Method of prophylaxis to prevent attacks of hereditary angioedema in pediatric patients

Abstract

Disclosed is a method for prophylaxis to prevent attacks of HAE in pediatric patients aged 2 to less than 12 years of age, the method comprising orally administering once daily berotralstat using a weight-based dosing regimen. Also provided are oral pharmaceutical compositions for use in such methods.

Description

[0001] BPX-06125

[0002] METHOD OF PROPHYLAXIS TO PREVENT ATTACKS OF HEREDITAR YANGIOEDEMA IN PEDIA TRIC PA TIENTS AND COMPOSITIONS FOR USE IN SUCH METHODS RELATED APPLICATIONS

[0003] This application claims the benefit of priority to United States Provisional Patent Application No. 63 / 756,641, filed February 10, 2025, United States Provisional Patent Application No. 63 / 851,180, filed July 25, 2025, and United States Provisional Patent Application No. 63 / 939,443, filed December 12, 2025.

[0004] BACKGROUND

[0005] Hereditary angioedema (HAE) is a rare, autosomal dominant genetic disorder characterized by unpredictable, acute, and recurrent episodes of nonpruritic swelling.

[0006] Swelling can occur on the face, limbs, trunk, respiratory tract, genitourinary tract, and gastrointestinal tract. Two types of HAE are associated with mutations in the serine protease inhibitor gene 1 (SERPING ) resulting in a deficiency (Type 1) or dysfunction (Type 2) of the Cl inhibitor (Cl -INH) protein, collectively known as HAE due to Cl inhibitor deficiency (HAE-CHNH). HAE Type 1 occurs in about 85% of cases and is associated with mutations in the SERVING 1 gene resulting in truncated or misfolded Cl -INH that cannot be effectively secreted. HAE Type 2 occurs in about 15% of cases and is associated with

[0007] SERVING] mutations at or near the active site that result in a Cl-INH protein that is secreted but dysfunctional. A third type of HAE has also been identified, HAE with normal Cl-INH (also referred to as HAE Type 3), that occurs in less than 1% of cases and has multiple variants. The absence of normal functioning Cl-INH protein leads to excessive bradykinin release, causing increased vascular permeability and submucosal swelling.

[0008] Regardless of the age of individuals with HAE, the disease pathophysiology is the same. Both adult and pediatric patients experience recurrent unpredictable acute attacks of painful subcutaneous or submucosal edema of the face, larynx, tongue, gastrointestinal tract, limbs, or genitalia which, if untreated, may last up to 5 days and can be fatal (Frank, Immunol Allergy Clin North Am, 2006;26(4):653-68). The frequency and severity of HAE symptoms show significant inter- and intra-individual variation in both adults and pediatric patients, with the frequency of attacks ranging from rarely in some patients to every few days in others (Bork et al., Am J Med, 2006; 119(3):267-74; Zuraw, et al., Am J Rhinol Allergy, 2011;25(6):373-8; Nanda, et al., J Allergy Clin Immunol Pract, 2015;3(3):392-5).

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[0011] There are no published prevalence studies of HAE in pediatric patients in the US. However, because HAE with Cl -INH deficiency is genetically determined, prevalence in pediatric patients is anticipated to be similar to adults, which has been estimated as 1 : 50,000 (Zuraw, New Engl J Medicine, 2008;359(10): 1027-36; Lumry, Am J Manag Care,

[0012] 2013 ; 19: si 03-10). HAE has not historically been considered severe in the pediatric population, especially prior to puberty given the role of estrogen in this disease. However, the present disclosure and others (Mauer et al., J Allergy Clin Immunol: Pr. 2024;12(l):201-21 l.e6) demonstrate that there is an underserved pediatric population with high disease burden similar to the adult population, and consequently an unmet medical need for long term prophylaxis in this patient population.

[0013] The 2021 World Allergy Organization and European Academy of Allergy and Clinical Immunology (WAO / EAACI) international HAE treatment guidelines recommend that all patients have on-demand treatment available for acute attacks and be considered for long-term prophylaxis to prevent attacks. There are no approved oral prophylactic HAE therapies for pediatric patients. Current IV and SC prophylactic therapies approved for pediatric patients carry a considerable burden of administration. In addition, IV and SC administration in young pediatric patients may be challenging and potentially traumatic, affecting future compliance and quality of life. Due to the burdens associated with parenteral administration of LTP, limited LTP options, and overall disease burden in children, there remains an unmet medical need for oral prophylaxis to prevent HAE attacks in pediatric patients.

[0014] The present disclosure provides a solution to the described unmet medical needs by providing new methods of oral prophylaxis to prevent attacks of HAE in pediatric patients as well as oral pharmaceutical compositions for use in such methods.

[0015] SUMMARY OF THE INVENTION

[0016] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat free base based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat free base selected from the following:

[0017] a. about 120 mg to about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;

[0018] b. about 96 mg to about 120 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;

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[0021] c. about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or

[0022] d. about 60 mg to about 90 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg.

[0023] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat free base based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat free base selected from the following:

[0024] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat based on a body weight of the pediatric subject, wherein the dose is between about 60 mg and about 144 mg.

[0025] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat, wherein the dose is between about 60 mg and about 144 mg.

[0026] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 40 kg or greater, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 120 mg and about 144 mg.

[0027] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 32 kg to less than 40 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 96 mg and about 120 mg.

[0028] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 24 kg to less than 32 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 84 mg and about 108 mg.

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[0031] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 40 kg or greater, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 120 mg and about 144 mg.

[0032] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 32 kg to less than 40 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 96 mg and about 120 mg.

[0033] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 24 kg to less than 32 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 84 mg and about 108 mg.

[0034] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 5 kg to less than 24 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 60 mg and about 90 mg.

[0035] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 5 kg to less than 24 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 54 mg and about 84 mg.

[0036] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 35 kg or greater, the method comprising orally administering once daily to the pediatric a dose of berotralstat between about 114 mg and about 144 mg.

[0037] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 20 kg to less than 35 kg, the method

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[0040] comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 84 mg and about 114 mg.

[0041] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat based between about 60 mg and about 90 mg.

[0042] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old a pediatric dose of berotralstat based on a body weight of the pediatric subject, wherein the pediatric dose is between about 60 mg and about 144 mg.

[0043] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of 40 kg or greater, a pediatric dose of berotralstat between about 120 mg and about 144 mg.

[0044] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of 32 kg to less than 40 kg, a pediatric dose of berotralstat between about 96 mg and about 120 mg.

[0045] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old,

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[0048] the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat between about 110 mg and about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of 24 kg to less than 32 kg, a pediatric dose of berotralstat between about 84 mg and about 108 mg.

[0049] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of: i) less than 24 kg; ii) 12 kg to less than 24 kg a pediatric; or iii) 15 kg to less than 24 kg, a pediatric dose of berotralstat between about 60 mg and about 90 mg.

[0050] In some embodiments, the present disclosure relates to a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of: i) less than 24 kg; ii) 12 kg to less than 24 kg a pediatric; or iii) 15 kg to less than 24 kg, a pediatric dose of berotralstat between about 54 mg and about 84 mg.

[0051] In some embodiments, the present disclosure relates to a solid oral dosage form comprising crystalline berotralstat dihydrochloride and a mixture of excipients, wherein the excipients are selected from the group consisting of: pregelatinized starch, crospovidone, colloidal anhydrous silica, and magnesium stearate.

[0052] BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of berotralstat dihydrochloride.

[0053] FIG.2 shows an exemplary process for the manufacture of the solid oral granules / oral pellets described herein.

[0054] FIG. 3 shows mean (SEM) and median adjusted HAE attack rate and patients with zero adjusted HAE attacks during Parts 1 and 2.

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[0057] DETAILED DESCRIPTION HAE is characterized by recurrent episodes of swelling of the skin, pharynx, larynx, gastrointestinal tract, genitals, and extremities, with the frequency of HAE attacks varying from rarely in some patients to every few days in others. The severity of HAE symptoms also shows significant variation in both adult and pediatric patients. HAE attacks may or may not be precipitated by a stimulus (such as stress, trauma, or estrogen) and typically progress over several hours, with symptoms, if left untreated, subsiding gradually over the following 3 to 5 days. Oropharyngeal swelling can be life-threatening, while attacks in other sites, including limbs, genitalia, face, and intestines, can be painful, disabling, and disfiguring, and have a significant impact on functionality and quality of life (QoL). Laryngeal edema is less common in pediatric patients 11 years of age and younger compared to adults with HAE (Bork, et al., Transfus Apher Sci. 2003;29(3):235-8). However nearly half of patients will have an upper airway attack by the age of 18 years (MacGinnitie, et al., Pediatr Allergy Immunol [Internet], 2014;25(5):420-7). Although mortality risk from asphyxiation is much higher in undiagnosed patients with HAE, deaths still occur in diagnosed patients with access to care.

[0058] Extensive evidence from animal models and clinical studies supports the role of BK as the principal mediator of HAE. Regardless of the age of individuals with HAE, their disease pathophysiology is similar. Plasma kallikrein is a serine protease integral to the contact activation pathway. Plasma kallikrein circulates in plasma as a zymogen, prekallikrein (PKK), bound to one of its main substrates, high-molecular-weight kininogen (HK). During contact activation, PKK is cleaved by activated factor XII, forming the active plasma kallikrein protease, which in turn cleaves HK, producing BK. The activation of the BK B2 receptor by BK results in vasodilation, increased vascular permeability, and smooth muscle contraction, all of which lead to the tissue swelling that characterizes HAE.

[0059] The applicant conducted a Phase III clinical trial (referred to as Study 304) in pediatric patients aged 2 to less than 12 years of age to explore additional options for oral prophylaxis of HAE in pediatric patients. The mean age of HAE diagnosis varies greatly and is significantly affected by family history and symptoms. A retrospective questionnaire of a large cohort of 731 US adult patients found that symptom onset was commonly around 11 years of age (6 to 15 years), and some patients become symptomatic earlier (48.2% reporting onset of swelling by the age of 10 years). Contrary to the findings of the art prior to the initiation of Study 304, the majority of participants in Study 304 experienced an onset of first symptoms at 6 years of age or earlier (37.9% from birth to less than 2 years of age and 44.8%

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[0062] from 2 to less than 6 years of age), substantially earlier than puberty. Median age for onset of HAE symptoms in Study 304 was 2.9 years. At this age, patients may not be able to verbalize their attack symptoms. In addition, self-reported HAE severity was related to age of onset in this survey, with adult patients who reported their first symptoms at a younger age reporting more severe HAE (p = 0.0002) (Christiansen et al., Clin Pediatr (Phila), 2016;55(10):935— 42). Early onset of HAE symptoms is also associated with an increased frequency of HAE attacks, increased perceived severity of HAE attacks, and negative life impact.

[0063] The enrolled patients in Study 304 reflected these characteristics, with all 29 patients (100%) reporting a median of 11 attacks in the 6 months prior to enrollment, 27 patients (93.1%) reporting a median of 10.0 missed days of education in the year prior to enrollment, and 4 patients (13.8%) reporting laryngeal attacks at any time prior to enrollment.

[0064] Prior studies have demonstrated a substantial burden on HAE caregivers as well, particularly caregivers caring for those with severe HAE attacks and / or high HAE attack rates. In addition to missed days of education for the patient, the majority of caregivers report missing days of work or education as a direct result of caring for a patient with HAE (Aygoren-Pursun et al., Orphanet J Rare Dis, 2014;9( 1 ) :99). A recent survey reported that caregivers spent an average of 20.6 hours / week in caregiving activities (monitoring symptoms, managing medication and medical appointments, supporting daily activities, and providing emotional support). Caregivers report a range of impacts on their daily lives, including exhaustion and lack of sleep, difficulty performing household, work, leisure, and social activities, and emotional strain. Therefore, disease burden is not limited solely to those suffering from HAE. HAE has high healthcare utilization as well, with the majority of participants in Study 304 (51.7%) requiring a median of 3.0 ER visits per year and 5 participants (17.2%) requiring a median of 3.0 hospitalizations the year prior to enrollment. A retrospective cohort study using Komodo claims data (2016-2024) identified pediatric patients aged 2 to <12 years with HAE (n=411) and matched the patients with HAE to non-HAE controls (n=l,233) based on key demographic characteristics. The results showed young children with HAE experience greater healthcare resource utilization than matched controls without HAE, including more frequent outpatient, emergency room, and inpatient visits and longer inpatient hospital stays.

[0065] Together these data establish the high disease burden of the enrolled population, similar to what has been reported in prior adult studies. Prophylaxis is a vital and potentially life-saving component of HAE management for patients, and the identified pediatric population is underserved by the treatments currently available.

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[0068] Despite the need for LTP options for pediatric patients, only 3 therapies are currently approved for prophylaxis in pediatric patients less than 12 years and all 3 are administered by injection (intravenous Cinryze® or subcutaneous Haegarda® and Takhzyro®). Two of these therapies (Haegarda, marketed as Berinert® 2000 / 3000 in some regions, and Cinryze) are approved for pediatric patients aged 6 years and older while the third therapy, Takhzyro, is approved for pediatric patients 2 years or older.

[0069] A survey of 75 patients with HAE conducted in 2020 indicated that although most patients were satisfied with their prophylactic treatment options, they reported injections could be painful and burdensome, and they desired medication with simpler routes of administration (Radojicic et al., Allergy Asthma Proc, 2021;42(3):S4-10). The favored route of drug administration by both pediatric patients and their parents / caregivers is the peroral route (Herziger et al., Eur J Pediatr, 2022; 181 (5):2161— 71). HAE patients have expressed a strong preference for new oral prophylactic treatments as well as expanding research and clinical studies focused on product development for pediatric patients 2 to 12 years of age with HAE (Tachdjian et al., J Allergy Clin Immunol 2023, AAAAI Abstract 417). In addition, Johnston and Smith reported that early initiation of LTP in pediatric patients may potentially reduce anxiety and improve disease burden and has been hypothesized as a preventative strategy for alexithymia in patients with more severe HAE (Johnston & Smith, Allergy Asthma Proc, 2020;41(Suppl 1):S43— 6).

[0070] The data collected in Study 304 and described herein was used to determine the pharmacokinetics of QD orally administered berotralstat at doses of 78 mg to 150 mg. Study 304 allowed adult to pediatric dose extrapolation using collected safety and pharmacokinetic data, resulting in determination of dosages and weight bands for pediatric patients aged 2 to less than 12 years of age that correlated with effective and safe exposures in the reference population (adult subjects). Further, Study 304 showed the use of berotralstat solid oral granules / oral pellets for oral administration in the pediatric population 2 to less than 12 years of age with HAE was safe and effective.

[0071] The present disclosure provides for a method for prophylaxis to prevent attacks of HAE in pediatric patients aged 2 to less than 12 years of age by orally administering once daily berotralstat using a weight-based dosing regimen. The present disclosure further provides for oral pharmaceutical compositions for use in such methods. As such the present disclosure provides a new oral treatment paradigm for prophylaxis of HAE attacks in pediatric patients aged 2 to less than 12 years of age and provides a solution to unmet needs in the art.

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[0074] Definitions

[0075] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0076] Unless specifically stated, as used herein the term “about” means within 10% plus or minus of the stated range or stated value. For example, a range of “about 120 mg to about 138 mg” encompasses a range from 108 mg to 151.8 mg, 120 mg, and 138 mg. As another example, “about 78 mg” includes a range from 70.2 mg to 85.8 mg and 78 mg.

[0077] As used herein, the term “adolescent subject” means a subject from 12 years of age to less than 18 years of age. As used herein the term “adolescent patient” has the same meaning.

[0078] As used herein, the term “adult subject” means a subject 18 years of age and older. As used herein the term “adult patient” has the same meaning.

[0079] As used herein, the term “excipient” means any non-active ingredient of the liquid pharmaceutical formulation intended to facilitate handling, stability, dispersibility, wettability, release kinetics, and / or injection of the drug.

[0080] As used herein, the term “in need of thereof’ means a subject requires or will benefit from administration of berotralstat. Such a determination may be made by a healthcare professional that based on a variety of factors that are in the realm of a healthcare professional's expertise, such as, but not limited to, the knowledge that the subject is ill, or will be ill, as the result of a disease or condition that is treatable by a method or pharmaceutical composition comprising berotralstat described herein.

[0081] As used herein, the term “pediatric subject” means a subject from birth to less than 18 years of age. In certain descriptions of the methods of prophylaxis described herein, a “pediatric subject” may have a defined age range within the broad range, such as, without limitation, less than 12 years of age, from 2 to less than 12 years of age, less than 18 years of age, or from 12 years to less than 18 years of age. As used herein the term “pediatric patient” has the same meaning.

[0082] As used herein, the term “pharmaceutically acceptable” means an agent or ingredient that is compatible with the other ingredients of a composition and not deleterious to the subject. In some embodiments, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

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[0085] As used herein, the term “prophylaxis to prevent” means a reduction the number and / or severity of HAE attacks experienced by a subject after being administered berotralstat dihydrochloride as described herein. Such a reduction may be exemplified in one or more of the following: 1) a reduction in the number of HAE attacks (for example, a reduction in the number of attacks / month); 2) a reduction in the proportion of days with HAE symptoms (for example, a reduction in the proportion of days with HAE symptoms / month); 3) the number of HAE attacks requiring treatment with targeted HAE medications such as Berinert, Cinryze, Kalbitor, Firazyr, Ruconest, and fresh frozen plasma (for example, a reduction in the number of HAE attacks requiring treatment with targeted HAE medications / month); and 4) a reduction in attack severity (for example, a reduction in the number of HAE attacks requiring professional care). For the sake of clarity, the term “prophylaxis to prevent” does not include the complete prevention of HAE attacks by a subject and / or a complete absence of severe HAE attacks.

[0086] As used herein, the term “subject” or “patient” means a human; a “subject” or “patient” may be male or female.

[0087] Active Pharmaceutical Ingredient

[0088] Berotralstat (l-[3-(aminomethyl)phenyl]-A-(5-{(A)-(3-cyanophenyl)[(cyclopropylmethyl)amino]methyl}-2-fluorophenyl)-3-(trifluoromethyl)-U / -pyrazole-5-carboxamide dihydrochloride) is a potent, highly specific synthetic small molecule inhibitor of plasma kallikrein that has been developed by applicant. Berotralstat is administered as a dihydrochloride (bis-HCl) salt. Berotralstat dihydrochloride is a white to off-white powder that is soluble in water at pH <4. The molecular formula is C30H26F4N6O • 2HC1 and the molecular weight is 635.49 (dihydrochloride). The molecular weight of the free base of berotralstat is 562.56. The chemical structure of berotralstat dihydrochloride is:

[0089]

[0090] Berotralstat 150 mg and 110 mg capsules, taken orally once daily with food was approved by the United States (US) Food and Drug Administration (FDA) under New Drug Application 214,094 for prophylaxis to prevent attacks of HAE in adult and pediatric patients 11

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[0092] 12 years of age and older. Berotralstat is also approved in the European Union, United Kingdom, Switzerland, Mexico, Japan, and other markets. In contrast to parenterally administered options for prophylaxis against HAE attacks, berotralstat offers the advantage of oral administration.

[0093] In the solid oral dosage forms described herein (i.e., oral granules or oral pellets), berotralstat is present as the dihydrochloride salt. In the methods of prophylaxis described herein berotralstat is administered as the dihydrochloride salt. The berotralstat dihydrochloride salt provides for certain advantages in manufacture of the drug substance and stability of the final drug product. After administration of berotralstat dihydrochloride salt to a subject, berotralstat circulates in the plasma as the free base form. Therefore, unless specifically specified otherwise herein, when referring to an amount (i.e., mg) of berotralstat in a dose administered to a subject in the methods described herein or an amount of berotralstat in a solid oral dosage forms described herein, such amount refers to an amount of berotralstat free base (and not an amount of berotralstat dihydrochloride). The equivalent amount of berotralstat dihydrochloride can be determined by dividing the molar mass of the dihydrochloride form (635.49 g / mol) by the molar mass of the free base form (562.56 g / mol) and multiplying the amount of berotralstat free base by this ratio. For example, to determine the amount of berotralstat dihydrochloride equivalent to 78 mg of berotralstat free base the following calculation is performed:

[0094] (635.49 g / mol / 562.56 g / mol) x 78 mg berotralstat free base = 88.1 mg berotralstat dihydrochloride

[0095] Stated in another way, when a method described herein states a dose of about 78 mg of berotralstat is administered, such a dose would contain about 88.1 mg of berotralstat dihydrochloride.

[0096] The solid oral dosage forms of berotralstat described herein contain as the active pharmaceutical ingredient crystalline berotralstat dihydrochloride. The crystalline dihydrochloride form of berotralstat results in improved physicochemical properties, including but not limited to solid state properties (e.g., crystallinity, hygroscopicity, melting point, or hydration), pharmaceutical properties (e.g., solubility / dissolution rate, stability, or compatibility), as well as crystallization characteristics (e.g., purity, yield, or morphology). For example, crystalline berotralstat dihydrochloride enables production of the active pharmaceutical ingredient with consistent and predictable purity levels. Additionally, the uniform particle sizes resulting from crystallization lead to improved processibility of the

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[0099] crystalline form relative to the amorphous form. The crystalline dihydrochloride form of berotralstat leads to a consistent and predictable pharmacokinetic profile.

