Intravenous ZMA001 for Pulmonary Arterial Hypertension

Overseen By Jason M Elinoff, M.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Must not be taking: Herbal supplements

Disqualifiers: HIV, Drug use, Alcohol abuse, others

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

Duration: 48 hours

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Background: A number of diseases can cause a type of lung injury called pulmonary arterial hypertension (PAH). Most people who develop PAH do not survive more than a few years. A new study drug (ZMA001) may help. ZMA001 is a monoclonal antibody. This type of drug consists of proteins, made in a facility, that are very similar to proteins in a human body. But before giving ZMA001 to people sick with PAH, researchers want to find out how the drug affects healthy people. Objective: To test a drug (ZMA001) in healthy volunteers. Eligibility: Healthy adults aged 18 to 60 years. Design: Participants will be screened. They will have a physical exam with blood tests. They will have a urine test for drug use. They will have a test of their heart function. Participants will come to the clinic for 1 inpatient visit of up to 48 hours. ZMA001 is a liquid administered through a tube attached to a needle inserted into a vein in the arm. Participants will receive this drug only once, during their inpatient stay. Some participants will receive the drug; others will receive a placebo. A placebo is a treatment that looks just like the real drug but contains no medicine. Participants will not know which treatment they are getting. After a screening visit, participants will have 1 inpatient visit and up to 6 outpatient visits over 16 weeks after receiving the treatment. Blood draws and other tests will be repeated. Each outpatient visit is approximately 2 hours long. This study is the first time ZMA001 will be administered to people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you have used tobacco, recreational drugs, or herbal supplements recently, or if you have a significant uncontrolled medical condition.

How does the drug ZMA001 differ from other treatments for pulmonary arterial hypertension?

ZMA001 is administered intravenously, which is a common route for treating pulmonary arterial hypertension, but it may offer a novel formulation or mechanism compared to existing intravenous prostacyclin treatments. Unlike traditional prostacyclin therapies that require external pumps and carry risks of infections and malfunctions, ZMA001 might provide a new approach to mitigate these issues. ^{1 2 3 4 5}

What evidence supports the effectiveness of the drug ZMA001 for treating pulmonary arterial hypertension?

The research highlights that various drugs targeting the prostacyclin, endothelin, and nitric oxide pathways have improved symptoms and survival in pulmonary arterial hypertension. While ZMA001 is not specifically mentioned, similar treatments have shown benefits, suggesting potential effectiveness. ^{6 7 8 9 10}

Who Is on the Research Team?

Jason M Elinoff, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

Healthy adults aged 18-60 can join this study testing ZMA001, a new drug for lung injury from PAH. Participants must be in good health, not use tobacco or certain drugs recently, and agree to lifestyle rules and contraception methods. More women are needed as the trial aims for gender balance.

Inclusion Criteria

Agreement to adhere to Lifestyle Considerations throughout study duration

Stated willingness to comply with all study procedures and availability for the duration of the study

I am a man who will use a condom or am surgically sterile, and won't donate sperm for 120 days after treatment.

Exclusion Criteria

I have not had a fever or infection in the last 2 weeks.

My BMI is either below 17 or above 32.

I have a significant ongoing medical condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants receive a single intravenous dose of ZMA001 or placebo during a 48-hour inpatient stay

48 hours

1 inpatient visit

Follow-up

Participants are monitored for safety and pharmacokinetics with up to 6 outpatient visits over 16 weeks

16 weeks

6 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• ZMA001

Trial Overview The trial is giving healthy volunteers either ZMA001 or a placebo through an IV to see how it affects them. It's the first time people will get ZMA001. They'll stay at the clinic up to 48 hours then have follow-up visits over 16 weeks with blood tests and heart checks.

How Is the Trial Designed?

Group I: ZMA001 (BC-NKA-20008) Experimental Treatment 1 Intervention

ZMA001 is a fully human, monoclonal antibody (IgG1) that inhibits migration of activated monocytes and macrophages and reduces pulmonary vascular remodeling and pulmonary artery pressure in pre-clinical rodent models of pulmonary arterial hypertension (PAH).

Group II: Placebo Placebo Group 1 Intervention

Placebo for ZMA001 is supplied in a single-use 10 mL glass vial. Each vial contains 30 mg/mL of sucrose.Placebo drug is manufactured using the same ingredients as active drug (20 mM histidine-HCl buffer \[pH 5.6\], 30 mg/mL sucrose, 0.070 w/v% polysorbate 80) excluding ZMA001 antibody and is packed in the same vial.

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Zymedi, Co., Ltd.

Collaborator

Trials

1

Recruited

100+

Published Research Related to This Trial

Since the mid-1990s, nine medications targeting the prostacyclin, endothelin, and nitric oxide pathways have been developed for treating pulmonary arterial hypertension (PAH), leading to significant improvements in patients' functional capacity, symptoms, and survival rates.

While current treatments for WHO Group 1 PAH are effective, they are not curative, and ongoing research aims to develop new therapies that may halt or reverse disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

WHO Group 1 pulmonary arterial hypertension: current and investigative therapies. Ventetuolo, CE., Klinger, JR.[2014]

Recent advancements in therapies have significantly enhanced the treatment options available for pulmonary arterial hypertension (PAH), leading to better management of the condition.

These new therapies aim to improve patient outcomes by targeting the underlying mechanisms of PAH, although specific details on the types of therapies and their efficacy were not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Understanding pulmonary arterial hypertension. Holcomb, SS.[2019]

A comprehensive review of clinical trials has led to an evidence-based treatment algorithm for pulmonary arterial hypertension (PAH), emphasizing the importance of tailored therapies based on patient classification, particularly for idiopathic and heritable PAH.

