Prelude Therapeutics' PRT3789 Shows Promise in SMARCA4-Mutated Cancers

Prelude Therapeutics查看公司主页 Incorporated (NASDAQ: PRLD) has announced promising initial clinical data from its Phase 1 trial of PRT3789查看药品详情, a first-in-class SMARCA2 (搜索)搜索该靶点 degrader, in patients with advanced solid tumors harboring SMARCA4 (搜索)搜索该靶点 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 (搜索)搜索该疾病 (NSCLC) and esophageal cancer (搜索)搜索该疾病.

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查看药品详情 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 (搜索)搜索该疾病 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 (搜索)搜索该靶点-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 (搜索)搜索该靶点 degradation can yield antitumor activity in certain SMARCA4 (搜索)搜索该靶点-mutated cancers. The company intends to confirm the biologically active dose for PRT3789查看药品详情 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 (搜索)搜索该疾病 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 (搜索)搜索该靶点 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 (搜索)搜索该靶点 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 (搜索)搜索该靶点, indicating high selectivity of PRT3789查看药品详情.

Prelude's Broader Strategy

In addition to PRT3789查看药品详情, Prelude Therapeutics查看公司主页 is developing precision degrader antibody conjugates. Preclinical data suggest that a potent dual SMARCA2 (搜索)搜索该靶点/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 (搜索)搜索该靶点 mutations.

Prelude Therapeutics查看公司主页 is also collaborating with Merck (搜索)搜索该词条 to initiate a Phase 2 clinical trial, combining PRT3789查看药品详情 with Merck's anti-PD-1 therapy, KEYTRUDA查看药品详情.