[0100] As is common in the art, the crystalline dihydrochloride form is characterized by X-ray powder diffraction (XRPD), where 9 represents the diffraction angle, measured in degrees. In certain embodiments, the diffractometer used in XRPD measures the diffraction angle as two times the diffraction angle 9. The peak value at the diffraction angle 9, or at two times the diffraction angle 9 (29), may exhibit a minor measurement error due to the XRPD instruments or the conditions under which the measurement is taken. Accordingly, the characteristic peaks in the XRPD pattern described herein may have a value of °29 ± 9.1° or a value of °29 ± 9.2°.

[0101] Preferably, the berotralstat present in the solid oral dosage forms (i.e., oral granules or oral pellets) described herein is a crystalline berotralstat dihydrochloride.

[0102] In a preferred embodiment, the crystalline berotralstat dihydrochloride has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (°29 ± 9.2°) of 5.3, 9.9, and 22.9 or at values of two theta (°29 ± 9.2°) of 5.28, 8.96, and 22.91.

[0103] In a further preferred embodiment, the crystalline berotralstat dihydrochloride has characteristic peaks in the XRPD pattern at values of two theta (°29 ± 9.2°) of 5.3, 9.9, 19.8, 21.2, 22.9, and 23.3 or at values of two theta (°29 ± 9.2°) of 5.28, 8.96, 19.79, 21.16, 22.91, and 23.31.

[0104] In yet another preferred embodiment, the crystalline berotralstat dihydrochloride has characteristic peaks in the XRPD pattern at values of two theta (°29 ± 9.2°) of 5.3, 9.9, 14.3, 16.2, 19.8, 21.2, 22.9, 23.3, 24.6, and 39.3 or at values of two theta (°29 ± 9.2°) of 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.91, 23.31, 24.64, and 39.31.

[0105] In certain embodiments, the crystalline berotralstat dihydrochloride has an XRPD pattern substantially similar to that shown in FIG. 1. The relative intensity, as well as the two theta value of each peak in the XRPD patterns described above, and as shown in FIG. 1, may change or shift under certain conditions, although the crystalline form is the same.

[0106] In certain embodiments, the crystalline berotralstat dihydrochloride has characteristic peaks in the XRPD pattern at values of °29 ± 9.2° as described herein above and is substantially pure. The term “substantially pure” as used herein, refers to a crystalline polymorph that is greater than 99% pure, meaning that it contains less than 19% of any other compound, including the corresponding amorphous compound or an alternative polymorph of the crystalline salt, preferably greater than 95% pure, or more preferably greater than 98% pure.

[0107] 13

[0108] FH 13299433.1BPX-06125

[0109] Methods of producing the above described crystalline berotralstat dihydrochloride with the characteristic peaks in the XRPD pattern are described herein.

[0110] Pharmaceutical Compositions

[0111] The present disclosure provides a new solid oral dosage form (i.e., oral granules or oral pellets) developed as an age-appropriate dosage form to allow for dosing flexibility for patients, particularly pediatric patients aged 2 years of age to less than 12 years of age. The disclosed solid oral dosage forms comprise crystalline berotralstat dihydrochloride and a mixture of excipients. Such solid oral dosage forms may be used in the methods of prophylaxis described herein. Such solid oral dosage forms may further comprise a tastemasking agent or coating. Suitably, the solid oral dosage form is an oral granule or oral pellet.

[0112] In certain embodiments, the excipients are pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, disintegrants, binders, glidants, and flow agents. In a particular embodiment, suitable pharmaceutically acceptable excipients include, but are not limited to, pregelatinized starch, crospovidone (polyvinyl polypyrrolidone), colloidal anhydrous silica, and magnesium stearate.

[0113] In a first embodiment, the solid oral dosage form (i.e., oral granules or oral pellets) comprises the following (% concentration; w / w): crystalline berotralstat dihydrochloride (about 57.8% to about 77.8%), binder (about 17.2% to about 37.2%), disintegrants (about 1% to about 5%), glidant (about 0.125% to about 1.5%), and flow agents (about 0.5% to about 3%).

[0114] In a second embodiment, the solid oral dosage form (i.e., oral granules or oral pellets) comprises the following (% concentration; w / w): crystalline berotralstat dihydrochloride (about 62.8% to about 72.8%), binder (about 22.2% to about 32.2%), disintegrants (about 2% to about 4%), glidant (about 0.25% to about 1%), and flow agents (about 1% to about 2%).

[0115] In a third embodiment, the solid oral dosage form (i.e., oral granules or oral pellets) comprises the following (% concentration; w / w): crystalline berotralstat dihydrochloride (about 65.8% to about 69.8%), binder (about 25.2% to about 29.2%), disintegrants (about 2.5% to about 3.5%), glidant (about 0.25% to about 0.75%), and flow agents (about 1.25% to about 1.75%).

[0116] In a fourth embodiment, the solid oral dosage form (i.e., oral granules or oral pellets) comprises the following (% concentration; w / w): crystalline berotralstat dihydrochloride (about 57.8% to about 77.8%), pregelatinized starch (about 17.2% to about 37.2%),

[0117] 14

[0118] FH 13299433.1BPX-06125

[0119] crospovidone (about 1% to about 5%), colloidal anhydrous silica (about 0.125% to about 1.5%), and magnesium stearate (about 0.5% to about 3%).

[0120] In a fifth embodiment, the solid oral dosage form (i.e., oral granules or oral pellets) comprises the following (% concentration; w / w): crystalline berotralstat dihydrochloride (about 62.8% to about 72.8%), pregelatinized starch (about 22.2% to about 32.2%), crospovidone (about 2% to about 4%), colloidal anhydrous silica (about 0.25% to about 1%), and magnesium stearate (about 1% to about 2%).

[0121] In a sixth embodiment, the solid oral dosage form (i.e., oral granules or oral pellets) comprises the following (% concentration; w / w): crystalline berotralstat dihydrochloride (about 65.8% to about 69.8%), pregelatinized starch (about 25.2% to about 29.2%), crospovidone (about 2.5% to about 3.5%), colloidal anhydrous silica (about 0.25% to about 0.75%), and magnesium stearate (about 1.25% to about 1.75%).

[0122] In a seventh embodiment, the solid oral dosage form (i.e., oral granules or oral pellets) comprises the following (% concentration; w / w): intragranular: crystalline berotralstat dihydrochloride (about 57.8% to about 77.8%), pregelatinized starch (about 17.2% to about 37.2%), crospovidone (about 0.5% to about 2.5%), colloidal anhydrous silica (about 0.05% to about 0.75%), and magnesium stearate (about 0.075% to about 1.5%); extragranular: crospovidone (about 0.5% to about 2.5%), colloidal anhydrous silica (about 0.05% to about 0.75%), and magnesium stearate (about 0.25% to about 2%).

[0123] In an eighth embodiment, the solid oral dosage form (i.e., oral granules or oral pellets) comprises the following (% concentration; w / w): intragranular: crystalline berotralstat dihydrochloride (about 62.8% to about 72.8%), pregelatinized starch (about 22.2% to about 32.2%), crospovidone (about 1% to about 2%), colloidal anhydrous silica (about 0.125% to about 0.5%), and magnesium stearate (about 0.125% to about 1%); extragranular: crospovidone (about 1% to about 2%), colloidal anhydrous silica (about 0.125% to about 0.5%), and magnesium stearate (about 0.5% to about 1.5%).

[0124] In a ninth embodiment, the solid oral dosage form (i.e., oral granules or oral pellets) comprises the following (% concentration; w / w): intragranular: crystalline berotralstat dihydrochloride (about 65.8% to about 69.8%), pregelatinized starch (about 25.2% to about 29.2%), crospovidone (about 1.25% to about 1.75%), colloidal anhydrous silica (about 0.15% to about 0.35%), and magnesium stearate (about 0.25% to about 0.75%); extragranular: crospovidone (about 1.25% to about 1.75%), colloidal anhydrous silica (about 0.15% to about 0.35%), and magnesium stearate (about 0.75% to about 1.25%).

[0125] 15

[0126] FH 13299433.1BPX-06125

[0127] In a tenth embodiment, the solid oral dosage form (i.e., oral granules or oral pellets) has the composition described in Tables 1 and 3.

[0128] In a preferred embodiment of the tenth embodiment, the solid oral dosage form (i.e., oral granules or oral pellets) have the composition described in Table 1, with the “Quantity (mg)” column indicating the amount of each component present in a single granule and the “Quantity % (w / w)” column indicating the amount of each component present on a weight-to weight basis in a single granule. In Table 1 the amount and percentages recited are based on the amount of crystalline berotralstat dihydrochloride; the equivalent amount of crystalline berotralstat free base is also provided.

[0129]

[0130] aTheoretical amount as crystalline berotralstat free base (adjusted based on potency value); equivalent to about 6.78 mg or 67.8% crystalline berotralstat dihydrochloride

[0131] bTheoretical amount as crystalline berotralstat dihydrochloride (adjusted based on potency value)cAmount of starch is adjusted based on the amount of crystalline berotralstat free base used with potency adjustment

[0132] Berotralstat, regardless of form, has a bitter taste. A variety of taste-masking agents may be used to improve the palatability of solid oral dosage form described herein (i.e., oral granules or oral pellets). Hydrophobic or hydrophilic polymers, lipids, and sweeteners can be used as coating materials, alone or in combination to produce a single or multi-layer coat. A variety of natural (i.e., polysaccharides) and synthetic polymers, such as ethacrylic acid and

[0133] 16

[0134] FH 13299433.1BPX-06125

[0135] methacrylic ester copolymers (EudragitPO, E-100, RL 30D,-55, 1100-55, L30 D, S100, RL, RS, RL 30D, RS 30D, L30D-55, and NE 30D), polyacrylic acid (Carbopol 934, Carbopol 934P, Carbopol 971), polyvinyl pyrollidone (PVPK90 + PVPAP, Kollidon VA 64), ethylcellulose polymers (Aquacoat® ECD), hydroxypropyl methylcellulose polymers (Sepifilm® LP, Opadry®), methyl methacrylate and diethylaminoethyl methacrylate copolymer (Kollicoat SmartSeal® 30 D), polyvinyl alcohol (Opadry® AMB, Opadry® AMB II), methylcellulose (Methocel® and Metolose® SM-4) have been effectively used for tastemasking with polymer coat levels varying from 10% to 40%, depending on the drug bitterness.

[0136] In any of the first to tenth embodiments, and any preferred embodiments thereof, the solid oral dosage form further comprises a taste-masking agent.

[0137] In any of the first to tenth embodiments, and any preferred embodiments thereof, the solid oral dosage form further comprises a taste-masking agent comprising basic butylated methacrylate copolymer from about 50% to about 60%, sodium lauryl sulfate from about 2.5 to about 8.5%, colloidal anhydrous silica from about 5.5% to about 11.5%, stearic acid from about 4.5% to about 10.5%, talc from about 2.5% to about 8.5%, and titanium dioxide from about 10% to about 20%, the percentages determined on a weight-to-weight basis.

[0138] In any of the first to tenth embodiments, and any preferred embodiments thereof, the taste masking agent is Eudragit E PO ReadyMix white polymer blend having the composition described in Table 2.

[0139]

[0140] A particular embodiment of the solid oral granules / oral pellets with a taste-masking coating is provided in Table 3.

[0141] 17

[0142] FH 13299433.1BPX-06125

[0143]

[0144] aTheoretical amount as crystalline berotralstat free base (adjusted based on potency value); equivalent to about 6.78 mg or 67.8% crystalline berotralstat dihydrochloride

[0145] bTheoretical amount as crystalline berotralstat dihydrochloride (adjusted based on potency value)cAmount of starch is adjusted based on the amount of crystalline berotralstat free base used with potency adjustment

[0146] dwater is removed during processing

[0147] The solid oral dosage forms (i.e., oral granules or oral pellets) of the first to tenth embodiments may optionally comprise a taste-masking agent. When a taste making agent is present, the taste making agent is present at a concentration of from about 2.5% to about 17.5%, from about 5% to about 15%, from about 7.5% to about 12.5%, or about 10% (each of the foregoing % on a weight-to weigh basis). Suitably, the taste masking agent is Eudragit E PO ReadyMix white.

[0148] The solid oral dosage forms (i.e., oral granules or oral pellets) of the first to tenth embodiments may be provided in a unit-dose packet containing an amount of the solid oral dosage forms sufficient to deliver an appropriate dose of berotralstat free base on administration to a pediatric subject. Suitable doses include, but are not limited to, about 120 mg to about 144 mg, about 126 mg to about 138 mg, about 114 mg to about 144 mg, about 120 mg to about 138 mg, about 132 mg, about 96 mg to about 120 mg, about 102 mg to about

[0149] 18

[0150] FH 13299433.1BPX-96125

[0151] 114 mg, about 84 mg to about 114 mg, about 90 mg to about 108 mg, about 108 mg, about 84 mg to about 108 mg, about 90 mg to about 102 mg, about 96 mg, about 60 mg to about 90 mg, about 66 mg to about 84 mg, about 54 mg to about 84 mg, about 60 mg to about 78 mg, about 72 mg, or about 78 mg berotralstat free base.

[0152] The solid oral dosage forms (i.e., oral granules or oral pellets) of the first to tenth embodiments may be provided in a unit-dose packet containing a plurality of solid oral dosage forms sufficient to deliver an appropriate dose of berotralstat free base on administration to a pediatric subject. Suitable doses include, but are not limited to, about 132 mg, about 108 mg, about 96 mg, about 78 mg or about 72 mg of berotralstat free base.

[0153] In any of the first to tenth embodiments, and any preferred embodiments thereof, the crystalline berotralstat dihydrochloride has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (°29 ± 0.2°) of 5.3, 9.0, and 22.0 or at values of two theta (°29 ± 9.2°) of 5.28, 8.96, and 22.01.

[0154] In any of the first to tenth embodiments, and any preferred embodiments thereof, the crystalline berotralstat dihydrochloride has characteristic peaks in the XRPD pattern at values of two theta (°29 ± 0.2°) of 5.3, 9.0, 19.8, 21.2, 22.0, and 23.3 or at values of two theta (°29 ± 0.2°) of 5.28, 8.96, 19.79, 21.16, 22.01, and 23.31.

[0155] In any of the first to tenth embodiments, and any preferred embodiments thereof, the crystalline berotralstat dihydrochloride has characteristic peaks in the XRPD pattern at values of two theta (°29 ± 0.2°) of 5.3, 9.0, 14.3, 16.2, 19.8, 21.2, 22.0, 23.3, 24.6, and 30.3 or at values of two theta (°29 ± 0.2°) of 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31.

[0156] In any of the first to tenth embodiments, and any preferred embodiments thereof, the crystalline berotralstat dihydrochloride has an XRPD pattern substantially similar to that shown in FIG. 1.

[0157] In any of the first to tenth embodiments, and any preferred embodiments thereof, the solid oral dosage form is about 2 mm in diameter and about 3 mm in length. In a preferred embodiment, such solid oral dosage form contains about 4 mg to about 7 mg of berotralstat free base (about 4.5 mg to 7.9 mg crystalline berotralstat dihydrochloride), preferably about 6 mg (about 6.8 mg crystalline berotralstat dihydrochloride). Preferably, the solid oral dosage form is an oral granule or oral pellet.

[0158] In any of the first to tenth embodiments, and any preferred embodiments thereof, the solid oral dosage form is about 2 mm in diameter and about 3 mm in length and comprises about 4 mg to about 7 mg of berotralstat free base (about 4.5 mg to 7.9 mg crystalline

[0159] 19

[0160] FH 13299433.1BPX-06125

[0161] berotralstat dihydrochloride), preferably about 6 mg (about 6.8 mg crystalline berotralstat dihydrochloride). Preferably, the solid oral dosage form is an oral granule or oral pellet.

[0162] In any of the first to tenth embodiments, and any preferred embodiments thereof, the solid oral dosage form is an oral granule or an oral pellet. Exemplary dimensions of such oral granule or oral pellet are approximately 2 mm in diameter and approximately 3 mm in length. In a preferred embodiment, such oral granule or oral pellet contains about 4 mg to about 7 mg of berotralstat free base (about 4.5 mg to 7.9 mg crystalline berotralstat dihydrochloride), preferably about 6 mg (about 6.8 mg crystalline berotralstat dihydrochloride).

[0163] An exemplary manufacturing process for the berotralstat oral granules / oral pellets described in Tables 1 and 3 is described below and shown in FIG. 2.

[0164] The intra-granular components minus magnesium stearate are dispensed into an appropriately sized blender and blended at approximately 21 rpm for approximately 12 minutes. Magnesium stearate is added to the above mixture and blended at approximately 21 rpm for approximately 3 minutes. The blended material is dry granulated. The milled granules are charged into an appropriate blender along with the extra granular components minus magnesium stearate and blended at approximately 21 rpm for approximately 12 minutes. Magnesium stearate is added to the above mixture and blended at approximately 21 rpm for approximately 3 minutes. The final blend is compressed into finished bulk granules / pellets using a rotary tablet press. The granules are coated with the taste masking agent using a pan coater to produce finished bulk coated granules / pellets. The finished bulk coated granules or pellets are then filled into their primary unit-dose packaging.

[0165] Methods of Prophylaxis

[0166] The present disclosure provides a method for prophylaxis to prevent attacks of hereditary angioedema (HAE) in a pediatric subject by administering a dose of berotralstat to the pediatric subject using a weight-based dosing regimen. As discussed above, when referring to an amount (i.e., mg) of berotralstat in a dose administered to a subject in the methods described herein or an amount of berotralstat in a solid oral dosage forms described herein (i.e., oral granules or oral pellets), such amount refers to an amount of berotralstat free base and not an amount of berotralstat dihydrochloride. Such weight-based dosing regimen allows exposure in the pediatric subject to be similar to the exposure observed in adult subjects administered a dose of 150 mg of berotralstat (free base).

[0167] In a first embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose 20

[0168] FH 13299433.1BPX-06125

[0169] of berotralstat free base based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat free base selected from the following: 1) about 120 mg to about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 90 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg.

[0170] In preferred embodiments of the first embodiment, the dose provides an amount of berotralstat free base selected from the following:

[0171] A. 1) about 126 mg to about 138 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is less than 24 kg;

[0172] B. 1) about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 78 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg; and

[0173] C. 1) about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 72 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg.

[0174] In a second embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat free base based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat free base selected from the following: 1) about 120 mg to 21

[0175] FH 13299433.1BPX-06125

[0176] about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 90 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg.

[0177] In preferred embodiments of the second embodiment, the dose provides an amount of berotralstat free base selected from the following:

[0178] A. 1) about 126 mg to about 138 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 66 mg to about 84 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg;

[0179] B. 1) about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 78 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg;

[0180] C. 1) about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 72 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg.

[0181] In a third embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat free base based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat free base selected from the following: 1) about 120 mg to about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat free base when the body weight of 22

[0182] FH 13299433.1BPX-06125

[0183] the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 90 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg.

[0184] In preferred embodiments of the third embodiment, the dose provides an amount of berotralstat free base selected from the following:

[0185] A. 1) about 126 mg to about 138 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 66 mg to about 84 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg;

[0186] B. 1) about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 78 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg; and

[0187] C. 1) about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 72 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg.

[0188] In a fourth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat free base based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat free base selected from the following: 1) about 120 mg to about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32

[0189] 23

[0190] FH 13299433.1BPX-06125

[0191] kg; or 4) about 54 mg to about 84 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg.

[0192] In preferred embodiments of the fourth embodiment, the dose provides an amount of berotralstat free base selected from the following:

[0193] A. 1) about 126 mg to about 138 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 78 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg; or

[0194] B. 1) about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 72 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg.

[0195] In a fifth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat free base based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat free base selected from the following: 1) about 120 mg to about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 54 mg to about 84 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg.

[0196] In preferred embodiments of the fifth embodiment, the dose provides an amount of berotralstat free base selected from the following:

[0197] A. 1) about 126 mg to about 138 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat free base when the 24

[0198] FH 13299433.1BPX-06125

[0199] body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 78 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg; and

[0200] B. 1) about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 72 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg.

[0201] In a sixth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat free base based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat free base selected from the following: 1) about 120 mg to about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 54 mg to about 84 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg.

[0202] In preferred embodiments of the sixth embodiment, the dose provides an amount of berotralstat free base selected from the following:

[0203] A. 1) about 126 mg to about 138 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 78 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg; and

[0204] B. 1) about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less

[0205] 25

[0206] FH 13299433.1BPX-06125

[0207] than 32 kg; or 4) about 72 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg.

[0208] In a seventh embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat selected from the following: 1) about 114 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 84 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 60 mg to about 90 mg of berotralstat when the body weight of the pediatric subject is less than 20 kg.

