MANP for High Blood Pressure

(BOLD-HTN Trial)

Recruiting at 28 trial locations

Overseen By Danny Sugimoto, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: E-Star BioTech, LLC

Must be taking: Antihypertensives, Diuretics, ACEi or ARB

Disqualifiers: Secondary hypertension, Recent MI, CHF, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called MANP (M-Atrial Natriuretic Peptide) to determine its effectiveness in lowering daytime systolic blood pressure for individuals with high blood pressure who are already on three or more different medications. Participants will receive either the MANP treatment or a placebo (a look-alike with no active ingredient) to compare effects. Ideal participants have been taking at least three different blood pressure medications, including a diuretic and an ACE inhibitor or ARB, but still experience high blood pressure. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important medical advancements.

Do I need to stop my current medications for the trial?

The trial does not specify that you need to stop your current medications. In fact, you must be taking at least three different blood pressure medications to participate.

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

Research shows that MANP is generally safe and well-tolerated in people. Studies have found that MANP helps relax blood vessels, increases sodium removal from the body, and lowers blood pressure. Most participants in these studies did not experience serious side effects. However, one person stopped treatment due to symptoms from low blood pressure. Overall, previous research suggests that MANP is likely safe for most people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for high blood pressure, like ACE inhibitors or beta-blockers, focus on relaxing blood vessels or slowing heart rates. But MANP works differently, targeting the natriuretic peptide pathway to help the body naturally eliminate sodium, which can lower blood pressure in a novel way. Researchers are excited about MANP because it offers a fresh approach that might benefit patients who don't respond well to traditional therapies. This unique mechanism could lead to more effective blood pressure control with potentially fewer side effects.

What evidence suggests that MANP might be an effective treatment for high blood pressure?

Research has shown that MANP, one of the treatments studied in this trial for high blood pressure, is promising in lowering blood pressure levels. One study found that MANP reduced the top number in blood pressure readings by 5.7 mmHg after six hours, while the placebo group showed no change. Other studies have found that MANP is safe, easy to tolerate, and works by helping blood vessels relax, which lowers blood pressure. Additionally, MANP has improved kidney function while lowering blood pressure. These findings suggest that MANP could be a good option for people whose high blood pressure is hard to control with other medications. ^{1 2 3 6 7}

Who Is on the Research Team?

David Smith, MD

Principal Investigator

E-Star BioTech, LLC

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with resistant hypertension, taking three or more blood pressure medications including a diuretic and an ACEi/ARB. They must have a certain level of kidney function (eGFR ≥ 30 mL/min/1.73m2), not be able to bear children or agree to use contraception, and have specific high blood pressure readings.

Inclusion Criteria

My kidney function, measured by eGFR, is between 20-30 ml/min/1.73m^2.

I am not able to become pregnant.

My kidney function, measured by eGFR, is at least 30.

Exclusion Criteria

Subjects who are pregnant or breastfeeding

My cancer was diagnosed or came back in the last 3 years.

I am on dialysis or have had a kidney transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive subcutaneous MANP or placebo once daily for 42 days to evaluate safety and efficacy in reducing systolic blood pressure

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and metabolic biomarkers

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• MANP

Trial Overview The study tests MANP injections against placebo in lowering daytime systolic blood pressure in patients with difficult-to-control hypertension. It's a Phase 2 trial where doses are adjusted over time while monitoring the effects using ambulatory blood pressure measurements.

How Is the Trial Designed?

Group I: MANP Active Control 1 Intervention

MANP in vehicle

Group II: Placebo-matched control Placebo Group 1 Intervention

Placebo-matched vehicle (vehicle minus the active component)

Who Is Running the Clinical Trial?

