Long-term Safety and Efficacy Evaluation of Inhaled Seralutinib in WHO Group 1 Pulmonary Arterial Hypertension

Trial ID: 2024-516754-22-00
Protocol: GB002-2102
Sponsor: GB002 Inc.

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Diseases & Conditions

Pulmonary arterial hypertension

Objectives

The primary objective of this study is to evaluate the long-term **safety** and tolerability of orally inhaled **seralutinib** in subjects with World Health Organization (WHO) Group 1 Pulmonary Arterial Hypertension (PAH). This is clinically relevant as it aims to ensure that the treatment is safe for prolonged use in managing PAH, a progressive disease characterized by high blood pressure in the pulmonary arteries, which can lead to heart failure if untreated.

Secondary objectives include evaluating the long-term effect of orally inhaled seralutinib on exercise capacity. This is important as improved exercise capacity can significantly enhance the quality of life and functional status of patients with PAH.

Participants

The clinical trial involves a total of **80 participants** diagnosed with **Pulmonary Arterial Hypertension (PAH)**. The study population includes both adult female subjects aged 18 to 80 years and adult male subjects aged 50 to 80 years. Participants were selected based on their completion of a prior seralutinib PAH study, with a requirement for compliance with study procedures and treatment plans. The trial includes individuals who are on stable doses of standard PAH disease-specific background therapies. Lifestyle considerations such as the use of effective contraception methods are emphasized, particularly for women of childbearing potential and non-sterilized male subjects. The trial population is characterized by a mix of both genders and includes a vulnerable population, ensuring a comprehensive evaluation of the long-term safety and tolerability of orally inhaled seralutinib in subjects with World Health Organization (WHO) Group 1 PH.

Plans and Procedures

The clinical trial is designed as a **Phase 4**, open-label extension study to evaluate the long-term safety and tolerability of orally inhaled **seralutinib** in subjects with **Pulmonary Arterial Hypertension (PAH)**. The trial will involve adult female subjects aged 18 to 80 years and adult male subjects aged 50 to 80 years who have completed a prior seralutinib PAH study. The study will utilize **GB002**, an inhalation powder in hard capsule form, administered via a dry powder inhaler. The trial is expected to run from June 2021 to April 2027, with a maximum treatment period of 72 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria. These criteria include compliance with previous study protocols, treatment with stable doses of standard PAH therapies, and, for women of childbearing potential, a negative pregnancy test. Following the screening, participants will attend regular follow-up visits to monitor the incidence of treatment-emergent adverse events (TEAEs) and assess changes in the distance achieved on the six-minute walk test (6MWT). The study will conclude with an end-of-study visit to evaluate the overall safety and efficacy outcomes.

The expected length of participant involvement is up to 72 weeks, contingent upon adherence to the study protocol. Conditions that may lead to early termination from the study include non-compliance with study procedures, withdrawal of consent, or the occurrence of significant adverse events. The trial aims to provide comprehensive data on the long-term use of seralutinib in managing PAH, contributing valuable insights into its safety profile and therapeutic potential.

Treatment

The clinical trial involves the administration of the experimental medication **GB002**, which contains the active substance **seralutinib**. This medication is formulated as an **inhalation powder, hard capsule** and is intended for the treatment of World Health Organization (WHO) Group 1 Pulmonary Arterial Hypertension (PAH). The pharmaceutical form is designed for administration via **inhalation** using a dry powder inhaler. The maximum daily dose of seralutinib is 180 mg, and the treatment period extends up to 72 weeks. The inhalation device used is the Plastiape RS01L, a monodose dry powder inhaler classified as a Class I non-sterile device according to Directive 93/42/CEE - Annex IX - Rule 5. This device is CE marked and facilitates the delivery of the medication directly to the lungs.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the long-term safety and tolerability of the orally inhaled seralutinib. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to assess the efficacy and safety of the experimental treatment over an extended period, providing valuable data on its potential benefits and risks for individuals with PAH.

