A Study to Assess the Effect of Dexpramipexole in Adolescents and Adults With Severe Eosinophilic Asthma (EXHALE-3)

Inclusion Criteria:

1. Signed informed consent form and assent form, as appropriate.

2. Male or female ≥12 years of age at Screening Visit 1. Asthma-related criteria

3. Documented physician diagnosis of asthma for ≥12 months prior to Screening Visit 1.

4. Eosinophil count of ≥0.30x10⁹/L at Screening Visit 1. If the initial value isbetween 0.250x10⁹/L to 0.299x10⁹/L, then this may be repeated once at an unscheduledvisit (prior to Screening Visit 2).

5. Treatment of asthma, participants must satisfy all the below (items a to c):

6. Participants who have received asthma controller medication with medium or highdose inhaled corticosteroids (ICS ≥500 μg/day fluticasone propionate dry powderformulation daily or clinically comparable, per GINA 2021) on a regular basisfor at least 12 months prior to Screening Visit 1.

7. Documented treatment with a stable dose of either medium or high dose ICS forat least 3 months prior to Visit 1. The ICS may be contained within anICS/long-acting β2 agonist (LABA) combination product. Daily oralcorticosteroids are an allowed concomitant medication; participants on dailyoral corticosteroids must be on a stable dose for 3 months before ScreeningVisit 1.

8. Use of one of more additional daily maintenance asthma controller medicationsaccording to standard practice of care is required. Use of a stable dose of anyadditional asthma controller medications must be documented for at least 3months prior to Screening Visit 1.

9. Pre-BD FEV₁ ≥40% and <80% (<90% for participants 12 to 17 years of age) of predictedat Screening Visit 2.

10. Variable airflow obstruction documented with at least one of the following criteria:

11. Bronchodilator reversibility at Screening Visit 2, as evidenced by ≥12% and ≥200 mL improvement in FEV₁, 15 to 30 minutes following inhalation of 400 µg (four puffs) of albuterol/salbutamol (≥12% and ≥160 mL for ages 12 to 17).Participants who do not meet the bronchodilator reversibility inclusioncriterion but have ≥10% and ≥160 mL reversibility, may repeat the reversibilityspirometry assessment once during the Screening period, at an unscheduled visitat least 7 days prior to baseline.

12. Bronchodilator reversibility, using the criteria above, documented in the past 24 months prior to Screening Visit 1 or during Screening.

13. Peak flow variation of ≥20% over a 2-week period, documented in the past 24months prior to Screening Visit 1 or during Screening.

14. Airflow variability in clinic FEV₁ ≥20% between two consecutive clinic visits,documented in the past 24 months prior to Screening Visit 1.

15. Airway hyperresponsiveness (provocative concentration causing a 20% fall inFEV₁ of methacholine <8 mg/mL or other clinically relevant bronchoprovocationtesting) documented in the past 24 months prior to Screening Visit 1 or duringScreening.

16. ACQ-6 ≥1.5 at Screening Visit 2.

17. Documented history of at least two asthma exacerbations requiring treatment withsystemic corticosteroids (intramuscular, intravenous, or oral) within the past 12-month period prior to Screening Visit 1. General medical history

18. Negative urine pregnancy test for women of childbearing potential (WOCBP; aftermenarche) at the Screening and Baseline visits.

19. WOCBP must use either of the following methods of birth control, from ScreeningVisit 1 through the End of Study Visit:

20. A highly effective form of birth control (confirmed by the investigator).Highly effective forms of birth control include: true sexual abstinence, avasectomized sexual partner, Implanon, female sterilization by tubal occlusion,any effective Intrauterine device (IUD), IUD/intrauterine system (IUS),Levonorgestrel Intrauterine system, or oral contraceptive.

• Or

2. Two protocol acceptable methods of contraception in tandem.Women not of childbearing potential are defined as women who are eitherpermanently sterilized (hysterectomy, bilateral oophorectomy, or bilateralsalpingectomy), or who are postmenopausal. Women will be consideredpostmenopausal if they have been amenorrheic for ≥12 months prior to theplanned date of the Baseline Visit without an alternative medical cause. Thefollowing age specific requirements apply:

3. Women <50 years old will be considered postmenopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatment and follicle stimulating hormone levels in the postmenopausal range.

