -0.5 ; 0.8 -0.2 ; 0.7 Percent change from baseline Number 24 16 Mean (SD) -1.48 (16.21) 10.71 (16.43) Median -5.47 4.52 Q1;Q3 -9.15 ; 13.20 -0.45 ; 24.37 Min ; Max -30.1 ; 28.2 -11.9 ; 45.6 Week 12 Number 19 23 Mean (SD) 2.13 (0.71) 1.97 (0.81) Median 2.04 1.82 Q1;Q3 1.67; 2.47 1.43 ; 2.30 Min ; Max 1.0 ; 3.5 0.6 ; 3.8 Change from baseline Number 19 22 Mean (SD) -0.04 (0.20) -0.03 (0.40) Median -0.08 -0.05 Q1;Q3 -0.19 ; 0.14 -0.23 ; 0.31 Min ; Max -0.4 ; 0.3 -1.0 ; 0.7 Percent change from baseline Number 19 22 Mean (SD) -1.25 (11.01) -3.27 (20.46) Median -2.79 -2.70 Q1;Q3 -8.91 ; 8.26 -11.12 ; 9.91 Min ; Max -18.0; 23.4 -54.6 ; 32.7 Week 16 Number 19 19 Mean (SD) 2.21 (0.80) 2.30 (0.84) 97 Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Median 2.09 2.01 Q1;Q3 1.48 ; 2.66 1.80 ; 2.67 Min ; Max 1.0 ; 3.8 0.9 ; 4.2 Change from baseline Number 19 18 Mean (SD) 0.06 (0.29) 0.29 (0.37) Median 0.12 0.28 Q1;Q3 -0.12; 0.28 -0.03 ; 0.44 Min ; Max -0.7 ; 0.6 -0.3 ; 1.1 Percent change from baseline Number 19 18 Mean (SD) 2.89 (15.39) 13.96 (17.98) Median 4.48 15.23 Q1;Q3 -5.52 ; 9.15 -1.39; 22.70 Min ; Max -33.5 ; 34.5 -12.4 ; 57.3 All 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 cohort Pre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400 FEV1 (L) (N=32) mg BID (N=68) mg TID (N=32) (N=64) Baseline Number 32 31 67 63 Mean (SD) 2.16(0.77) 2.11 (0.67) 2.42 (0.90) 2.50 (0.95) Median 2.10 1.94 2.15 2.36 Q1;Q3 1.47; 2.50 1.59; 2.52 1.77 ; 2.98 1.73 ; 3.10 Min ; Max 1.2 ; 3.9 1.0 ; 3.8 1.0 ; 5.0 1.1 ; 5.3 Week 2 Number 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 2.37 Q1;Q3 1.66; 2.55 1.79; 2.64 1.75 ; 3.07 1.76; 3.06 Min ; Max 1.2; 4.0 1.0 ; 4.0 1.0 ; 5.2 1.1 ;4.1 Change from baseline Number 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 -0.02 Q1;Q3 -0.04 ; 0.17 -0.08 ; 0.22 -0.12 ; 0.15 -0.17 ; 0.10 98 400 mg BID cohort 400 mg TID cohort Pre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400 FEV1 (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 ; 0.7 LS 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. placebo 0.9752 0.3401 Week 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 2.50 Q1;Q3 1.66; 2.75 1.70; 2.56 1.75 ; 3.12 1.82 ; 3.14 Min ; Max 1.0 ; 3.9 1.0 ; 3.3 1.0 ; 5.3 1.2 ; 4.8 Change from baseline Number 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 -0.01 Q1;Q3 -0.08 ; 0.18 -0.07 ; 0.17 -0.17 ; 0.13 -0.13 ; 0.13 Min ; Max -0.4 ; 0.9 -0.3 ; 0.6 -0.9 ; 0.8 -0.5 ; 0.6 LS 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. placebo 0.8701 0.3010 Week 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 2.37 Q1;Q3 1.46; 2.53 1.70; 2.64 1.65 ; 2.97 1.84 ; 3.17 Min ; Max 1.0 ; 3.6 1.0 ; 3.9 1.0 ; 5.0 1.0 ; 4.8 Change from baseline Number 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 -0.09 Q1;Q3 -0.06 ; 0.18 -0.10 ; 0.22 -0.22 ; 0.08 -0.23 ; 0.08 Min ; Max -0.7 ; 0.9 -0.7 ; 1.2 -0.6 ; 0.4 -1.3 ; 0.9 LS Mean (SE) -0.00 (0.08) -0.03 (0.08) -0.11 (0.04) -0.07 (0.04) 99 400 mg BID cohort 400 mg TID cohort Pre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400 FEV1 (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-value vs. placebo 0.7797 0.4831 Week 8 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 2.38 Q1;Q3 1.44; 2.48 1.51 ; 2.58 1.60 ; 3.03 1.81 ; 2.96 Min ; Max 0.9 ; 3.6 0.9 ; 3.9 0.7 ; 5.0 1.1 ; 4.3 Change from baseline Number 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 -0.10 Q1;Q3 -0.12 ; 0.13 -0.09 ; 0.23 -0.26 ; 0.04 -0.21 ; 0.08 Min ; Max -0.6 ; 0.7 -1.1 ; 0.7 -0.6 ; 0.4 -2.3 ; 0.6 LS 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. placebo 0.7849 0.6679 Week 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 2.50 Q1;Q3 1.38 ; 2.40 1.76; 2.57 1.62 ; 2.98 1.78 ; 3.15 Min ; Max 0.8 ; 3.8 1.3 ; 4.2 0.9 ; 5.0 1.1 ; 4.4 Change from baseline Number 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 -0.09 Q1;Q3 -0.17 ; 0.18 -0.05 ; 0.36 -0.25 ; 0.05 -0.26 ; 0.09 Min ; Max -0.6 ; 0.8 -0.7 ; 0.7 -1.0 ; 0.6 -1.0 ; 0.4 LS Mean (SE) -0.05 (0.08) 0.02 (0.09) -0.10(0.04) -0.09 (0.04) LS Mean Diff vs. placebo (95% CI) 0.06 (-0.13,0.26) 0.00 (-0.10,0.11) 400 mg BID cohort 400 mg TID cohort Pre-bronchodilator Placebo BID Rilzabrutinib 400 Placebo TID Rilzabrutinib 400 FEV1 (L) (N=32) mg BID (N=68) mg TID (N=32) (N=64) P-value vs. placebo 0.5282 0.9509 Week 12 Number 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 2.39 Q1;Q3 1.44; 2.33 1.57; 2.57 1.76 ; 3.10 1.86 ; 2.80 Min ; Max 1.0 ; 3.6 0.6 ; 3.8 0.9 ; 5.0 1.1 ; 4.5 Change from baseline Number 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 -0.12 Q1;Q3 -0.18 ; 0.10 -0.21 ; 0.12 -0.21 ; 0.06 -0.28 ; 0.05 Min ; Max -0.6 ; 0.3 -1.0 ; 0.7 -0.7 ; 1.2 -1.1 ; 0.4 LS 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. placebo 0.9466 0.1523 LATAM: Latin America, ROW: Rest of the world

[0235] Table 34. Subgroup analysis: change from baseline in pre-bronchodilator FEV1 (L) at EOT (Week 12) by demographics subgroups (mITT population). 400 mg BID cohort 400 mg TID cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Age group 1 (years) <45 Number 8 9 26 22 Mean (SD) -0.06 (0.21) -0.05 (0.52) -0.07 (0.24) -0.24 (0.34) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.01 (0.19) -0.13 (0.19) -0.13 (-0.60, 0.35) 0.6056 -0.06 (0.08) -0.24 (0.08) -0.18 (-0.38, 0.02) 0.0756 >45 Number 17 16 28 26 Mean (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 TIP cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (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 0.8854 Overall p-value for interaction 0.9627 0.1988 Gender Male Number 6 11 22 21 Mean (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 0.3923 Female Number 19 14 32 27 Mean (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 0.2138 Overall p-value for interaction 0.7567 0.9813 Baseline weight group (kg) <60 Number 4 3 3 0 Mean (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 28 Mean (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 18 Mean (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 0.5184 400 mg BID cohort_________400 mg TIP cohort Pre-bronchodilator FEV1 (L) Placebo BID Rilzabrutinib (N=32)    400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Overall p-value for interaction 0.8383 0.9293 Baseline BMI group (kg / m2) <25 Number 5              7 19 8 Mean (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 - < 30 Number 14            12 20 25 Mean (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 >30 Number 6              6 15 15 Mean (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 0.5078 Overall p-value for interaction 0.7816 0.6728 Region Eastern Europe Number 4                1 38 32 Mean (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 0.2618 Latin America Number 19            21 14 14 Mean (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 0.3256 Western Countries Number 1                2 1 2 Mean (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 cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo NC (NC, NC) NC NC (NC, NC) NC APAC Number 1 1 1 0 Mean (SD) -0.07 (NC) -0.09 (NC) 0.02 (NC) NC (NC) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo Overall p-value for interaction NC (NC) NC (NC) NC (NC, NC) NC 0.8887 NC (NC) NC (NC) NC (NC, NC) NC 0.8187 LATAM: Latin America, ROW: Rest of the world

[0236] Table 35. Subgroup analysis: change from baseline in pre-bronchodilator FEV1 (L) at EOT (Week 12) by disease and other characteristics subgroups (mITT population). 400 mg BID cohort 400 mg TID cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Age at onset of asthma (years) < 12 Number 7 8 12 11 Mean (SD) -0.08 (0.21) 0.00 (0.48) -0.07 (0.25) -0.25 (0.38) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.06 (0.25) 0.12 (0.32) 0.18 (-0.43, 0.80) 0.5568 -0.05 (0.10) -0.34 (0.11) -0.28 (-0.58, 0.01) 0.0576 > 12-< 18 Number 1 4 5 4 Mean (SD) -0.01 (NC) 0.12 (0.29) 0.31 (0.56) -0.01 (0.38) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo NC (NC) NC (NC) NC (NC, NC) NC 0.45 (0.42) 0.05 (0.41) -0.40 (-1.36, 0.57) 0.4199 > 18 -<40 Number 11 11 23 21 Mean (SD) -0.06 (0.28) -0.08 (0.36) -0.13 (0.30) -0.17 (0.23) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.14(0.13) -0.14(0.13) 0.00 (-0.29, 0.29) 0.9979 -0.10(0.06) -0.18 (0.07) -0.08 (-0.24, 0.09) 0.3506 400 mg BID cohort 400 mg TID cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) >40 Number 6 2 14 12 Mean (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 0.5330 Overall p-value for interaction 0.9178 0.2462 Age at onset of asthma (years) < 18 Number 8 12 17 15 Mean (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 > 18 Number 17 13 37 33 Mean (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 0.7110 Overall p-value for interaction 0.4111 0.0777 Number of asthma exacerbations within 2 years before screening visit 1 Number 5 10 40 31 Mean (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 0.0625 2 Number 14 9 14 14 Mean (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 >2 Number 6 6 0 3 Mean (SD) -0.05 (0.10) -0.15 (0.34) NC (NC) 0.01 (0.06) 105 400 mg BID cohort 400 mg TID cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.20 (0.18) -0.36(0.14) -0.16(-0.52, 0.20) 0.3826 NC (NC) NC (NC) NC (NC, NC) NC Overall p-value for interaction 0.7653 0.4094 Atopic medical conditions Yes Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 15 0.02 (0.18) 0.05 (0.09) 16 0.03 (0.25) 0.02 (0.08) -0.03 (-0.19, 0.12) 0.6793 16 -0.07 (0.25) -0.07 (0.07) 16 -0.09 (0.25) -0.12 (0.07) -0.04 (-0.23, 0.14) 0.6505 No Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 10 -0.17(0.23) -0.25 (0.16) 9 -0.16(0.56) -0.15 (0.19) 0.10 (-0.39, 0.60) 0.6862 38 -0.06 (0.34) -0.04 (0.07) 32 -0.18 (0.28) -0.15 (0.07) -0.11 (-0.26, 0.04) 0.1594 Overall p-value for interaction 0.8948 0.6133 Background ICS dose level at randomization (400 mg TID only) Medium Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 29 -0.06 (0.26) -0.05 (0.06) 21 -0.18 (0.28) -0.15 (0.07) -0.10 (-0.25, 0.05) 0.1837 High Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 25 -0.07 (0.37) -0.07 (0.07) 27 -0.13 (0.27) -0.13 (0.07) -0.07 (-0.25, 0.11) 0.4593 Overall p-value for interaction 0.7498 Smoking history Former Number Mean (SD) 7 -0.07 (0.28) 106 4 -0.36 (0.39) 3 -0.06 (0.09) 3 -0.21 (0.28) 400 mg BID cohort_________400 mg TIP cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.36 (0.22) -0.57 (0.43) -0.21 (-0.96, 0.55) 0.5908 -0.07 (0.16) -0.12 (0.16) -0.05 (-0.46, 0.37) 0.8328 Never Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 18 -0.05 (0.19) -0.08 (0.11) 21 0.02 (0.37) -0.05 (0.10) 0.03 (-0.18, 0.24) 0.7800 51 -0.06 (0.32) -0.04 (0.05) 45 -0.15 (0.27) -0.13 (0.05) -0.09 (-0.21, 0.04) 0.1745 Overall p-value for interaction 0.1306 0.9511 Baseline pre-bronchodilator FEV1 (L) (400 mg BID only) < Median (2.022) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 12 -0.08 (0.25) -0.12(0.13) 13 -0.06 (0.27) -0.08 (0.14) 0.04 (-0.19, 0.27) 0.7330 > Median (2.022) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 13 -0.04 (0.19) -0.07 (0.13) 12 -0.02 (0.50) -0.09 (0.14) -0.03 (-0.38, 0.32) 0.8705 Overall p-value for interaction 0.8540 Baseline pre-bronchodilator percent predicted FEV 1 (%) (400 mg BID only) < Median (68) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 11 -0.08 (0.26) -0.24 (0.16) 16 -0.05 (0.41) -0.21 (0.16) 0.03 (-0.27, 0.34) 0.8283 > Median (68) Number Mean (SD) LS Mean (SE) 14 -0.04 (0.18) -0.06 (0.13) 107 9 -0.02 (0.39) -0.07 (0.13) 400 mg BID cohort_________400 mg TIP cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.01 (-0.28, 0.26) 0.9404 Overall p-value for interaction 0.7813 Baseline pre-bronchodilator FEV1 (L) (400 mg TID only) < Median (2.1955) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo > Median (2.1955) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo Overall p-value for interaction Baseline pre-bronchodilator percent predicted FEV1 group 1 (%) (400 mg TID only) < Median (77) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo > Median (77) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo Overall p-value for interaction Baseline pre-bronchodilator percent predicted FEV 1 group 2 (%) (400 mg TID only) 24            18 0.05 (0.35)    -0.05 (0.23) 0.05 (0.07)    -0.03 (0.08) -0.09 (-0.28, 0.10) 0.3726 30           30 -0.15 (0.26)    -0.21 (0.28) -0.13 (0.06)    -0.22 (0.06) -0.09 (-0.24, 0.07) 0.2881 0.9725 28           21 -0.01 (0.37)    -0.10 (0.25) 0.01 (0.07)    -0.03 (0.08) -0.04 (-0.24, 0.15) 0.6453 26 -0.12(0.24) -0.09 (0.06) 27 -0.19(0.28) -0.21 (0.06) -0.13 (-0.28, 0.03) 0.1033 0.4854 400 mg BID cohort_________400 mg TIP cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) < 80 Number 33 26 Mean (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 > 80 Number 21 22 Mean (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 0.2034 Overall p-value for interaction 0.8177 Baseline FEV1 reversibility (%) < 12 Number 14 10 40 35 Mean (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 > 12 Number 9 14 9 10 Mean (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 0.8822 Overall p-value for interaction 0.4867 0.4422 Baseline ACQ-5 score <2 Number 12 14 20 12 Mean (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 >2 Number 13 11 34 36 Mean (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 cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.04 (-0.29, 0.20) 0.7321 -0.16 (-0.31, 0.00) 0.0511 Overall p-value for interaction 0.9187 0.2088 LATAM: Latin America, ROW: Rest of the world

