A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Oral Inhalation of Seralutinib for the Treatment of Pulmonary Arterial Hypertension (PAH)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

GB002 Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

14 Dec 2023 → 23 Dec 2025

Decision date (initial)

2023-11-23

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

GB002, Inc.

External identifiers

EU CT number

2023-503614-80-00

ClinicalTrials.gov

NCT05934526

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Phase 3 Primary:
To evaluate the effect of seralutinib compared to placebo on exercise capacity after 24 weeks of treatment when added to background PAH disease-specific medication.

Secondary objectives 1

1. Phase 3 Key Secondary: - To evaluate the effect of seralutinib compared to placebo on time to Clinical Worsening (TTCW) - To evaluate the effect of seralutinib compared to placebo on clinical improvement - To evaluate the effect of seralutinib compared to placebo on NT-proBNP - To evaluate the effect of seralutinib compared to placebo on PAH risk assessment Phase 3 Safety: - To evaluate the safety and tolerability of seralutinib

Conditions and MedDRA coding

Pulmonary Arterial Hypertension

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002972-PIP01-21

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. 1-9 1.Adult subjects aged 18 to 75 years. 2. Body mass index (BMI) ≥ 15 kg/m2 and ≤ 40 kg/m2. 3. Diagnosis of PAH classified by one of the following: a. Idiopathic PAH (IPAH) or heritable PAH (HPAH). b. PAH associated with connective tissue disease (CTD-APAH); c. PAH associated with anorexigen or PAH associated with methamphetamine use. d. Congenital heart disease with simple systemic to pulmonary shunt at least 1 year after surgical repair. 4. 6MWDs ≥ 150 meters and ≤ 475 meters during Screening prior to randomization. 5. WHO FC II or III. 6. US Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) Lite 2 Risk Score ≥ 5 OR NT-proBNP ≥ 300 ng/L OR PVR ≥ 800 dyne∙s/cm5. 7. Cardiac catheterization within the screening period, or a standard of care RHC (with pressure wave forms available for review) up to 48 weeks prior to Screening: a. Mean pulmonary arterial pressure (mPAP) > 20 mmHg (at rest), AND b. Pulmonary vascular resistance (PVR) ≥ 400 dyne∙s/cm5, AND c. Pulmonary capillary wedge pressure (PCWP) or left ventricle end-diastolic pressure (LVEDP) ≤ 15 mmHg 8. Treatment with at least one allowed background PAH disease-specific medication(s) prior to Screening, a. Subjects receiving treatment with endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, guanylate cyclase stimulators, and/or prostacyclin analogues or prostacyclin receptor agonists are eligible only if on a stable dose for at least 12 weeks prior to and throughout Screening. b. Subjects receiving treatment with sotatercept are eligible only if on a stable dose of sotatercept for at least 24 weeks prior to and throughout Screening, with a RHC performed during Screening (or within 2 weeks prior to Screening).9. Pulmonary function tests (PFTs) at Screening or completed no more than 12 weeks prior to Screening.
2. 10-12 10. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at Screening and on Day 1 before first administration of Investigational Product (IP). 11. WOCBP who are not abstinent and intend to be sexually active with a non-sterilized male partner must be willing to use a highly effective method of contraception from consent through 30 days following the last administration of IP12. Women of nonchildbearing potential (WONCBP), classified by one of the following: a. Surgical sterilization. b. Evidence of post-menopausal status. 13. Male subjects: Non-sterilized male subjects who are not abstinent and intend to be sexually active with a female partner of childbearing potential must use a male condom from consent through 90 days after the last dose of IP.