E-Star BioTech, LLC

Lead Sponsor

Trials

2

Recruited

160+

PPD

Industry Sponsor

Trials

162

Recruited

36,600+

Dr. Austin Smith

PPD

Chief Medical Officer since 2020

Doctor of Medicine from the Royal College of Surgeons in Ireland

David Simmons

PPD

Chief Executive Officer since 2012

Bachelor’s degree in Applied Mathematics and Industrial Management from Carnegie Mellon University

Mayo Clinic

Collaborator

Trials

3,427

Recruited

3,221,000+

PPD DEVELOPMENT, LP

Industry Sponsor

Trials

167

Recruited

38,000+

David Simmons

PPD DEVELOPMENT, LP

Chief Executive Officer since 2012

BSc in Applied Science from Georgia Institute of Technology

Martina Flammer

PPD DEVELOPMENT, LP

Chief Medical Officer since 2024

MD

PPD Development, LP

Industry Sponsor

Published Research Related to This Trial

In a study of 194 hypertensive patients, those with left ventricular hypertrophy (LVH) had significantly higher levels of mid-regional pro-atrial natriuretic peptide (MRproANP) compared to those without LVH, suggesting a potential link between MRproANP levels and LVH.

While MRproANP showed promise as a marker for monitoring therapy response, its diagnostic ability for detecting LVH was limited, indicating that further research is needed to fully understand its prognostic value.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The diagnostic performance of mid-regional portion of pro-atrial natriuretic peptide for the detection of left ventricular hypertrophy in Caucasian hypertensive patients. Bhandari, SS., Davies, JE., Struck, J., et al.[2022]

In a study of 1,034 African Americans and 880 non-Hispanic whites, higher levels of MR-proANP in the blood were significantly linked to increased systolic blood pressure (SBP), pulse pressure, and severity of hypertension, indicating its potential role as a biomarker for hypertension.

The associations between MR-proANP levels and hypertension metrics were consistent across both ethnic groups, suggesting that MR-proANP could be a useful indicator of arterial stiffness and hypertension severity in diverse populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma midregional pro-atrial natriuretic peptide is associated with blood pressure indices and hypertension severity in adults with hypertension. Khaleghi, M., Saleem, U., Morgenthaler, NG., et al.[2022]

M-atrial natriuretic peptide (M-ANP) significantly lowers blood pressure and systemic vascular resistance while enhancing renal function, as demonstrated in a canine model of acute hypertension with 40 amino acid peptide infusion.

Compared to human B-type natriuretic peptide, M-ANP not only has similar cardiovascular effects but also produces a greater natriuretic effect, indicating its potential as a more effective treatment for acute hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel atrial natriuretic peptide based therapeutic in experimental angiotensin II mediated acute hypertension. McKie, PM., Cataliotti, A., Boerrigter, G., et al.[2022]

In a study of 17 patients with primary hypertension, plasma levels of alpha-human atrial natriuretic peptide (hANP) were significantly elevated compared to 9 normotensive controls, indicating a potential link between hANP levels and hypertension.

The hypertensive patients showed a correlation between plasma hANP levels and both systolic and diastolic blood pressure, suggesting that hANP may play a role in blood pressure regulation and could be a target for further research in hypertension management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma levels of atrial natriuretic peptide are raised in essential hypertension during low and high sodium intake. Wambach, G., Götz, S., Suckau, G., et al.[2019]

Atrial natriuretic peptide (IR-ANP) levels increase in response to high sodium diets and are elevated in conditions like heart failure and chronic renal failure, suggesting a physiological role in fluid balance and blood pressure regulation.

Infusion of atrial peptides leads to diuresis, reduced blood pressure, and increased heart rate, indicating potential therapeutic benefits for conditions such as heart failure and hypertension, especially if stable analogues are developed for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atrial natriuretic peptides in man. Nicholls, MG., Ikram, H., Crozier, IG., et al.[2019]

In a study involving 60 spontaneously hypertensive rats, MANP significantly reduced blood pressure and increased levels of cyclic guanosine monophosphate (cGMP), indicating its effectiveness as a potent activator of the pGC-A receptor.

When combined with furosemide, MANP not only enhanced the blood pressure-lowering effects but also reduced the increase in aldosterone production typically caused by furosemide, suggesting a beneficial role in managing hypertension and preserving renal function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MANP (M-Atrial Natriuretic Peptide) Reduces Blood Pressure and Furosemide-Induced Increase in Aldosterone in Hypertension. Dzhoyashvili, NA., Iyer, SR., Chen, HH., et al.[2023]

Mutant atrial natriuretic peptide (mANP) activates cGMP in human cardiac fibroblasts and shows significantly enhanced diuretic and natriuretic effects compared to native ANP in vivo, particularly at high doses (33 pmol/kg/min).