Efficacy

The efficacy of the clinical trial evaluating the long-term use of orally inhaled **seralutinib** for the treatment of World Health Organization (WHO) Group 1 Pulmonary Arterial Hypertension (PAH) will be assessed using specific endpoints. The primary endpoint focuses on the incidence of treatment-emergent adverse events (TEAEs), which will provide insights into the safety profile of the treatment. A secondary endpoint involves measuring the change in the distance achieved on the six-minute walk test (6MWT), denoted as Δ6MWD, which serves as an indicator of functional exercise capacity and potential improvement in symptoms associated with PAH.

The six-minute walk test (6MWT) will be conducted at specified intervals throughout the study to monitor changes in exercise capacity. The data collected from these tests will be analyzed to determine any significant improvements or declines in the participants' ability to perform physical activities. The use of validated scales and standardized procedures will ensure the reliability and accuracy of the measurements. The trial is designed as an open-label extension study, allowing for the continuous assessment of efficacy parameters over an extended period, with the estimated end date set for April 2027.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Adult female subjects aged 18 to 80 years, inclusive, or adult male subjects aged 50 to 80 years, inclusive, at the time of signing the informed consent form (ICF).
Subjects must have completed a prior seralutinib PAH study and, in the opinion of the Investigator and Sponsor, have been compliant with study procedures and have completed treatment with IP through parent study EOT visit. See exception(s) for public health emergency visit/procedure delays specified in Appendix 6, Section 10.6.
Treatment with standard of care PAH disease-specific background therapies (stable dose).
Women of childbearing potential must have a negative urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [hCG]) at extension enrollment visit before first administration of seralutinib in this study. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required, and results must be negative.
Women of nonchildbearing potential: Evidence of post-menopausal status. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy tubal ligation [if considered an effective form of sterilization in a specific country or region], or hysterectomy). − Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, tubal ligation [if considered an effective form of sterilization in a specific country or region], or hysterectomy).
Women of childbearing potential 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 (defined in Appendix 4, Section 10.4) from consent through 30 days following the last administration of seralutinib; acceptable methods include hormonal contraception (oral contraceptives – as long as on stable dose, patch, implant, or injection), intrauterine devices or other form of highly effective contraception.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable.
Nota: la abstinencia sexual solamente es aceptable si está en consonancia con el estilo de vida preferido y habitual de la paciente. La abstinencia periódica, el método del ritmo y el coitus interruptus (marcha atrás) no se consideran aceptables.
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 seralutinib. Male subjects should refrain from sperm donation throughout this period (except for male subjects participating in fertility analysis as part of this protocol).
. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable.
Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any protocol-mandated procedures.
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