[0209] In preferred embodiments of the seventh embodiment, the dose provides an amount of berotralstat selected from the following:

[0210] A. 1) about 120 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 90 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is less than 20 kg; or

[0211] B. 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 96 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 78 mg of berotralstat when the body weight of the pediatric subject is less than 20 kg.

[0212] In an eighth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat selected from the following: 1) about 114 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 84 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 60 mg to about 90 mg of berotralstat when the body weight of the pediatric subject is 12 kg to less than 20 kg.

[0213] In preferred embodiments of the eighth embodiment, the dose provides an amount of berotralstat selected from the following:

[0214] 26

[0215] FH 13299433.1BPX-06125

[0216] A. 1) about 120 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 90 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is 12 kg to less than 20 kg; or

[0217] B. 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 96 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 78 mg of berotralstat when the body weight of the pediatric subject is 12 kg to less than 20 kg.

[0218] In a ninth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat selected from the following: 1) about 114 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 84 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 60 mg to about 90 mg of berotralstat when the body weight of the pediatric subject is 15 kg to less than 20 kg.

[0219] In preferred embodiments of the ninth embodiment, the dose provides an amount of berotralstat selected from the following:

[0220] C. 1) about 120 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 90 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is 15 kg to less than 20 kg; or

[0221] D. 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 96 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 78 mg of berotralstat when the body weight of the pediatric subject is 15 kg to less than 20 kg.

[0222] In a tenth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof and having a body weight of 40 kg or greater, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat, wherein the dose provides an amount of berotralstat selected from the following: 1) about 120 mg to about 144

[0223] 27

[0224] FH 13299433.1BPX-06125

[0225] mg of berotralstat; 2) about 126 mg to about 138 mg of berotralstat; or 3) about 132 mg of berotralstat.

[0226] In an eleventh embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof and having a body weight 32 kg to less than 40 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat, wherein the dose provides an amount of berotralstat selected from the following: 1) about 96 mg to about 120 mg of berotralstat; 2) about 102 mg to about 114 mg of berotralstat; or 3) about 108 mg of berotralstat.

[0227] In a twelfth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof and having a body weight of 24 kg to less than 32 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat, wherein the dose provides an amount of berotralstat selected from the following: 1) about 84 mg to about 108 mg of berotralstat; 2) about 90 mg to about 102 mg of berotralstat; or 3) about 96 mg of berotralstat.

[0228] In a thirteenth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof and having a body weight of 12 kg to less than 24 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat, wherein the dose provides an amount of berotralstat selected from the following: 1) about 60 mg to about 90 mg of berotralstat; 2) about 66 mg to about 84 mg of berotralstat; or 3) about 78 mg of berotralstat.

[0229] In a fourteenth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof and having a body weight of 15 kg to less than 24 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat, wherein the dose provides an amount of berotralstat selected from the following: 1) about 60 mg to about 90 mg of berotralstat; 2) about 66 mg to about 84 mg of berotralstat; or 3) about 78 mg of berotralstat.

[0230] In a fifteenth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof and having a body weight less than 24 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat, wherein the dose 28

[0231] FH 13299433.1BPX-06125

[0232] provides an amount of berotralstat selected from the following: 1) about 60 mg to about 90 mg of berotralstat; 2) about 66 mg to about 84 mg of berotralstat; or 3) about 78 mg of berotralstat.

[0233] In a sixteenth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof and having a body weight of 12 kg to less than 24 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat, wherein the dose provides an amount of berotralstat selected from the following: 1) about 54 mg to about 84 mg of berotralstat; 2) about 60 mg to about 78 mg of berotralstat; or 3) about 72 mg of berotralstat.

[0234] In a seventeenth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof and having a body weight of 15 kg to less than 24 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat, wherein the dose provides an amount of berotralstat selected from the following: 1) about 54 mg to about 84 mg of berotralstat; 2) about 60 mg to about 78 mg of berotralstat; or 3) about 72 mg of berotralstat.

[0235] In an eighteenth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof and having a body weight less than 24 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat, wherein the dose provides an amount of berotralstat selected from the following: 1) about 54 mg to about 84 mg of berotralstat; 2) about 60 mg to about 78 mg of berotralstat; or 3) about 72 mg of berotralstat.

[0236] In a nineteenth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat based on a body weight of the pediatric subject, wherein the dose is between about 60 mg and about 144 mg.

[0237] In a preferred embodiment of the nineteenth embodiment, the dose is 1) about 120 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 90

[0238] 29

[0239] FH 13299433.1BPX-06125

[0240] mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0241] In a preferred embodiment of the nineteenth embodiment, the dose is 1) about 126 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0242] In a preferred embodiment of the nineteenth embodiment, the dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0243] In a preferred embodiment of the nineteenth embodiment, the dose is 1) about 120 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 54 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0244] In a preferred embodiment of the nineteenth embodiment, the dose is 1) about 126 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0245] In a preferred embodiment of the nineteenth embodiment, the dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less

[0246] 30

[0247] FH 13299433.1BPX-06125

[0248] than 32 kg; or 4) about 72 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0249] In a preferred embodiment of the nineteenth embodiment, the dose is 1) about 114 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 84 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 60 mg to about 90 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

[0250] In a preferred embodiment of the nineteenth embodiment, the dose is 1) about 120 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 90 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

[0251] In a preferred embodiment of the nineteenth embodiment, the dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 96 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

[0252] In a twentieth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat, wherein the dose is between about 60 mg and about 144 mg.

[0253] In a preferred embodiment of the twentieth embodiment, the dose is 1) about 120 mg to about 144 mg of berotralstat when a body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 90 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0254] In a preferred embodiment of the twentieth embodiment, the dose is 1) about 126 mg to about 138 mg of berotralstat when a body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat 31

[0255] FH 13299433.1BPX-06125

[0256] when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0257] In a preferred embodiment of the twentieth embodiment, the dose is 1) about 132 mg of berotralstat when a body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0258] In a preferred embodiment of the twentieth embodiment, the dose is 1) about 120 mg to about 144 mg of berotralstat when a body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 54 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0259] In a preferred embodiment of the twentieth embodiment, the dose is 1) about 126 mg to about 138 mg of berotralstat when a body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0260] In a preferred embodiment of the twentieth embodiment, the dose is 1) about 132 mg of berotralstat when a body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 72 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0261] In a preferred embodiment of the twentieth embodiment, the dose is 1) about 114 mg to about 144 mg of berotralstat when a body weight of the pediatric subject is 35 kg or greater; 2) about 84 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 60 mg to about 90 mg of berotralstat when the

[0262] 32

[0263] FH 13299433.1BPX-06125

[0264] body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

[0265] In a preferred embodiment of the twentieth embodiment, the dose is 1) about 120 mg to about 138 mg of berotralstat when a body weight of the pediatric subject is 35 kg or greater; 2) about 90 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

[0266] In a preferred embodiment of the twentieth embodiment, the dose is 1) about 132 mg of berotralstat when a body weight of the pediatric subject is 35 kg or greater; 2) about 96 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

[0267] In a twenty-first embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 40 kg or greater, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 120 mg and about 144 mg.

[0268] In a preferred embodiment of the twenty-first embodiment, the dose is about 126 mg to about 138 mg of berotralstat.

[0269] In a preferred embodiment of the twenty-first embodiment, the dose is about 132 mg of berotralstat.

[0270] In a twenty-second embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight 32 kg to less than 40 kg, the method comprising orally administering once daily to the pediatric a dose of berotralstat between about 96 mg and about 120 mg.

[0271] In a preferred embodiment of the twenty-second embodiment, the dose is about 102 mg to about 114 mg of berotralstat.

[0272] In a preferred embodiment of the twenty-second embodiment, the dose is about 108 mg of berotralstat.

[0273] In a twenty-third embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 24 kg to less than 32 kg,

[0274] 33

[0275] FH 13299433.1BPX-06125

[0276] the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 84 mg and about 108 mg.

[0277] In a preferred embodiment of the twenty-third embodiment, the dose is about 90 mg to about 102 mg of berotralstat.

[0278] In a preferred embodiment of the twenty-third embodiment, the dose is about 96 mg of berotralstat.

[0279] In a twenty-fourth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 60 mg and about 90 mg.

[0280] In a preferred embodiment of the twenty-fourth embodiment, the dose is about 66 mg to about 84 mg of berotralstat.

[0281] In a preferred embodiment of the twenty-fourth embodiment, the dose is about 78 mg of berotralstat.

[0282] In a preferred embodiment of the twenty-fourth embodiment, the dose is about 72 mg of berotralstat.

[0283] In a twenty-fifth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 54 mg and about 84 mg.

[0284] In a preferred embodiment of the twenty-fifth embodiment, the dose is about 60 mg to about 78 mg of berotralstat.

[0285] In a preferred embodiment of the twenty-fifth embodiment, the dose is about 72 mg of berotralstat.

[0286] In a twenty-sixth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 35 kg or greater, the method comprising orally administering once daily to the pediatric a dose of berotralstat between about 114 mg and about 144 mg.

[0287] 34

[0288] FH 13299433.1BPX-06125

[0289] In a preferred embodiment of the twenty-sixth embodiment, the dose is about 120 mg to about 138 mg of berotralstat.

[0290] In a preferred embodiment of the twenty-sixth embodiment, the dose is about 132 mg of berotralstat.

[0291] In a twenty-seventh embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 20 kg to less than 35 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 84 mg and about 114 mg.

[0292] In a preferred embodiment of the twenty-seventh embodiment, the dose is about 90 mg to about 108 mg of berotralstat.

[0293] In a preferred embodiment of the twenty-seventh embodiment, the dose is about 96 mg of berotralstat.

[0294] In a twenty-eighth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 60 mg and about 90 mg.

[0295] In a preferred embodiment of the twenty-eighth embodiment, the dose is about 66 mg to about 84 mg of berotralstat.

[0296] In a preferred embodiment of the twenty-eighth embodiment, the dose is about 78 mg of berotralstat.

[0297] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat is provided as a plurality of solid oral dosage and provides an exposure of berotralstat in the pediatric subject that is similar to an exposure in adult subjects and / or pediatric subjects 12 to less than 18 years of age administered a 150 mg dose of berotralstat. As used in this paragraph “similar to” means an exposure in the pediatric subject that is within about 20% (i.e., 20% higher or lower) of the exposure observed in the adult subjects and / or pediatric subjects 12 to less than 18 years of age, preferably within about 15% of the exposure, within about 10% of the exposure, or within about 5% of the exposure of adult subjects.

[0298] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat is provided as a plurality of solid oral dosage and provides a 35

[0299] FH 13299433.1BPX-06125

[0300] Cmax of berotralstat in the pediatric subject that is similar to a Cmax in adult subjects and / or pediatric subjects 12 to less than 18 years of age administered a 150 mg dose of berotralstat. As used in this paragraph “similar to” means a Cmax in the pediatric subject that is within about 25% (i.e., 25% higher or lower) of the Cmax observed in the adult subjects and / or pediatric subjects 12 to less than 18 years of age, preferably within about 15% of the Cmax, within about 10% of the Cmax, or within about 5% of the Cmax of adult subjects.

[0301] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat is provided as a plurality of solid oral dosage and provides a Ctrough of berotralstat in the pediatric subject that is similar to a Ctrough in adult subjects and / or pediatric subjects 12 to less than 18 years of age administered a 150 mg dose of berotralstat. As used in this paragraph “similar to” means a Ctrough in the pediatric subject that is within about 20% (i.e., 20% higher or lower) of the Ctrough observed in the adult subjects and / or pediatric subjects 12 to less than 18 years of age, preferably within about 15% of the Ctrough, within about 10% of the Ctrough, or within about 5% of the Ctrough of adult subjects.

[0302] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat is provided in a unit dose package containing one of the recited doses.

[0303] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat is administered to the pediatric subject 2 to less than 12 years old by pouring the dose directly into the mouth of the pediatric subject, optionally with a non-acidic liquid. Suitable non-acidic liquids include, but are not limited to, milk and water.

[0304] Suitably, the dose of berotralstat is swallowed within 1 minute, preferably immediately, after being poured into the mouth of the pediatric subject.

[0305] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat is administered to the pediatric subject 2 to less than 12 years old by sprinkling the dose over a non-acidic food (such as 1-2 tablespoons or about 15-30 ml). Suitable non-acidic foods include, but are not limited to, pudding, mashed potatoes, creamed corn, pureed peas, bananas, or carrots. Suitably, the dose of berotralstat is consumed within 10 minutes of, preferably immediately after, being sprinkled over the non-acidic food.

[0306] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat is administered to the pediatric subject 2 to less than 12 years old subject within 1 hour before or after a meal is consumed, preferably just before of just after a meal is consumed.

[0307] 36

[0308] FH 13299433.1BPX-06125

[0309] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat administered to the pediatric subject 2 to less than 12 years old is not altered if the pediatric subject is diagnosed with or is suspected of suffering from mild hepatic impairment (Child-Pugh Class A).

[0310] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat is not administered to the pediatric subject 2 to less than 12 years old if the pediatric subject is diagnosed with or is suspected of suffering from moderate hepatic impairment (Child-Pugh Class B) or severe hepatic impairment (Child-Pugh Class C).

[0311] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat administered is not altered if the pediatric subject to the pediatric subject 2 to less than 12 years old experiences persistent gastrointestinal reactions following administration of the dose of berotralstat.

[0312] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat is not administered to the pediatric subject 2 to less than 12 years old if the pediatric subject is concurrently being administered a P-gp inducer.

[0313] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the HAE is HAE with deficient Cl -INH (also referred to as type 1 HAE).

[0314] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the HAE is HAE with dysfunctional Cl -INH (also referred to as type 2 HAE).

[0315] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the HAE is HAE with normal Cl-INH (also referred to as type 3 HAE).

[0316] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat administered to the pediatric subject 2 to less than 12 years old comprises a plurality of solid oral dosage forms. Preferably the plurality of solid oral dosage forms is a plurality of oral granules or oral pellets.

[0317] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat administered to the pediatric subject 2 to less than 12 years old comprises a plurality of solid oral dosage forms comprising an amount of berotralstat dihydrochloride sufficient to deliver the recited amount of berotralstat on administration to the pediatric subject. Preferably the plurality of solid oral dosage forms is a plurality of oral granules or oral pellets.

[0318] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat administered to the pediatric subject 2 to less than 12 years old comprises a plurality of solid oral dosage forms comprising an amount of crystalline 37

[0319] FH 13299433.1BPX-06125

[0320] berotralstat dihydrochloride sufficient to deliver the recited amount of her otr al stat on administration to the pediatric subject. Preferably the plurality of solid oral dosage forms is a plurality of oral granules or oral pellets. Preferably, the crystalline berotralstat dihydrochloride has characteristic peaks in the X-ray powder diffraction substantially similar to that shown in FIG. 1 or has characteristic peaks in the XRPD pattern at values of two theta (°20 ± 0.2°) of: i) 5.3, 9.0, and 22.0; ii) 5.28, 8.96, and 22.01; iii) 5.3, 9.0, 19.8, 21.2, 22.0, and 23.3; iv) 5.28, 8.96, 19.79, 21.16, 22.01, and 23.31; v) 5.3, 9.0, 14.3, 16.2, 19.8, 21.2, 22.0, 23.3, 24.6, and 30.3; orvi) 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31.

[0321] In any of the first to twenty-eighth embodiments, and any preferred embodiments thereof, the dose of berotralstat administered to the pediatric subject 2 to less than 12 years old is provided as one or more solid oral dosage form as described herein, particularly a solid oral dosage form of the first to tenth embodiments, and any aspects thereof, as described herein. Preferably the plurality of solid oral dosage forms is a plurality of oral granules or oral pellets as described herein.

[0322] In a twenty-ninth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old a pediatric dose of berotralstat based on a body weight of the pediatric subject, wherein the pediatric dose is between about 60 mg and about 144 mg.

[0323] In a preferred embodiment of the twenty-ninth embodiment, the pediatric dose is 1) about 120 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 90 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0324] In a preferred embodiment of the twenty-ninth embodiment, the pediatric dose is 1) about 126 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of

[0325] 38

[0326] FH 13299433.1BPX-06125

[0327] berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0328] In a preferred embodiment of the twenty-ninth embodiment, the pediatric dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0329] In a preferred embodiment of the twenty-ninth embodiment, the pediatric dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 72 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0330] In a preferred embodiment of the twenty-ninth embodiment, the pediatric dose is 1) about 120 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 54 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0331] In a preferred embodiment of the twenty-ninth embodiment, the pediatric dose is 1) about 126 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0332] In a preferred embodiment of the twenty-ninth embodiment, the pediatric dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32

[0333] 39

[0334] FH 13299433.1BPX-06125

[0335] kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 72 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

[0336] In a preferred embodiment of the twenty-ninth embodiment, the pediatric dose is 1) about 114 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 84 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 60 mg to about 90 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

[0337] In a preferred embodiment of the twenty-ninth embodiment, the pediatric dose is 1) about 120 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 90 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

[0338] In a preferred embodiment of the twenty-ninth embodiment, the pediatric dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 96 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

[0339] In a thirtieth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of 40 kg or greater, a pediatric dose of berotralstat between about 120 mg and about 144 mg.

[0340] In a preferred embodiment of the thirtieth embodiment, the pediatric dose is about 126 mg to about 138 mg of berotralstat.

[0341] In a preferred embodiment of the thirtieth embodiment, the pediatric dose is about 132 mg of berotralstat.

[0342] 40

[0343] FH 13299433.1BPX-06125

[0344] In a thirty-first embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of 32 kg to less than 40 kg, a pediatric dose of berotralstat between about 96 mg and about 120 mg.

[0345] In a preferred embodiment of the thirty-first embodiment, the pediatric dose is about 102 mg to about 114 mg of berotralstat.

[0346] In a preferred embodiment of the thirty-first embodiment, the pediatric dose is about 108 mg of berotralstat.

[0347] In a thirty-second embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of 24 kg to less than 32 kg, a pediatric dose of berotralstat between about 84 mg and about 108 mg.

[0348] In a preferred embodiment of the thirty-second embodiment, the pediatric dose is about 90 mg to about 102 mg of berotralstat.

[0349] In a preferred embodiment of the thirty-second embodiment, the pediatric dose is about 96 mg of berotralstat.

[0350] In a thirty-third embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of i) less than 24 kg; ii) 12 kg to less than 24 kg a pediatric; or iii) 15 kg to less than 24 kg, a pediatric dose of berotralstat between about 60 mg and about 90 mg.

[0351] 41

[0352] FH 13299433.1BPX-06125

[0353] In a preferred embodiment of the thirty-third embodiment, the pediatric dose is about 66 mg to about 84 mg of berotralstat.

[0354] In a preferred embodiment of the thirty-third embodiment, the pediatric dose is about 78 mg of berotralstat.

[0355] In a preferred embodiment of the thirty-third embodiment, the pediatric dose is about 72 mg of berotralstat.

[0356] In a thirty-fourth embodiment, the present disclosure provides a method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of: i) less than 24 kg; ii) 12 kg to less than 24 kg a pediatric; or iii) 15 kg to less than 24 kg, a pediatric dose of berotralstat between about 54 mg and about 84 mg.

[0357] In a preferred embodiment of the thirty-fourth embodiment, the pediatric dose is about 60 mg to about 78 mg of berotralstat.

[0358] In a preferred embodiment of the thirty-fourth embodiment, the pediatric dose is about 72 mg of berotralstat.

[0359] In a preferred embodiment of the twenty-ninth to thirty-fourth embodiments, the adult dose is 110 mg.

[0360] In a preferred embodiment of the twenty-ninth to thirty-fourth embodiments, the adult dose is 150 mg.

[0361] In a preferred embodiment of the twenty-ninth to thirty-fourth embodiments, the adult dose is a capsule comprising an amount of berotralstat dihydrochloride sufficient to deliver the recited amount of berotralstat on administration to the adult or pediatric subject 12 to less than 18 years old.

[0362] In a preferred embodiment of the twenty-ninth to thirty-fourth embodiments, the adult dose is a capsule comprising an amount of crystalline berotralstat dihydrochloride sufficient to deliver the recited amount of berotralstat on administration to the adult or pediatric subject 12 to less than 18 years old and the crystalline berotralstat dihydrochloride has characteristic peaks in the XRPD pattern at values of two theta (°29 ± 0.2°) of: i) 5.3, 9.0, and 22.0; ii) 5.28, 8.96, and 22.01; iii) 5.3, 9.0, 19.8, 21.2, 22.0, and 23.3; iv) 5.28, 8.96, 19.79, 21.16, 22.01,

[0363] 42

[0364] FH 13299433.1BPX-06125

[0365] and 23.31; v) 5.3, 9.0, 14.3, 16.2, 19.8, 21.2, 22.0, 23.3, 24.6, and 30.3; or vi) 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.3.

[0366] In a preferred embodiment of the twenty-ninth to thirty-fourth embodiments, the pediatric subject 12 to less than 18 years old has a body weight 40 kg or greater.

