Citations

Introduction: Obstructive hypertrophic cardiomyopathy (oHCM) consists of a constellation of LV hypercontractility, LV outflow tract obstruction (LVOTO), and impaired relaxation, often resulting in dyspnea and reduced exercise capacity. In healthy dogs, the novel myosin modulator mavacamten (MAVA), decreased LV hypercontractility and improved compliance. In the PIONEER-HCM clinical study, improvements in post-exercise LVOT gradient, exercise capacity, and symptoms were reported. To examine whether MAVA could also limit residual myosin-actin cross-bridges during diastole, and improve LV compliance, its effects on diastolic indices were evaluated. Methods: In PIONEER-HCM, an open-label, multi-site, prospective study, oHCM subjects received MAVA for 12 weeks at either 10-20 mg/d (n = 11, Cohort A; 10 completed) or at 2-5 mg/d (n = 10, Cohort B). Echo-Doppler indices of LV filling and relaxation were compared at baseline to week 12. The p-values are from Wilcoxon signed rank tests, evaluating the distribution of within-subject 12-wk changes from baseline around a null of zero. Results: MAVA reduced hypercontractility in a dose-dependent fashion, with relief of LVOTO in all subjects achieving plasma MAVA concentration >350 ng/ml (data previously reported). There was also an increase in mitral annular velocity during early diastole (e’ lat ). There was a concomitant reduction in E/e’ lat and increase in LV end-diastolic volume (LVEDV) consistent with improved LV compliance (Table). MAVA improved dyspnea score with a trend towards reduction in NT-proBNP. Conclusions: Administration of MAVA is associated with improvement in measures of myocardial relaxation (e’ lat ) and compliance in parallel with reduction in LVOT gradient. These findings are consistent with preclinical findings reported in healthy dogs and support additional evaluation of MAVA in patients with obstructive or non-obstructive HCM.

2549 Background: BDC-1001 is a novel ISAC consisting of an investigational trastuzumab biosimilar chemically conjugated to a TLR 7/8 agonist with a non-cleavable linker. BDC-1001 was designed to activate the innate immune system, eliciting antibody-mediated effector functions (eg, antibody-dependent cellular phagocytosis) and a durable adaptive immune response. In preclinical tumor models resistant to anti-HER2 treatments, BDC-1001 demonstrated potent and durable immune-mediated antitumor efficacy. Methods: A 4-part, phase 1/2 dose-escalation/expansion study was initiated to evaluate BDC-1001 ± PD1 inhibitor pembrolizumab in pts with HER2-expressing solid tumors who had progressive disease on standard of care (NCT04278144). Preliminary results of the monotherapy dose escalation (Part 1) are reported. Pts with advanced metastatic HER2-expressing (IHC2/3+) or amplified solid tumors received BDC-1001 IV q3w in a 3+3 design w/ 12 pts/cohort backfill allowed. Primary objectives were to evaluate safety, tolerability, dose-limiting toxicities (DLTs) and determine a phase 2 dose; secondary objectives were to assess pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity. Results: As of Jan 29, 2021, 20 pts w/ a median age of 65 (46-85) have enrolled in 4 dose levels (0.15mg/kg to 5 mg/kg). Cancer types include breast, biliary, cervical, colorectal (CRC), lung, gastroesophageal, salivary, urinary tract and endometrial. Pts had received a median of 4 (1-7) prior therapies; 65% received >1 prior anti-HER2 therapy. All pts completed the 21-day DLT period; no DLTs or drug-related serious adverse events (AEs) have been observed. AEs deemed related to BDC-1001 have been mild to moderate including infusion-related reactions. The MTD has not been reached (treatment duration 5-17+wk); enrollment is ongoing. PK evaluations showed Cmax levels consistent with predicted modeling based on non-human primates (NHP). One pt with microsatellite stable (MSS) HER2+ CRC with lung metastases had a confirmed partial response after 4 cycles and remains on study; 2 additional pts with metastatic MSS HER2+ CRC had stable disease (SD) and a pt with heavily pretreated MSS endometrial cancer with lung metastases had confirmed SD and remains on treatment 17+ wk; 3 of these pts had received 2 prior anti-HER2 therapies. Conclusions: In this first-in-human study, BDC-1001 appears to be well-tolerated up to the dose tested to date (5 mg/kg), with Cmax levels achieved as predicted by NHP modeling. Evidence of clinical activity have been observed, including in pts previously treated with anti-HER2 therapy. Dose escalation is ongoing and will be followed by combination dosing with CPI and the phase 2 component in selected tumors. Clinical trial information: NCT04278144.