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Exclusion Criteria

Medical Conditions: 1. Persistent and clinically significant systemic hypertension as evidenced by sitting systolic blood pressure > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg after a period of rest at the extension study initial visit, or hypotension as evidenced by systolic blood pressure < 90 mm Hg during the extension study initial visit. 2. Interval history of newly developed left-sided heart disease with onset or severity increased after participation in the parent study, and/or clinically significant cardiac disease, including but not limited to any of the following: a. Aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild aortic insufficiency, mild aortic stenosis (AS), mild mitral stenosis (MS), moderate mitral regurgitation (MR); b. Mechanical or bioprosthetic cardiac valve; c. Pericardial constriction or pericardial effusion with tamponade physiology; d. Restrictive or congestive cardiomyopathy; e. Left ventricular ejection fraction (LVEF) ≤50%. f. Symptomatic coronary disease; g. Significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation; h. Acutely decompensated left heart failure within 1 month (30 days) of extension enrollment visit; i. History of severe and untreated obstructive sleep apnea. 3. Potentially life-threatening cardiac arrhythmia with an ongoing risk. 4. Uncontrolled bacterial, viral, or fungal infections which require systemic therapy. 5. Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or seralutinib administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study; including but not necessarily limited to the following: malignancy within 5 years of extension enrollment visit, with the exception of effectively treated or excised localized non-metastatic basal cell carcinoma of the skin and in situ carcinoma of the cervix; psychiatric disorder that compromises ability to give informed consent, substance abuse, coagulopathy, history of stroke, transient ischemic attack (TIA) requiring concurrent oral coagulation therapy, or intracranial hemorrhage; history of pulmonary embolus or deep vein thrombosis (DVT), history of vasovagal syncope with phlebotomy. 6. Currently pregnant or breastfeeding or intends to become pregnant during the duration of the study. 7. History of portopulmonary hypertension or portal hypertension due to cirrhosis classified as Child-Pugh Class A or higher.
Interval history of newly developed left-sided heart disease with onset or severity increased after participation in the parent study, and/or clinically significant cardiac disease, including but not limited to any of the following: a. Aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild aortic insufficiency, mild aortic stenosis (AS), mild mitral stenosis (MS), moderate mitral regurgitation (MR); b. Mechanical or bioprosthetic cardiac valve; c. Pericardial constriction or pericardial effusion with tamponade physiology; d. Restrictive or congestive cardiomyopathy; e. Left ventricular ejection fraction (LVEF) ≤50%. f. Symptomatic coronary disease; g. Significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation; h. Acutely decompensated left heart failure within 1 month (30 days) of extension enrollment visit; i. History of severe and untreated obstructive sleep apnea.
Potentially life-threatening cardiac arrhythmia with an ongoing risk.
Uncontrolled bacterial, viral, or fungal infections which require systemic therapy.
Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or seralutinib administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study; including but not necessarily limited to the following: malignancy within 5 years of extension enrollment visit, with the exception of effectively treated or excised localized non-metastatic basal cell carcinoma of the skin and in situ carcinoma of the cervix; psychiatric disorder that compromises ability to give informed consent, substance abuse, coagulopathy, history of stroke, transient ischemic attack (TIA) requiring concurrent oral coagulation therapy, or intracranial hemorrhage; history of pulmonary embolus or deep vein thrombosis (DVT), history of vasovagal syncope with phlebotomy.
Currently pregnant or breastfeeding or intends to become pregnant during the duration of the study.
History of portopulmonary hypertension or portal hypertension due to cirrhosis classified as Child-Pugh Class A or higher.
Subjects with a history of severe milk protein allergy. In addition, subjects with known intolerance or hypersensitivity to lactose who, in the opinion of the Investigator, may experience severe symptoms following the ingestion of lactose.
Sujetos con antecedentes de alergia severa a proteínas de la leche. Asimismo, sujetos con intolerancia o hipersensibilidad conocida a la lactosa que, en opinión del investigador, puedan experimentar síntomas intensos tras la ingestión de lactosa.
Current alcohol use disorder as defined by DSM-5, and/or history of current utilization of drugs of abuse (amphetamines, methamphetamines, cocaine, phencyclidine [PCP]).
Have any other condition or reason that, in the opinion of the Investigator and/or the Sponsor’s Medical Monitor (or designee), would prohibit the subject from participating in the study. Diagnostic Assessments The most recent laboratory assessment from the parent study may be used to evaluate laboratory-associated exclusion criterion, if performed within 6 weeks (± 2 days) of the extension enrollment visit.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN) or total bilirubin ≥ 2 × ULN.
Chronic renal insufficiency as defined by an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m2 via CKD-EPI (Levey, 2009) at extension study initial visit or requires dialytic therapy or hemofiltration.
Hemoglobin (Hgb) concentration < 8.5 g/dL.
Absolute neutrophil count (ANC) < 1 x 109/L.
Platelet count < 50 x 109/L.
Body weight ≤ 40 kg at extension study initial visit.
Body weight ≤ 40 kg at extension study initial visit. Prior Therapy
Use of inhaled prostanoids.
Chronic use of oral anticoagulants (ie, vitamin K antagonist such as warfarin or novel oral anticoagulant [NOAC]/direct oral anticoagulant [DOAC]); if on warfarin or a NOAC it is clinically acceptable to be withdrawn 1 month prior to start of GB002 (see Appendix 5, Section 10.5 for examples of prohibited anticoagulants).
Uso crónico de anticoagulantes orales (es decir, antagonistas de la vitamina K, como warfarina o anticoagulantes orales nuevos [NOAC]/anticoagulantes orales de acción directa [DOAC]); si se está recibiendo warfarina o algún NOAC, es aceptable desde el punto de vista clínico retirarlo 1 mes antes de comenzar la administración de GB002 (véase el apéndice 5, sección 10.5 para obtener ejemplos de anticoagulantes prohibidos).