[0367] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat is provided as a plurality of solid oral dosage and provides an exposure of berotralstat in the pediatric subject that is similar to an exposure in adult subjects and / or pediatric subjects 12 to less than 18 years of age administered a 150 mg dose of berotralstat. As used in this paragraph “similar to” means an exposure in the pediatric subject that is within about 20% (i.e., 20% higher or lower) of the exposure observed in the adult subjects and / or pediatric subjects 12 to less than 18 years of age, preferably within about 15% of the exposure, within about 10% of the exposure, or within about 5% of the exposure of adults subjects.

[0368] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat is provided as a plurality of solid oral dosage and provides a Cmax of berotralstat in the pediatric subject that is similar to a Cmax in adult subjects and / or pediatric subjects 12 to less than 18 years of age administered a 150 mg dose of berotralstat. As used in this paragraph “similar to” means a Cmax in the pediatric subject that is within about 25% (i.e., 25% higher or lower) of the Cmax observed in the adult subjects and / or pediatric subjects 12 to less than 18 years of age, preferably within about 15% of the Cmax, within about 10% of the Cmax, or within about 5% of the Cmax of adult subjects.

[0369] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat is provided as a plurality of solid oral dosage and provides a Ctrough of berotralstat in the pediatric subject that is similar to a Ctrough in adult subjects and / or pediatric subjects 12 to less than 18 years of age administered a 150 mg dose of berotralstat. As used in this paragraph “similar to” means a Ctrough in the pediatric subject that is within about 20% (i.e., 20% higher or lower) of the Ctrough observed in the adult subjects and / or pediatric subjects 12 to less than 18 years of age, preferably within about 15% of the Ctrough, within about 10% of the Ctrough, or within about 5% of the Ctrough of adult subjects.

[0370] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat is provided in a unit dose package containing one of the recited doses.

[0371] 43

[0372] FH 13299433.1BPX-06125

[0373] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat is administered by pouring the dose directly into the mouth of the pediatric subject, optionally with a non-acidic liquid. Suitable non-acidic liquids include, but are not limited to, milk and water. Suitably, the pediatric dose of berotralstat is swallowed within 1 minute, preferably immediately, after being poured into the mouth of the pediatric subject.

[0374] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat is administered by sprinkling the dose over a non-acidic food (such as 1-2 tablespoons or about 15-30 ml). Suitable non-acidic foods include, but are not limited to, pudding, mashed potatoes, creamed corn, pureed peas, bananas, or carrots. Suitably, the pediatric dose of berotralstat is consumed within 10 minutes of, preferably immediately after, being sprinkled over the non-acidic food.

[0375] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat is administered within 1 hour before or after a meal is consumed, preferably just before of just after a meal is consumed.

[0376] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat administered is not altered if the pediatric subject is diagnosed with or is suspected of suffering from mild hepatic impairment (Child-Pugh Class A).

[0377] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat is not administered if the pediatric subject is diagnosed with or is suspected of suffering from moderate hepatic impairment (Child-Pugh Class B) or severe hepatic impairment (Child-Pugh Class C).

[0378] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat administered is not altered if the pediatric subject experiences persistent gastrointestinal reactions following administration of the dose of berotralstat.

[0379] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat is not administered to the pediatric subject if the pediatric subject is concurrently being administered a P-gp inducer.

[0380] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the HAE is HAE with deficient Cl -INH (also referred to as type 1 HAE).

[0381] 44

[0382] FH 13299433.1BPX-06125

[0383] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the HAE is HAE with dysfunctional Cl -INH (also referred to as type 2 HAE).

[0384] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the HAE is HAE with normal Cl -INH (also referred to as type 3 HAE).

[0385] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat administered comprises a plurality of solid oral dosage forms. Preferably the plurality of solid oral dosage forms is a plurality of oral granules or oral pellets.

[0386] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat administered comprises a plurality of solid oral dosage forms comprising an amount of berotralstat dihydrochloride sufficient to deliver the recited amount of berotralstat on administration to the pediatric subject. Preferably the plurality of solid oral dosage forms is a plurality of oral granules or oral pellets.

[0387] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat administered comprises a plurality of solid oral dosage forms comprising an amount of crystalline berotralstat dihydrochloride sufficient to deliver the recited amount of berotralstat on administration to the pediatric subject. Preferably the plurality of solid oral dosage forms is a plurality of oral granules or oral pellets. Preferably, the crystalline berotralstat dihydrochloride has characteristic peaks in the X-ray powder diffraction substantially similar to that shown in FIG. 1 or has characteristic peaks in the XRPD pattern at values of two theta (°29 ± 0.2°) of: i) 5.3, 9.0, and 22.0; ii) 5.28, 8.96, and 22.01; iii) 5.3, 9.0, 19.8, 21.2, 22.0, and 23.3; iv) 5.28, 8.96, 19.79, 21.16, 22.01, and 23.31; v) 5.3, 9.0, 14.3, 16.2, 19.8, 21.2, 22.0, 23.3, 24.6, and 30.3; or vi) 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31.

[0388] In any of the twenty-ninth to thirty -fourth embodiments, and any preferred embodiments thereof, the pediatric dose of berotralstat administered to the pediatric subject 2 to less than 12 years old is provided as one or more solid oral dosage form as described herein, particularly a solid oral dosage form of the first to tenth embodiments, and any aspects thereof, as described herein. Preferably the plurality of solid oral dosage forms is a plurality of oral granules or oral pellets as described herein.

[0389] 45

[0390] FH 13299433.1BPX-06125

[0391] EQUIVALENTS

[0392] The foregoing writen specification is considered to be sufficient to enable one skilled in the art to practice the invention. The present invention is not to be limited in scope by examples provided, since the examples are intended as a single illustration of one aspect of the invention and other functionally equivalent embodiments are within the scope of the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. The advantages and objects of the invention are not necessarily encompassed by each embodiment of the invention.

[0393] EXAMPLES

[0394] Example 1 : Synthetic protocol for racemic compound 54e (Reproduced from WO

[0395]

[0396] Preparation of l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e) Step-1: Preparation of 3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b)

[0397] To a solution of 3 -formylbenzonitrile (54a) (29 g, 217 mmol) in tetrahydrofuran (200 mL) cooled to 0 °C was added freshly prepared Grignard reagent (52c) (245 mL, 221 mmol, ~ 0.9 M in THF) stirred at 0 °C for 1 h, and room temperature for 18 h. The reaction mixture 46

[0398] FH 13299433.1BPX-06125

[0399] was quenched with 1 N HC1 (aq. 440 mL), stirred for 3 h, neutralized with NaOH (2 N, aq.) to pH = ~ 8. The reaction mixture was extracted with ethyl acetate (600, 300 mL). The combined extracts were washed with brine (120 mL), dried over MgSOq, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography [silica gel, eluting with hexanes / ethyl acetate (1 :0 to 1 : 1) to give 3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b) (36.28 g) as a brown gum which was used as such for next step; MS (ES+) 265.3 (M+23).

[0400] Step-2: Preparation of tert-butyl 3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)- IH-pyrazol- 1 -yl)benzylcarbamate (54c)

[0401] To a solution of 3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b) (24.682 g, 102 mmol) in DMF (480 mL) was added l-(3-((tert-butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxylic acid (lOd) (35.0 g, 91 mmol), N-ethyl-N-isopropylpropan-2-amine (132 mL, 758 mmol), bromotripyrrolidin-l-ylphosphonium hexafluorophosphate(V) (PyBrOP, 42.8 g, 91 mmol) and stirred at room temperature for 19 h. The reaction mixture was diluted with ethyl acetate (1000 mL), washed with water (500, 400 mL), brine (400 mL), dried over MgSOq, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography [silica gel, eluting with hexanes / ethyl acetate (1:0 to 1:1)] to afford tert-butyl 3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54c) (4.583 g, 5% for two steps) as a yellow solid; 'H NMR (300 MHz, DMSO-t / 6) 6 10.57 (s, 1H), 7.81 (t, J= 1.7 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.64 - 7.19 (m, 10H), 6.25 (d, J= 4.0 Hz, 1H), 5.78 (d, J= 4.0 Hz, 1H), 4.19 (d, J= 6.1 Hz, 2H), 1.37 (s, 9H);19F NMR (282 MHz, DMSO-tL) 6 -60.81 , -123.09; MS (ES+) 632.3 (M+23).

[0402] Step-3: Preparation of tert-butyl 3-(5-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54d)

[0403] To a solution of tert-butyl 3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54c) (1.333 g, 2.187 mmol) in dichloromethane (40 mL) at 0°C was added thionyl chloride (0.340 mL, 4.59 mmol) and warmed to room temperature over 2 h. The reaction mixture was quenched with tri ethyl amine (2.0 mL, 14.35 mmol) stirred at room temperature for 1 h. It was then treated with cyclopropylmethanamine (4.30 mL, 48.0 mmol), concentrated to remove most of dichloromethane followed by addition of acetonitrile (30 mL), stirring at 70 °C for 14 h, and

[0404] 47

[0405] FH 13299433.1BPX-06125

[0406] concentration in vacuum to dryness. The residue was treated with chloroform (200 mL), washed with water (100 mL), dried over MgSOq followed by filtration and concentration. The crude product was purified by flash column chromatography [silica gel eluting with hexanes / ethyl acetate (1:0 to 2:1)] to afford tert-butyl 3-(5-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54d) (184 mg, 13%) as colorless gum; 'HNMR (300 MHz, DMSO-t / r,) 8 10.56 (s, 1H), 7.89 (t, J= 1.7 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.70 - 7.30 (m, 10H), 7.22 (dd, J= 10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 4.19 (d, J= 6.2 Hz, 2H), 2.26 (d, J= 6.6 Hz, 2H), 1.37 (s, 9H), 1.00 - 0.80 (m, 1H), 0.45 - 0.28 (m, 2H), 0.12 - -0.01 (m, 2H);19F NMR (282 MHz, DMSO-t / r,) 6 -60.80 , -123.20; MS (ES+) 663.4 (M+l). Step-4: Preparation of l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e) To a solution of tert-butyl 3-(5-(5-((3-cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54d) (161 mg, 0.243 mmol) in 1,4-Dioxane (18 mL) was added hydrogen chloride (2.60 mL, 10.40 mmol, 4 M in 1,4-dioxane) and stirred at room temperature for 16 h. the reaction mixture was treated with hexanes, decanted, washed with hexanes, and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluting with chloroform / CMA80 (1:0 to 2:1)] to afford l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e).

[0407] The pure product was dissolved in methanol (10 mL) and added 4 N HC1 (aq. 0.14 mL) followed by concentration in vacuum to dryness to give HC1 salt of l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e) (74 mg, 48%) white solid;XH NMR (300 MHz, DMSO-t / 6, D2O ex NMR) 6 8.13 (t, J= 1.7 Hz, 1H), 7.98 - 7.84 (m, 3H), 7.73 - 7.64 (m, 3H), 7.63 - 7.48 (m, 4H), 7.44 (dd, J = 10.2, 8.6 Hz, 1H), 5.75 (s, 1H), 4.12 (s, 2H), 2.76 (d, J = 7.2 Hz, 2H), 1.17 -0.94 (m, 1H), 0.68 - 0.47 (m, 2H), 0.34-0.24 (m, 2H);19F NMR (282 MHz, DMSO-t / 6) 6 -60.82, -120.02; MS (ES+): 563.3 (M+l); Analysis calculated for C30H26F4N6O 2.O HCF3.0 H2O: C, 52.26; H, 4.97; N, 12.19; Found: C, 52.26; H, 5.00; N, 11.72.

[0408] Example 2: Separation of enantiomers of racemic compound 54e (Reproduced from WO

[0409]

[0410] 48

[0411] FH 13299433.1BPX-06125

[0412]

[0413] Compound I (free base) Separation of (+)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (Compound I), and (-)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer)

[0414] Isomers of Racemic l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e) (0.4 g) were separated by using preparative SFC method using the following conditions to furnish:

[0415] Preparative SFC Method used:

[0416] Column 20mm x 25.0 cm ChromegaChiral CCS from Regis Technologies (Morton Grove, IL)

[0417] CO2 Co-solvent (Solvent B) Methanol: Isopropanol (1:1) with 1%

[0418] Isopropylamine

[0419] Isocratic Method 20 % Co-solvent at 80 mL / min

[0420] System Pressure 200 bar

[0421] Column Temperature 25 °C

[0422] Sample Diluent Methanol: Isopropanol

[0423] Chiral Purity of peaks was determined by following Analytical SFC Method:

[0424] Column 4.6 x 100 mm ChiralPak AS from Chiral Technologies (West Chester, PA)

[0425] CO2 Co-solvent (Solvent B) Methanol: Isopropanol (1 : 1) with 0.1%

[0426] Isopropylamine

[0427] Isocratic Method 5-65 % Co-solvent Gradient at 4 mL / min System Pressure 100 bar

[0428] Column Temperature 25 °C

[0429] 49

[0430] FH 13299433.1BPX-06125

[0431] Sample Diluent Methanol

[0432] Peak-1 (Compound I)

[0433] 2.1 min 144 mg >95% ee (UV 254) 98.6 % purity (UV 254)

[0434] Peak-2 ((-)-enantiomer)

[0435] 2.4 min 172 mg 95.5 % ee (UV 254) 96.5 % purity (UV 254)

[0436] 1. Peak-1 assigned as (+)-l-(3-(aminomethyl)phenyl)-N-(5-((3- cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)- lH-pyrazole-5-carboxamide (Compound I) (144 mg, >95%ee) free base as white solid; Optical rotation: [a]D= (+) 6.83 [CH3OH, 1.2]; *HNMR (300 MHz, DMSO r,) 8 10.53 (s, 1H, D2O exchangeable), 7.88 (t, J= 1.7 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.67 (dt, J= 7.7, 1.4 Hz, 1H), 7.63 (dd, J= 7.5, 2.1 Hz, 1H), 7.56 (s, 1H), 7.54 - 7.47 (m, 2H), 7.47 - 7.38 (m, 2H), 7.34 (ddt, J= 8.6, 5.9, 2.8 Hz, 2H), 7.22 (dd, J= 10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 3.77 (s, 2H), 2.31 - 2.21 (m, 2H), 0.97 - 0.80 (m, 1H), 0.42 - 0.33 (m, 2H), 0.10 - -0.02 (m, 2H);19F NMR (282 MHz, DMSO-t / 6) 6 -60.73 , - 123.20; MS (ES+) 563.3 (M+l), 561.3 (M-l). To a solution of free base mixture of (+)- 1 -(3 -(aminomethyl)phenyl)-N-(5 -((3 -cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5- carboxamide (Compound I) (120 mg) in methanol (15 mL) was added hydrogen chloride (0.969 mL, 1.938 mmol), stirred at room temperature for 10 min, evaporated to dryness to afford (+)-l-(3-(aminomethyl)phenyl)-N-(5-((3- cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)- lH-pyrazole-5-carboxamide (Compound I) (100 mg) hydrochloride salt as white solid;XH NMR (300 MHz, DMSO r,) 6 10.84 (s, 1H, D2O exchangeable), 10.44 (s, 2H, D2O exchangeable), 8.44 (s, 3H, D2O exchangeable), 8.30 (s, 1H, D2O exchangeable), 8.09 (d, J= 7.9 Hz, 1H), 7.99 (d, J= 6.8 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.80 - 7.50 (m, 7H), 7.42 (dd, J= 10.3, 8.6 Hz, 1H), 5.78 (d, J= 6.9 Hz, 1H), 4.13 (d, J= 5.7 Hz, 2H), 2.88 - 2.62 (m, 2H), 1.42 - 0.99 (m, 1H), 0.73 - 0.46 (m, 2H), 0.32 (d, J= 4.4 Hz, 2H);19F NMR (282 MHz, DMSO-t / 6) 6 -60.81 , -119.99; MS (ES+): MS (ES+) 563.3 (M+l), MS (ES-) 561.3 (M-l), 597.3 (M+Cl); Analysis calculated for C30H26F4N6O 2HC1 1.75H2O: C, 54.02; H, 4.76; Cl, 10.63; N, 12.60; Found: C, 54.12; H, 4.83; Cl, 10.10; N, 11.97.

[0437] 2. Peak-2 assigned as (-)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer) (172 mg, 95.5 % ee) as free base was repurified by flash column

[0438] 50

[0439] FH 13299433.1BPX-06125

[0440] chromatography (silica gel 12 g, eluting 0-30% MeOH in chloroform for 15 min) to afford (-)- 1 -(3 -(aminomethyl)phenyl)-N-(5 -((3 -cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer) free base as an off-white solid; Optical rotation: [a]o = (-) 5.44 [CH3OH, 1.25]; 'HNMR (300 MHz, DMSO r,) 67.88 (t, J= 1.6 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.70 - 7.61 (m, 2H), 7.57 (s, 1H), 7.54 - 7.47 (m, 2H), 7.45 - 7.41 (m, 2H), 7.34 (ddq, J= 8.7, 6.1, 3.5, 2.8 Hz, 2H), 7.22 (dd, J= 10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 3.78 (s, 2H), 2.25 (d, J= 6.9 Hz, 2H), 0.90 (ddd, J= 9.8, 8.0, 5.2 Hz, 1H), 0.47 - 0.29 (m, 2H), 0.04 (dd, J= 5.0, 1.5 Hz, 2H);19F NMR (282 MHz, DMSO-t / 6) 6 -60.73 , -123.19; MS (ES+) 563.3 (M+l), MS (ES-), 561.3 (M-l). To a solution of free base of (-)-l-(3- (aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2- fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer) (0.124 g, 0.220 mmol) in methanol (15 mL) was added hydrogen chloride (1.102 mL, 2.204 mmol), stirred at room temperature for 10 min, evaporated to dryness to afford (-)-l-(3- (aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2- fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer) (0.121 g) hydrochloride salt as an off-white solid;1H NMR:1H NMR (300 MHz, DMSO-tL) 6 10.82 (s, 1H, D2O exchangeable), 10.36 (s, 2H, D2O exchangeable), 8.38 (s, 3H, D2O exchangeable), 8.27 (s, 1H), 8.06 (d, J= 7.9 Hz, 1H), 7.98 (d, J= 6.7 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.78 - 7.49 (m, 7H), 7.48 - 7.37 (m, 1H), 5.78 (s, 1H), 4.13 (d, J= 5.7 Hz, 2H), 2.72 (s, 2H), 1.14 (s, 1H), 0.56 (d, J= 7.7 Hz, 2H), 0.31 (d, J= 5.0 Hz, 2H);19F NMR (282 MHz, DMSO-t / 6) 6 -60.82 , -120.03; MS (ES+): MS (ES+) 563.3 (M+l), MS (ES-), 561.3 (M-l), 597.2 (M+Cl); Analysis calculated for C30H26F4N6O.2HCI.I.75H2O: C, 54.02; H, 4.76; Cl, 10.63; N, 12.60; Found: C, 54.12; H, 4.83; Cl, 10.10; N, 11.97. Example 3: Preparation of a Seed Crystal of Berotralstat *2(HC1) (Reproduced from WO 2020 / 092898)

[0441] A solution of berotralstat (see Example 2) in methyl tert-butyl ether (MTBE) (1 equiv) is added to a solution of HC1 (aq) (2 equiv) in methanol (cold), followed by heating to about 30°C, and keeping it at about 30°C for not longer than 5 hours while stirring at about 115 rpm. berotralstat bis(HCl) is collected by filtration and dried. The crystalline material obtained can be used as a seed for the crystallization protocol described in Example 4.

[0442] Example 4: Large-Scale Synthetic & Crystallization Protocol for Berotralstat*2(HCl ) (Reproduced from WO 2020 / 092898)

[0443] 51

[0444] FH 13299433.1BPX-06125

[0445]

[0446] 37% aqueous hydrochloric acid (38.1 kg, 32.3 L, 2.14 equiv.) was charged to a clean and empty crystallization vessel, methanol (228.9 kg, 39.5 equiv.) was added, and the contents were cooled to -7 ± 3°C. A solution of her otr al stat free base (approx. 101.8 kg; 180.9 moles) in MTBE (approx. 1,300 L) was filtered through a polish filter into the crystallization vessel at temperature -5 ± 5°C. After rinse with MTBE, pre-weighed berotralstat»2(HCl) seed crystals (1.39 kg, 0.012 equiv.; Example 3) were charged to the crystallization vessel via the manhole. The vessel content was heated to 30-33°C, and the agitation speed was set to 25-50 rpm. After confirmed crystallization, the slurry was agitated for another three to four hours. The product slurry was transferred to centrifuge and isolated by centrifugation. The product was washed with MTBE (585 L). After dry spinning the wet product, berotralstat»2(HCl), it was discharged from the centrifuge, and the product was dried at < 40°C under vacuum in a cone drier. Product berotralstat»2(HCl) yield: 100 kg; 157.4 mol; approx. 85%.

[0447] H NMR (300 MHz, DMSO-t / r,) data is shown in Table 4:

[0448] 52

[0449] FH 13299433.1BPX-06125

[0450] <

[0451]

[0452]

[0453] Berotralstat has two basic sites. The conjugate acid of the primary amine was calculated to have a pKa value of 8.89, and the conjugate acid of the secondary amine was calculated to have a pKa value of 7.86.