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

[0238] Table 37. Subgroup analysis: change from baseline in pre-bronchodilator FEV1 (L) at EOT (Week 12) by baseline biomarker subgroups (mITT population). 400 mg BID cohort 400 mg TID cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Baseline IgE level (lU / mL) < 100 Number 7 7 22 18 Mean (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 400 mg BID cohort_________400 mg TIP cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 18 -0.04 (0.19) -0.06 (0.20) 18 -0.02 (0.35) -0.04 (0.18) 0.02 (-0.20, 0.23) 0.8821 32 -0.05 (0.37) -0.06 (0.09) 30 -0.12 (0.24) -0.13 (0.09) -0.07 (-0.24, 0.10) 0.4002 Overall p-value for interaction 0.5502 0.6890 Baseline median IgE level (lU / mL) (400 mg BID only) < Median (210.8) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 8 -0.11 (0.28) -0.13 (0.15) 17 -0.02 (0.37) -0.11 (0.13) 0.01 (-0.34, 0.37) 0.9444 > Median (210.8) Number Mean (SD) LS Mean (SE LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 17 -0.03 (0.19) -0.04 (0.11) 8 -0.08 (0.45) -0.02 (0.14) 0.01 (-0.29, 0.31) 0.9284 Overall p-value for interaction 0.8938 Baseline median IgE level (lU / mL) (400 mg TID only) < Median (121.85) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 28 -0.10(0.23) -0.08 (0.07) 24 -0.17 (0.29) -0.16 (0.07) -0.08 (-0.23, 0.07) 0.3135 > Median (121.85) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 26 -0.03 (0.39) -0.22 (0.22) 24 -0.13 (0.25) -0.33 (0.23) -0.11 (-0.30, 0.07) 0.2365 Overall p-value for interaction 0.8457 400 mg BID cohort_________400 mg TIP cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Baseline median IgA level (mg / L) (400 mg TID only) < Median (2190) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 29 -0.04 (0.23) -0.03 (0.06) 21 -0.12 (0.26) -0.12 (0.07) -0.09 (-0.25, 0.07) 0.2572 > Median (2190) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 25 -0.09 (0.39) -0.06 (0.07) 27 -0.17 (0.28) -0.15 (0.07) -0.09 (-0.27, 0.09) 0.3176 Overall p-value for interaction 0.9795 Baseline blood eosinophil level 1 (10A9 / L) <0.15 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 5 0.03 (0.18) -0.04 (0.26) 8 -0.10 (0.49) -0.08 (0.16) -0.04 (-0.65, 0.57) 0.8932 22 -0.15 (0.27) -0.13 (0.07) 22 -0.17 (0.32) -0.17 (0.07) -0.05 (-0.23, 0.14) 0.6211 >0.15 (400 mg BID only) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 20 -0.08 (0.22) -0.10(0.10) 17 -0.01 (0.35) -0.03 (0.11) 0.07 (-0.15, 0.28) 0.5498 Overall p-value for interaction 0.3640 Baseline blood eosinophil level 2 (10A9 / L) (400 mg BID only) <0.3 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo 14 14 -0.01 (0.25) -0.10 (0.42) -0.08 (0.11) -0.15 (0.12) -0.07 (-0.35, 0.20) 0.6075 400 mg BID cohort 400 mg TID cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) >0.3 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 11 -0.11 (0.16) -0.07 (0.17) 11 0.04 (0.36) 0.00 (0.14) 0.07 (-0.21, 0.35) 0.6310 Overall p-value for interaction 0.2578 Baseline blood eosinophil level 1 (10A9 / L) (400 mg TID only) <0.15 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 22 -0.15 (0.27) -0.13 (0.07) 22 -0.17 (0.32) -0.17 (0.07) -0.05 (-0.23, 0.14) 0.6211 >0.15 -<0.3 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 18 -0.04 (0.25) -0.00 (0.08) 13 -0.10 (0.16) -0.04 (0.09) -0.04 (-0.24, 0.17) 0.7282 >0.3 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 14 0.04 (0.42) 0.04 (0.12) 13 -0.16 (0.27) -0.16 (0.11) -0.20 (-0.45, 0.05) 0.1159 Overall p-value for interaction 0.5643 Baseline blood eosinophil level 2 (10A9 / L) (400 mg TID only) <0.3 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 40 -0.10(0.27) -0.08 (0.05) 35 -0.15 (0.27) -0.13 (0.05) -0.05 (-0.19, 0.09) 0.4664 >0.3 Number 14 13 400 mg BID cohort 400 mg TID cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 0.04 (0.42) 0.04 (0.12) -0.16 (0.27) -0.16 (0.11) -0.20 (-0.45, 0.05) 0.1159 Overall p-value for interaction 0.3072 Baseline FeNO level 1 (ppb) <25 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 11 -0.04 (0.26) -0.18 (0.15) 9 -0.12 (0.51) -0.16 (0.14) 0.03 (-0.32, 0.37) 0.8792 31 -0.06 (0.25) -0.04 (0.05) 32 -0.19 (0.28) -0.16 (0.05) -0.12 (-0.26, 0.02) 0.0953 >25 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 14 -0.07 (0.19) 0.01 (0.11) 16 0.01 (0.32) -0.00 (0.11) -0.01 (-0.23, 0.22) 0.9359 19 -0.06 (0.41) -0.04 (0.10) 14 -0.09 (0.25) -0.09 (0.11) -0.04 (-0.32, 0.23) 0.7523 Overall p-value for interaction 0.6767 0.5841 Baseline FeNO level 2 (ppb) <35 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 14 -0.03 (0.25) -0.15 (0.13) 17 -0.10 (0.43) -0.19 (0.11) -0.04 (-0.30, 0.21) 0.7398 38 -0.09 (0.27) -0.06 (0.05) 36 -0.18 (0.27) -0.14 (0.05) -0.09 (-0.22, 0.04) 0.1794 >35 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 11 -0.09 (0.17) -0.01 (0.12) 8 0.08 (0.29) 0.05 (0.14) 0.06 (-0.26, 0.38) 0.7100 12 0.02 (0.44) 0.04 (0.17) 10 -0.07 (0.27) -0.07 (0.16) -0.12 (-0.49, 0.26) 0.5388 Overall p-value for interaction 0.2631 0.8679 LATAM: Latin America, ROW: Rest of the world