4. Women ≥50 years old will be considered postmenopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatment.

Exclusion Criteria:

Asthma-related criteria

1. A participant who experiences a severe asthma exacerbation (defined as adeterioration of asthma that results in emergency treatment, hospitalization due toasthma, or treatment with systemic corticosteroids) at any time from 4 weeks priorto Screening Visit 1. Participants who experience an asthma exacerbation during the Screening/Run-inPeriod may remain in screening and proceed with study visits 14 days after they havecompleted their course of oral steroids or returned to their pre-Screening Visitmaintenance dose of oral steroids and the investigator considers participant hasreturned to baseline status.

2. Current diagnosis of diseases which may confound interpretation of this study'sfindings such as allergic bronchopulmonary aspergillosis, eosinophilicgranulomatosis with polyangiitis, eosinophilic gastrointestinal diseases,hypereosinophilic syndrome, or lung diseases (eg, chronic obstructive pulmonarydisease, idiopathic pulmonary fibrosis).

3. Respiratory infection: Upper or lower respiratory tract, sinus, or middle earinfection within the 4 weeks before Screening Visit 1. Prohibited medications/procedures

4. Treatment with a biologic investigational drug in the last 5 months prior toScreening Visit 1. Treatment with non-biologic investigational drugs in the previous 30 days or five-half-lives prior to Screening Visit 1, whichever is longer.Treatment with GSK3511294 (long-acting anti-IL-5) in the past 12 months.

5. Treatment with any of the following monoclonal antibody therapies within 120 daysprior to Baseline: benralizumab, dupilumab, mepolizumab, reslizumab, omalizumab,tezepelumab, or tralokinumab.

6. Treatment with pramipexole (Mirapex®) within 30 days of Baseline.

7. Treatment with selected drugs known to have a substantial risk of neutropenia in thepast 30 days prior to Screening Visit 1.

8. Bronchial thermoplasty procedure in the past 12 months prior to Screening Visit 1 orplanned during the coming year. General medical history

9. Weight <40 kg at Screening Visit 1.

10. Current smoking within 12 months prior to Screening Visit 1 or a smoking history of >10 pack-years. Smoking includes tobacco, vaping, and/or marijuana use.

11. Known or suspected alcohol or drug abuse

12. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolicblood pressure >110 mmHg prior to Baseline Visit despite anti-hypertensive therapy.

13. History of malignancy that required surgery (excluding local and wide-localexcision), radiation therapy and/or systemic therapy during the 5 years prior toBaseline Visit.

14. History of human immunodeficiency virus (HIV) infection or chronic infection withhepatitis B or C.

15. A helminth parasitic infection diagnosed within 24 weeks prior Screening Visit 1that has not been treated with or has failed to respond to standard of care (SoC)therapy.

16. Medical or other condition likely to interfere with participant's ability to undergostudy procedures, adhere to visit schedule, or comply with study requirements.

17. Known or suspected noncompliance with medication.

18. Unwillingness or inability to follow the procedures outlined in the protocol. Clinical safety labs

19. Absolute neutrophil count <2.000x10⁹/L at screening at Screening Visit 1 orScreening Visit 2.

20. Renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) <60mL/min/1.73m² at Screening Visit 2 (using the Chronic Kidney Disease EpidemiologyCollaboration [CKD-EPI] formula [Levey et al, 2009] for age ≥18 years at screening;using the Bedside Schwartz [Schwartz and Work, 2009] eGFR formula for age <18).

21. Active liver disease defined as any known current infectious, neoplastic, ormetabolic pathology of the liver or unexplained elevations in alanineaminotransferase (ALT), aspartate aminotransferase (AST), >3x the upper limit ofnormal (ULN), or total bilirubin >2x ULN at Screening Visit 2 confirmed by a repeatabnormal measurement of the relevant value(s), at least 1 week apart. Cardiac safety

22. History of New York Heart Association class IV heart failure or last known leftventricular ejection fraction <25%.

23. History of major adverse cardiovascular event (MACE) within 3 months prior to theBaseline Visit.

24. History of cardiac arrhythmia within 3 months prior to Baseline Visit that is notcontrolled by medication or via ablation.

25. History of long QT syndrome.

26. Corrected QT interval by Fridericia (QTcF) interval >450 ms for males and >470 msfor females at Screening Visit 2 or QTcF ≥480 ms for participants with bundle branchblock.

27. Clinically important abnormalities in resting ECG that may interfere with theinterpretation of QTcF interval changes at Screening Visit 2, including heart rate <45 beats per minute (bpm) or >100 bpm. Pregnancy/Lactation

28. Pregnant women or women breastfeeding.

29. Males who are unwilling to use an acceptable method of birth control during theentire study period (ie, condom with spermicide).

30. Allergy or hypersensitivity to dexpramipexole or any of its components.