[0454] Example 5- A Phase 3 study to evaluate the safety and pharmacokinetics of berotralstat prophylaxis in children with hereditary angioedema who are 2 to less than 12 years of age

[0455] Study 304 is an ongoing sequential, single arm, open-label, 3-part study to evaluate the safety and PK of berotralstat oral granules / oral pellets formulation in participants 2 to less than 12 years of age at enrollment with HAE. All enrolled patients had a laboratory confirmation of HAE-C1INH and a documented history of >2 HAE attacks in the 6 months prior to enrollment. Median (range) age of patients was 8.0 (3, 11) years at the time of

[0456] 53

[0457] FH 13299433.1BPX-06125

[0458] screening, and 48.3% were female (Table 7). The study enrolled patients in 9 countries across the EU, UK, Canada, and Israel.

[0459] Based on the analysis of the data, the recommended doses for oral administration of the solid oral granules / oral pellets based on body weight are 72 mg once daily for patients with body weight 12 to less than 24 kg or 15 to less than 24 kg, 96 mg once daily for patients with body weight 24 kg to less than 32 kg, 108 mg once daily for patients with body weight 32 to less than 40 kg, and 132 mg once daily for patients with body weight 40 kg or greater.

[0460] The primary objective of the study was to describe the PK parameters of berotralstat administered orally to pediatric participants 2 to less than 12 years of age with HAE and weighing 12 kg or greater. The primary endpoint was the characterization of the PK profile of berotralstat in subjects aged 2 to less than 12 years HAE and weighing 12 kg or greater.

[0461] The secondary objectives were to assess the safety and tolerability of berotralstat administered orally to pediatric subjects with HAE aged 2 to less than 12 years old and weighing 12 kg or greater and to summarize the effectiveness of berotralstat in pediatric subjects with HAE aged 2 to less than 12 years old and weighing 12 kg or greater. The secondary endpoint for safety were the frequency and severity of adverse events (AEs) and serious adverse events (SAEs), laboratory analyses (clinical chemistry, hematology, coagulation), height, weight, vital signs, electrocardiograms (ECGs), and physical examination findings. Safety endpoints are assessed at the end of each Part (i.e., Weeks 12 [Part 1], 48 [Part 2], and 144 / end of study). The secondary effectiveness endpoints were the frequency (number and rate) of attacks, duration of symptoms, anatomical location of attack, number and proportion of attacks requiring on-demand treatment, number and proportion of days with angioedema symptoms, assessment of attack severity, discontinuations due to lack of efficacy, and number of hospitalizations and clinic visits from Week 1 through Weeks 12 and 48.

[0462] An interim analysis of PK, safety, and effectiveness was conducted after at least 15 participants completed 48 weeks of treatment (through Part 2) using interim locked data (last participant observation 11 September 2024). As of 11 September 2024, all 29 enrolled participants (100%) had completed Part 1 of the study (Week 12), 26 participants (89.7%) had completed all visits through Week 24, and 17 participants (58.6%) had completed Part 2 of the study (through Week 48). A total of 25 participants (86.2%) were still ongoing in the study, including 10 participants in Part 2 and 15 participants in Part 3. Across all cohorts, 4 participants (13.8%) discontinued the study, including 2 participants in Cohort 2 before Week 48 (Part 2), and 1 participant each in Cohorts 1 and 2 after Week 48 (Part 3).

[0463] 54

[0464] FH 13299433.1BPX-06125

[0465] A second interim analysis of safety and effectiveness was conducted after all participants remaining on study completed Part 2 (through Week 48) using interim locked data (last participant observation 24 March 2025). As of 24 March 2025, all 29 enrolled participants (100%) completed Part 1 of the study (through Week 12), and 27 of 29 participants (93.1%) completed Part 2 (through Week 48). All 25 participants (86.2%) remaining in the study are currently in Part 3 (Weeks 48 through 144). No participants have yet completed the study.

[0466] PK data was not collected after the 11 September 2024 interim data cutoff date. Data for all participants are presented under the same cohort in which they were enrolled based on their original assigned dose regardless of dose adjustments made during the study. Unless otherwise indicated, the data reported reflect data through 24 March 2025.

[0467] The study consists of 2 treatment periods: a 12-week SOC treatment period followed by an open-label berotralstat treatment period lasting up to 144 weeks. Subjects were enrolled into 4 or more dose cohorts; subject weight was used to determine assignment to each cohort with the higher weight cohorts (Cohorts 1 and 2) enrolling first and in parallel. Cohort 3 opened for enrollment after > 4 subjects from Cohorts 1 and 2, with > 2 of the subjects from Cohort 2, reached Week 2. Cohort 4 opened for enrollment after > 4 subjects in Cohort 3 reached Week 2. The berotralstat treatment period is divided into 3 parts (Parts 1 to 3) as described below.

[0468] For the SOC treatment period, subjects continued taking their SOC therapy for HAE (either short-term or long-term prophylaxis, or acute treatment for HAE attacks) for 12 weeks from the screening visit. No additional in-person visits are required during the SOC treatment period; however, at approximately 4 and 8 weeks following screening, site personnel contacted the parent / caregiver to assess AEs and the overall status of the subject.

[0469] For Part 1, subjects returned for the Day 1 (baseline) visit after completing 12 weeks on SOC. Prior to the Day 1 visit, subjects were required to discontinue all prophylaxis for prevention of HAE attacks, however use of on-demand medication to manage acute HAE attacks was allowed throughout the study. At the Day 1 visit, the site confirmed concomitant medications, reviewed subject diary entries, and discussed any AEs that occurred during the SOC treatment period. Beginning on Day 1, subjects took berotralstat orally once each day, with food, for 12 weeks. Additional study visits in Part 1 occurred at Weeks 2, 6, and 12. All safety assessments were assessed at each visit. In addition to the clinic visits, the site contacted the parent / caregiver at Week 9 to assess safety and subject status.

[0470] 55

[0471] FH 13299433.1BPX-06125

[0472] For Part 2, beginning at the Week 12 visit, all subjects were provided continued access to open-label berotralstat through Week 48. Study visits in Part 2 occurred every 12 weeks (Weeks 24, 36, and 48) and the parent / caregiver was contacted at 4-week intervals between study visits (i.e., at Weeks 16, 20, 28, 32, 40, and 44) to assess the subjects’ overall wellbeing. At the Week 48 visit, the site collected all subject diaries.

[0473] For Part 3, after Week 48, subjects may continue to receive open label berotralstat through Week 144 (up to a total of 96 weeks). Visits in Part 3 will occur every 24 weeks (Weeks 72, 96, 120, and 144) and the parent / caregiver will be contacted at 12-week intervals between study visits (i.e., at Weeks 60, 84, 108, and 132) to assess the subjects’ overall wellbeing. Berotralstat will be provided in Part 3 through Study Week 144 or until another mechanism is available to provide drug to the subject (e.g., market access, separate study).

[0474] At Week 2 in Part 1, plasma samples for PK analysis were collected immediately prior to dosing and at designated timepoints post dose. Based on the PK results, the dose regimen of berotralstat may be adjusted for an individual subject or for all subjects in the cohort to ensure exposures fall within the acceptable safety range; the dose of berotralstat will not be adjusted based on changes to the subject’s weight during Part 1. In Part 2, one random sample for PK analysis will be drawn at Weeks 12, 24, 36, and 48. Reduced PK sampling may be performed in subjects, especially subjects in Cohort 4, to maintain blood volumes within acceptable ranges. Additional PK samples will be drawn if the berotralstat dose is adjusted.

[0475] The main criteria for inclusion were: i) age 2 to less than 12 years of age and weighing 12 kg or greater; ii) parent / caregiver willing and able to provide written, informed consent (with assent from the child where appropriate); iii) subjects with a clinical diagnosis of HAE (as defined below); iv) for subjects who are not currently receiving prophylaxis for HAE, documented history of > 2 HAE attacks in the 6 months prior to the enrollment visit; v) access to and ability to use one or more acute medications approved by the relevant competent authority for the treatment of acute attacks of HAE; vi) in the opinion of the investigator, the subject would benefit from long-term oral prophylaxis. A clinical diagnosis of HAE defined as i) a screening result that document immunogenic Cl esterase inhibitor (Cl -INH) antigenic level below the lower limit of normal (LLN) reference range or Cl -INH function less than 50%, and a complement 4 level below the LLN reference range; ii) laboratory documentation of historical Cl -INH functional level below the assay lower limit of normal; iii) for subjects with Cl -INH function > 50% but less than the assay LLN, a SERPING-1 gene mutation known or likely to be associated with HAE Type I or II, as 56

[0476] FH 13299433.1BPX-06125

[0477] assessed during the screening period or a repeat Cl -INH functional level less than 50%; iv) historical or new laboratory documentation of a SERPING-1 mutation known or likely to be associated with HAE; or v) for subjects who currently use plasma-derived or recombinant Cl-INH-based prophylactic therapies, a confirmed family history of Cl -INH deficiency.

[0478] The main criteria for exclusion were: i) concurrent diagnosis of any other type of recurrent angioedema; ii) any clinically significant history of angina, myocardial infarction, syncope, clinically significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, myocarditis, pericarditis, congenital heart defects, or any other clinically significant cardiovascular abnormality such as poorly controlled hypertension; iii) known family history of sudden cardiac death at a young age (i.e., less than 40 years of age); family history of sudden death from HAE is not exclusionary; iv) history of or current implanted defibrillator or pacemaker; v) moderate to severe hepatic impairment (Child-Pugh B or C); vi) calculated creatinine clearance using the Modified Schwartz formula of < 30 mL / min / 1.73 m2 or aspartate aminotransferase or alanine aminotransferase value > 3 / the upper limit of the age-appropriate normal reference range value; vii) history of severe hypersensitivity to multiple medicinal products or severe hypersensitivity / anaphylaxis with unclear etiology; viii) current participation in any other investigational drug study or received another investigational drug within 30 days of enrollment; not willing to refrain from participation in another clinical study after enrollment and for the duration of the study. Drugs / vaccines approved under FDA emergency use authorization (or country-specific analogous regulations) are not considered excluded or prohibited under this criterion; ix) an immediate family relationship to either sponsor employees, the investigator, or employees of the study site named on the delegation log; x) any result at screening that, in the opinion of the investigator, is clinically significant and relevant for this study; xi) any clinically significant medical condition or medical history (including altered mental status) that, in the opinion of the investigator or sponsor, would interfere with the subject’s safety or ability to participate in the study; xii) clinically significant abnormal ECG including but not limited to, a corrected QT interval calculated using Fridericia’s correction (QTcF = QT / RR0.33) > 450 msec, or ventricular and / or atrial premature contractions that are more frequent than occasional, and / or as couplets or higher in grouping; and xiii) known hypersensitivity to berotralstat or any of its formulation excipients.

[0479] Berotralstat 150 mg capsules in multidose bottles and pellets for oral administration packaged in unit-dose packets were taken orally, once daily, with food. The doses for Cohorts 1, 2, 3, and 4 are shown in Table 6. The berotralstat dose for Part 1 will be determined based 57

[0480] FH 13299433.1BPX-06125

[0481] on subject weight on Day 1. In Parts 2 and 3, subjects will continue open label berotralstat for a total of up to an additional 132 weeks. Cohorts 1 and 2 were the first cohorts to enroll participants and started in parallel, enabling the collection of PK, safety, and effectiveness data from participants whose age and weight were most similar to the approved population. Dose modifications were allowed throughout the study for safety and / or PK reasons and in Parts 2 and 3 based on weight.

[0482]

[0483] aThe 150 mg capsules was identical to commercial product (Orladeyo®), which is approved for adult and pediatric patients 12 years of age and older.

[0484] All participant-reported attacks as recorded in the diaries were entered into the database.

[0485] Attacks meeting pre-specified criteria were included in effectiveness analyses as adjusted attacks Participant-reported attacks must have met the following criteria (applied in order) for inclusion in adjusted effectiveness analyses using programmatically adjusted attacks: (1) attack must have included at least 1 symptom of swelling; (2) participant response to diary question, “In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (i.e., allergic reaction, viral cold etc.)?” must have been “no”; (3) attack must have been unique (attack began > 24 hours from the end of the prior attack); (4) any attack that began within 24 hours from the end of a prior attack was combined with the prior attack; and (5) if the entire adjusted attack was untreated, it must have had a duration > 24 hours. Using the above criteria, adjusted attacks were determined programmatically. For adjusted attacks that spanned 2 or more participant-reported attacks, attack triggers, locations, symptoms, duration, and other characteristics were based on the information from each component participant-reported attack. Additionally, the start date / time of the adjusted attack was the start date / time from the first attack, and the end date / time of the adjusted attack was the end date / time from the last attack being collapsed programmatically. Most participants (89.7%) reported a family history of Type 1 or 2 HAE as expected given the autosomal dominant inheritance pattern of HAE and reported rate of de novo mutations in the broader HAE population.

[0486] 58

[0487] FH 13299433.1BPX-06125

[0488] Safety and effectiveness analyses were based on all study participants who received at least 1 dose of berotralstat on study (i.e., the Safety Population). No imputation for missing data occurred. For effectiveness endpoints, the baseline values were based on the attacks that occurred during the 12-week SOC period. For participants who prematurely discontinued the study, all available data were included in the analysis. The pharmacokinetic population included participants in the safety population who had at least 1 evaluable and quantifiable post dose PK sample obtained (PK Population). The PK population was the primary population for noncompartmental and population PK analyses.

[0489] Descriptive statistics were generated for PK, safety, and efficacy endpoints. Maximum serum concentration (Cmax), time to Cmax (Tmax), and area under the curve (AUCo-iast), were estimated using non-compartmental analysis tools and were summarized by median (Tmax) or geometric mean (Cmax and AUCo-iast). Statistical summaries include sample size (n), mean, standard deviation (SD) or standard error of the mean (SEM), median, minimum and maximum for continuous data (range), and frequency and percentages for categorical data. Patient-reported HAE attacks were programmatically confirmed or rejected for inclusion in the efficacy analyses as described herein. Analysis of safety and tolerability are descriptive. Descriptive analyses of efficacy endpoints are provided for Part 1 (Day 1 to Week 12) and Parts 1 and 2 combined (Day 1 to Week 48) unless otherwise noted.

[0490] Demographics of the study participants is shown in Table 7. The age of the study population ranged from 3 to 11 years at screening, and weight ranged from 14.9 to 69.7 kg at baseline. Three cohorts (Cohorts 2, 3, and 4) included participants who were 6 years of age, indicating the broad distribution of weight among enrolled participants of similar age.

[0491] Enrollment was similar between males and females (51.7% males and 48.3% females), and all 4 participants in Cohort 4 were male. All participants who reported known race and ethnicity were White and not Hispanic or Latino.

[0492]

[0493] 59

[0494] FH 13299433.1BPX-06125

[0495] <

[0496]

[0497] <

[0498] 60

[0499] FH 13299433.1BPX-06125

[0500] <

[0501] < < <

[0502]

[0503] Abbreviations: BMI = body mass index; max = maximum; min = minimum; SD = standard deviation.

[0504] Note: Height, weight, and BMI were baseline values defined as the latest non-missing result prior to administration of the first dose of berotralstat.

[0505] aCohort 1: 40 kg or greater, Cohort 2: 32 to less than 40 kg, Cohort 3: 24 to less than 32 kg, and Cohort 4: 12 to less than 24 kg at baseline.

[0506] bSome French sites reported “Unknown” for race and “Not Reported” for ethnicity in accordance with local regulations.

[0507] cBMI is calculated as weight (kg) / [height (m)]2

[0508] The median age at onset of HAE symptoms was 2.0 years (mean age of onset 2.9 years). The majority of enrolled participants, 24 (82.8%), experienced the onset of first symptoms at 6 years of age or earlier (with a median (range) age at HAE symptom onset of 2.0 (0.3, 8.0) years), with onset in 11 participants (37.9%) from birth to less than 2 years of age and in 13 participants (44.8%) from 2 to less than 6 years of age. HAE symptom onset at an early age is associated with a more severe disease course, including more HAE episodes per year and more hospitalizations.

[0509] The majority of the participants (51.7%) required a median of 3.0 ER visits, and 5 of 29 participants reported a median of 3.0 hospitalizations due to HAE symptoms in the year prior to enrollment. Only 2 (6.9%) participants did not miss any days of education in the year prior to enrollment. The remaining 27 participants (93.1%) missed a median of 10.0 days of education due to HAE symptoms (range: 0 to 90 missed days) in the year prior to enrollment. The mean (SD) number of days of education missed in the year prior to enrollment was 18 (20.49).

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[0512] All participants reported at least 2 HAE attacks in the 6 months prior to enrollment. Participants reported a median of 11 attacks in the 6 months prior to enrollment (range: 2 to 24 attacks) or 1.8 attacks / month (range: 0.3 to 4 attacks / month), including those on LTP. In the 12 months prior to enrollment, the most common anatomic region where swelling occurred was the stomach / abdomen (89.7%), and correspondingly the most common symptoms of an HAE attack were abdominal pain (79.3%), vomiting (69.0%), and nausea (62.1%). Visible swelling was also observed in the hands and arms (72.4%), feet and legs (65.5%), and face / head (55.2%) during an HAE attack 12 months prior to enrollment.

[0513] Laryngeal attacks (any time prior to study enrollment) were reported less frequently but still occurred in 4 participants (13.8%). Despite the high disease burden, only eleven participants in the Safety Population (37.9%) reported the use of prophylactic treatments for HAE in the past, including Cinryze (3.4%), Takhzyro (3.4%), Berinert (24.1%) and tranexamic acid (20.7%). Of these patients, five utilized LTP during the SOC period (tranexamic acid, 13.8%; and Takhzyro, 3.4%).

[0514] Across all cohorts through 24 March 2025, the median overall compliance rate was 97.60% (range: 83.4 to 107.2%), with 79.3% of participants reporting compliance above 90%. Median compliance for Day 1 to Week 12 (Part 1) was 98.8 (range: 72.6 to 100.0) and for Weeks 13 through 48 (Part 2) was similarly high at 96.8% (range: 83.0 to 100.4%). There were no discernable differences in compliance with berotralstat dosing between cohorts. Pharmacokinetic Results

[0515] A series of blood samples were drawn at the Week 2 visit to allow for determination of PK parameters including C max, AUCo -last, AUCo -6, Tmax, Ciast, and Tiast using noncompartmental methods. In Cohorts 1, 2, and 3, plasma samples for PK analysis were collected pre-dose and at 1 ± 0.5, 2 ± 0.5, 4 ± 1, and 6 ± 1 hours post dose. In Cohort 4, plasma samples for PK analysis were collected pre-dose, 1 to 2 hours post dose, and 4 to 6 hours post dose.

[0516] PK parameters were calculated following the collection of 141 serum samples from 24 patients. The plasma concentrations of berotralstat at Week 2 for the serial measurements for the PK population are summarized in Table 8. Average steady-state concentrations were similar for Cohorts 2, 3, and 4. The mean pre-dose concentration was slightly higher in Cohort 1 compared to the other cohorts, and mean concentrations in Cohort 1 remained higher than the other cohorts for the entirety of the sampling window. Mean concentrations were comparable for Cohorts 2 and 3 across the entire sampling window. Pre-dose concentrations for Cohort 4 are higher than Cohorts 2 or 3 but lower than Cohort 1.

[0517] 62

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[0519]

[0520] Note: Data presented as n, arithmetic mean (SD).

[0521] Table 9A summarizes the plasma concentrations of berotralstat following dose modifications for participants from all cohorts in the PK population. Across all participants, 9 experienced a dose modification (2 in Cohort 1, 5 in Cohort 2, and 2 in Cohort 3) and PK data was available for 6 of the 9 participants. All participants in Table 9 A were in Cohort 2 (4 participants had a dose increase from 108 mg QD oral granules to 150 mg QD capsules) or Cohort 3 (2 participants had a dose increase from 96 mg QD oral granules to 108 mg QD oral granules) and had a dose increase due to weight gain. Plasma samples were collected

[0522] 2 - 6 weeks after dose modification. Mean concentrations after dose modification were comparable to the corresponding timepoint values from Cohort 1 (see Table 9B). A single participant (Cohort 2) had no reported value for the 20-24 hr post-dose sample and the same participant had 2 values from 2 separate visits for the 2 to 4 hr post-dose sample (both of which are included).

[0523] 63

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[0525]

[0526] aThe 20 - 24 hour post dose draw was relative to the modified dose taken on the day prior to the clinic visit.bThe 2 - 4 hour post dose draw was relative to the dose administered at the clinic visit.

[0527] cn = number of plasma samples.