[0239] Table 38. Subgroup analysis: change from baseline in pre-bronchodilator FEV1 (L) at EOT (Week 12) in the baseline low EOS and low FeNO subgroup (mITT population). 400 mg BID cohort 400 mg TID cohort Pre-bronchodilator FEV1 (L) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Baseline blood eosinophil (10A9 / L) and FeNO (ppb) Low EOS (< 0.15) and low FeNO (<25) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 3 0.02 (0.17) NC (NC) 3 -0.17(0.85) NC (NC) NC (NC, NC) NC 16 -0.08 (0.23) -0.06 (0.07) 16 -0.24 (0.35) -0.20 (0.07) -0.14(-0.33, 0.06) 0.1770 All others Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 22 -0.07 (0.22) -0.08 (0.09) 22 -0.02 (0.32) -0.05 (0.09) 0.03 (-0.16, 0.21) 0.7753 34 -0.05 (0.35) -0.02 (0.06) 30 -0.11 (0.22) -0.09 (0.06) -0.07 (-0.23, 0.09) 0.3909 Overall p-value for interaction 0.3586 0.6290 FLATAM: Latin America, ROW: Rest of the world Bronchodilator 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 32 Mean (SD) 2.52 (3.02) 1.57 (1.98) Median 1.29 0.62 Q1;Q3 0.00; 4.71 0.00 ; 2.93 Min ; Max 0.0 ; 12.3 0.0 ; 7.4 Week 1 Number (observed / LOCF 32 (32 / 0) 32 (32 / 0) imputed) Mean (SD) 2.02 (2.56) 1.15 (1.78) Median 0.59 0.21 Q1;Q3 0.00 ; 3.50 0.00 ; 1.93 Min ; Max 0.0 ; 10.3 0.0 ; 7.4 Change from baseline Number (observed / LOCF 32 (32 / 0) 32 (32 / 0) imputed) Mean (SD) -0.50 (1.03) -0.41 (1.03) Median 0.00 0.00 Q1;Q3 -0.69 ; 0.00 -0.62 ; 0.00 Min ; Max -3.5 ; 0.7 -5.3 ; 1.0 LS 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 0.5052 Week 2 Number (observed / LOCF 32 (31 / 1) 31 (31 / 0) imputed) Mean (SD) 1.91 (2.63) 0.94 (1.76) Median 0.37 0.14 Q1;Q3 0.00 ; 3.21 0.00 ; 0.80 Min ; Max 0.0 ; 9.5 0.0 ; 7.4 Change from baseline Number (observed / LOCF 32 (31 / 1) 31 (31 / 0) imputed) Mean (SD) -0.61 (1.34) -0.68 (1.24) Median 0.00 0.00 Q1;Q3 -1.50 ; 0.00 -1.14 ; 0.00 Min ; Max -4.0 ; 2.9 -5.3 ; 0.3 LS 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 0.3228 Week 3 Albuterol or levalbuterol for symptom relief Placebo BID (N=32) Rilzabrutinib 400 mg BID (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 0.00 Q1;Q3 0.00; 4.00 0.00 ; 0.67 Min ; Max 0.0 ; 9.0 0.0 ; 5.3 Change from baseline Number (observed / LOCF 31 (30 / 1) 31 (31 / 0) imputed) Mean (SD) -0.24(1.98) -0.83 (1.48) Median 0.00 0.00 Q1;Q3 -0.67 ; 0.00 -1.33 ; 0.00 Min ; Max -5.4 ; 6.3 -5.0 ; 1.3 LS 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 0.0539 Week 4 Number (observed / LOCF 31 (29 / 2) 30 (29 / 1) imputed) Mean (SD) 1.92 (2.71) 0.86 (1.72) Median 0.29 0.00 Q1;Q3 0.00 ; 3.43 0.00 ; 0.50 Min ; Max 0.0 ; 9.0 0.0 ; 6.0 Change 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 -0.29 Q1;Q3 -1.29 ; 0.00 -1.71 ; 0.00 Min ; Max -5.4 ; 6.3 -5.5 ; 2.0 LS 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 0.0573 Week 5 Number (observed / LOCF 30 (28 / 2) 31 (29 / 2) imputed) Mean (SD) 1.89 (2.65) 1.11 (1.80) Median 0.25 0.00 Q1;Q3 0.00; 4.00 0.00 ; 2.50 Min ; Max 0.0 ; 9.0 0.0 ; 5.7 Change 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 0.00 Albuterol or levalbuterol for symptom relief Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Q1;Q3 -1.29 ; 0.00 -0.83 ; 0.00 Min ; Max -4.9 ; 6.3 -3.5 ; 1.0 LS 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 0.3824 Week 6 Number (observed / LOCF 30 (28 / 2) 31 (29 / 2) imputed) Mean (SD) 2.13 (2.77) 1.00 (1.92) Median 1.14 0.00 Q1;Q3 0.00 ; 3.14 0.00 ; 0.50 Min ; Max 0.0 ; 9.0 0.0 ; 7.3 Change from baseline Number (observed / LOCF 30 (28 / 2) 31 (29 / 2) imputed) Mean (SD) -0.15 (1.94) -0.61 (1.44) Median 0.00 0.00 Q1;Q3 -0.83 ; 0.00 -1.00 ; 0.05 Min ; Max -4.9 ; 6.3 -5.0 ; 1.3 LS 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 0.0589 Week 7 Number (observed / LOCF 30 (27 / 3) 31 (29 / 2) imputed) Mean (SD) 1.64 (2.52) 1.61 (3.82) Median 0.57 0.00 Q1;Q3 0.00; 2.00 0.00 ; 0.86 Min ; Max 0.0 ; 9.0 0.0 ; 19.4 Change from baseline Number (observed / LOCF 30 (27 / 3) 31 (29 / 2) imputed) Mean (SD) -0.63 (2.16) -0.00 (3.35) Median -0.05 0.00 Q1;Q3 -1.43 ; 0.00 -1.00 ; 0.00 Min; Max -4.9 ; 6.3 -4.3 ; 16.8 LS 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 0.7812 Week 8 Number (observed / LOCF 30 (27 / 3) 30 (27 / 3) imputed) Mean (SD) 1.59(2.52) 1.66 (3.98) Median 0.21 0.00 Albuterol or levalbuterol for symptom relief Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Q1;Q3 0.00 ; 3.00 0.00 ; 1.14 Min ; Max 0.0 ; 9.0 0.0 ; 19.4 Change from baseline Number (observed / LOCF 30 (27 / 3) 30 (27 / 3) imputed) Mean (SD) -0.68 (2.34) -0.01 (3.76) Median 0.00 0.00 Q1;Q3 -1.86; 0.00 -1.00; 0.00 Min ; Max -5.9 ; 6.3 -5.5 ; 16.8 LS 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 0.7344 Week 9 Number (observed / LOCF 30 (27 / 3) 29 (25 / 4) imputed) Mean (SD) 1.70 (2.55) 1.66 (3.98) Median 0.29 0.00 Q1;Q3 0.00 ; 2.29 0.00 ; 1.00 Min ; Max 0.0 ; 9.0 0.0 ; 19.4 Change from baseline Number (observed / LOCF 30 (27 / 3) 29 (25 / 4) imputed) Mean (SD) -0.57 (2.40) -0.07 (3.96) Median 0.00 -0.29 Q1;Q3 -1.86 ; 0.00 -1.14 ; 0.00 Min ; Max -5.9 ; 6.3 -5.5 ; 16.8 LS 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 0.9891 Week 10 Number (observed / LOCF 29 (25 / 4) 29 (25 / 4) imputed) Mean (SD) 1.90 (2.72) 1.49 (3.98) Median 0.00 0.00 Q1;Q3 0.00 ; 3.29 0.00 ; 0.57 Min; Max 0.0; 9.0 0.0; 19.4 Change from baseline Number (observed / LOCF 29 (25 / 4) 29 (25 / 4) imputed) Mean (SD) -0.25 (2.97) -0.23 (3.88) Median 0.00 -0.29 Q1;Q3 -1.86 ; 0.33 -1.86 ; 0.00 Min ; Max -6.9 ; 6.3 -5.5 ; 16.8 LS Mean (SE) -0.13 (0.73) -0.68 (0.70) Albuterol or levalbuterol for symptom relief Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) LS Mean Diff vs. placebo (95% -0.55 (-2.20, 1.11) ci) P-value vs. placebo 0.5185 Week 11 Number (observed / LOCF 30 (24 / 6) 27 (23 / 4) imputed) Mean (SD) 2.37 (3.30) 1.61 (4.24) Median 0.33 0.00 Q1;Q3 0.00 ; 5.00 0.00 ; 0.67 Min ; Max 0.0 ; 11.0 0.0 ; 19.4 Change from baseline Number (observed / LOCF 30 (24 / 6) 27 (23 / 4) imputed) Mean (SD) 0.09 (3.30) -0.10(3.99) Median 0.00 -0.40 Q1;Q3 -1.71 ; 0.50 -1.43 ; 0.00 Min ; Max -6.5 ; 7.2 -5.5 ; 16.8 LS Mean (SE) 0.28 (0.82) -0.29 (0.79) LS Mean Diff vs. placebo (95% -0.57(-2.39, 1.25) ci) P-value vs. placebo 0.5406 Week 12 Number (observed / LOCF 28 (19 / 9) 26 (21 / 5) imputed) Mean (SD) 2.57 (3.34) 1.97 (4.32) Median 1.14 0.00 Q1;Q3 0.00; 4.60 0.00 ; 2.00 Min ; Max 0.0 ; 11.0 0.0 ; 19.4 Change from baseline Number (observed / LOCF 28 (19 / 9) 26 (21 / 5) imputed) Mean (SD) 0.16(3.31) 0.26 (3.85) Median 0.00 -0.19 Q1;Q3 -2.41 ; 1.00 -1.00 ; 0.00 Min ; Max -5.3 ; 7.2 -4.3 ; 16.8 LS Mean (SE) 0.19(0.77) 0.07 (0.76) LS Mean Diff vs. placebo (95% -0.12(-1.90, 1.66) ci) P-value vs. placebo 0.8932 LATAM: 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 (N=32) Rilzabrutinib 400 mg BID (N=32) Baseline Number 32 32 Mean (SD) 2.52 (3.02) 1.57 (1.98) Median 1.29 0.62 Q1;Q3 0.00 ; 4.71 0.00 ; 2.93 Min ; Max 0.0 ; 12.3 0.0 ; 7.4 Week 1 Number (observed / LOCF imputed) 32 (32 / 0) 32 (32 / 0) Mean (SD) 2.02 (2.56) 1.15 (1.78) Median 0.59 0.21 Q1;Q3 0.00 ; 3.50 0.00 ; 1.93 Min ; Max 0.0 ; 10.3 0.0 ; 7.4 Change from baseline Number (observed / LOCF imputed) 32 (32 / 0) 32 (32 / 0) Mean (SD) -0.50 (1.03) -0.41 (1.03) Median 0.00 0.00 Q1;Q3 -0.69 ; 0.00 -0.62 ; 0.00 Min ; Max -3.5 ; 0.7 -5.3 ; 1.0 LS 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 0.6691 Week 2 Number (observed / LOCF imputed) 32 (31 / 1) 31 (31 / 0) Mean (SD) 1.91 (2.63) 0.94 (1.76) Median 0.37 0.14 Q1;Q3 0.00 ; 3.21 0.00 ; 0.80 Min ; Max 0.0 ; 9.5 0.0 ; 7.4 Change from baseline Number (observed / LOCF imputed) 32 (31 / 1) 31 (31 / 0) Mean (SD) -0.61 (1.34) -0.68 (1.24) Median 0.00 0.00 Q1;Q3 -1.50 ; 0.00 -1.14 ; 0.00 Min ; Max -4.0 ; 2.9 -5.3 ; 0.3 LS 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 0.3848 Week 3 Number (observed / LOCF imputed) 31 (30 / 1) 31 (31 / 0) Mean (SD) 1.96 (2.75) 0.79 (1.48) Median 0.29 0.00 Q1;Q3 0.00 ; 4.00 0.00 ; 0.67 Min ; Max 0.0 ; 9.0 0.0 ; 5.3 Albuterol or levalbuterol for symptom relief Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Change from baseline Number (observed / LOCF imputed) 31 (30 / 1) 31 (31 / 0) Mean (SD) -0.24(1.98) -0.83 (1.48) Median 0.00 0.00 Q1;Q3 -0.67 ; 0.00 -1.33 ; 0.00 Min ; Max -5.4 ; 6.3 -5.0 ; 1.3 LS 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 0.0826 Week 4 Number (observed / LOCF imputed) 31 (29 / 2) 30 (29 / 1) Mean (SD) 1.92 (2.71) 0.86 (1.72) Median 0.29 0.00 Q1;Q3 0.00 ; 3.43 0.00 ; 0.50 Min ; Max 0.0 ; 9.0 0.0 ; 6.0 Change from baseline Number (observed / LOCF imputed) 31 (29 / 2) 30 (29 / 1) Mean (SD) -0.28 (2.14) -0.81 (1.41) Median 0.00 -0.29 Q1;Q3 -1.29 ; 0.00 -1.71 ; 0.00 Min ; Max -5.4 ; 6.3 -5.5 ; 2.0 LS 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 0.1245 Week 5 Number (observed / LOCF imputed) 30 (28 / 2) 31 (29 / 2) Mean (SD) 1.89 (2.65) 1.11 (1.80) Median 0.25 0.00 Q1;Q3 0.00 ; 4.00 0.00 ; 2.50 Min ; Max 0.0 ; 9.0 0.0 ; 5.7 Change from baseline Number (observed / LOCF imputed) 30 (28 / 2) 31 (29 / 2) Mean (SD) -0.39(1.97) -0.51 (1.14) Median 0.00 0.00 Q1;Q3 -1.29 ; 0.00 -0.83 ; 0.00 Min ; Max -4.9 ; 6.3 -3.5 ; 1.0 LS 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 0.5339 Week 6 Number (observed / LOCF imputed) 30 (28 / 2) 31 (29 / 2) Mean (SD) 2.13 (2.77) 1.00 (1.92) Median 1.14 0.00 Q1;Q3 0.00 ; 3.14 0.00 ; 0.50 Min ; Max 0.0 ; 9.0 0.0 ; 7.3 Albuterol or levalbuterol for symptom relief Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Change from baseline Number (observed / LOCF imputed) 30 (28 / 2) 31 (29 / 2) Mean (SD) -0.15 (1.94) -0.61 (1.44) Median 0.00 0.00 Q1;Q3 -0.83 ; 0.00 -1.00 ; 0.05 Min ; Max -4.9 ; 6.3 -5.0 ; 1.3 LS 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 0.1706 Week? Number (observed / LOCF imputed) 30 (27 / 3) 31 (29 / 2) Mean (SD) 1.64 (2.52) 1.61 (3.82) Median 0.57 0.00 Q1;Q3 0.00 ; 2.00 0.00 ; 0.86 Min ; Max 0.0 ; 9.0 0.0 ; 19.4 Change from baseline Number (observed / LOCF imputed) 30 (27 / 3) 31 (29 / 2) Mean (SD) -0.63 (2.16) -0.00 (3.35) Median -0.05 0.00 Q1;Q3 -1.43 ; 0.00 -1.00 ; 0.00 Min ; Max -4.9 ; 6.3 -4.3 ; 16.8 LS 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 0.5396 Week 8 Number (observed / LOCF imputed) 30 (27 / 3) 30 (27 / 3) Mean (SD) 1.59 (2.52) 1.66 (3.98) Median 0.21 0.00 Q1;Q3 0.00 ; 3.00 0.00 ; 1.14 Min ; Max 0.0 ; 9.0 0.0 ; 19.4 Change from baseline Number (observed / LOCF imputed) 30 (27 / 3) 30 (27 / 3) Mean (SD) -0.68 (2.34) -0.01 (3.76) Median 0.00 0.00 Q1;Q3 -1.86 ; 0.00 -1.00 ; 0.00 Min ; Max -5.9 ; 6.3 -5.5 ; 16.8 LS 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 0.5291 Week 9 Number (observed / LOCF imputed) 30 (27 / 3) 29 (25 / 4) Mean (SD) 1.70 (2.55) 1.66 (3.98) Median 0.29 0.00 Q1;Q3 0.00 ; 2.29 0.00 ; 1.00 Min ; Max 0.0 ; 9.0 0.0 ; 19.4 Albuterol or levalbuterol for symptom relief Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Change from baseline Number (observed / LOCF imputed) 30 (27 / 3) 29 (25 / 4) Mean (SD) -0.57 (2.40) -0.07 (3.96) Median 0.00 -0.29 Q1;Q3 -1.86 ; 0.00 -1.14 ; 0.00 Min ; Max -5.9 ; 6.3 -5.5 ; 16.8 LS 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 0.7514 Week 10 Number (observed / LOCF imputed) 29 (25 / 4) 29 (25 / 4) Mean (SD) 1.90 (2.72) 1.49 (3.98) Median 0.00 0.00 Q1;Q3 0.00 ; 3.29 0.00 ; 0.57 Min ; Max 0.0 ; 9.0 0.0 ; 19.4 Change from baseline Number (observed / LOCF imputed) 29 (25 / 4) 29 (25 / 4) Mean (SD) -0.25 (2.97) -0.23 (3.88) Median 0.00 -0.29 Q1;Q3 -1.86 ; 0.33 -1.86 ; 0.00 Min ; Max -6.9 ; 6.3 -5.5 ; 16.8 LS 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 0.6832 Week 11 Number (observed / LOCF imputed) 30 (24 / 6) 27 (23 / 4) Mean (SD) 2.37 (3.30) 1.61 (4.24) Median 0.33 0.00 Q1;Q3 0.00 ; 5.00 0.00 ; 0.67 Min ; Max 0.0 ; 11.0 0.0 ; 19.4 Change from baseline Number (observed / LOCF imputed) 30 (24 / 6) 27 (23 / 4) Mean (SD) 0.09 (3.30) -0.10 (3.99) Median 0.00 -0.40 Q1;Q3 -1.71 ; 0.50 -1.43 ; 0.00 Min ; Max -6.5 ; 7.2 -5.5 ; 16.8 LS 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 0.6865 Week 12 Number (observed / LOCF imputed) 28 (19 / 9) 26 (21 / 5) Mean (SD) 2.57 (3.34) 1.97 (4.32) Median 1.14 0.00 Q1;Q3 0.00 ; 4.60 0.00 ; 2.00 Min ; Max 0.0 ; 11.0 0.0 ; 19.4 Albuterol or levalbuterol for symptom relief Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Change from baseline Number (observed / LOCF imputed) 28 (19 / 9) 26 (21 / 5) Mean (SD) 0.16 (3.31) 0.26 (3.85) Median 0.00 -0.19 Q1;Q3 -2.41 ; 1.00 -1.00 ; 0.00 Min ; Max -5.3 ; 7.2 -4.3 ; 16.8 LS 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 0.9303 LATAM: Latin America, ROW: Rest of the world Table 40B. Number of participants requiring >2, >3, >4, or >5 reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol BID cohort               TID cohort Placebo BID (N=32) Rilzabrutinib 400mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400m g TID (N=64) Number of participants     11(34.4) with > 2 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol compared with baseline on 2 consecutive days during the treatment period 6 (18.8) 24 (35.3) 11 (17.2) Number of participants 7 (21.9) with > 3 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol compared with baseline on 2 consecutive days during the treatment period 3 (9.4) 16 (23.5) 4 (6.3) Number of participants 6 (18.8) with > 4 additional reliever puffs of salbutamol / albuterol or levosalbutamol / levalbuterol compared with baseline on 2 consecutive days during the treatment period, 2 (6.3) 12 (17.6) 3 (4.7) Placebo BID (N=32) BID cohort TID cohort Rilzabrutinib 400mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400m g TID (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 period ACQ-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 the two 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 cohort ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Baseline Number 32 32 68 64 Mean (SD) 2.19 (0.40) 2.04 (0.37) 2.18(0.40) 2.24 (0.48) Median 2.20 2.00 2.20 2.20 Q1;Q3 2.00 ; 2.40 1.80 ; 2.20 1.80 ; 2.40 2.00 ; 2.60 Min; Max 1.4 ; 3.2 1.4 ; 2.8 1.2; 3.2 1.4; 4.0 Week 2 Number 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 1.20 2.00 2.20 Q1;Q3 1.60; 2.20 0.80 ; 1.80 1.60 ; 2.40 1.20; 2.60 Min; Max 0.4 ; 3.8 0.4 ; 2.6 0.4 ; 3.4 0.0 ; 3.4 Change from baseline Number 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 0.00 -0.20 400 mg BID cohort 400 mg TID cohort ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Q1;Q3 -0.80 ; 0.00 -1.20 ; -0.20 -0.60 ; 0.20 -0.80 ; 0.20 Min; Max -1.8 ; 1.6 -1.8 ; 0.4 -1.8 ; 1.6 -2.0 ; 1.2 LS Mean (SE) -0.20 (0.14) -0.74 (015) -0.19(0.09) -0.47 (0.10) LS Mean Diff -0.54 (-0.89, - -0.27 (-0.53, -0.02) vs. placebo 0.19) (95% CI) P-value vs. 0.0026 0.0335 placebo Week 4 Number 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 1.00 2.00 1.80 Q1;Q3 1.20 ; 2.20 0.40 ; 1.80 1.40 ; 2.60 1.00; 2.40 Min; Max 0.0 ; 3.4 0.0 ; 2.6 0.0 ; 4.0 0.0 ; 3.4 Change from baseline Number 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 -0.20 -0.40 Q1;Q3 -0.80 ; 0.20 -1.60 ; -0.40 -0.60 ; 0.20 -1.00 ; 0.00 Min; Max -2.6 ; 1.6 -2.0 ; 0.4 -2.2 ; 2.0 -2.4 ; 1.0 LS 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, - -0.37 (-0.64, -0.09) vs. placebo 0.14) (95% CI) P-value vs. 0.0085 0.0088 placebo Week 6 Number 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 1.00 1.60 2.00 Q1;Q3 1.20 ; 2.50 0.40 ; 1.60 1.20; 2.20 0.80 ; 2.40 Min; Max 0.4 ; 4.0 0.0 ; 3.2 0.0 ; 3.2 0.0 ; 3.2 Change from baseline 400 mg BID cohort 400 mg TID cohort ACQ-5 Placebo BID Rilzabrutinib (N=32)     400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Number 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 -0.40 -0.60 Q1;Q3 -1.00; 0.40 -1.60 ; -0.60 -1.00; 0.20 -1.00; 0.00 Min; Max -2.4 ; 1.4 -1.8 ; 1.0 -2.0 ; 0.8 -2.8 ; 1.2 LS Mean (SE) -0.16 (0.18) -0.89 (0.19) -0.30 (0.12) -0.62 (0.12) LS Mean Diff -0.72 (-1.16, - -0.32 (-0.62, -0.01) vs. placebo 0.28) (95% CI) P-value vs. placebo 0.0013 0.0412 Week8 Number 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 1.80 Q1;Q3 0.80 ; 2.20 0.60 ; 1.40 1.20 ; 2.40 1.00; 2.00 Min; Max 0.0 ; 4.0 0.0 ; 3.6 0.0 ; 5.2 0.0 ; 3.2 Change from baseline Number 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 -0.60 Q1;Q3 -1.20 ; 0.00 -1.40 ; -0.80 -1.00 ; 0.40 -1.20 ; -0.20 Min; Max -3.2 ; 1.4 -2.2 ; 1.0 -2.0 ; 3.0 -2.6 ; 1.0 LS Mean (SE) -0.40 (0.19) -0.80 (0.22) -0.29 (0.11) -0.75 (0.12) LS Mean Diff -0.40 (-0.87, -0.46 (-0.76, -0.17) vs. placebo 0.07) (95% CI) P-value vs. placebo 0.0968 0.0023 Week 10 Number 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 1.00 1.80 1.60 400 mg BID cohort 400 mg TID cohort ACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=32) (N=68) 400 mg TID (N=64) Q1;Q3 0.90 ; 2.50 0.40 ; 1.60 1.00 ; 2.60 0.90 ; 2.00 Min; Max Change from baseline 0.0 ; 4.0 0.0 ; 3.2 0.0 ; 4.0 0.0 ; 3.2 Number (observed / LOCF imputed) 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) 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 -0.70 Q1;Q3 -1.20 ; 0.40 -1.60 ; -0.40 -1.00 ; 0.40 -1.40 ; -0.20 Min; Max -2.6 ; 1.6 -2.4 ; 1.0 -2.2 ; 1.4 -2.6 ; 1.2 LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo Week 12 -0.15 (0.18) -0.73 (0.19) -0.59 (-1.03, - 0.14) 0.0095 -0.33 (0.13) -0.84 (0.13) -0.51 (-0.84, -0.18) 0.0022 Number (observed / LOCF imputed) 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49 (46 / 3) 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 1.60 Q1;Q3 1.10 ; 2.20 0.40 ; 2.00 1.10; 2.50 1.00; 2.00 Min; Max Change from baseline 0.0 ; 4.0 0.0 ; 3.2 0.0 ; 5.4 0.0 ; 3.2 Number (observed / LOCF imputed) 28 (19 / 9) 28 (23 / 5) 60 (50 / 10) 49 (46 / 3) 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 -0.80 Q1;Q3 -1.00 ; 0.10 -1.60 ; -0.20 -1.00 ; 0.40 -1.40 ; -0.20 Min; Max -3.0 ; 1.6 -2.4 ; 1.0 -1.8 ; 3.2 -2.2 ; 0.4 LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo -0.12 (0.20) -0.70 (0.22) -0.59 (-1.07, - 0.10) 0.0184 -0.31 (0.12) -0.85 (0.13) -0.54 (-0.86, -0.21) 0.0013 LATAM: 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 cohort ACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID (N=32) (N=64) Mean score Baseline Number 32 32 68 64 Mean (SD) 2.19 (0.40) 2.04 (0.37) 2.18 (0.40) 2.24 (0.48) Median 2.20 2.00 2.20 2.20 Q1;Q3 2.00 ; 2.40 1.80; 2.20 1.80; 2.40 2.00; 2.60 Min ; Max 1.4 ; 3.2 1.4 ; 2.8 1.2 ; 3.2 1.4; 4.0 Week 2 Number (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 2.20 Q1;Q3 1.60 ; 2.20 0.80 ; 1.80 1.60; 2.40 1.20; 2.60 Min ; Max 0.4 ; 3.8 0.4 ; 2.6 0.4 ; 3.4 0.0 ; 3.4 Change 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 -0.20 Q1;Q3 -0.80 ; 0.00 -1.20 ; -0.20 -0.60 ; 0.20 -0.80 ; 0.20 Min ; Max -1.8 ; 1.6 -1.8 ; 0.4 -1.8 ; 1.6 -2.0 ; 1.2 LS 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 0.0335 Week 4 Number (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 1.80 Q1;Q3 1.20 ; 2.20 0.40; 1.80 1.40; 2.60 1.00; 2.40 Min ; Max 0.0 ; 3.4 0.0 ; 2.6 0.0; 4.0 0.0 ; 3.4 Change 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 -0.40 Q1;Q3 -0.80 ; 0.20 -1.60 ; -0.40 -0.60 ; 0.20 -1.00 ; 0.00 400 mg BID cohort__________400 mg TIP cohort ACQ-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 ; 1.0 LS 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 0.0088 Week 6 Number (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 2.00 Q1;Q3 1.20 ; 2.50 0.40 ; 1.60 1.20; 2.20 0.80; 2.40 Min ; Max 0.4 ; 4.0 0.0 ; 3.2 0.0 ; 3.2 0.0 ; 3.2 Change 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 -0.60 Q1;Q3 -1.00 ; 0.40 -1.60 ; -0.60 -1.00 ; 0.20 -1.00 ; 0.00 Min ; Max -2.4 ; 1.4 -1.8 ; 1.0 -2.0 ; 0.8 -2.8 ; 1.2 LS 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 0.0412 Week 8 Number (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 1.80 Q1;Q3 0.80 ; 2.20 0.60 ; 1.40 1.20; 2.40 1.00; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.6 0.0 ; 5.2 0.0 ; 3.2 Change 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 -0.60 Q1;Q3 -1.20 ; 0.00 -1.40 ; -0.80 -1.00 ; 0.40 -1.20 ; -0.20 Min ; Max -3.2 ; 1.4 -2.2 ; 1.0 -2.0 ; 3.0 -2.6 ; 1.0 LS 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 TIP cohort ACQ-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 0.0023 Week 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 1.60 Q1;Q3 0.90 ; 2.50 0.40 ; 1.60 1.00; 2.60 0.90; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.2 0.0; 4.0 0.0 ; 3.2 Change 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 -0.70 Q1;Q3 -1.20 ; 0.40 -1.60 ; -0.40 -1.00 ; 0.40 -1.40 ; -0.20 Min ; Max -2.6 ; 1.6 -2.4 ; 1.0 -2.2 ; 1.4 -2.6 ; 1.2 LS Mean (SE) -0.15 (0.18) -0.73 (0.19) -0.33 (0.13) -0.84 (0.13) LS Mean Diff vs. placebo -0.59 (-1.03,- -0.51 (-0.84, - (95% CI) 0.14) 0.18) P-value vs. placebo 0.0095 0.0022 Week 12 Number (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 1.60 Q1;Q3 1.10 ; 2.20 0.40 ; 2.00 1.10; 2.50 1.00; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.2 0.0 ; 5.4 0.0 ; 3.2 Change 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 -0.80 Q1;Q3 -1.00 ; 0.10 -1.60 ; -0.20 -1.00 ; 0.40 -1.40 ; -0.20 Min ; Max -3.0 ; 1.6 -2.4 ; 1.0 -1.8 ; 3.2 -2.2 ; 0.4 LS 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 0.0013 Frequency of awakening by asthma 400 mg BID cohort 400 mg TID cohort ACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID (N=32) (N=64) Baseline Number 32 32 68 64 Mean (SD) 1.91 (0.64) 1.63 (0.66) 1.91 (0.69) 1.89 (0.72) Median 2.00 2.00 2.00 2.00 Q1;Q3 2.00 ; 2.00 1.00; 2.00 2.00; 2.00 2.00; 2.00 Min; Max 0.0; 3.0 0.0; 3.0 0.0; 3.0 0.0; 4.0 Week 2 Number (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 2.00 Q1;Q3 1.00 ; 2.00 0.00; 2.00 1.00; 2.00 1.00; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 2.0 0.0 ; 5.0 0.0; 4.0 Change from baseline Number (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 0.00 Q1;Q3 -1.