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

96 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new drug, ZMA001, to observe its behavior in healthy individuals. ZMA001 is a monoclonal antibody, a special protein designed to potentially treat pulmonary arterial hypertension (PAH), a serious lung condition. The trial aims to understand how ZMA001 affects the body and assess its safety. It seeks healthy adults willing to participate and undergo various health checks. Participants will receive either ZMA001 or a placebo (a substance with no therapeutic effect) and will be monitored closely over several weeks. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the unique opportunity to be among the first to receive this new drug.

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.

Is there any evidence suggesting that ZMA001 is likely to be safe for humans?

Research shows that ZMA001 is a monoclonal antibody, a type of protein designed to target specific cells in the body. This treatment has not yet been tested in humans. However, early animal studies indicated that ZMA001 helped reduce symptoms of pulmonary arterial hypertension (PAH), such as high pressure in the lungs.

As a Phase 1 trial, the main goal is to determine if ZMA001 is safe for people. The trial involves healthy volunteers to closely monitor any side effects. Although human safety data is not yet available, early trials like this are crucial first steps to ensure a treatment's safety before testing it in larger groups or in people with the disease.

Additionally, the FDA has granted ZMA001 orphan drug status, recognizing its potential for treating rare conditions like PAH. This status often suggests that the treatment is promising enough to warrant further study. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for pulmonary arterial hypertension, which typically include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs, ZMA001 offers a novel approach by using a fully human monoclonal antibody. This antibody specifically targets and inhibits the migration of activated monocytes and macrophages, which can reduce pulmonary vascular remodeling and lower pulmonary artery pressure. Researchers are excited about ZMA001 because its unique mechanism of action directly addresses the underlying inflammation and vascular changes in the lungs, potentially offering a more targeted and effective treatment for patients with this challenging condition.

What evidence suggests that ZMA001 might be an effective treatment for pulmonary arterial hypertension?

Research has shown that ZMA001, a monoclonal antibody, may help treat pulmonary arterial hypertension (PAH) by reducing inflammation and slowing disease progression. In animal studies, ZMA001 outperformed sildenafil, a common PAH treatment, in lowering lung blood pressure and improving the condition. This medicine blocks certain immune cells, reducing lung damage and improving blood flow. Although human studies provide limited information, these early results suggest potential benefits for people with PAH. Participants in this trial will receive either ZMA001 or a placebo to further evaluate its effectiveness in treating PAH. ^{1 2 4 5 6}

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 Cohort 1 (1.5 mg/kg/dose) only 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

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]

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]

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]

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]

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]

Citations

1. zymedi.com zymedi.com/our-pipeline/pah/

ZMA001 for PAH This mechanistic paradigm shift modulates inflammatory responses and fibrosis, halting disease progression and improving patient outcomes in PAH ...

2. pharmacytimes.com pharmacytimes.com/view/fda-grants-orphan-drug-designation-to-zma001-for-pulmonary-arterial-hypertension

FDA Grants Orphan Drug Designation to ZMA001 for ... The designation is based on animal model studies that have demonstrated superior efficacy in comparison to sildenafil.

3. respiratory-therapy.com respiratory-therapy.com/disorders-diseases/cardiopulmonary-thoracic/pulmonary-hypertension/fda-grants-orphan-drug-status-pulmonary-arterial-hypertension-treatment/

FDA Grants Orphan Drug Status to Pulmonary Arterial ... ZMA001, in development for pulmonary arterial hypertension, has been designated as an Orphan Drug by the US Food and Drug Administration.

4. clinicaltrialsarena.com clinicaltrialsarena.com/news/zymedi-pah-treatment-trial/

Zymedi doses first subject in Phase I PAH treatment trial The placebo-controlled trial aims to evaluate the safety and optimal dosage of ZMA001 to treat pulmonary arterial hypertension (PAH).

5. withpower.com withpower.com/trial/phase-1-pulmonary-arterial-hypertension-7-2023-80ad3

Intravenous ZMA001 for Pulmonary Arterial Hypertension The research highlights that various drugs targeting the prostacyclin, endothelin, and nitric oxide pathways have improved symptoms and survival in pulmonary ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05967299

Study of Intravenous ZMA001 in Healthy Subjects ZMA001 is a fully human, monoclonal antibody (IgG1) that inhibits migration of activated monocytes and macrophages and reduces pulmonary vascular remodeling and ...