Exclusion criteria 2

1. 1.-20. 1. Evidence of chronic thromboembolic disease or acute pulmonary embolism. 2. Uncontrolled systemic hypertension as evidenced by systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg. 3. Systolic blood pressure < 90 mm Hg during Screening. 4. WHO Pulmonary Hypertension Group 2 – 5. 5. Human immunodeficiency virus (HIV)-associated PAH, schistosomiasis-associated PAH, PAH associated with portal hypertension, or pulmonary veno-occlusive disease (PVOD). 6. Recent history of left-sided heart disease and/or clinically significant cardiac disease within 48 weeks of Screening. 7. Left ventricular ejection fraction (LVEF) ≤ 50% within 24 weeks of Screening. 8. Hemodynamically significant valvular heart disease or uncontrolled symptomatic coronary disease. 9. History of atrial septostomy. 10. Uncontrolled atrial fibrillation or paroxysmal atrial fibrillation. 11. Three or more of the following risk factors for left ventricular disease: a. BMI > 32 kg/m2 b. Diagnosis of essential hypertension that is actively treated c. Diabetes mellitus d. Atrial fibrillation. 12. Untreated severe obstructive sleep apnea. 13. Hepatic dysfunction defined as Child-Pugh Class A or higher, or as evidenced by one of the following at Screening: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 2 x upper limit of normal (ULN) or total bilirubin ≥ 1.5 2 x ULN . 14. History of malignancy with 5 years prior to Screening, with the exception of localized non-metastatic basal cell carcinoma of the skin and in-situ carcinoma of the cervix. 15. History of a potentially life-threatening cardiac arrhythmia with an ongoing risk. 16. Uncontrolled bacterial, viral, or fungal infections which require ongoing systemic therapy 17. Severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or IP administration (eg, history of intracranial hemorrhage, recurrent syncope). 18. Any musculoskeletal disease, injury, or any other disease that limits evaluation of 6MWT. 19. Initiation of an exercise program for cardiopulmonary rehabilitation within 12 weeks prior to Screening or planned during the study. 20. Pregnant or nursing or intends to become pregnant during the duration of the study.
2. 21.-35. 21. Body weight < 37 kg at Screening. 22. Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m2. 23. Hemoglobin (Hgb) concentration < 8.5 g/dL at Screening. 24. Evidence of active or latent Human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C, or tuberculosis (TB) infection at Screening. 25. Tyrosine kinase inhibitors within 12 weeks prior to Screening. Prior/concurrent treatment with tyrosine kinase or activin signaling inhibitors: a. Tyrosine kinase inhibitors, other than Janus kinase inhibitors approved for systemic autoimmune rheumatic diseases, within 12 weeks prior to Screening; b. Activin signaling inhibitors within 5 half-lives prior to Screening 26. Requirement of IV inotropes (ie, levosimendan, dopamine, dobutamine, milrinone, norepinephrine) or IV diuretics for more than 24 hours within 4 weeks prior to Screening. 27. Subjects currently receiving oral anticoagulants (ie, warfarin/other vitamin K antagonists or direct-acting oral anticoagulants [DOACs]) if any of the following criteria are met: a. History within 24 weeks of Screening of: i. Syncope, or ii. Symptomatic bleeding in a critical area or organ iii. Intramuscular with compartment syndrome, or iv. Bleeding causing a fall in hemoglobin levels of 1.24 mmol/L (20 g/L or greater) or more, or v. Bleeding to a transfusion of 2 U or more of whole blood or red blood cells. b. History of central nervous system pathology. c. History of clinically significant (massive) hemoptysis. d. If on warfarin/other vitamin K antagonist, uncontrolled International normalized ratio (eg, INR > 3) as assessed. e. Platelet count < 150 x 109/L at Screening. f. Concomitant use of antiplatelet agents. g. CTD-APAH. h. Concomitant use of sotatercept. 28. Prior participation in seralutinib studies and/or prior treatment with seralutinib. 29. Currently participating in or has participated in a study of an investigational agent or has used an investigational device for the treatment of PAH within 8 weeks or 5 half-lives of the investigational agent, whichever is longer, prior to Screening. 30. Current use of inhaled tobacco- or nicotine-containing products (including e-vapor products) and/or inhaled marijuana. 31. Current alcohol use disorder based on the opinion of the Investigator, and/or a positive test for drugs of abuse. 32. Subjects with a history of severe milk protein allergy or known intolerance to lactose. 33. QT interval corrected for heart rate using Fridericia’s formula (QTcF) of > 500 msec. 34. Have any other condition or reason that, in the opinion of the Investigator or in the opinion of the Sponsor’s Medical Monitor (MM) (or designee) in consultation with the Investigator, would prohibit the subject from participating in the study 35. Subjects performing mandatory military service, subjects deprived of liberty, subjects who, due to a judicial decision, cannot take part in clinical studies, or subjects in residential care institutions, according to local/national regulations

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change in distance achieved on the six-minute walk test (6MWT) from baseline to Week 24

Secondary endpoints 2

1. 1.- 3. Time to first event of Clinical Worsening from first dose of Investigational Product (IP) through end of study 2. Proportion of subjects who achieve all of the components of a composite endpoint of clinical improvement at Week 24, in the absence of clinical worsening 3. Change in NT-proBNP from baseline to Week 24
2. 4.-5. 4. Proportion of subjects with ≥ 1 point decrease from baseline in REVEAL Lite 2 Risk Score at Week 24 5. Incidence of treatment-emergent adverse events (TEAEs), serious TEAEs (SAEs), and treatment-emergent adverse events of special interest (AESIs)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

GB002 Inc.

Sponsor organisation

GB002 Inc.

Address

3013 Science Park Road

City

San Diego

Postcode

92121-1101

Country

United States

Scientific contact point

Organisation

GB002 Inc.

Contact name

Conor O'Donovan

Public contact point

Organisation

GB002 Inc.

Contact name

Conor O'Donovan

Third parties 33

Locations

16 EU/EEA countries · 65 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 533 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

13 submissions — initial application plus substantial / non-substantial modifications