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -3.0; 2.0 -2.0 ; 1.0 -3.0 ; 2.0 -2.0 ; 2.0 LS 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 0.8553 Week 4 Number (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 2.00 Q1;Q3 0.00 ; 2.00 0.00; 2.00 1.00; 2.00 1.00; 2.00 Min ; Max 0.0 ; 3.0 0.0 ; 3.0 0.0; 4.0 0.0 ; 3.0 Change from baseline Number (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 0.00 Q1;Q3 -1.00 ; 0.00 -2.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -3.0 ; 1.0 -2.0 ; 2.0 -3.0 ; 3.0 -2.0 ; 2.0 LS 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 cohort ACQ-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 0.1165 Week 6 Number (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 2.00 Q1;Q3 1.00 ; 2.00 0.00 ; 1.00 1.00; 2.00 1.00; 2.00 Min ; Max 0.0 ; 3.0 0.0 ; 3.0 0.0; 4.0 0.0; 4.0 Change from baseline Number (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 0.00 Q1;Q3 -1.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -3.0 ; 1.0 -2.0 ; 1.0 -3.0 ; 2.0 -2.0 ; 1.0 LS 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 0.6678 Week 8 Number (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 1.50 Q1;Q3 0.00 ; 2.00 0.00 ; 1.50 1.00 ; 3.00 1.00; 2.00 Min ; Max 0.0 ; 3.0 0.0 ; 4.0 0.0 ; 5.0 0.0; 4.0 Change from baseline Number (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 0.00 Q1;Q3 -1.00 ; 0.00 -1.50 ; 0.00 -1.00 ; 1.00 -1.00 ; 0.00 Min ; Max -3.0 ; 1.0 -2.0 ; 2.0 -3.0 ; 3.0 -3.0 ; 2.0 LS 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 0.1389 400 mg BID cohort 400 mg TID cohort ACQ-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 1.00 Q1;Q3 0.00 ; 2.00 0.00; 1.00 1.00; 2.00 1.00; 2.00 Min ; Max 0.0 ; 3.0 0.0 ; 3.0 0.0; 4.0 0.0 ; 5.0 Change 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 -1.00 Q1;Q3 -1.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -3.0 ; 1.0 -3.0 ; 1.0 -3.0 ; 2.0 -2.0 ; 3.0 LS 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 0.2171 Week 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 1.00 Q1;Q3 0.50 ; 2.00 0.00 ; 1.50 1.00; 2.00 1.00; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 4.0 0.0 ; 5.0 0.0 ; 3.0 Change 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 -1.00 Q1;Q3 -1.00 ; 0.00 -1.50 ; 0.00 -1.00 ; 0.50 -1.00 ; 0.00 Min ; Max -2.0 ; 2.0 -3.0 ; 2.0 -3.0 ; 3.0 -3.0 ; 1.0 LS 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 0.0598 Asthma symptoms when woke up Baseline Number 32 32 68 64 Mean (SD) 2.25 (0.62) 2.16(0.51) 2.34 (0.61) 2.52 (0.67) 400 mg BID cohort 400 mg TID cohort ACQ-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 3.00 Q1;Q3 2.00 ; 3.00 2.00; 2.00 2.00 ; 3.00 2.00 ; 3.00 Min ; Max 1.0 ; 4.0 1.0 ; 3.0 1.0; 4.0 1.0; 4.0 Week 2 Number (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 2.00 Q1;Q3 1.00 ; 2.00 1.00; 2.00 2.00 ; 3.00 1.00 ; 3.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 3.0 0.0 ; 3.0 Change from baseline Number (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 0.00 Q1;Q3 -1.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -2.0 ; 1.0 -3.0 ; 1.0 -2.0 ; 2.0 -3.0 ; 1.0 LS 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 0.0333 Week 4 Number (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 2.00 Q1;Q3 1.00 ; 3.00 0.00; 2.00 2.00 ; 3.00 1.00 ; 3.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0; 4.0 0.0; 4.0 Change from baseline Number (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 0.00 Q1;Q3 -1.00 ; 0.00 -2.00 ; 0.00 -1.00 ; 0.00 -2.00 ; 0.00 Min ; Max -3.0 ; 3.0 -3.0 ; 1.0 -3.0 ; 2.0 -3.0 ; 1.0 LS 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 0.0252 400 mg BID cohort 400 mg TID cohort ACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID (N=32) (N=64) Week 6 Number (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 2.00 Q1;Q3 1.00; 3.00 1.00; 2.00 1.00; 3.00 1.00; 3.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0; 4.0 0.0 ; 3.0 Change from baseline Number (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 -1.00 Q1;Q3 -1.00 ; 1.00 -2.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -2.0 ; 2.0 -3.0 ; 1.0 -3.0 ; 1.0 -3.0 ; 1.0 LS 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 0.0947 Week 8 Number (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 2.00 Q1;Q3 1.00 ; 2.00 1.00; 2.00 1.00 ; 3.00 1.00; 2.50 Min ; Max 0.0 ; 4.0 0.0 ; 5.0 0.0 ; 5.0 0.0 ; 3.0 Change from baseline Number (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 -1.00 Q1;Q3 -1.00 ; 0.00 -2.00 ; 0.00 -1.00 ; 0.00 -2.00 ; 0.00 Min ; Max -3.0; 2.0 -3.0 ; 2.0 -3.0 ; 3.0 -3.0 ; 1.0 LS 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 0.0540 Week 10 Number (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 cohort ACQ-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 2.00 Q1;Q3 1.00 ; 3.00 1.00; 2.00 1.00 ; 3.00 1.00; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0; 4.0 0.0 ; 3.0 Change 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 -1.00 Q1;Q3 -1.50 ; 0.50 -2.00 ; 0.00 -1.00 ; 0.00 -2.00 ; 0.00 Min ; Max -3.0; 2.0 -2.0 ; 1.0 -2.0 ; 1.0 -3.0 ; 1.0 LS 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 0.0050 Week 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 2.00 Q1;Q3 1.00 ; 3.00 0.00; 2.00 1.00 ; 3.00 1.00; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 6.0 0.0 ; 3.0 Change 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 -1.00 Q1;Q3 -1.00 ; 1.00 -2.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -3.0; 2.0 -3.0 ; 1.0 -3.0 ; 4.0 -3.0 ; 1.0 LS 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 0.0494 Limitation activities by asthma Baseline Number 32 32 68 64 Mean (SD) 2.34 (0.87) 2.06 (0.56) 2.13 (0.64) 2.17(0.52) Median 2.00 2.00 2.00 2.00 Q1;Q3 2.00 ; 3.00 2.00; 2.00 2.00 ; 3.00 2.00; 2.00 Min ; Max 0.0 ; 4.0 1.0 ; 3.0 1.0 ; 3.0 1.0; 4.0 400 mg BID cohort 400 mg TID cohort ACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID (N=32) (N=64) Week 2 Number (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 2.00 Q1;Q3 1.00 ; 3.00 1.00; 2.00 2.00 ; 3.00 1.00 ; 3.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0; 4.0 0.0 ; 3.0 Change from baseline Number (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 0.00 Q1;Q3 -1.00 ; 0.00 -2.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -3.0 ; 3.0 -2.0 ; 2.0 -2.0 ; 2.0 -3.0 ; 2.0 LS 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 0.0323 Week 4 Number (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 2.00 Q1;Q3 1.00 ; 3.00 0.00; 2.00 2.00; 2.00 1.00; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0; 4.0 0.0 ; 3.0 Change from baseline Number (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 0.00 Q1;Q3 -1.00 ; 0.00 -2.00 ; 0.00 -1.00 ; 1.00 -1.00 ; 0.00 Min ; Max -3.0; 2.0 -3.0 ; 1.0 -2.0 ; 2.0 -3.0 ; 1.0 LS 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 0.0064 Week 6 Number (observed / LOCF imputed) 28 (26 / 2) 30 (28 / 2) 60 (58 / 2) 57 (56 / 1) ACQ-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 1.00 Q1;Q3 1.00 ; 3.00 0.00; 2.00 1.00; 2.00 1.00; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0; 4.0 0.0; 4.0 Change 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 -1.00 Q1;Q3 -1.00 ; 0.50 -2.00 ; 0.00 -1.00 ; 1.00 -2.00 ; 0.00 Min ; Max -3.0 ; 1.0 -3.0 ; 1.0 -3.0 ; 2.0 -3.0 ; 2.0 LS 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 0.0090 Week 8 Number (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 1.00 Q1;Q3 1.00 ; 3.00 0.00 ; 1.50 1.00; 2.00 1.00; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 5.0 0.0 ; 3.0 Change 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 -1.00 Q1;Q3 -2.00 ; 0.00 -2.00 ; 0.00 -1.00 ; 1.00 -1.00 ; 0.00 Min ; Max -3.0 ; 1.0 -3.0 ; 1.0 -3.0 ; 4.0 -3.0 ; 1.0 LS 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 0.0005 Week 10 Number (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 1.00 Q1;Q3 1.00 ; 3.00 0.00; 2.00 1.00 ; 3.00 1.00; 2.00 Min ; Max 0.0 ; 5.0 0.0 ; 3.0 0.0; 4.0 0.0 ; 3.0 400 mg BID cohort 400 mg TID cohort ACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID (N=32) (N=64) Change from baseline Number (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 -1.00 Q1;Q3 -2.00 ; 0.50 -2.00 ; 0.00 -1.00 ; 1.00 -1.00 ; 0.00 Min ; Max -3.0 ; 3.0 -2.0 ; 1.0 -2.0 ; 2.0 -3.0 ; 1.0 LS 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 0.0035 Week 12 Number (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 1.00 Q1;Q3 1.00 ; 3.00 0.00; 2.00 1.00 ; 3.00 0.00; 2.00 Min ; Max 0.0 ; 5.0 0.0 ; 3.0 0.0 ; 5.0 0.0; 4.0 Change from baseline Number (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 -1.00 Q1;Q3 -1.00 ; 0.50 -2.00 ; 0.00 -1.00 ; 1.00 -2.00 ; 0.00 Min ; Max -3.0 ; 3.0 -2.0 ; 1.0 -3.0 ; 4.0 -3.0 ; 2.0 LS 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 0.0020 Shortness of breath experienced Baseline Number 32 32 68 64 Mean (SD) 2.50 (0.62) 2.31 (0.69) 2.37 (0.62) 2.41 (0.71) Median 2.00 2.00 2.00 2.00 Q1;Q3 2.00 ; 3.00 2.00 ; 3.00 2.00 ; 3.00 2.00 ; 3.00 Min ; Max 2.0 ; 4.0 1.0 ; 4.0 1.0; 4.0 0.0; 4.0 Week 2 Number (observed / LOCF imputed) 30 (29 / 1) 30 (30 / 0) 63 (62 / 1) 61 (61 / 0) ACQ-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 2.00 Q1;Q3 2.00 ; 3.00 1.00; 2.00 2.00 ; 3.00 1.00 ; 3.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0; 4.0 0.0; 4.0 Change 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 0.00 Q1;Q3 -1.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -2.0 ; 2.0 -2.0 ; 1.0 -3.0 ; 2.0 -3.0 ; 2.0 LS 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 0.0409 Week 4 Number (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 2.00 Q1;Q3 2.00 ; 3.00 1.00; 2.00 2.00 ; 3.00 1.00 ; 3.00 Min ; Max 0.0 ; 4.0 0.0 ; 3.0 0.0 ; 5.0 0.0 ; 3.0 Change 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 -1.00 Q1;Q3 -1.00 ; 0.00 -2.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -3.0; 2.0 -3.0 ; 0.0 -3.0 ; 3.0 -3.0 ; 1.0 LS 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 0.0147 Week 6 Number (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 2.00 Q1;Q3 1.50 ; 3.00 1.00; 2.00 2.00 ; 3.00 1.00 ; 3.00 Min ; Max 0.0 ; 5.0 0.0 ; 4.0 0.0; 4.0 0.0; 4.0 400 mg BID cohort 400 mg TID cohort ACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID (N=32) (N=64) Change from baseline Number (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 0.00 Q1;Q3 -1.00 ; 1.00 -2.00 ; -1.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -3.0; 2.0 -3.0 ; 2.0 -3.0 ; 1.0 -4.0 ; 2.0 LS 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 0.0310 Week 8 Number (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 2.00 Q1;Q3 1.00 ; 3.00 1.00; 2.00 1.00 ; 3.00 1.00; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 5.0 0.0 ; 6.0 0.0 ; 3.0 Change from baseline Number (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 -1.00 Q1;Q3 -1.00 ; 0.00 -2.00 ; -1.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -4.0 ; 1.0 -3.0 ; 3.0 -2.0 ; 3.0 -3.0 ; 1.0 LS 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 0.0026 Week 10 Number (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 2.00 Q1;Q3 1.00 ; 3.00 0.00; 2.00 1.00 ; 3.00 1.00; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 4.0 0.0 ; 5.0 0.0 ; 3.0 Change from baseline Number (observed / LOCF imputed) 28 (22 / 6) 27 (23 / 4) 55 (51 / 4) 56 (53 / 3) 400 mg BID cohort 400 mg TID cohort ACQ-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 -1.00 Q1;Q3 -2.00 ; 0.50 -2.00 ; 0.00 -1.00 ; 1.00 -1.00 ; 0.00 Min ; Max -4.0 ; 1.0 -3.0 ; 2.0 -3.0 ; 2.0 -3.0 ; 2.0 LS 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 0.0080 Week 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 2.00 Q1;Q3 1.00 ; 3.00 0.50; 2.00 1.00 ; 3.00 1.00; 2.00 Min ; Max 0.0 ; 4.0 0.0 ; 4.0 0.0 ; 6.0 0.0 ; 3.0 Change 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 -1.00 Q1;Q3 -1.00 ; 0.00 -2.00 ; -1.00 -1.00 ; 1.00 -2.00 ; 0.00 Min ; Max -4.0 ; 1.0 -3.0 ; 2.0 -3.0 ; 3.0 -3.0 ; 1.0 LS 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 0.0039 Wheeze Baseline Number 32 32 68 64 Mean (SD) 1.97 (0.82) 2.06 (0.72) 2.13 (0.83) 2.23 (0.79) Median 2.00 2.00 2.00 2.00 Q1;Q3 1.00 ; 2.00 2.00; 2.00 2.00; 3.00 2.00; 3.00 Min ; Max 1.0 ; 4.0 1.0 ; 4.0 0.0 ; 5.0 1.0; 4.0 Week 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 2.00 Q1;Q3 1.00 ; 2.00 0.00; 2.00 1.00 ; 3.00 1.00 ; 3.00 ACQ-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 ; 5.0 Change 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 0.00 Q1;Q3 -1.00 ; 0.00 -2.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -2.0 ; 3.0 -3.0 ; 1.0 -4.0 ; 2.0 -2.0 ; 3.0 LS 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 0.3687 Week 4 Number (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 2.00 Q1;Q3 1.00 ; 2.00 0.00; 2.00 1.00 ; 3.00 1.00 ; 3.00 Min ; Max 0.0 ; 4.0 0.0 ; 5.0 0.0; 4.0 0.0 ; 5.0 Change from baseline Number (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 0.00 Q1;Q3 -1.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min ; Max -3.0; 2.0 -3.0 ; 2.0 -5.0 ; 2.0 -2.0 ; 3.0 LS 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 0.7130 Week 6 Number (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 2.00 Q1;Q3 1.00 ; 2.00 0.00; 2.00 1.00; 2.00 1.00; 2.00 Min ; Max 0.0 ; 6.0 0.0 ; 3.0 0.0; 4.0 0.0; 4.0 Change from baseline ACQ-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 -1.00 Q1;Q3 -1.00 ; 0.00 -2.00 ; 0.00 -1.00 ; 0.00 -1.00 ; 0.00 Min; Max -3.0; 3.0 -3.0 ; 1.0 -5.0 ; 2.0 -3.0 ; 2.0 LS 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 0.3907 Week 8 Number (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 2.00 Q1;Q3 1.00 ; 2.00 0.00; 2.00 1.00 ; 3.00 1.00; 2.00 Min ; Max 0.0 ; 5.0 0.0 ; 3.0 0.0 ; 5.0 0.0; 4.0 Change from baseline Number (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 -1.00 Q1;Q3 -1.00 ; 0.00 -2.00 ; 0.00 -1.00 ; 1.00 -1.00 ; 0.00 Min ; Max -4.0 ; 3.0 -3.0 ; 1.0 -5.0 ; 3.0 -3.0 ; 1.0 LS 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 0.0669 Week 10 Number (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 1.00 Q1;Q3 1.00 ; 2.50 0.00; 2.00 1.00 ; 3.00 1.00; 2.00 Min ; Max 0.0 ; 5.0 0.0 ; 3.0 0.0 ; 5.0 0.0; 4.0 Change from baseline Number (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 -1.00 400 mg BID cohort 400 mg TID cohort ACQ-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 ; 0.00 Min ; Max -3.0; 2.0 -4.0 ; 1.0 -5.0 ; 3.0 -3.0 ; 2.0 LS 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 0.0450 Week 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 2.00 Q1;Q3 1.00 ; 2.00 0.00; 2.00 1.00 ; 3.50 1.00; 2.00 Min ; Max 0.0 ; 5.0 0.0 ; 3.0 0.0 ; 5.0 0.0 ; 3.0 Change 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 -1.00 Q1;Q3 -1.00 ; 1.00 -2.00 ; 0.00 -1.00 ; 1.00 -1.00 ; 0.00 Min ; Max -4.0 ; 2.0 -2.0 ; 1.0 -3.0 ; 3.0 -3.0 ; 1.0 LS 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 0.0078 ACQ-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 at Week 12 (mITT population). 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID Rilzabrutinib (N=68)     400 mg TID (N=64) Week 12 Number (observed / LOCF imputed) 28 (19 / 9) 28 (23 / 5) 60 (50 / 10)      49 (46 / 3) Responder (observed / LOCF imputed) 10(35.7) (9 / 1) 19 (67.9) (17 / 2) 24 (40.0) (23 / 1) 31 (63.3) (31 / 0) Non-responder (observed / LOCF imputed) 18 (64.3) (10 / 8) 9(32.1)(6 / 3) 36 (60.0) (27 / 9) 18 (36.7) (15 / 3) 400 mg BID cohort 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Responder (including multiply imputed) OR vs. placebo (95% CI) P-value vs. placebo 11.5 (35.9) 21.2 (66.1) 5.18 (1.48, 18.15) 0.0100 26.8 (39.4) 38.3 (59.8) 2.38 (1.09, 5.18) 0.0297 LATAM: 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                TID 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) Responder (observed) Non-responder (observed / NR imputed) 32 (32 / 0)      32 (32 / 0)      68 (68 / 0)      64 (64 / 0) 0              0              0              0 32 (100) (32 / 0) 32 (100) (32 / 0) 68 (100) (68 / 0) 64 (100) (64 / 0) Week 2 Number (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 0.0590 Week 4 Number (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) (11 / 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 0.1003 Week 6 Number (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) (11 / 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 cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (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 0.0575 Week 8 Number (observed / LOCF 32 (27 / 3 / 2) 32 (24 / 4 / 4) 68 (60 / 3 / 5) 64 (49 / 3 / 12) imputed / NR imputed) Responder (observed / LOCF imputed) 6(18.8) (6 / 0) 9(28.1)(9 / 0) 4 (5.9) (4 / 0) 9 (14.1)(9 / 0) 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 0.0919 Week 10 Number (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 0.1146 Week 12 Number (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 0.6286 LATAM: 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 4 Number (observed / LOCF imputed / NR imputed) Responder (observed / LOCF imputed) 32 (28 / 2 / 2)           32 (30 / 1 / 1) 2(6.3)(2 / 0)        11(34.4)(11 / 0) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Non-responder (observed / LOCF imputed / NR imputed) 30 (93.8) (26 / 2 / 2) 21 (65.6)(19 / 1 / 1) Week 6 Number (observed / LOCF imputed) Responder (observed / LOCF imputed) OR vs. placebo (95% CI) P-value vs. placebo 2 (2 / 0) 1 (50.0) (1 / 0) 11 (10 / 0) 7 (63.6) (7 / 0) 0.81 (0.01, 126.85) 0.9356 Week 8 Number (observed / LOCF imputed) Responder (observed / LOCF imputed) OR vs. placebo (95% CI) P-value vs. placebo 2 (2 / 0) 1 (50.0) (1 / 0) 11 (10 / 1) 5 (45.5) (5 / 0) 0.26 (0.00, 28.99) 0.5729 Week 10 Number (observed / LOCF imputed) Responder (observed / LOCF imputed) OR vs. placebo (95% CI) P-value vs. placebo 2 (2 / 0) 1 (50.0) (1 / 0) 11 (8 / 1) 4 (36.4) (4 / 0) 0.12 (0.00, 16.67) 0.3991 Week 12 Number (observed / LOCF imputed) Responder (observed / LOCF imputed) OR vs. placebo (95% CI) P-value vs. placebo 2(1 / 1) 0 11 (8 / 2) 3 (27.3) (2 / 1) NC (NC, NC) NC LATAM: Latin America, ROW: Rest of the world, NR: non-responder

