How Effective is the New Blood Pressure Medication NPR1 Agonist XXB750?

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Once a Month”: How Effective is the New Blood Pressure Medication NPR1 Agonist XXB750?

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Once a Month”: How Effective is the New Blood Pressure Medication NPR1 Agonist XXB750?

Hypertension stands as one of the most prevalent and burdensome diseases globally.

Despite various effective methods for treating high blood pressure, 70-80% of patients fail to achieve proper control. In recent years, a plethora of novel antihypertensive drugs, such as the natriuretic peptide receptor 1 agonist (XXB750), endothelin A receptor antagonist (aprocitentan), aminopeptidase A inhibitor (firibastat), aldosterone synthase inhibitor (baxdrostat), and angiotensinogen RNAi (zilebesiran), have emerged, undergoing clinical trial development based on different mechanisms and targets.

Mechanism of NPR1 Agonist for Blood Pressure Reduction:

The natriuretic peptides (NPs) system plays a role in blood pressure regulation.

Previous studies have demonstrated that NPs, by binding to the receptors of atrial natriuretic peptide and B-type natriuretic peptide, specifically natriuretic peptide receptor 1 (NPR1), activate downstream guanylate cyclase, promoting the synthesis of cyclic guanosine monophosphate (cGMP). cGMP, as a second messenger in downstream signaling, induces effects such as natriuresis, diuresis, and vasodilation, contributing to blood pressure reduction.

Animal experiments have shown that disrupting the NPR1 gene in mice leads to elevated blood pressure (35-45 mmHg higher compared to the wild type), with heterozygous knockout mice at risk of salt-sensitive hypertension. Based on this foundational research, NPR1 agonists are hypothesized to have antihypertensive effects.

First Human Clinical Trial Results Presented at AHA 2023:

From November 11 to 13, 2023, the American Heart Association’s Scientific Sessions (AHA 2023) took place in Philadelphia. On the 12th, Professor YanLing He publicly disclosed the first human clinical trial results of the NPR1 agonist XXB750, evaluating its antihypertensive efficacy, safety, tolerability, and pharmacokinetics, laying the foundation for determining future safe and effective drug doses and administration methods.

Study Methodology:

This double-blind, placebo-controlled clinical trial included 77 healthy subjects randomly assigned to receive a single subcutaneous injection of XXB750 or a placebo in a 6:2 ratio. The XXB750 group was further divided into 10 dose groups (8 subjects each).

The study evaluated the incremental doses of XXB750 in the 10 groups:

• Healthy subjects received single subcutaneous injections of 1 mg, 3 mg, 10 mg, 30 mg, 60 mg, 120 mg, and 240 mg XXB750 in seven dose groups.
• Japanese subjects received a single subcutaneous injection of 240 mg XXB750.
• Hypertensive subjects received single subcutaneous injections of 450 mg and 600 mg XXB750 in two dose groups.

Study Endpoints included safety, pharmacokinetics, and pharmacodynamics, measured by dynamic blood pressure monitoring (ABPM) and plasma cGMP levels. Follow-up for all endpoints extended to 91 days.

Study Results:

Out of the 77 subjects, 73 completed the study, with 4 withdrawing for reasons unrelated to the study treatment. Results indicated overall safety and good tolerability of XXB750, with peak times at 4-10 days and a half-life of 15-25 days at doses ≥60 mg.

Key Findings:

1. Plasma cGMP Levels:

   • Doses ≥30 mg increased plasma cGMP levels 1.8-7.8 times on day 2 (p < 0.001) and 1.3 times on day 28.

   • Doses ≥60 mg maintained significantly elevated plasma cGMP levels on day 28 (increase of approximately 1.5-2.5 times, p < 0.05), compared to doses ≥30 mg (p = 0.115).

2. ABPM Measured Systolic Blood Pressure (SBP):

   • Dose-dependent reduction in SBP was observed.
   • Doses ≥30 mg lowered ABPM-measured SBP by 6.6-23 mmHg on day 2 (p < 0.01), except for the 60 mg dose group (p = 0.122).
   • Doses ≥120 mg maintained sustained SBP reduction on day 28 (decrease of 8-16 mmHg, p < 0.05).

3. ABPM Measured Diastolic Blood Pressure (DBP):

   • Limited effect on DBP, observed at doses ≥240 mg with a significant reduction on day 2 (6-11 mmHg decrease, p < 0.05).

4. Safety:

   • Adverse reactions were transient, with a temporary increase in heart rate observed at doses ≥30 mg.
   • Two subjects receiving 600 mg experienced symptomatic tachycardia (self-resolving).

Study Conclusion:

The novel long-acting NPR1 agonist XXB750 significantly increased plasma cGMP levels and demonstrated antihypertensive effects.

While promising, this study serves as preliminary verification of XXB750’s efficacy and safety, necessitating further confirmation in phase 2 and 3 clinical trials.

Expert Commentary:

Over the past decade, research has shown that components of the natriuretic peptide system regulate blood pressure.

XXB750, a new drug, leverages NPR1 activation to modulate this system pharmacologically.

The study highlights two significant advantages of XXB750:

1. XXB750, at doses ≥30 mg, rapidly lowered systolic blood pressure by 6.6-23 mmHg on day 2, with sustained effects at doses ≥120 mg on day 28 (8-16 mmHg reduction), indicating its potent single-agent efficacy for reducing systolic blood pressure. However, its effect on diastolic blood pressure is limited, observed significantly only at the maximum dose (≥240 mg) on day 2 (6-11 mmHg reduction).

2. Monthly dosing intervals significantly enhance patient compliance.

As a phase 1 clinical study, this trial preliminarily confirmed XXB750’s safety and tolerability with a single subcutaneous injection in humans.

Phase 2 clinical studies (NCT05562934, NCT05328752) are ongoing, assessing XXB750 further in patients with resistant hypertension and HFrEF/HFmrEF, with results expected in 2024.

These findings will provide further clarity on XXB750’s therapeutic effects and drug safety in target patient populations.

In summary, as a novel drug targeting the natriuretic peptide system, the first human study of NPR1 agonist XXB750 demonstrates powerful blood pressure reduction and extended dosing intervals, potentially significantly improving control and compliance in hypertensive patients, ultimately leading to a significant improvement in prognosis.

Once a Month”: How Effective is the New Blood Pressure Medication NPR1 Agonist XXB750?

References:

[1] Capri Y, Kwon T, Boyer O, et al. Biallelic NPR1 loss of function variants are responsible for neonatal systemic hypertension. J Med Genet. 2023 Oct;60(10):993-998. doi: 10.1136/jmg-2023-109176.
[2] YanLing He, et al. Safety and Blood Pressure Lowering Effects of a Novel and Long-Acting Natriuretic Peptide Receptor 1 Agonist in Healthy Participants: A First-in-Human Clinical Study. AHA 2023. Featured Science 3.

(source:internet, reference only)

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