For patients in World Health Organization (WHO) functional class III, oral phosphodiesterase-5 inhibitors or endothelin-receptor antagonists are recommended if they do not respond to acute vasoreactivity testing, while continuous intravenous epoprostenol is the preferred treatment for those in class IV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated evidence-based treatment algorithm in pulmonary arterial hypertension. Barst, RJ., Gibbs, JSR., Ghofrani, HA., et al.[2021]

Early recognition and referral of patients with pulmonary arterial hypertension (PAH) to specialized centers is crucial for improving outcomes, as novel treatments and rehabilitation programs can enhance exercise capacity and quality of life.

Current medical treatments, including prostanoids and endothelin antagonists, not only promote pulmonary vasodilation but may also address the underlying vascular abnormalities in PAH, with emerging evidence suggesting that combination therapy may be more effective than single-agent treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current treatment approaches to pulmonary arterial hypertension. Provencher, S., Granton, JT.[2022]

Recent clinical trials have shifted the treatment approach for pulmonary arterial hypertension (PAH) from a clinical-based strategy to an evidence-based therapy, allowing for a more systematic treatment algorithm based on the efficacy and side-effect profiles of various approved drugs.

The proposed treatment algorithm is specifically designed for patients in NYHA functional class III or IV, recommending oral anticoagulation for all, and suggesting specific therapies like endothelin receptor antagonists or prostanoids for nonresponders to acute vasoreactivity testing, with continuous intravenous epoprostenol as a rescue option for the most severe cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension. Galiè, N., Seeger, W., Naeije, R., et al.[2021]

A 74-year-old woman with severe pulmonary arterial hypertension successfully transitioned from subcutaneous to intravenous treprostinil using a new implantable, gas-driven pump device, which is a first-of-its-kind report.

This innovative pump system may reduce the risks associated with traditional battery-driven delivery systems, such as infections and malfunctions, offering a safer option for continuous intravenous prostacyclin treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous implantation of a new intravenous pump system for prostacyclin treatment in patients with pulmonary arterial hypertension. Desole, S., Velik-Salchner, C., Fraedrich, G., et al.[2014]

Selexipag is a newly approved oral medication that acts as an IP receptor agonist, targeting the prostacyclin pathway to treat pulmonary arterial hypertension (PAH) by promoting pulmonary vasodilation and improving right ventricular function.

While selexipag shows promise as a treatment option for PAH, its effectiveness as a first-line therapy is uncertain, and it is likely to be used in combination with other PAH-specific medications rather than as a standalone treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selexipag for the treatment of pulmonary arterial hypertension. Richter, MJ., Gall, H., Grimminger, J., et al.[2018]

Intravenous prostacyclin analogues, such as epoprostenol, iloprost, and treprostinil, are crucial for treating pulmonary arterial hypertension (PAH) and have been shown to potentially improve survival when used early and in combination with other therapies.

Recent advancements in fully implantable pump systems for delivering these medications have significantly reduced the risk of catheter-related infections, making long-term treatment safer and more convenient for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous prostacyclin-analogue therapy in pulmonary arterial hypertension - A review of the past, present and future. Stubbe, B., Opitz, CF., Halank, M., et al.[2021]

In a study of 78 patients with severe idiopathic, heritable, or anorexigen-use associated pulmonary arterial hypertension (IHA-PAH), treatment with intravenous epoprostenol led to significant improvements in functional class and exercise capacity, particularly in treatment-naïve patients, with 79% showing improvement in NYHA functional class and a 146-meter increase in 6-minute walk distance after 4 months.

The combination of epoprostenol with oral PAH therapy showed enhanced benefits, leading to higher survival rates of 92% at 1 year and 88% at 3 years for treatment-naïve patients, indicating that upfront combination therapy may be a more effective approach for managing severe IHA-PAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current epoprostenol use in patients with severe idiopathic, heritable or anorexigen-associated pulmonary arterial hypertension: data from the French pulmonary hypertension registry. Bergot, E., Sitbon, O., Cottin, V., et al.[2014]

A case series involving five stable patients with pulmonary arterial hypertension demonstrated successful transitions from intravenous prostacyclins to selexipag, indicating that this switch can be feasible.

The transitions were conducted using a standardized protocol in an outpatient setting, suggesting that with careful selection and monitoring, patients can safely move to selexipag therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transition from parenteral prostacyclins to selexipag: safety and feasibility in selected patients. Aldweib, N., Verlinden, NJ., Kassis-George, H., et al.[2021]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

WHO Group 1 pulmonary arterial hypertension: current and investigative therapies. [2014]

2. United States pubmed.ncbi.nlm.nih.gov

Understanding pulmonary arterial hypertension. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Updated evidence-based treatment algorithm in pulmonary arterial hypertension. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Current treatment approaches to pulmonary arterial hypertension. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Subcutaneous implantation of a new intravenous pump system for prostacyclin treatment in patients with pulmonary arterial hypertension. [2014]

7. England pubmed.ncbi.nlm.nih.gov

Selexipag for the treatment of pulmonary arterial hypertension. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Intravenous prostacyclin-analogue therapy in pulmonary arterial hypertension - A review of the past, present and future. [2021]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Current epoprostenol use in patients with severe idiopathic, heritable or anorexigen-associated pulmonary arterial hypertension: data from the French pulmonary hypertension registry. [2014]

10. United States pubmed.ncbi.nlm.nih.gov

Transition from parenteral prostacyclins to selexipag: safety and feasibility in selected patients. [2021]