[0254] Table 46. Subgroup analysis: change from baseline in ACQ-5 score at EOT (Week 12) by demographics subgroups (mITT population). 400 mg BID cohort 400 mg TID cohort ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Age group 1 (years) <45 Number 10 9 28 23 Mean (SD) -0.70 (0.91) -0.49 (0.94) -0.05 (1.02) -0.84 (0.62) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.70 (0.31) -0.68 (0.34) 0.02 (-0.76, 0.79) 0.9616 -0.25 (0.17) -0.95 (0.17) -0.70 (-1.15, 0.25) 0.0024 >45 Number 18 19 32 26 Mean (SD) -0.13 (1.05) -1.07 (0.88) -0.38 (1.04) -0.79 (0.81) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) 0.14 (0.23) -0.78 (0.25) -0.92 (-1.50, 0.35) -0.35 (0.17) -0.79 (0.18) -0.43 (-0.90, 0.03) ACQ-5 Placebo BID (N=32) Rilzabrutinib Placebo TID 400 mg BID    (N=68) (N=32) Rilzabrutinib 400 mg TID (N=64) P-value vs. placebo 0.0016 0.0643 Overall p-value for interaction 0.0568 0.5311 Gender Male Number 7 12            26 22 Mean (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 0.1396 Female Number 21 16            34 27 Mean (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 Diff vs. placebo (95% -0.56 (-1.19, -0.65 (-1.11, - ci) 0.06) 0.19) P-value vs. placebo 0.0747 0.0056 Overall p-value for interaction 0.9599 0.3680 Baseline weight group (kg) <60 Number 4 3              10 2 Mean (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 Diff vs. placebo (95% -2.03 (-5.03, -1.54 (-3.28, ci) 0.98) 0.21) P-value vs. placebo 0.1010 0.0847 > 60 -< 90 Number 21 20            35 29 Mean (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 Diff vs. placebo (95% -0.35 (-0.93, -0.54 (-0.97, - ci) 0.22) 0.11) P-value vs. placebo 0.2295 0.0130 >90 Number 3 5              15 18 Mean (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 Diff vs. placebo (95% -1.27 (-2.46,- -0.51 (-1.08, ci) 0.09) 0.05) P-value vs. placebo 0.0353 0.0737 Overall p-value for interaction 0.4298 0.4325 ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Baseline BMI group (kg / m2) <25 Number 6 8 20 8 Mean (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 - < 30 Number 15 13 23 26 Mean (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 Diff vs. placebo (95% -0.27 (-1.10, -0.59(-1.04,- ci) 0.56) 0.14) P-value vs. placebo 0.5253 0.0101 >30 Number 7 7 17 15 Mean (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 Diff vs. placebo (95% -1.17(-1.91,- -0.53 (-1.17, ci) 0.42) 0.11) P-value vs. placebo 0.0021 0.1017 Overall p-value for interaction 0.3782 0.9246 Region Eastern Europe Number 4 1 43 32 Mean (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 Diff vs. placebo (95% 0.88 (-1.58, -0.53 (-0.90, - ci) 3.35) 0.15) P-value vs. placebo 0.4823 0.0059 Latin America Number 22 24 15 15 Mean (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 Diff vs. placebo (95% -0.58 (-1.11, - -0.14 (-0.70, ci) 0.05) 0.43) P-value vs. placebo 0.0315 0.6394 Western Countries Number 1 2 1 2 Mean (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 cohort ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) P-value vs. placebo NC NC APAC Number 1 1 1 0 Mean (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 NC Overall p-value for interaction 0.6608 0.0007 LATAM: Latin America, ROW: Rest of the world

