HRS-1893 at 60 mg BID reduced resting LVOT gradient by 91% and Valsalva LVOT gradient by 87.4% by Day 5 in obstructive HCM with maintained LVEF safety.
Does HRS-1893 demonstrate safety, tolerability, and hemodynamic improvement in patients with symptomatic obstructive hypertrophic cardiomyopathy?
HRS-1893, a novel reversible cardiac myosin inhibitor, demonstrated a favorable safety profile and rapidly reduced left ventricular outflow tract gradients in a phase 1 trial of patients with obstructive hypertrophic cardiomyopathy.
Absolute Event Rate: 0% vs 0%
Abstract Background Hypertrophic cardiomyopathy (HCM) is characterized by increased left ventricular (LV) wall thickness and dynamic obstruction of the LV outflow tract (LVOT). HRS-1893 is a selective reversible cardiac myosin inhibitor designed to reduce hypercontractility in HCM by inhibiting the myosin adenosine triphosphate activity. Purpose This phase 1 clinical trial evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of HRS-1893 through single and multiple ascending dose (MAD) regimens in both healthy volunteers and patients with obstructive HCM (oHCM). Here, we focus on the oHCM patient cohort, presenting its safety profile, PK/PD characteristics, and preliminary efficacy data. Methods Patients with symptomatic oHCM meeting specific criteria (resting LVOT gradient LVOT-G ≥50 mmHg or resting LVOT-G ≥30 mmHg with post-Valsalva LVOT-G ≥50 mmHg, and LV ejection fraction LVEF ≥60%) were enrolled in the MAD part. Three dose cohorts (40 optional, 60, and 80 mg) were planned. In each cohort, eight patients were randomized (6:2) to receive either HRS-1893 or placebo orally twice daily for 14 consecutive days. The primary endpoints were safety and tolerability. Results In healthy volunteers, the 40 mg BID dose group showed favourable safety profiles in MAD studies, but a dose-dependent reduction in LVEF was observed. Given that oHCM patients tolerate myosin inhibition better due to their hypertrophic myocardium, the initial therapeutic dose for oHCM patients in MAD cohorts was set at 60 mg. HRS-1893 was well tolerated, with all adverse events being mild. The mean LVEF slightly decreased after HRS-1893 treatment, while the placebo group showed no obvious changes (Figure 1). No HRS-1893-treated patients had an LVEF 50% during the study, and all but one patient had an LVEF percentage reduction of 20% from baseline. LVEF returned to baseline after treatment discontinuation. HRS-1893 plasma concentration reached a steady state on Day 8. The ratio of accumulation at steady state was 1.30 for Cmax and 2.04 for AUCtau. HRS-1893 administration induced significant hemodynamic improvements, with mean resting LVOT-G decreasing 91.0% (71.2 mmHg to 6.0 mmHg) and Valsalva LVOT-G decreasing 87.4% (66.6 mmHg to 8.0 mmHg) by Day 5 (Figure 2). The effect in LVOT-G reduction was maintained up to the end of treatment. On Day 14, all patients in the HRS-1893 group had Valsalva LVOT-G of ≤30 mmHg. Cardiac biomarkers like N-terminal pro-B-type natriuretic peptide also showed consistent directional improvements, with a 60% reduction compared to baseline. Dose escalation was discontinued following successful proof-of-concept demonstration in the 60 mg cohort. Conclusion HRS-1893 demonstrated favourable safety and PK profiles. It rapidly and effectively reduced resting and Valsalva LVOT-G, while keeping LVEF within the safety limits, providing a novel treatment option for patients with obstruction HCM.Figure 1 Figure 2
Kang et al. (Sat,) reported a other. HRS-1893 at 60 mg BID reduced resting LVOT gradient by 91% and Valsalva LVOT gradient by 87.4% by Day 5 in obstructive HCM with maintained LVEF safety.