[0528] The plasma berotralstat PK parameters calculated using noncompartmental methods for the PK population are shown in Table 9B. Due to the limited sampling, PK parameters were not calculated for participants in Cohort 4. The median Tmax and geometric mean Cmax, AUCo-iast, and AUCo-6 were comparable between Cohorts 2 and 3. In Cohort 1, the median Tmax was slightly later and the geometric mean Cmax, AUCo-iast, and AUCo-6 were slightly higher compared to Cohorts 2 and 3. C values were generally consistent across cohorts and consistent with concentrations remaining quantifiable for the entire planned sampling window. At steady state in Cohorts 1-3 (n=24), the median (range) Tmax was 3.9 hrs (0.9, 6.0) and the geometric mean (CV [coefficient of variation]) for Cmax and AUCo-iast were 204 ng / mL (40%) and 915 ng»hr / mL (42%), respectively, after dosing.

[0529]

[0530] Abbreviations: AUC = area under the concentration vs. time curve; AUCo-e = AUC from time 0 to 6 hours post dose; AUCo-iast = AUC from time 0 to the last measurable concentration; Cw = last measurable concentration; maximum plasma concentration; observed concentration at the end of the dosing interval; CV = coefficient of variation; PK = pharmacokinetic; Tw = time to Cw; Tmax= time to

[0531] Note: Data presented as geometric mean (CV%) except for Tmax and Tw, which are presented as median (minimum - maximum).

[0532] Safety Results

[0533] Berotralstat was safe and generally well tolerated across all cohorts as of the interim data cutoff date. No safety signals were identified. Safety events were consistent with the events previously noted in Phase 2 and 3 clinical studies and in the approved berotralstat

[0534] 64

[0535] FH 13299433.1BPX-06125

[0536] labelling for adult and pediatric patients > 12 years of age. As of the data cutoff date, March 24, 2025, all ongoing participants completed at least the 48-week study visit. Overall, median (range) participant exposure to berotralstat was 71.29 weeks (18.1 to 108.0) weeks. Cohorts 1 and 2 were opened prior to Cohorts 3 and 4; therefore, participants in Cohorts 1 and 2 had longer exposure on berotralstat.

[0537] Overall, 25 participants (86.2%) have experienced AEs during the berotralstat treatment period to date. AEs experienced by participants during the SOC period and berotralstat treatment period in the study were similar. There were no TESAEs assessed by the investigator as related to berotralstat. No deaths were reported. No participant experienced treatment-emergent laboratory changes related to study intervention. No impact on vital signs or deviations from normal height and weight development based on World Health Organization Child Growth Standards were observed. No cardiac TEAEs were reported, and no participant experienced clinically meaningful QT observations.

[0538] Effectiveness Results

[0539] Effectiveness data for berotralstat were captured for up to 48 weeks, during Part 1 (Day 1 through Week 12) and Part 2 (Weeks 13 through 48) of the study. As relevant, the baseline value was based on HAE attacks reported during the 12-week SOC period. The use of prophylaxis during the SOC period was allowed per protocol and may have impacted the overall baseline attack rate. Five participants used LTP HAE medication during the SOC period, including 4 participants who used tranexamic acid daily and 1 participant who used lanadelumab. Three participants had access to Berinert for short-term prophylaxis as needed, 2 of whom used tranexamic acid for LTP.

[0540] A total of 135 adjusted attacks were reported during the 12-week SOC period across all participants. Only 50 adjusted attacks were reported in the first 12 weeks on berotralstat treatment (Part 1). A total of 162 adjusted attacks were reported during Day 1 to Week 48 (Parts 1 and 2). Five participants (17.2%) reported no adjusted attacks through Week 48. The incidence of adjusted attacks was similar across cohorts. A summary of HAE adjusted attacks at baseline, through Week 12 (Part 1), and through Week 48 (Parts 1 and 2) is shown in Table 10 A.

[0541] 65

[0542] FH 13299433.1BPX-06125

[0543]

[0544] Note: Summary includes all adjusted attacks occurring after the first dose of study intervention until 24 hours post last dose of the study intervention. An adjusted attack was defined per the rules discussed herein.

[0545] Note: Treated attacks were those attacks that were recorded in the diary as being treated with any medication.aCohort 1: 40 kg or greater, Cohort 2: 32 to less than 40 kg, Cohort 3: 24 to less than 32 kg, and Cohort 4: 12 to less than 24 kg at baseline.

[0546] bDenominator is number of participants with at least 1 adjusted attack.

[0547] Following berotralstat administration, the median attack rate was lower in Part 1, Part 2, and during Parts 1 and 2 of the study than observed at baseline (12-week SOC period). During the 12-week SOC period, the median attack rate (based on all 29 evaluable participants) was 0.955 attacks / month (range: 0.00 to 5.03 attacks / month). Participants reported a median attack rate of 0.333 (range: 0.00, 2.33) through Week 12 and a median attack rate of 0.339 (range: 0.00, 3,82) from week 13 to week 48 (Part 2). The overall median attack rate for Day 1 to week 48 (Parts 1 and 2) was 0.417 attacks / month (range: 0 to 1.77 attacks / month). A summary of HAE adjusted attack rate at baseline, through Week 12 (Part 1), and through Week 48 (Parts 1 and 2) is shown in Table 10B.

[0548] The safety and efficacy of berotralstat in participants who did not utilize LTP during the 12-week SOC Period (n=24; 5 in Cohort 1, 7 in Cohort 2, 8 in Cohort 3, and 4 in Cohort 4) were also analyzed independently. Summary demographics of the participants was as follows: 1) Mean age (SD) was 8.3 (2.3); 2) Race- 19 (79.2) white and 5 (20.8%) unknown; 3) Ethnicity- Hispanic / Latino 0, not Hispanic / Latino 22 (19.7%), and not reported 2 (8.3%);

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[0550] FH 13299433.1BPX-06125

[0551] and 4) Sex at birth- 12 male (50%) and 12 female (50%). Twenty-three participants (95.8%) completed at least 48 weeks of her otr al stat treatment and high treatment compliance was maintained across all participants.

[0552] There were no significant differences in reported TEAEs in this subpopulation as compared to the Safety Population (n=29). Following berotralstat treatment, median HAE adjusted attack rates declined in this subpopulation as compared to the SOC Period as observed with the Safety Population. Median (range) HAE adjusted attack rates were 0.93 (0-5.0) for the SOC Period, 0.33 (0-2.0) for Week 1 to Week 12 (Part 1), and 0.34 (0-1.8) for Week 1 to Week 48 (Part 1 and Part 2).

[0553]

[0554] 67

[0555] FH 13299433.1BPX-06125

[0556] Abbreviations: HAE = hereditary angioedema; Max = maximum; Min = minimum; SD = standard deviation; SOC = standard of care.

[0557] Note: Summary includes all adjusted attacks occurring during the SOC period (categorized as Baseline) and after the first dose of study intervention through the last day of the period or 24 hours post last dose of the study intervention if the participant discontinued during the period. An adjusted attack was defined per the rules discussed herein.

[0558] aThe adjusted attack rate was calculated as the number of adjusted attacks observed during a given period and standardized to number of attacks per month, where 1 month is defined as a 28-day (4 week) period. The Baseline adjusted attack rate was calculated using adjusted attacks observed during the SOC period.

[0559] bCohort 1: 40 kg or greater, Cohort 2: 32 to less than 40 kg, Cohort 3: 24 to less than 32 kg, and Cohort 4: 12 to less than 24 kg at baseline.

[0560] All participants had access to approved acute medications for the on-demand treatment of HAE attacks during the study. The overall median rate of attacks requiring targeted treatment decreased from 0.691 attacks / month (range: 0.00 to 5.03 attacks / month) at baseline (12-week SOC period) to 0.295 attacks / month (range: 0.00 to 2.33 attacks / month) through Week 12 (Part 1) and was 0.169 attacks / month (range: 0.00 to 1.75) through Week 48 (Parts 1 and 2). Each cohort exhibited low attack rates for attacks requiring targeted treatment during Part 2 of the study, although this measure was lower for Cohort 3 than other cohorts, with median (range) of 0.00 (0.00, 1.58) attacks / month. Median rate of attacks requiring targeted treatment for Cohorts 1-4 (Day 1 to Week 48) were 0.417 attacks / month (range: 0.00 to 1.00), 0.169 attacks / month (range: 0.00 to 1.75), 0.083 attacks / month (range: 0.00 to 1.52), and 0.211 attacks / month (range: 0.00 to 1.00), respectively. Cohort 1 reported the highest rate of attacks requiring targeted treatment through Week 48, with median (range) 0.417 (0.00, 1.00) attacks / month. The only targeted HAE medications used were Berinert and Firazyr. A summary of the adjusted attack rate for attacks requiring treatment with targeted HAE medications for all study parts is provided in Table 10C.

[0561]

[0562] 68

[0563] FH 13299433.1BPX-06125

[0564] <

[0565]

[0566] Note: Summary includes all adjusted attacks occurring during the SOC period (categorized as Baseline) and after the first dose of study drug through the last day of the period or 24 hours post last dose of the study drug if the subject

[0567] discontinued during the period. Targeted HAE medications included Berinert, Cinryze, Kalbitor, Firazyr, Ruconest, and fresh frozen plasma.

[0568] a- Cohort 1: 40 kg or greater, Cohort 2: 32 to less than 40 kg, Cohort 3: 24 to less than 32 kg, and Cohort 4: 12 to less than 24 kg at baseline.

[0569] b- The adjusted attack rate was calculated as the number of adjusted attacks observed during a given period and standardized to number of attacks per month, where 1 month is defined as a 28-day (4 week) period. The Baseline adjusted attack rate was calculated using adjusted attacks observed during the SOC period.

[0570] FIG. 3 shows the mean (SEM) and median adjusted HAE attack rate over time and patients with zero adjusted HAE attacks. The adjusted attack rate was calculated as the number of adjusted attacks observed during a given period and standardized to number of attacks per month, where 1 month is defined as a 28-day (4 week) period. The baseline-adjusted attack rate was calculated using adjusted attacks observed during the SOC period. Reduced patient numbers over the 48 weeks reflect discontinuations during the study, with one patient discontinuing due to perceived lack of efficacy and one patient discontinuing following lack of compliance with prescribed dosing. Analysis of HAE attack rates was completed every 4 weeks for up to 48 weeks on berotralstat (Parts 1 and 2) to evaluate the durability of response. Median attack rates across the safety population decreased from 0.955 attacks / month (range: 0.00 to 5.03 attacks / month) at baseline (12-week SOC period) to 0 attacks / month starting at Month 1 on treatment and remained at 0 attacks / month for each

[0571] 69

[0572] FH 13299433.1BPX-06125

[0573] month through Parts 1 and 2 (up to Week 48) with the exception of Week 24 (median 0.500 attacks / month). Generally, at least 50% of patients remained attack-free at each 4-week interval. Mean (SEM) HAE attack rates also decreased from 1.5 (0.2) attacks / month at baseline (12-week SOC period) to 0.5 (0.2) attacks / month at Week 4, 0.5 (0.2) attacks / month at Week 20, 0.5 (0.1) attacks / month at Week 36, and 0.4 (0.1) attacks / month at Week 40 illustrating a sustained reduction in attacks / month was maintained through Week 48. One (3.4%) of the 29 patients was free of HAE attacks during the baseline period. During Part 1, 12 patients (41.4%) were attack-free and during Parts 1 and 2, 5 (17.2%) participants were attack-free.

[0574] The proportion of days patients reported with angioedema symptoms decreased during the study as compared to the baseline (12-week SOC) period. During the baseline period, the median percentage of days with angioedema symptoms was 9% (range: 0 to 40%) with a mean (SD) of 11% (9.4) and was generally similar across cohorts. The median percentage of days with angioedema symptoms decreased to 2% (range: 0 to 20%; median reduction 4%) during Part 1 and 2% (range: 0 to 20%; median reduction 4%) during Part 2. Overall (Parts 1 and 2), the median percentage of days with symptoms was 3% (range: 0 to 10%; median reduction 5%). The proportion of days with reported angioedema symptoms from HAE attacks by study part is summarized in Table 11.

[0575]

[0576]

[0577] 70

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[0579]

[0580] Abbreviations: Max = maximum; Min = minimum; SAP = Statistical Analysis Plan; SD = standard deviation; SOC = standard of care.

[0581] Note: Summary includes days calculated from all adjusted attacks occurring during the SOC period (categorized as Baseline) and after the first dose of study intervention until the visit indicated or 24 hours post last dose of the study intervention if the participant discontinued on or prior to the visit indicated. An adjusted attack was defined per the rules provided herein.

[0582] aCohort 1: 40 kg or greater, Cohort 2: 32 to less than 40 kg, Cohort 3: 24 to less than 32 kg, and Cohort 4: 12 to less than 24 kg at baseline.

[0583] bThe proportion of days with angioedema symptoms was based on the number of days with reported symptoms and the number of days the participant was on treatment.

[0584] The median duration of adjusted attacks was similar at baseline (12-week SOC period) (18.00 hours [range: 0.5 to 129.0 hours]), through Week 12 (17.24 hours [range: 0.5 to 80.0 hours]), and through Week 48 (18.63 hours [range: 0.3 to 132.0 hours]). The median duration of attacks while on berotralstat was consistent across cohorts at all timepoints tested. Through Week 48, the median (range) duration of abdominal-only adjusted attacks was 14.00 (0.5, 132 hours) while the median (range) duration of non-abdominal -peripheral adjusted attacks and laryngeal adjusted attacks was 32.50 (2.8, 99.5 hours) and 37.49 (4.0, 99.5 hours), respectively. A summary of the duration of all adjusted attacks at baseline, through Week 12 (Part 1), and through Week 48 (Parts 1 and 2) is shown in Table 12.

[0585]

[0586]

[0587] 71

[0588] FH 13299433.1BPX-06125

[0589]

[0590] aSummary includes all adjusted attacks occurring after the first dose of study intervention until the Week 48 visit or 24 hours post last dose of the study intervention if the participant discontinued prior to Week 48. An adjusted attack was defined per the rules described herein.

[0591] bDuration of each participant-reported attack was calculated in hours, based on the start and stop dates and times of the reported attack. For an adjusted attack that includes more than one participant-reported attack, the duration was calculated from the start of the first participant-reported attack to the end of the last participant-reported attack.

[0592] cCohort 1: 40 kg or greater, Cohort 2: 32 to less than 40 kg, Cohort 3: 24 to less than 32 kg, and Cohort 4: 12 to less than 24 kg at baseline.

[0593] Participants experienced swelling in a variety of locations during adjusted HAE attacks. In the year prior to enrollment, the most common anatomic region where swelling occurred was the stomach / abdomen (89.7%), and correspondingly the most common symptoms of an HAE attack were abdominal pain (79.3%), vomiting (69.0%), and nausea (62.1%). Visible swelling was also observed in the hands and arms (72.4%), feet and legs (65.5%), and face / head (55.2%) during an HAE attack in the past year. Laryngeal attacks (any time prior to study enrollment) were reported less frequently but still occurred in 4 participants (13.8%) with 3 participants reporting attacks in the year prior to enrollment.

[0594] The anatomical location of each participant-reported and adjusted attack was determined based on the symptoms indicated in the diary as follows. For abdominal only adjusted attacks, symptoms must include only one or more of the following: internal swelling or symptoms of internal swelling in the abdomen, nausea, abdominal discomfort, cramps (colicky pain), vomiting, diarrhea, and / or abdominal pain. For non-abdominal-peripheral (non-laryngeal) adjusted attacks symptoms must include only one or more of the following: visible swelling (to face / head, neck [outer swelling], legs, buttocks / genitals, eyes, arms, feet, stomach [outside], hands, chest / back, and or joints) and / or pink rings (erythema marginatum) with other swelling. For non-abdominal- laryngeal adjusted attacks symptoms must include only one or more of the following: internal swelling or symptoms of internal swelling of the airways (mouth / tongue / lips, lump in throat / tightness, change in voice, difficulty swallowing, and / or difficulty breathing). Participant diaries did not discern swelling of the lips from swelling of the mouth or tongue. Although swelling of the lips is not generally considered a laryngeal symptom, swelling of the mouth / tongue / lips while on study was considered

[0595] 72

[0596] FH 13299433.1BPX-06125

[0597] symptomatic of a laryngeal event. A mixed adjusted attack must have included at least one symptom from the abdominal-only, non-abdominal-peripheral, or non-abdominal-laryngeal attack characterization described above. Symptoms of headache and substantial fatigue may be checked by the participant but play no role in the characterization of the location of a participant-reported attack.

[0598] Similar proportions of attacks at baseline (12-week SOC period; 5.2%), through Week 12 (6.0%), and through Week 48 (4.9%) included at least 1 symptom of laryngeal involvement. Berotralstat treatment did not discernably alter the location of HAE attack symptoms experienced by participants and reduction in number of attacks appeared generally consistent across all locations. A summary of attack location at baseline, through Week 12 (Part 1) and through Week 48 (Parts 1 and 2) is shown in Tables 13, 14, and 15, respectively.

[0599]

[0600] Note: Summary includes all adjusted attacks occurring after the first dose of study intervention until 24 hours post last dose of the study intervention. An adjusted attack was defined per the rules described herein.

[0601] Abdominal-only, non-abdominal-peripheral, non-abdominal-laryngeal, and mixed attacks were defined per the categories described herein. Note that both peripheral and laryngeal attacks were defined as sub-categories of non-abdominal attacks.

[0602] aCohort 1: 40 kg or greater, Cohort 2: 32 to less than 40 kg, Cohort 3: 24 to less than 32 kg, and Cohort 4: 12 to less than 24 kg at baseline.

[0603] bDenominator is number of participants with at least 1 adjusted attack.

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[0606]

[0607] Note: Summary includes all adjusted attacks occurring after the first dose of study intervention until 24 hours post last dose of the study intervention. An adjusted attack was defined per the rules described herein.

[0608] Abdominal-only, non-abdominal-peripheral, non-abdominal-laryngeal, and mixed attacks were defined per the categories described herein. Note that both peripheral and laryngeal attacks were defined as sub-categories of non-abdominal attacks.

[0609] aCohort 1: 40 kg or greater, Cohort 2: 32 to less than 40 kg, Cohort 3: 24 to less than 32 kg, and Cohort 4: 12 to less than 24 kg at baseline.

[0610] bDenominator is number of participants with at least 1 adjusted attack.

[0611]

[0612] 74

[0613] FH 13299433.1BPX-06125

[0614]

[0615] Note: Summary includes all adjusted attacks occurring after the first dose of study intervention until 24 hours post last dose of the study intervention. An adjusted attack was defined per the rules described herein.

[0616] Abdominal-only, non-abdominal, mixed, peripheral, and laryngeal attacks were defined per the categories described herein. Note that both peripheral and laryngeal attacks were defined as sub-categories of non- abdominal attacks.

[0617] aCohort 1: 40 kg or greater, Cohort 2: 32 to less than 40 kg, Cohort 3: 24 to less than 32 kg, and Cohort 4: 12 to less than 24 kg at baseline.

[0618] bDenominator is number of participants with at least 1 adjusted attack.

[0619] The proportion of HAE attacks rated as moderate or severe by patients was similar during Parts 1 and 2 of the study as compared to the baseline (12-week SOC) period. Similar proportions of attacks were rated by the participant as negligible or mild in severity at baseline (12-week SOC) period and during Parts 1 and 2 of the study. Attack severity was assessed during the study by study part and severity: (1) 12-week SOC period: mild (19.3%), moderate (43.7%), and severe (32.6%); (2) Part 1: mild (22.0%), moderate (56.0%), and severe (16.0%); and (3) Parts 1 and 2: mild (24.7%), moderate (42.0%), and severe (29.0%). Table 16 summarizes attack severity for adjusted HAE attacks at baseline, through Week 12 (Part 1), and through Week 48 (Parts 1 and 2).

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[0621] FH 13299433.1BPX-06125

[0622]

[0623]

[0624]

[0625] Note: Summary includes all adjusted attacks occurring after the first dose of study intervention until the Week 48 visit or until 24 hours post last dose of the study intervention if the participant discontinued on or prior to Week 48. An adjusted attack was defined per the rules described herein.

[0626] aCohort 1: > 40 kg, Cohort 2: 32 to < 40 kg, Cohort 3: 24 to < 32 kg, and Cohort 4: 12 to < 24 kg at baseline.bThe denominator for calculating percentages was based on the number of adjusted attacks.

[0627] The rate of patients requiring professional medical care (occurring at either a physician’s office, urgent care, ER, or home) decreased during the study as compared to the baseline (12-week SOC) period. Twenty-two attacks (16.3%) required professional healthcare services during the 12-week SOC period. A total of 9 attacks (5.6%) required professional healthcare through Week 48 on berotralstat, demonstrating a reduction in both the number and percentage of attacks requiring professional healthcare services. Participants across all cohorts reported fewer and a lower proportion of attacks that required professional medical care during Parts 1 and 2 of the study than during SOC. Table 17 summarizes the number and proportion of attacks that utilized professional medical care at baseline, through Week 12 (Part 1), and through Week 48 (Parts 1 and 2).

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[0629] FH 13299433.1BPX-06125

[0630]

[0631]

[0632]

[0633] Note: Summary includes all adjusted attacks occurring after the first dose of study intervention until the Week 48 visit or until 24 hours post last dose of the study intervention if the participant discontinued on or prior to Week 48.