[0255] Table 47. Subgroup analysis: change from baseline in ACQ-5 score at EOT (Week 12) by disease and other characteristics subgroups (mITT population). 400 mg BID cohort_________400 mg TIP cohort ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Age at onset of asthma (years) < 12 Number 7 8 14 12 Mean (SD) -0.49 (0.80) -0.68 (1.13) 0.09 (0.93) -0.58 (0.67) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.70 (0.42) -0.71 (0.55) -0.01 (-1.21, 1.18) 0.9822 -0.02 (0.22) -0.63 (0.24) -0.61 (-1.24, 0.02) 0.0595 > 12-< 18 Number 2 4 5 5 Mean (SD) -0.40 (0.57) -1.30 (0.20) -0.76 (1.18) -1.04 (0.65) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.14 (0.88) -0.96 (0.54) -0.82 (-3.23, 1.59) 0.2812 -1.10 (0.84) -1.08 (0.64) 0.01 (-1.86, 1.89) 0.9849 > 18 -<40 Number 13 13 24 20 Mean (SD) -0.25 (1.06) -0.97 (0.98) -0.11 (1.24) -0.87 (0.69) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 0.15 (0.27) -0.71 (0.27) -0.85 (-1.52, -0.19) 0.0119 -0.20 (0.23) -0.77 (0.24) -0.57(-1.15, 0.01) 0.0537 >40 Number 6 3 17 12 Mean (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) ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (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 0.0660 Overall p-value for interaction 0.5580 0.8917 Age at onset of asthma (years) < 18 Number 9 12 19 17 Mean (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 32 Mean (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 0.0089 Overall p-value for interaction 0.4014 0.8634 Number of asthma exacerbations within 2 years before screening visit 1 Number 8 10 45 31 Mean (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 0.0016 2 Number 14 10 15 15 Mean (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 3 Mean (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 NC ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Overall p-value for interaction 0.8549 0.4193 Atopic medical conditions Yes Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 16 -0.75 (1.04) -0.41 (0.29) 19 -0.89 (0.92) -0.71 (0.28) -0.30 (-0.92, 0.32) 0.3393 19 -0.38 (0.97) -0.23 (0.21) 16 -0.80 (0.83) -0.79 (0.24) -0.56(-1.15, 0.03) 0.0640 No Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 12 0.22 (0.71) 0.27 (0.28) 9 -0.87 (1.00) -0.69 (0.33) -0.96 (-1.71, 0.21) 0.0118 41 -0.15 (1.06) -0.36 (0.17) 33 -0.82 (0.67) -0.87 (0.17) -0.51 (-0.92, -0.10) 0.0149 Overall p-value for interaction 0.1288 0.8698 Background ICS dose level at randomization (400 mg TID only) Medium Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 32 -0.11 (0.96) -0.29 (0.19) 19 -0.72 (0.72) -0.76 (0.20) -0.46 (-0.93, 0.00) 0.0518 High Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 28 -0.36 (1.11) -0.32 (0.18) 30 -0.88 (0.73) -0.92 (0.18) -0.60 (-1.08, 0.11) 0.0167 Overall p-value for interaction 0.6694 Smoking history Former Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 7 -0.03 (0.88) 0.75 (0.48) 4 -1.20 (1.07) -0.50 (0.62) -1.25 (-2.44, -0.06) 0.0396 3 0.33 (0.42) 0.27 (0.44) 3 0.07 (0.42) -0.56 (0.47) -0.83 (-1.97, 0.31) 0.1522 ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Never Number 21 24 57 46 Mean (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 0.0025 Overall p-value for interaction 0.2052 0.7507 Baseline pre-bronchodilator FEV1 (L) (400 mg BID only) : Median (2.022) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 13 -0.31 (1.08) 0.04 (0.28) 15 -0.88 (0.81) -0.42 (0.30) -0.45 (-1.09, 0.19) 0.1647 : Median (2.022) Number 15 12 Mean (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 0.1073 Overall p-value for interaction                       0.7510 Baseline pre-bronchodilator percent predicted FEV 1 (%) (400 mg BID only) < Median (68) Number 12 16 Mean (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 11 Mean (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 0.1642 400 mg BID cohort         400 mg TID cohort ACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32)    400 mg BID    (N=68)    400 mg TID (N=32)                    (N=64) Overall p-value for interaction 0.9232 Baseline pre-bronchodilator FEV1 (L) (400 mg TID only) < Median (2.1955) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 28 -0.24(1.11) -0.23 (0.18) 19 -0.91 (0.74) -0.89 (0.21) -0.66 (-1.18, - 0.15) 0.0120 > Median (2.1955) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 31 -0.21 (0.99) -0.39 (0.17) 29 -0.76 (0.72) -0.83 (0.16) -0.44 (-0.88, - 0.01) 0.0467 Overall p-value for interaction 0.4527 Baseline pre-bronchodilator percent predicted FEV 1 group 1 (%) (400 mg TID only) < Median (77) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo > Median (77) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo Overall p-value for interaction Baseline pre-bronchodilator percent predicted FEV 1 group 2 (%) (400 mg TID only) < 80 Number Mean (SD) LS Mean (SE) 31            21 -0.14 (1.04)    -0.72(0.70) -0.23 (0.18)    -0.74(0.22) -0.52 (-1.01, 0.03) 0.0393 29            27 -0.32 (1.03)    -0.89 (0.75) -0.38 (0.17)    -0.90(0.16) -0.52 (-0.98, -0.05) 0.0286 0.9797 36            26 -0.13 (1.03)    -0.75 (0.73) -0.21(0.17)    -0.75(0.19) ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.54 (-0.98, -0.10) 0.0165 > 80 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 24 -0.36 (1.04) -0.38 (0.18) 22 -0.89 (0.73) -0.95 (0.19) -0.57(-1.08, 0.06) 0.0295 Overall p-value for interaction 0.9237 Baseline FEV1 reversibility (%) < 12 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 17 -0.14 (0.82) -0.15 (0.23) 12 -0.65 (0.88) -0.61 (0.28) -0.46 (-1.10, 0.18) 0.1609 43 -0.33 (1.11) -0.41 (0.15) 33 -0.79 (0.75) -0.85 (0.17) -0.45 (-0.87, -0.03) 0.0375 > 12 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 9 -0.31 (1.06) 0.12(0.33) 14 -1.03 (1.01) -0.29 (0.35) -0.41 (-1.10, 0.28) 0.2413 10 -0.20 (0.72) -0.22 (0.30) 10 -0.94 (0.68) -0.85 (0.32) -0.63 (-1.36, 0.10) 0.0907 Overall p-value for interaction 0.9399 0.6991 Baseline ACQ-5 score <2 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 13 -0.15 (0.83) 0.12(0.28) 16 -0.76 (0.96) -0.60 (0.27) -0.72 (-1.32,0.12) 0.0197 25 -0.29 (0.80) -0.27 (0.18) 14 -0.91 (0.89) -0.81 (0.21) -0.54 (-1.06,0.02) 0.0426 >2 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 15 -0.49 (1.17) -0.20 (0.34) 12 -1.05 (0.89) -0.78 (0.39) -0.58 (-1.39, 0.23) 0.1633 35 -0.18 (1.18) -0.34 (0.17) 35 -0.78 (0.65) -0.89 (0.17) -0.55 (-0.98, -0.12) 0.0118 ACQ-5 Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID (N=32) (N=64) Overall p-value for interaction_______________________0,8615________________________0,9369 LATAM: 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 (N=32) Rilzabrutinib 400 mg BID (N=32) Background ICS / LABA dose level at randomization Medium Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo 3 0.00(1.00) 0.02 (0.94) 3 -1.07 (0.70) -0.79 (0.75) -0.80 (-2.49, 0.88) 0.3496 High Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo 25 -0.38 (1.04) -0.12 (0.22) 25 -0.86 (0.96) -0.70 (0.23) -0.57(-1.12, -0.03) 0.0372 Overall p-value for interaction 0.9013 LATAM: Latin America, ROW: Rest of the world