At low doses (2 pmol/kg/min), mANP provides natriuretic and diuretic benefits without affecting systemic blood flow, unlike native ANP, indicating its potential for safer therapeutic applications in managing fluid balance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A human atrial natriuretic peptide gene mutation reveals a novel peptide with enhanced blood pressure-lowering, renal-enhancing, and aldosterone-suppressing actions. McKie, PM., Cataliotti, A., Huntley, BK., et al.[2022]

In a study of 43 subjects with essential hypertension, plasma levels of atrial natriuretic polypeptide (ANP) were significantly higher compared to those with borderline hypertension and normotensive controls, indicating a potential role of ANP in hypertension.

Effective antihypertensive therapy led to a significant reduction in plasma ANP levels after 4 weeks, suggesting that ANP could be a useful biomarker for monitoring treatment response in hypertensive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating atrial natriuretic polypeptide in essential hypertension. Kohno, M., Yasunari, K., Matsuura, T., et al.[2019]

In a study involving 11 patients with high blood pressure during surgery, intravenous injections of human atrial natriuretic peptide (hANP) significantly reduced blood pressure by an average of 27.6 mmHg with a 50 microg dose and 40.7 mmHg with a 100 microg dose, both with high statistical significance (P < 0.001).

The administration of hANP also led to a substantial increase in urine output without affecting heart rate or oxygen levels, suggesting it is a safe and effective option for managing acute hypertension during anesthesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of intravenously administered human atrial natriuretic peptide on elevated blood pressure during surgery. Iwatsuki, N., Katoh, M., Yasuda, A., et al.[2018]

The mutant form of atrial natriuretic peptide (mANP) negatively affects heart cell function, leading to decreased action potential upstroke velocity and increased risk of atrial fibrillation, while the normal form (wild-type ANP) has protective effects against arrhythmias.

In experiments with mice, mANP slowed electrical conduction in the atria and induced arrhythmias in 62.5% of cases, whereas wild-type ANP improved conduction and completely prevented arrhythmias, highlighting its potential as an antiarrhythmic agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Wild-Type and Mutant Forms of Atrial Natriuretic Peptide on Atrial Electrophysiology and Arrhythmogenesis. Hua, R., MacLeod, SL., Polina, I., et al.[2015]

Citations

1. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.121.18837

MANP (M-Atrial Natriuretic Peptide) Reduces Blood ... Data confirmed renal protective properties of MANP, which enhanced renal function despite a decrease in BP, whereas nitroglycerin did not appear ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8666702/

A FIRST IN HUMAN STUDY OF MANP: A NOVEL ATRIAL ... MANP was safe, well-tolerated and activated cGMP, induced natriuresis, reduced aldosterone, and decreased BP at or below the maximal tolerated dose. Thus, MANP ...

3. jacc.org jacc.org/doi/10.1016/j.jacbts.2023.08.011

MANP in Hypertension With Metabolic Syndrome: Proof-of- ... The study showed that 3 single ascending doses of MANP were safe, well-tolerated, and increased plasma levels of cGMP. Moreover, MANP lowered BP ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2452302X23004163

MANP in Hypertension With Metabolic Syndrome: Proof-of- ... The study showed that 3 single ascending doses of MANP were safe, well-tolerated, and increased plasma levels of cGMP. Moreover, MANP lowered BP values and ...

5. academic.oup.com academic.oup.com/eurheartj/article/44/Supplement_2/ehad655.2365/7393102

Cardiovascular and metabolic effects of MANP. a novel GC-A ... At 6 hours, systolic BP decreased by 5.7 ± 2.9 mmHg (P = 0.06) in the MANP group, whereas no reduction in BP was observed in placebo group.

6. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.121.17159

First-in-Human Study of MANP: A Novel ANP (Atrial ... MANP was safe, well tolerated, activated cGMP, induced natriuresis, reduced aldosterone, and decreased blood pressure at or below the maximal ...

7. academic.oup.com academic.oup.com/eurheartj/article/45/Supplement_1/ehae666.2582/7835499

Safety, tolerability and blood pressure lowering of the ... MANP was safe and well tolerated. One patient in the 7 ug/kg cohort was discontinued due to symptomatic hypotension. Compared to baseline, ...