[0634] 77

[0635] FH 13299433.1BPX-06125

[0636] aCohort 1: > 40 kg, Cohort 2: 32 to < 40 kg, Cohort 3: 24 to < 32 kg, and Cohort 4: 12 to < 24 kg at baseline.bThe denominator for calculating percentages was based on the number of adjusted attacks.

[0637] Conclusions

[0638] The ongoing, open-label APeX-P study is the largest trial of LTP in pediatric HAE patients aged 2 to less than 12 years, to date. The effectiveness data collection for the study is complete and no further effectiveness data will be generated.

[0639] Berotralstat was safe and generally well tolerated in the pediatric population

[0640] < 12 years of age with no safety signals observed in 29 participants. A total of 4 TEAEs (PTs: nausea, headache, vomiting, weight increase) related to study intervention have been reported to date, none of which led to discontinuation or interruption of study intervention. No clinically significant Grade 3 or 4 laboratory abnormalities related to study intervention, TESAEs related to study intervention, or deaths were reported. The safety profile is consistent with what has been observed in prior studies of berotralstat in the adult and adolescent population. No TEAEs related to study intervention were reported in the Hypersensitivity, Anaphylactic reaction, or Severe cutaneous adverse reaction SMQs.

[0641] No clinically relevant elevations in liver function tests related to use of berotralstat were observed. No clinically significant or persistent QTc prolongation was observed. No QTcF > 450 msec was observed, and no participants had a QTcF change from baseline > 60 msec. No PTs contained in the Torsade de Pointes (TDP) / QT Prolongation Standardized MedDRA Query and no events of palpitation or seizure were reported.

[0642] Participants treated with berotralstat demonstrated a median attack rate of 0.417 attacks / month through Week 48 (Parts 1 and 2), below the attack rate of 0.955 attacks / month reported during the SOC period. Participants on berotralstat demonstrated low rates of angioedema attacks across all locations, including laryngeal attacks, as well as low rates of attacks requiring treatment with targeted HAE medication.

[0643] Participants treated with berotralstat had sustained low attack rates with no evidence for development of drug tolerance. In an analysis of attacks by month, the median attack rate was 0 by Month 1 and remained 0 through Month 12 with the exception of Month 6 (median of 0.500 attacks / month). While monthly attack rates across cohorts were variable as a result of the small sample size and the periodic nature of HAE attacks (Winnewisser et al., J Intern Med 1997;241(l):39-46; Zuraw et al., New Engl J Medicine 2008;359(10): 1027-36) variability was not discernably greater during Parts 1 and 2 of the study than at baseline (SOC period). Despite month-to-month variability in attack rates within each cohort, no cohort

[0644] 78

[0645] FH 13299433.1BPX-06125

[0646] reported an increased median change from SOC attack rates in any month during Parts 1 and 2.

[0647] In addition to sustained low attack rates, other measures of HAE disease burden consistently supported the benefit of berotralstat in pediatric patients 2 to < 12 years of age, as previously described for adults (Zuraw et al., J Allergy Clin Immunol 2021; 148(1): 164-172. e9). The percentage of days with angioedema symptoms was similar across cohorts, with a median of 9% during the SOC period, which decreased to 3% from Day 1 through Week 48 on treatment.

[0648] The median duration of adjusted attacks was similar at baseline (SOC period) (18.00 hours), and Day 1 through Week 48 (18.63 hours). These results suggest that treatment with berotralstat led to consistently low attack rates regardless of attack duration.

[0649] The overall median attack rate requiring targeted treatment decreased from

[0650] 0.691 attacks / month at baseline (SOC period) to 0.169 attacks / month through Week 48. Similarly low attack rates for attacks requiring targeted treatment were observed for each cohort during Parts 1 and 2 of the study relative to baseline (SOC period).

[0651] Five participants (17.2%) remained attack-free through Week 48. Only 1 participant (3.4%) was attack-free during the 12-week SOC period. Only 1 participant (3.4%) discontinued berotralstat due to perceived lack of efficacy before Week 48 in this study.

[0652] Twenty-two attacks (16.3%) required professional healthcare services during the 12-week SOC period. A total of 9 attacks (5.6 %) required professional healthcare through Week 48 on berotralstat, demonstrating a reduction in both the number and percentage of attacks requiring professional healthcare services. The majority of these attacks reported at baseline (SOC period) and through Week 48 were from Cohort 3 participants (19 of 22 attacks and 5 of 9 attacks, respectively). Berinert, which is administered intravenously, was favored by Cohort 3 and may have contributed to the required professional healthcare services.

[0653] Participants across all cohorts reported fewer and a lower proportion of attacks that required professional medical care during Parts 1 and 2 of the study than during SOC. The majority of participants did not routinely require hospitalization or clinic visits for attacks during the SOC or during Parts 1 and 2 of the study given the ability of P / C to administer on-demand HAE medications at home.

[0654] Similar proportions of attacks were rated by the participant as negligible or mild in severity during the SOC period and Study Parts 1 and 2. A similar proportion of attacks were rated as moderate and severe on treatment (42.0% and 29.0% through Week 48, respectively) as the SOC period (43.7% and 32.6%, respectively).

[0655] 79

[0656] FH 13299433.1BPX-06125

[0657] The results provide compelling and consistent evidence for a lower disease burden during berotralstat treatment compared with the baseline (12-week SOC) period. These results support the use of berotralstat for prophylaxis to prevent attacks of HAE in pediatric HAE patients, with safety and efficacy similar to those in the placebo-controlled berotralstat studies conducted in adults and adolescents age 12 years old and greater.

[0658] INCORPORATION BY REFERENCE

[0659] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0660] EQUIVALENTS

[0661] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0662] 80

[0663] FH 13299433.1

Claims

1. BPX-06125What is claimed is:

1. A method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat free base based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 120 mg to about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 96 mg to about 120 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 60 mg to about 90 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg.

2. The method of claim 1, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 120 mg to about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 96 mg to about 120 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 60 mg to about 90 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg.

3. The method of claim 1, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 120 mg to about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 96 mg to about 120 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 60 mg to about 90 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg.81FH 13299433.1BPX-061254. The method of claim 1, wherein the dose provides an amount of her otr al stat free base selected from the following:a. about 126 mg to about 138 mg of b er otr al stat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 102 mg to about 114 mg of b er otr al stat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 90 mg to about 102 mg of b er otr al stat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 66 mg to about 84 mg of b er otr al stat free base when the body weight of the pediatric subject is less than 24 kg.

5. The method of claim 1, wherein the dose provides an amount of b er otr al stat free base selected from the following:a. about 126 mg to about 138 mg of b er otr al stat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 102 mg to about 114 mg of b er otr al stat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 90 mg to about 102 mg of b er otr al stat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 66 mg to about 84 mg of b er otr al stat free base the body weight of the pediatric subject is 12 kg to less than 24 kg.

6. The method of claim 1, wherein the dose provides an amount of b er otr al stat free base selected from the following:a. about 126 mg to about 138 mg of b er otr al stat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 102 mg to about 114 mg of b er otr al stat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 90 mg to about 102 mg of b er otr al stat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 66 mg to about 84 mg of b er otr al stat free base the body weight of the pediatric subject is 15 kg to less than 24 kg.

7. The method of claim 1, wherein the dose provides an amount of b er otr al stat free base selected from the following:a. about 132 mg of b er otr al stat free base when the body weight of the pediatric subject is 40 kg or greater;82FH 13299433.1BPX-06125b. about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg;d. about 78 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg; ore. about 72 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg.

8. The method of claim 1, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg;d. about 78 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg; ore. about 72 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg.

9. The method of claim 1, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg;d. about 78 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg; ore. about 72 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg.

10. A method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 years old to less than 12 years old in need thereof, the method comprising orally administering 83FH 13299433.1BPX-06125once daily to the pediatric subject a dose of berotralstat free base based on a body weight of the pediatric subject, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 120 mg to about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 96 mg to about 120 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 54 mg to about 84 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg.

11. The method of claim 10, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 120 mg to about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 96 mg to about 120 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 54 mg to about 84 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg.

12. The method of claim 10, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 120 mg to about 144 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 96 mg to about 120 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 84 mg to about 108 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 54 mg to about 84 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg.

13. The method of claim 10, wherein the dose provides an amount of berotralstat free base selected from the following:84FH 13299433.1BPX-06125a. about 126 mg to about 138 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 102 mg to about 114 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 90 mg to about 102 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 60 mg to about 78 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg.

14. The method of claim 10, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 126 mg to about 138 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 102 mg to about 114 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 90 mg to about 102 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 60 mg to about 78 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg.

15. The method of claim 10, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 126 mg to about 138 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 102 mg to about 114 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 90 mg to about 102 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 60 mg to about 78 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg.

16. The method of claim 10, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;85FH 13299433.1BPX-06125c. about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 72 mg of berotralstat free base when the body weight of the pediatric subject is less than 24 kg.

17. The method of claim 10, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 72 mg of berotralstat free base when the body weight of the pediatric subject is 12 kg to less than 24 kg.

18. The method of claim 16, wherein the dose provides an amount of berotralstat free base selected from the following:a. about 132 mg of berotralstat free base when the body weight of the pediatric subject is 40 kg or greater;b. about 108 mg of berotralstat free base when the body weight of the pediatric subject is 32 kg to less than 40 kg;c. about 96 mg of berotralstat free base when the body weight of the pediatric subject is 24 kg to less than 32 kg; ord. about 72 mg of berotralstat free base when the body weight of the pediatric subject is 15 kg to less than 24 kg.

19. A method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat based on a body weight of the pediatric subject, wherein the dose is between about 60 mg and about 144 mg.

20. The method of claim 19, wherein the dose is 1) about 120 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to86FH 13299433.1BPX-06125about 90 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

21. The method of claim 19, wherein the dose is 1) about 126 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

22. The method of claim 19, wherein the dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

23. The method of claim 19, wherein the dose is 1) about 120 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 54 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

24. The method of claim 19, wherein the dose is 1) about 126 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

25. The method of claim 19, wherein the dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg 87FH 13299433.1BPX-06125to less than 32 kg; or 4) about 72 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

26. The method of claim 19, wherein the dose is 1) about 114 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 84 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 60 mg to about 90 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

27. The method of claim 19, wherein the dose is 1) about 120 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 90 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

28. The method of claim 19, wherein the dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 96 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

29. A method of prophylaxis to prevent attacks of HAE in a pediatric subject 2 to less than 12 years old in need thereof, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat, wherein the dose is between about 60 mg and about 144 mg.

30. The method of claim 29, wherein the dose is 1) about 120 mg to about 144 mg of berotralstat when a body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 90 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

31. The method of claim 29, wherein the dose is 1) about 126 mg to about 138 mg of berotralstat when a body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat when the body weight of the pediatric subject 88FH 13299433.1BPX-06125is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

32. The method of claim 29, wherein the dose is 1) about 132 mg of berotralstat when a body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

33. The method of claim 29, wherein the dose is 1) about 120 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 54 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

34. The method of claim 29, wherein the dose is 1) about 126 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

35. The method of claim 29, wherein the dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 72 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

36. The method of claim 29, wherein the dose is 1) about 114 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 89FH 13299433.1BPX-0612584 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 60 mg to about 90 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

37. The method of claim 29, wherein the dose is 1) about 120 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 90 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

38. The method of claim 29, wherein the dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 96 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

39. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 40 kg or greater, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 120 mg and about 144 mg.

40. The method of claim 39, wherein the dose is about 126 mg to about 138 mg of berotralstat.

41. The method of claim 39, wherein the dose is about 132 mg of berotralstat.

42. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 32 kg to less than 40 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 96 mg and about 120 mg.

43. The method of claim 42, wherein the dose is about 102 mg to about 114 mg of berotralstat.

44. The method of claim 42, wherein the dose is about 108 mg of berotralstat.

45. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 24 kg to less than 32 kg, the method comprising orally administering once90FH 13299433.1BPX-06125daily to the pediatric subject a dose of berotralstat between about 84 mg and about 108 mg.

46. The method of claim 45, wherein the dose is about 90 mg to about 102 mg of berotralstat.

47. The method of claim 45, wherein the dose is about 96 mg of berotralstat.

48. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 5 kg to less than 24 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 60 mg and about 90 mg.

49. The method of claim 48, wherein the dose is about 66 mg to about 84 mg of berotralstat.

50. The method of claim 48, wherein the dose is about 78 mg of berotralstat.

51. The method of claim 48, wherein the dose is about 72 mg of berotralstat.

52. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 5 kg to less than 24 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 54 mg and about 84 mg.

53. The method of claim 52, wherein the dose is about 60 mg to about 78 mg of berotralstat.

54. The method of claim 52, wherein the dose is about 72 mg of berotralstat.

55. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 35 kg or greater, the method comprising orally administering once daily to the pediatric a dose of berotralstat between about 114 mg and about 144 mg.

56. The method of claim 55, wherein the dose is about 120 mg to about 138 mg of berotralstat.

57. The method of claim 55, wherein the dose is about 132 mg of berotralstat.

58. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of 20 kg to less than 35 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat between about 84 mg and about 114 mg.91FH 13299433.1BPX-0612559. The method of claim 58, wherein the dose is about 90 mg to about 108 mg of berotralstat.

60. The method of claim 58, wherein the dose is about 96 mg of berotralstat.

61. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is a pediatric subject 2 to less than 12 years old having a body weight of: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg, the method comprising orally administering once daily to the pediatric subject a dose of berotralstat based between about 60 mg and about 90 mg.

62. The method of claim 61, wherein the dose is about 66 mg to about 84 mg of berotralstat.

63. The method of claim 61, wherein the dose is about 78 mg of berotralstat.

64. The method of any one of claims 1 to 63, wherein the dose of berotralstat is provided as a plurality of solid oral dosage and provides an exposure of berotralstat in the pediatric subject 2 to less than 12 years old that is similar to an exposure in an adult subject or a pediatric subject 12 to less than 18 years old administered a 150 mg dose of berotralstat.

65. The method of any one of claims 1 to 63, wherein the dose of berotralstat is provided as a plurality of solid oral dosage and provides a Cmax of berotralstat in the pediatric subject 2 to less than 12 years old that is similar to the Cmax in an adult subject or a pediatric subject 12 to less than 18 years old administered a 150 mg dose of berotralstat.

66. The method of any one of claims 1 to 63, wherein the dose of berotralstat is provided as a plurality of solid oral dosage and provides a Ctrough of berotralstat in the pediatric subject 2 to less than 12 years old that is similar to the Ctrough in an adult subject or a pediatric subject 12 to less than 18 years of age administered a 150 mg dose of berotralstat.

67. The method of any one of claims 1 to 66, wherein the dose of berotralstat administered is provided as a plurality of solid oral dosage forms comprising an amount of berotralstat dihydrochloride sufficient to deliver the recited amount of berotralstat on administration to the pediatric subject.

68. The method of claim 67, wherein the solid oral dosage forms comprise crystalline berotralstat dihydrochloride from about 57.8% to about 77.8%, pregelatinized starch from about 17.2% to about 37.2%, crospovidone from about 1% to about 5%, colloidal92FH 13299433.1BPX-06125anhydrous silica from about 0.125% to about 1.5%, and magnesium stearate from about 0.5% to about 3%, the percentages determined on a weight-to-weight basis.

69. The method of claim 67, wherein the solid oral dosage forms comprise crystalline berotralstat dihydrochloride from about 62.8% to about 72.8%, pregelatinized starch from about 22.2% to about 32.2%, crospovidone from about 2% to about 4%, colloidal anhydrous silica from about 0.25% to about 1%, and magnesium stearate from about 1% to about 2%, the percentages determined on a weight-to-weight basis.

70. The method of claim 67, wherein the solid oral dosage forms comprise crystalline berotralstat dihydrochloride from about 65.8% to about 69.8%, pregelatinized starch from about 25.2% to about 29.2%, crospovidone from about 2.5% to about 3.5%, colloidal anhydrous silica from about 0.25% to about 0.75%, and magnesium stearate from about 1.25% to about 1.75%, the percentages determined on a weight-to-weight basis.

71. The method of claim 67, wherein the solid oral dosage forms comprise an intragranular portion comprising crystalline berotralstat dihydrochloride from about 57.8% to about 77.8%, pregelatinized starch from about 17.2% to about 37.2%, crospovidone from about 0.5% to about 2.5%, colloidal anhydrous silica from about 0.05% to about 0.75%, and magnesium stearate from about 0.075% to about 1.5%, and an extragranular portion comprising crospovidone from about 0.5% to about 2.5%, colloidal anhydrous silica from about 0.05% to about 0.75%, and magnesium stearate from about 0.25% to about 2%, the percentages determined on a weight-to-weight basis.

72. The method of claim 67, wherein the solid oral dosage forms comprise an intragranular portion comprising crystalline berotralstat dihydrochloride from about 62.8% to about 72.8%, pregelatinized starch from about 22.2% to about 32.2%, crospovidone from about 1% to about 2%, colloidal anhydrous silica from about 0.125% to about 0.5%, and magnesium stearate from about 0.125% to about 1%, and an extragranular portion comprising crospovidone from about 1% to about 2%, colloidal anhydrous silica from about 0.125% to about 0.5%, and magnesium stearate from about 0.5% to about 1.5%, the percentages determined on a weight-to-weight basis.

73. The method of claim 67, wherein the solid oral dosage forms comprise an intragranular portion comprising crystalline berotralstat dihydrochloride from about 65.8% to about 69.8%, pregelatinized starch from about 25.2% to about 29.2%, crospovidone from about 1.25% to about 1.75%, colloidal anhydrous silica from about 0.15% to about 93FH 13299433.1BPX-061250.35%, and magnesium stearate from about 0.25% to about 0.75%, and an extragranular portion comprising crospovidone from about 1.25% to about 1.75%, colloidal anhydrous silica from about 0.15% to about 0.35%, and magnesium stearate from about 0.75% to about 1.25%, the percentages determined on a weight-to-weight basis.

74. The method of any one of claims 64 to 73, wherein the solid oral dosage forms further comprise a taste masking agent.

75. The method of claim 74, wherein the taste masking agent comprises basic butylated methacrylate copolymer from about 50% to about 60%, sodium lauryl sulfate from about 2.5 to about 8.5%, colloidal anhydrous silica from about 5.5% to about 11.5%, stearic acid from about 4.5% to about 10.5%, talc from about 2.5% to about 8.5%, and titanium dioxide from about 10% to about 20%, the percentages determined on a weight-to-weight basis.

76. The method of claim 74, wherein the taste masking agent is Eudragit E PO ReadyMix white.

77. The method of any one of claims 74 to 76, wherein the taste masking agent is present at a concentration of from about 2.5% to about 17.5%, from about 5% to about 15%, from about 7.5% to about 12.5%, or about 10%, the percentages determined on a weight-to-weight basis.

78. The method of any one of claims 64 to 77, wherein the plurality of solid oral dosage forms are a plurality of oral granules or oral pellets.

79. The method of any one of claims 64 to 78, wherein the crystalline berotralstat dihydrochloride has characteristic peaks in the X-ray powder diffraction pattern at values of two theta (°29 ± 0.2°) of: i) 5.3, 9.0, and 22.0; ii) 5.28, 8.96, and 22.01; iii) 5.3, 9.0, 19.8, 21.2, 22.0, and 23.3; iv) 5.28, 8.96, 19.79, 21.16, 22.01, and 23.31; v) 5.3, 9.0, 14.3, 16.2, 19.8, 21.2, 22.0, 23.3, 24.6, and 30.3; or vi) 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31.

80. The method of any one of claims 64 to 78, wherein the crystalline berotralstat dihydrochloride has characteristic peaks in the X-ray powder diffraction substantially similar to that shown in FIG. 1.

81. The method of any one of claims 1 to 80, wherein the dose of berotralstat is administered to the pediatric subject 2 to less than 12 years old by pouring the dose directly into the mouth of the pediatric subject, optionally with a non-acidic liquid.94FH 13299433.1BPX-0612582. The method of any one of claims 1 to 80, wherein the dose of her otr al stat is administered to the pediatric subject 2 to less than 12 years old by sprinkling the dose over a non-acidic food.

83. The method of any one of claims 1 to 82, wherein the dose of b er otr al stat is administered to the pediatric subject 2 to less than 12 years old within 1 hour before or after a meal is consumed.

84. The method of any one of claims 1 to 83, wherein the dose of b er otr al stat administered to the pediatric subject 2 to less than 12 years old is not altered if the pediatric subject is diagnosed with or is suspected of suffering from mild hepatic impairment (Child- Pugh Class A).

85. The method of any one of claims 1 to 83, wherein the dose of b er otr al stat administered to the pediatric subject 2 to less than 12 years old is not altered if the pediatric subject if the pediatric subject experiences persistent gastrointestinal reactions following administration of the dose of berotralstat.

86. The method of any one of claims 1 to 83, wherein the dose of berotralstat is not administered to the pediatric subject 2 to less than 12 years old if the pediatric subject is diagnosed with or is suspected of suffering from moderate hepatic impairment (Child-Pugh Class B) or severe hepatic impairment (Child-Pugh Class C).