[0257] Table 49. Subgroup analysis: change from baseline in ACQ-5 score at EOT (Week 12) by baseline biomarker subgroups (mITT population). 400 mg BID cohort 400 mg TID cohort ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo BID (N=68) Rilzabrutinib 400 mg TID (N=64) Baseline IgE level (lU / mL) < 100 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 8 -0.50(1.22) -0.35 (0.50) 7 -0.83 (0.76) -0.63 (0.50) -0.28 (-1.44, 0.88) 0.6362 24 -0.20 (0.93) -0.40 (0.37) 18 -0.93 (0.66) -1.08 (0.40) -0.67 (-1.19, - 0.16) 0.0107 > 100 Number Mean (SD) LS Mean (SE) 20 -0.27 (0.96) -0.24 (0.51) 21 -0.90 (1.00) -0.83 (0.48) 36 -0.24(1.11) -0.18 (0.22) 31 -0.75 (0.76) -0.64 (0.24) 400 mg BID cohort 400 mg TID cohort ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo BID (N=68) Rilzabrutinib 400 mg TID (N=64) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.59 (-1.14, -0.04) 0.0358 -0.46 (-0.89, -0.03) 0.0366 Overall p-value for interaction 0.8951 0.5332 Baseline median IgE level (lU / mL) (400 mg BID only) < Median (210.8) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 10 -0.44(1.09) -0.14(0.33) 18 -0.76 (0.94) -0.60 (0.26) -0.46 (-1.24, 0.32) 0.2488 > Median (210.8) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 18 -0.28 (1.01) -0.08 (0.24) 10 -1.12 (0.90) -0.87 (0.36) -0.79 (-1.49, 0.08) 0.0282 Overall p-value for interaction 0.5416 Baseline median IgE level (lU / mL) (400 mg TID only) < Median (121.85) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 30 0.01 (1.11) 0.02 (0.23) 23 -0.95 (0.63) -0.79 (0.23) -0.81 (-1.30, -0.32) 0.0011 > Median (121.85) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 30 -0.46 (0.91) -0.71 (0.43) 26 -0.70 (0.79) -0.99 (0.46) -0.27 (-0.71, 0.16) 0.2121 Overall p-value for interaction 0.0955 Baseline median IgA level (mg / L) (400 mg TID only) < Median (2190) Number 32           23 ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo BID (N=68) Rilzabrutinib 400 mg TID (N=64) Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo -0.06(1.02) -0.23 (0.17) -0.86 (0.68) -0.90 (0.19) -0.67 (-1.14, - 0.19) 0.0060 > Median (2190) Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 28 -0.41 (1.03) -0.38 (0.18) 26 -0.78 (0.77) -0.80 (0.18) -0.41 (-0.89, 0.07) 0.0925 Overall p-value for interaction 0.4742 Baseline blood eosinophil level 1 (10A9 / L) (400 mg BID only) <0.15 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo >0.15 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo 6              8 -0.80(1.40)   -0.50 (0.99) -0.34 (0.65)   -0.57 (0.45) -0.23 (-2.01, 1.56) 0.7785 22          20 -0.21 (0.90)   -1.04 (0.88) -0.07(0.21)   -0.85 (0.26) -0.78 (-1.31, -0.24) 0.0044 Overall p-value for interaction                        0.1355 Baseline blood eosinophil level 2 (10A9 / L) (400 mg BID only) <0.3 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 17 -0.52(1.21) -0.13 (0.24) 16 -1.04 (0.92) -0.81 (0.27) -0.68 (-1.33, -0.03) 0.0399 >0.3 Number 11 12 Mean (SD) -0.05 (0.57) -0.68 (0.94) LS Mean (SE) -0.16(0.35) -0.72 (0.35) ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo BID (N=68) Rilzabrutinib 400 mg TID (N=64) LS Mean Diff vs. placebo (95% -0.55 (-1.22, ci) 0.12) P-value vs. placebo 0.1049 Overall p-value for interaction 0.8601 Baseline blood eosinophil level 1 (10A9 / L) (400 mg TID only) <0.15 Number 27 21 Mean (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 -<0.3 Number 18 13 Mean (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 >0.3 Number 15 15 Mean (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 0.0451 Overall p-value for interaction 0.5667 Baseline blood eosinophil level 2 (10A9 / L) (400 mg TID only) <0.3 Number 45 34 Mean (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 >0.3 Number 15 15 Mean (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) ACQ-5 Placebo BID Rilzabrutinib Placebo BID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID (N=32) (N=64) P-value vs. placebo                                                                 0.0451 Overall p-value for interaction                                                      0.7504 Baseline FeNO level 1 (ppb) <25 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 14 -0.39(1.12) -0.01 (0.32) 11 -1.02 (0.80) -0.81 (0.32) -0.80 (-1.53, 0.06) 0.0344 37 -0.26 (0.97) -0.43 (0.15) 30 -0.84 (0.71) -0.93 (0.15) -0.51 (-0.89, -0.12) 0.0101 >25 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 14 -0.29 (0.95) -0.15 (0.26) 17 -0.80 (1.02) -0.62 (0.30) -0.47 (-1.15, 0.22) 0.1826 19 -0.31 (1.18) -0.29 (0.27) 17 -0.84 (0.78) -0.82 (0.26) -0.53 (-1.19, 0.13) 0.1127 Overall p-value for interaction 0.5887 0.9211 Baseline FeNO level 2 (ppb) <35 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 17 -0.36 (1.05) 0.11 (0.27) 20 -0.91 (0.86) -0.64 (0.24) -0.75 (-1.32, - 0.19) 0.0089 44 -0.25 (1.08) -0.36(0.15) 35 -0.81 (0.72) -0.85 (0.15) -0.49 (-0.89, - 0.10) 0.0141 >35 Number Mean (SD) LS Mean (SE) LS Mean Diff vs. placebo (95% ci) P-value vs. placebo 11 -0.29(1.02) -0.26 (0.32) 8 -0.83 (1.15) -0.67 (0.46) -0.41 (-1.47, 0.66) 0.4551 12 -0.37 (0.90) -0.38 (0.36) 12 -0.92 (0.77) -0.89 (0.32) -0.51 (-1.24, 0.23) 0.1744 Overall p-value for interaction 0.4819 0.8970 LATAM: Latin America, ROW: Rest of the world

