Prelude Therapeutics Incorporated (NASDAQ: PRLD) has announced promising initial clinical data from its Phase 1 trial of PRT3789, a first-in-class SMARCA2 degrader, in patients with advanced solid tumors harboring SMARCA4 mutations. The data, presented at the European Society for Medical Oncology (ESMO) Congress 2024, suggest that PRT3789 is well-tolerated and demonstrates encouraging anti-tumor activity, particularly in non-small cell lung cancer (NSCLC) and esophageal cancer.
The Phase 1 open-label, dose-escalation trial enrolled 65 patients, with 46 being efficacy evaluable. As of the August 5, 2024, data cutoff, PRT3789 was generally well-tolerated across eight dosing cohorts, with dose escalation continuing into the ninth cohort. The majority of adverse events reported were mild to moderate, and a maximum tolerated dose has not yet been identified.
Clinical Activity and Safety
Of the 26 advanced NSCLC or esophageal cancer patients evaluable for efficacy, 7 exhibited tumor shrinkage. Three patients achieved RECIST-confirmed partial responses (2 esophageal, 1 NSCLC). Additional patients demonstrated clinical benefit through prolonged stable disease, with one patient remaining on treatment for over a year. According to Robin Guo, M.D., Memorial Sloan Kettering Cancer Center, SMARCA4-mutated cancers are aggressive with poor prognosis, making these early results encouraging.
Jane Huang, M.D., President and Chief Medical Officer of Prelude, stated that the data provide initial proof of concept that selective SMARCA2 degradation can yield antitumor activity in certain SMARCA4-mutated cancers. The company intends to confirm the biologically active dose for PRT3789 as monotherapy by year-end and continue to advance monotherapy and docetaxel combination studies.
Detailed Trial Data
The Phase 1 trial included patients with solid tumors harboring any SMARCA4 mutation refractory to standard of care. Patients had received a median of 3 prior treatments (range 1-10). Of the patients, 52.3% had a Class 1 (loss of function) SMARCA4 mutation, 36.9% had a Class 2 (missense, VUS) SMARCA4 mutation, and 10.8% had a loss of SMARCA4 protein.
Adverse events of any grade included nausea (24.5%), decreased appetite (18.5%), fatigue (18.5%), abdominal pain (16.9%), anemia (16.9%), and constipation (15.4%). No dose-limiting toxicities or study drug-related serious adverse events were reported.
Pharmacokinetics and Pharmacodynamics
Preliminary pharmacokinetic data from 24 mg to 376 mg dose cohorts showed a general trend of increased exposure with dose. Mean concentrations exceeded the SMARCA2 plasma DC50 (21 nM) for approximately 8 hours at the 376 mg dose. No accumulation was observed with repeat dosing. The pharmacodynamic effect was more prolonged than the pharmacokinetic half-life, reaching trough inhibition of 70-75% at higher doses. Evaluation of the AUC of PD demonstrated a dose-dependent decrease of SMARCA2 but not SMARCA4, indicating high selectivity of PRT3789.
Prelude's Broader Strategy
In addition to PRT3789, Prelude Therapeutics is developing precision degrader antibody conjugates. Preclinical data suggest that a potent dual SMARCA2/4 degrader payload can be attached to an antibody to specifically target tumor cells, potentially offering an alternative to chemotherapy payloads on antibody-drug conjugates (ADCs) and expanding treatment possibilities beyond cancers with SMARCA4 mutations.
Prelude Therapeutics is also collaborating with Merck to initiate a Phase 2 clinical trial, combining PRT3789 with Merck's anti-PD-1 therapy, KEYTRUDA.