87. The method of any one of claims 1 to 83, wherein the dose of berotralstat is not administered to the pediatric subject 2 to less than 12 years old if the pediatric subject is concurrently using a P-gp inducer.

88. The method of any one of claims 1 to 87, wherein the HAE is HAE with deficient Cl- inhibitor.

89. The method of any one of claims 1 to 87, wherein the HAE is HAE with dysfunctional Cl -inhibitor.

90. The method of any one of claims 1 to 87, wherein the HAE is HAE with normal Cl- inhibitor.

91. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old a pediatric95FH 13299433.1BPX-06125dose of berotralstat based on a body weight of the pediatric subject, wherein the pediatric dose is between about 60 mg and about 144 mg.

92. The method of claim 91, wherein the pediatric dose is 1) about 120 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 90 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

93. The method of claim 91, wherein the pediatric dose is 1) about 126 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

94. The method of claim 91, wherein the pediatric dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

95. The method of claim 91, wherein the pediatric dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 72 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

96. The method of claim 91, wherein the pediatric dose is 1) about 120 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 96 mg to about 120 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 84 mg to about 108 mg of berotralstat 96FH 13299433.1BPX-06125when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 54 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

97. The method of claim 91, wherein the pediatric dose is 1) about 126 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 102 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 90 mg to about 102 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 60 mg to about 78 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

98. The method of claim 91, wherein the pediatric dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 40 kg or greater; 2) about 108 mg of berotralstat when the body weight of the pediatric subject is 32 kg to less than 40 kg; 3) about 96 mg of berotralstat when the body weight of the pediatric subject is 24 kg to less than 32 kg; or 4) about 72 mg of berotralstat when the body weight of the pediatric subject is: i) less than 24 kg; ii) 12 kg to less than 24 kg; or iii) 15 kg to less than 24 kg.

99. The method of claim 91, wherein the pediatric dose is 1) about 114 mg to about 144 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 84 mg to about 114 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 60 mg to about 90 mg of berotralstat when the body weight of the pediatric subject is: i) less than 20 kg; ii) 12 kg to less than 20 kg; or iii) 15 kg to less than 20 kg.

100. The method of claim 91, wherein the pediatric dose is 1) about 120 mg to about 138 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 90 mg to about 108 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 66 mg to about 84 mg of berotralstat when the body weight of the pediatric subject is less than 20 kg or when the body weight of the pediatric subject is 12 kg to less than 20 kg.

101. The method of claim 91, wherein the pediatric dose is 1) about 132 mg of berotralstat when the body weight of the pediatric subject is 35 kg or greater; 2) about 96 mg of berotralstat when the body weight of the pediatric subject is 20 kg to less than 35 kg; or 3) about 78 mg of berotralstat when the body weight of the pediatric subject is less97FH 13299433.1BPX-06125than 20 kg or when the body weight of the pediatric subject is 12 kg to less than 20 kg- 102. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of 40 kg or greater, a pediatric dose of berotralstat between about 120 mg and about 144 mg.

103. The method of claim 102, wherein the pediatric dose is about 126 mg to about 138 mg of berotralstat.

104. The method of claim 102, wherein the pediatric dose is about 132 mg of berotralstat.

105. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of 32 kg to less than 40 kg, a pediatric dose of berotralstat between about 96 mg and about 120 mg.

106. The method of claim 105, wherein the pediatric dose is about 102 mg to about 114 mg of berotralstat.

107. The method of claim 105, wherein the pediatric dose is about 108 mg of berotralstat.

108. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat between about 110 mg and about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of 24 kg to less than 32 kg, a pediatric dose of berotralstat between about 84 mg and about 108 mg.

109. The method of claim 108, wherein the pediatric dose is about 90 mg to about 102 mg of berotralstat.98FH 13299433.1BPX-06125110. The method of claim 108, wherein the pediatric dose is about 96 mg of berotralstat.

111. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of: i) less than 24 kg; ii) 12 kg to less than 24 kg a pediatric; or iii) 15 kg to less than 24 kg, a pediatric dose of berotralstat between about 60 mg and about 90 mg.

112. The method of claim 111, wherein the pediatric dose is about 66 mg to about 84 mg of berotralstat.

113. The method of claim 111, wherein the pediatric dose is about 78 mg of berotralstat.

114. The method of claim 111, wherein the pediatric dose is about 72 mg of berotralstat.

115. A method of prophylaxis to prevent attacks of HAE in a subject in need thereof, wherein the subject is an adult subject, a pediatric subject 12 to less than 18 years old, or a pediatric subject 2 to less than 12 years old, the method comprising orally administering once daily to the adult subject or the pediatric subject 12 to less than 18 years old an adult dose of berotralstat of about 110 mg or about 150 mg and orally administering once daily to the pediatric subject 2 to less than 12 years old having a body weight of: i) less than 24 kg; ii) 12 kg to less than 24 kg a pediatric; or iii) 15 kg to less than 24 kg, a pediatric dose of berotralstat between about 54 mg and about 84 mg.

116. The method of claim 115, wherein the pediatric dose is about 60 mg to about 78 mg of berotralstat.

117. The method of claim 115, wherein the pediatric dose is about 72 mg of berotralstat.

118. The method of any one of claims 91 to 117, wherein the adult dose is 110 mg.

119. The method of any one of claims 91 to 117, wherein the adult dose is 150 mg.

120. The method of any one of claims 91 to 119, wherein the adult dose is a capsule comprising an amount of berotralstat dihydrochloride sufficient to deliver the recited amount of berotralstat on administration to the adult or pediatric subject 12 to less than 18 years old.

121. The method of any one of claim 120, wherein the crystalline berotralstat dihydrochloride has characteristic peaks in the XRPD pattern at values of two theta 99FH 13299433.1BPX-06125(°26 ± 0.2°) of: i) 5.3, 9.0, and 22.0; ii) 5.28, 8.96, and 22.01; iii) 5.3, 9.0, 19.8, 21.2, 22.0, and 23.3; iv) 5.28, 8.96, 19.79, 21.16, 22.01, and 23.31; v) 5.3, 9.0, 14.3, 16.2, 19.8, 21.2, 22.0, 23.3, 24.6, and 30.3; orvi) 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.3.

122. The method of any one of claims 91 to 121, wherein the pediatric subject 12 to less than 18 years old has a body weight 40 kg or greater.

123. The method of any one of claims 91 to 122, wherein the pediatric dose of berotralstat is provided as a plurality of solid oral dosage and provides an exposure of berotralstat in the pediatric subject 2 to less than 12 years old that is similar to an exposure in the adult subject or the pediatric subject 12 to less than 18 years old administered a 150 mg dose of berotralstat.

124. The method of any one of claims 91 to 122, wherein the pediatric dose of berotralstat is provided as a plurality of solid oral dosage and provides a Cmax of berotralstat in the pediatric subject 2 to less than 12 years old that is similar to the Cmax in the adult subject or the pediatric subject 12 to less than 18 years old administered a 150 mg dose of berotralstat.

125. The method of any one of claims 91 to 122, wherein the pediatric dose of berotralstat is provided as a plurality of solid oral dosage and provides a Ctrough of berotralstat in the pediatric subject 2 to less than 12 years old that is similar to the Ctrough in the adult subject or the pediatric subject 12 to less than 18 years of age administered a 150 mg dose of berotralstat.

126. The method of any one of claims 91 to 125, wherein the pediatric dose of berotralstat is provided as a plurality of solid oral dosage forms comprising an amount of berotralstat dihydrochloride sufficient to deliver the recited amount of berotralstat on administration to the pediatric subject.

127. The method of claim 126, wherein the solid oral dosage forms comprise crystalline berotralstat dihydrochloride from about 57.8% to about 77.8%, pregelatinized starch from about 17.2% to about 37.2%, crospovidone from about 1% to about 5%, colloidal anhydrous silica from about 0.125% to about 1.5%, and magnesium stearate from about 0.5% to about 3%, the percentages determined on a weight-to-weight basis.

128. The method of claim 126, wherein the solid oral dosage forms comprise crystalline berotralstat dihydrochloride from about 62.8% to about 72.8%, pregelatinized starch from about 22.2% to about 32.2%, crospovidone from about 2% to about 4%, colloidal100FH 13299433.1BPX-06125anhydrous silica from about 0.25% to about 1%, and magnesium stearate from about 1% to about 2%, the percentages determined on a weight-to-weight basis.

129. The method of claim 126, wherein the solid oral dosage forms comprise crystalline berotralstat dihydrochloride from about 65.8% to about 69.8%, pregelatinized starch from about 25.2% to about 29.2%, crospovidone from about 2.5% to about 3.5%, colloidal anhydrous silica from about 0.25% to about 0.75%, and magnesium stearate from about 1.25% to about 1.75%, the percentages determined on a weight-to-weight basis.

130. The method of claim 126, wherein the solid oral dosage forms comprise an intragranular portion comprising crystalline berotralstat dihydrochloride from about 57.8% to about 77.8%, pregelatinized starch from about 17.2% to about 37.2%, crospovidone from about 0.5% to about 2.5%, colloidal anhydrous silica from about 0.05% to about 0.75%, and magnesium stearate from about 0.075% to about 1.5%, and an extragranular portion comprising crospovidone from about 0.5% to about 2.5%, colloidal anhydrous silica from about 0.05% to about 0.75%, and magnesium stearate from about 0.25% to about 2%, the percentages determined on a weight-to-weight basis.

131. The method of claim 126, wherein the solid oral dosage forms comprise an intragranular portion comprising crystalline berotralstat dihydrochloride from about 62.8% to about 72.8%, pregelatinized starch from about 22.2% to about 32.2%, crospovidone from about 1% to about 2%, colloidal anhydrous silica from about 0.125% to about 0.5%, and magnesium stearate from about 0.125% to about 1%, and an extragranular portion comprising crospovidone from about 1% to about 2%, colloidal anhydrous silica from about 0.125% to about 0.5%, and magnesium stearate from about 0.5% to about 1.5%, the percentages determined on a weight-to-weight basis.

132. The method of claim 126, wherein the solid oral dosage forms comprise an intragranular portion comprising crystalline berotralstat dihydrochloride from about 65.8% to about 69.8%, pregelatinized starch from about 25.2% to about 29.2%, crospovidone from about 1.25% to about 1.75%, colloidal anhydrous silica from about 0.15% to about 0.35%, and magnesium stearate from about 0.25% to about 0.75%, and an extragranular portion comprising crospovidone from about 1.25% to about 1.75%, colloidal anhydrous silica from about 0.15% to about 0.35%, and magnesium stearate101FH 13299433.1BPX-06125from about 0.75% to about 1.25%, the percentages determined on a weight-to-weight basis.

133. The method of any one of claims 123 to 132, wherein the solid oral dosage forms further comprise a taste masking agent.

134. The method of claim 133, wherein the taste masking agent comprises basic butylated methacrylate copolymer from about 50% to about 60%, sodium lauryl sulfate from about 2.5 to about 8.5%, colloidal anhydrous silica from about 5.5% to about 11.5%, stearic acid from about 4.5% to about 10.5%, talc from about 2.5% to about 8.5%, and titanium dioxide from about 10% to about 20%, the percentages determined on a weight-to-weight basis.

135. The method of claim 133, wherein the taste masking agent is Eudragit E PO ReadyMix white.

136. The method of any one of claims 123 to 135, wherein the plurality of solid oral dosage forms are a plurality of oral granules or oral pellets.

137. The method of any one of claims 134 to 136, wherein the taste masking agent is present at a concentration of from about 2.5% to about 17.5%, from about 5% to about 15%, from about 7.5% to about 12.5%, or about 10%, the percentages determined on a weight-to-weight basis.

138. The method of any one of claims 123 to 137, wherein the crystalline berotralstat dihydrochloride has characteristic peaks in the X-ray powder diffraction pattern at values of two theta (°29 ± 0.2°) of: i) 5.3, 9.0, and 22.0; ii) 5.28, 8.96, and 22.01; iii) 5.3, 9.0, 19.8, 21.2, 22.0, and 23.3; iv) 5.28, 8.96, 19.79, 21.16, 22.01, and 23.31; v) 5.3, 9.0, 14.3, 16.2, 19.8, 21.2, 22.0, 23.3, 24.6, and 30.3; or vi) 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31.

139. The method of any one of claims 123 to 137, wherein the crystalline berotralstat dihydrochloride has characteristic peaks in the X-ray powder diffraction substantially similar to that shown in FIG. 1.

140. The method of any one of claims 91 to 139, wherein the pediatric dose of berotralstat is administered by pouring the dose directly into the mouth of the pediatric subject, optionally with a non-acidic liquid.

141. The method of any one of claims 91 to 139, wherein the pediatric dose of berotralstat is administered by sprinkling the dose over a non-acidic food.

142. The method of any one of claims 91 to 139, wherein the pediatric dose of berotralstat is administered within 1 hour before or after a meal is consumed.102FH 13299433.1BPX-06125143. The method of any one of claims 91 to 142, wherein the pediatric dose of her otr al stat administered is not altered if the pediatric subject is diagnosed with or is suspected of suffering from mild hepatic impairment (Child-Pugh Class A).

144. The method of any one of claims 91 to 142, wherein the pediatric dose of b er otr al stat administered is not altered if the pediatric subject if the pediatric subject experiences persistent gastrointestinal reactions following administration of the dose of berotralstat.

145. The method of any one of claims 91 to 142, wherein the pediatric dose of berotralstat is not administered if the pediatric subject is diagnosed with or is suspected of suffering from moderate hepatic impairment (Child-Pugh Class B) or severe hepatic impairment (Child-Pugh Class C).

146. The method of any one of claims 91 to 142, wherein the pediatric dose of berotralstat is not administered if the pediatric subject is concurrently using a P-gp inducer.

147. The method of any one of claims 91 to 146, wherein the HAE is HAE with deficient Cl -inhibitor.

148. The method of any one of claims 91 to 146, wherein the HAE is HAE with dysfunctional Cl -inhibitor.

149. The method of any one of claims 91 to 146, wherein the HAE is HAE with normal Cl- inhibitor.

150. A solid oral dosage form comprising crystalline berotralstat dihydrochloride and a mixture of excipients, wherein the excipients are selected from the group consisting of: pregelatinized starch, crospovidone, colloidal anhydrous silica, and magnesium stearate.

151. The solid oral dosage form of claim 150, wherein the solid oral dosage form comprises crystalline berotralstat dihydrochloride from about 57.8% to about 77.8%, pregelatinized starch from about 17.2% to about 37.2%, crospovidone from about 1% to about 5%, colloidal anhydrous silica from about 0.125% to about 1.5%, and magnesium stearate from about 0.5% to about 3%, the percentages determined on a weight-to-weight basis.

152. The solid oral dosage form of claim 150, wherein the solid oral dosage form comprises crystalline berotralstat dihydrochloride from about 62.8% to about 72.8%, pregelatinized starch from about 22.2% to about 32.2%, crospovidone from about 2% to about 4%, colloidal anhydrous silica from about 0.25% to about 1%, and magnesium stearate from about 1% to about 2%, the percentages determined on a weight-to-weight basis.103FH 13299433.1BPX-06125153. The solid oral dosage form of claim 150, wherein the solid oral dosage form comprises crystalline berotralstat dihydrochloride from about 65.8% to about 69.8%, pregelatinized starch from about 25.2% to about 29.2%, crospovidone from about 2.5% to about 3.5%, colloidal anhydrous silica from about 0.25% to about 0.75%, and magnesium stearate from about 1.25% to about 1.75%, the percentages determined on a weight-to-weight basis.

154. The solid oral dosage form of claim 150, wherein the solid oral dosage form comprises an intragranular portion comprising crystalline berotralstat dihydrochloride from about 57.8% to about 77.8%, pregelatinized starch from about 17.2% to about 37.2%, crospovidone from about 0.5% to about 2.5%, colloidal anhydrous silica from about 0.05% to about 0.75%, and magnesium stearate from about 0.075% to about 1.5%, and an extragranular portion comprising crospovidone from about 0.5% to about 2.5%, colloidal anhydrous silica from about 0.05% to about 0.75%, and magnesium stearate from about 0.25% to about 2%, the percentages determined on a weight-to-weight basis.

155. The solid oral dosage form of claim 150, wherein the solid oral dosage form comprises an intragranular portion comprising crystalline berotralstat dihydrochloride from about 62.8% to about 72.8%, pregelatinized starch from about 22.2% to about 32.2%, crospovidone from about 1% to about 2%, colloidal anhydrous silica from about 0.125% to about 0.5%, and magnesium stearate from about 0.125% to about 1%, and an extragranular portion comprising crospovidone from about 1% to about 2%, colloidal anhydrous silica from about 0.125% to about 0.5%, and magnesium stearate from about 0.5% to about 1.5%, the percentages determined on a weight-to- weight basis.

156. The solid oral dosage form of claim 150, wherein the solid oral dosage form comprises an intragranular portion comprising crystalline berotralstat dihydrochloride from about 65.8% to about 69.8%, pregelatinized starch from about 25.2% to about 29.2%, crospovidone from about 1.25% to about 1.75%, colloidal anhydrous silica from about 0.15% to about 0.35%, and magnesium stearate from about 0.25% to about 0.75%, and an extragranular portion comprising crospovidone from about 1.25% to about 1.75%, colloidal anhydrous silica from about 0.15% to about 0.35%, and magnesium stearate from about 0.75% to about 1.25%, the percentages determined on a weight-to-weight basis.104FH 13299433.1BPX-06125157. The solid oral dosage form of any one of claims 150 to 156, wherein the solid oral dosage form further comprises a taste-masking agent.

158. The solid oral dosage form of claim 157, wherein the taste masking agent comprises basic butylated methacrylate copolymer from about 50% to about 60%, sodium lauryl sulfate from about 2.5 to about 8.5%, colloidal anhydrous silica from about 5.5% to about 11.5%, stearic acid from about 4.5% to about 10.5%, talc from about 2.5% to about 8.5%, and titanium dioxide from about 10% to about 20%, the percentages determined on a weight-to-weight basis.

159. The solid oral dosage form of claim 157, wherein the taste masking agent is Eudragit E PO ReadyMix white.

160. The solid oral dosage form of any one of claims 157 to 159, wherein the taste masking agent is present at a concentration of from about 2.5% to about 17.5%, from about 5% to about 15%, from about 7.5% to about 12.5%, or about 10%, the percentages determined on a weight-to-weight basis.

161. The solid oral dosage form of any one of claims 150 to 160 wherein the crystalline berotralstat dihydrochloride has characteristic peaks in the X-ray powder diffraction pattern at values of two theta (°29 ± 0.2°) of: i) 5.3, 9.0, and 22.0; ii) 5.28, 8.96, and 22.01; iii) 5.3, 9.0, 19.8, 21.2, 22.0, and 23.3; iv) 5.28, 8.96, 19.79, 21.16, 22.01, and 23.31; v) 5.3, 9.0, 14.3, 16.2, 19.8, 21.2, 22.0, 23.3, 24.6, and 30.3; orvi) 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31.

162. The solid oral dosage form of any one of claims 150 to 160, wherein the crystalline berotralstat dihydrochloride has characteristic peaks in the X-ray powder diffraction substantially similar to that shown in FIG. 1.

163. The solid oral dosage form of any one of claims 150 to 162, wherein the solid oral dosage form is packaged in a unit-dose packet.

164. The solid oral dosage form of claim 163, wherein the unit dose packet contains an amount of the solid oral dosage forms sufficient to deliver a dose of berotralstat free base selected from the following: about 120 mg to about 144 mg, about 126 mg to about 138 mg, about 114 mg to about 144 mg, about 120 mg to about 138 mg, about 132 mg, about 96 mg to about 120 mg, about 102 mg to about 114 mg, about 84 mg to about 114 mg, about 90 mg to about 108 mg, about 108 mg, about 84 mg to about 108 mg, about 90 mg to about 102 mg, about 96 mg, about 60 mg to about 90 mg, about 66 mg to about 84 mg, about 54 mg to about 84 mg, about 60 mg to about 78 mg, about 72 mg, or about 78 mg berotralstat free base.105FH 13299433.1BPX-06125165. The solid oral dosage form of claim 163, wherein the unit dose packet contains a plurality of solid oral dosage forms sufficient to deliver a dose of her otr al stat free base selected from the following: about 132 mg, about 108 mg, about 96 mg, about 78 mg or about 72 mg of b er otr al stat free base.

166. The solid oral dosage form of claim 150 or claim 165, wherein the solid oral dosage form is about 2 mm in diameter and about 3 mm in length.

167. The solid oral dosage form of anyone of claims 150 to 166, wherein the solid oral dosage form comprises about 4 mg to about 7 mg of b er otr al stat free base.

168. The solid oral dosage form of claim 167, wherein each of the solid oral dosage form comprises about 6 mg of b er otr al stat free base.

169. The solid oral dosage form of any one of claims 150 to 168, wherein the solid oral dosage form is an oral granule or an oral pellet.106FH 13299433.1

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