[0258] Table 50. Subgroup analysis: change from baseline in ACQ-5 score at EOT (Week 12) in the baseline low EOS and low FeNO subgroup (mITT population). ACQ-5 Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo BID (N=68) Rilzabrutinib 400 mg TID (N=64) Baseline blood eosinophil (10A9 / L) and FeNO (ppb) Low EOS (< 0.15) and low FeNO (<25) Number 4 3 21 14 Mean (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 Diff vs. placebo (95% -2.44 (-11.51, -0.61 (-1.13, - CI) 6.64) 0.09) P-value vs. placebo 0.3675 0.0214 All others Number 24 25 35 33 Mean (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 Diff vs. placebo (95% -0.59 (-1.08,- -0.50 (-0.95, - CI) 0.11) 0.06) P-value vs. placebo 0.0172 0.0267 Overall p-value for interaction 0.9709 0.8721 LATAM: Latin America, ROW: Rest of the world AQLQ 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 cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Week 12 Number (observed / LOCF 29 (20 / 9) 29 (24 / 5) 62 (52 / 10) 53 (50 / 3) imputed) 400 mg TID cohort Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (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 0.0456 LATAM: 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 cohort AQLQ(S) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID (N=32) (N=64) Global score Baseline Number 31 32 67 62 Mean (SD) 4.67 (1.07) 4.91 (1.04) 4.68 (0.83) 4.96 (0.71) Median 4.69 5.19 4.56 4.94 Q1;Q3 4.13 ; 5.59 4.31 ; 5.64 4.00 ; 5.41 4.38 ; 5.44 Min ; Max 2.1 ; 6.2 2.4 ; 6.4 2.8 ; 6.3 3.7 ; 6.6 Week 4 Number (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 5.03 Q1;Q3 4.03 ; 5.50 5.34 ; 6.28 4.22 ; 5.59 4.44 ; 6.03 Min ; Max 1.9 ; 6.7 3.1 ; 6.7 2.2 ; 6.7 2.5 ; 6.9 Change from baseline Number (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 0.13 Q1;Q3 -0.50 ; 0.63 0.09 ; 1.09 -0.19 ; 0.59 -0.25 ; 0.67 Min ; Max -3.7; 2.2 -0.8 ; 3.2 -1.9 ; 1.7 -2.2 ; 2.7 LS 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 0.4929 Week 8 400 mg BID cohort 400 mg TID cohort AQLQ(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 5.06 Q1;Q3 3.88 ; 6.00 5.53 ; 6.28 4.06 ; 5.81 4.59 ; 6.16 Min ; Max 2.8 ; 6.8 4.0 ; 7.0 2.6 ; 7.0 3.5 ; 6.9 Change from baseline Number (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 0.34 Q1;Q3 -0.19 ; 0.88 0.22 ; 1.31 -0.25 ; 1.00 -0.09 ; 0.75 Min ; Max -3.0 ; 1.9 -0.4; 2.8 -1.6; 2.6 -1.3 ; 2.0 LS 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 0.4993 Week 12 Number (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 5.23 Q1;Q3 3.88 ; 5.97 5.41 ; 6.34 4.13 ; 5.88 4.91 ; 6.13 Min ; Max 2.9 ; 7.0 4.0 ; 7.0 1.4 ; 6.7 3.1 ; 7.0 Change from baseline Number (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 0.53 Q1;Q3 -0.13 ; 1.25 0.16 ; 1.38 -0.41 ; 0.78 0.00 ; 1.00 Min ; Max -2.5 ; 2.3 -0.7 ; 3.1 -1.7 ; 3.1 -1.9 ; 2.6 LS 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 0.0620 Symptoms score Baseline Number 31 32 67 62 Mean (SD) 4.59 (1.05) 5.05 (1.05) 4.70 (0.80) 4.97 (0.73) Median 4.75 5.21 4.75 4.83 Q1;Q3 4.25 ; 5.25 4.42 ; 5.83 4.08 ; 5.33 4.33 ; 5.42 Min ; Max 1.7 ; 6.0 2.6 ; 6.6 3.0 ; 6.8 3.8 ; 6.6 Week 4 Number (observed / LOCF 30 (28 / 2) 31 (30 / 1) 65 (64 / 1) 61 (61 / 0) imputed) 400 mg BID cohort 400 mg TID cohort AQLQ(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 5.08 Q1;Q3 4.00 ; 5.50 5.50 ; 6.33 4.42 ; 5.58 4.42 ; 6.00 Min ; Max 1.8 ; 6.8 3.7 ; 6.7 2.2 ; 6.6 2.4 ; 7.0 Change from baseline Number (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 0.25 Q1;Q3 -0.25 ; 0.75 0.08 ; 1.25 -0.25 ; 0.67 -0.29 ; 0.67 Min ; Max -3.2; 2.4 -0.8 ; 3.3 -1.8 ; 1.7 -2.3 ; 2.8 LS 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 0.3018 Week 8 Number (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 5.17 Q1;Q3 4.25 ; 5.83 5.67 ; 6.50 4.17 ; 5.75 4.58 ; 6.08 Min ; Max 2.3 ; 6.9 3.5 ; 6.9 2.6 ; 7.0 3.7 ; 7.0 Change from baseline Number (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 0.38 Q1;Q3 -0.08 ; 0.83 0.25 ; 1.25 -0.42 ; 1.08 -0.08 ; 0.75 Min ; Max -1.8 ; 2.6 -0.6 ; 3.0 -1.6; 2.3 -1.8 ; 2.0 LS 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 0.3792 Week 12 Number (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 5.25 Q1;Q3 4.67 ; 5.83 5.50 ; 6.50 4.42 ; 5.92 4.83 ; 6.08 Min ; Max 3.0 ; 7.0 3.8 ; 7.0 1.0 ; 6.8 3.7 ; 7.0 Change from baseline Number (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 0.58 400 mg BID cohort 400 mg TID cohort AQLQ(S) Placebo BID (N=32) Rilzabrutinib 400 mg BID (N=32) Placebo TID (N=68) Rilzabrutinib 400 mg TID (N=64) Q1;Q3 -0.08 ; 1.17 0.08 ; 1.58 -0.58 ; 0.92 0.00 ; 0.92 Min ; Max -1.8 ; 2.6 -1.3 ; 3.3 -2.3 ; 3.2 -2.0 ; 2.8 LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo 0.17 (0.18) 0.84 (0.19) 0.67 (0.22, 1.11) 0.0032 0.26 (0.13) 0.59(0.14) 0.34 (-0.01, 0.68) 0.0542 Activity limitation score Baseline Number 31 32 67 62 Mean (SD) 4.74 (1.13) 4.78 (1.12) 4.70 (0.83) 4.99 (0.78) Median 4.73 5.00 4.64 4.91 Q1;Q3 4.09 ; 5.73 4.09 ; 5.55 4.00 ; 5.36 4.45 ; 5.45 Min ; Max 2.4 ; 6.6 1.9 ; 6.5 3.0 ; 6.6 3.4 ; 6.7 Week 4 Number (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 5.18 Q1;Q3 4.00 ; 5.45 5.09 ; 6.18 4.27 ; 5.64 4.45 ; 6.00 Min ; Max 2.5 ; 7.0 3.2 ; 7.0 2.5 ; 6.7 2.6 ; 6.9 Change from baseline Number (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 0.09 Q1;Q3 -0.64 ; 0.55 0.00 ; 1.18 -0.18 ; 0.64 -0.41 ; 0.59 Min ; Max -3.2; 2.1 -1.1 ; 3.0 -2.2 ; 1.9 -2.0 ; 2.9 LS Mean (SE) LS Mean Diff vs. placebo (95% CI) P-value vs. placebo -0.03 (0.20) 0.72 (0.21) 0.75 (0.26, 1.24) 0.0029 0.26 (0.10) 0.34 (0.11) 0.08 (-0.20, 0.35) 0.5846 Week 8 Number (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 5.27 Q1;Q3 3.91 ; 6.27 5.09 ; 6.18 4.18 ; 5.82 4.64 ; 6.00 Min ; Max 2.6 ; 6.9 3.9 ; 7.0 3.0 ; 7.0 3.5 ; 6.9 Change from baseline Number (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 0.36 Q1;Q3 -0.18 ; 0.73 0.18 ; 1.55 -0.18 ; 0.91 -0.27 ; 0.91 Min ; Max -3.1 ; 1.5 -0.4; 2.8 -1.8 ; 2.9 -1.4 ; 2.2 400 mg BID cohort 400 mg TID cohort AQLQ(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 0.4877 Week 12 Number (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 5.36 Q1;Q3 3.82 ; 6.00 5.18 ; 6.36 4.18 ; 5.82 4.91 ; 6.18 Min ; Max 2.7 ; 7.0 3.8 ; 7.0 2.1 ; 6.6 3.1 ; 7.0 Change from baseline Number (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 0.55 Q1;Q3 -0.18 ; 0.91 0.18 ; 1.27 -0.27 ; 0.91 -0.18 ; 1.09 Min ; Max -3.0; 2.3 -0.7; 2.9 -1.8 ; 2.8 -1.3 ; 2.8 LS 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 0.0339 Emotional function score Baseline Number 31 32 67 62 Mean (SD) 4.70 (1.71) 5.21 (1.26) 4.87 (1.14) 5.15 (1.14) Median 5.40 5.30 4.80 5.20 Q1;Q3 3.80 ; 5.80 4.10 ; 6.50 4.20 ; 5.60 4.40 ; 6.00 Min ; Max 1.2 ; 7.0 2.0 ; 7.0 1.8 ; 6.8 1.2 ; 7.0 Week 4 Number (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 5.40 Q1;Q3 3.60 ; 5.80 5.00 ; 7.00 4.40 ; 5.80 4.80 ; 6.40 Min; Max 1.0; 7.0 1.6; 7.0 2.0; 7.0 1.2; 7.0 Change from baseline Number (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 0.20 Q1;Q3 -0.60 ; 0.60 -0.40 ; 1.60 -0.40 ; 0.80 -0.40 ; 0.80 Min ; Max -5.2; 2.8 -2.4 ; 3.0 -2.4 ; 3.0 -2.6 ; 2.8 LS 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 cohort AQLQ(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 0.2202 Week 8 Number (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 5.40 Q1;Q3 3.40 ; 6.20 5.80 ; 7.00 4.40 ; 6.20 4.80 ; 6.60 Min ; Max 1.0 ; 7.0 2.8 ; 7.0 2.0 ; 7.0 1.2 ; 7.0 Change from baseline Number (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 0.40 Q1;Q3 -0.40 ; 1.00 0.00 ; 1.40 -0.60 ; 1.20 0.00 ; 0.80 Min ; Max -3.8 ; 2.2 -1.2; 4.2 -1.8 ; 3.0 -1.8 ; 2.6 LS 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 0.4378 Week 12 Number (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 5.60 Q1;Q3 4.00 ; 6.20 5.20 ; 7.00 4.40 ; 6.40 5.20 ; 6.60 Min ; Max 1.0 ; 7.0 3.2 ; 7.0 1.0 ; 7.0 1.2 ; 7.0 Change from baseline Number (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 0.40 Q1;Q3 0.00 ; 1.20 0.00 ; 1.40 -0.40 ; 1.00 0.00 ; 1.00 Min ; Max -3.8 ; 4.8 -0.8 ; 3.4 -3.8 ; 3.4 -2.4 ; 2.8 LS 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 0.1134 Environmental stimuli score Baseline Number 31 32 67 62 Mean (SD) 4.62 (1.46) 4.43 (1.64) 4.31 (1.16) 4.64(1.06) Median 4.75 4.75 4.25 4.75 Q1;Q3 3.75 ; 5.75 3.63 ; 5.75 3.50 ; 5.25 4.00 ; 5.25 400 mg BID cohort__________400 mg TIP cohort AQLQ(S) Placebo BID Rilzabrutinib Placebo TID Rilzabrutinib (N=32) 400 mg BID (N=68) 400 mg TID (N=32) (N=64) Min ; Max 1.8 ; 7.0 1.0 ; 7.0 1.0 ; 7.0 1.0 ; 7.0 Week 4 Number (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 4.75 Q1;Q3 3.00 ; 5.75 4.25 ; 6.00 3.75 ; 5.50 4.00 ; 5.75 Min ; Max 1.3 ; 6.5 2.0 ; 7.0 1.0 ; 7.0 1.8 ; 7.0 Change from baseline Number (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 0.25 Q1;Q3 -0.50 ; 1.25 -0.75 ; 1.75 -0.25 ; 0.75 -0.50 ; 0.63 Min ; Max -5.8 ; 2.5 -2.3 ; 4.8 -2.5 ; 2.8 -2.5 ; 2.3 LS 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 0.8468 Week 8 Number (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 4.75 Q1;Q3 3.75 ; 5.75 4.50 ; 6.00 3.75 ; 5.75 4.00 ; 6.00 Min ; Max 1.3 ; 6.8 2.0 ; 7.0 1.0 ; 7.0 2.0 ; 7.0 Change from baseline Number (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 0.25 Q1;Q3 -0.50 ; ...

Claims

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 FEV1.

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; andb. 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 patient 400 mg of rilzabrutinib twice a day.

46. 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-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.

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-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).

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-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.

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-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).

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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