Prelude Therapeutics' PRT3789 Shows Promising Activity and Safety in Phase 1 Trial

Prelude Therapeutics Incorporated, a precision oncology company, has announced the first interim clinical data from its ongoing Phase 1 trial of PRT3789. This investigational drug is a first-in-class SMARCA2 degrader designed for cancer patients with SMARCA4 mutations. The data was presented at the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain.

As of August 5, 2024, the trial had enrolled and treated 65 patients, out of which 46 were evaluated for efficacy. The trial's primary aim is to determine the safety and efficacy of PRT3789. Encouraging results were observed, with the drug being generally well-tolerated across eight dosing cohorts. No dose-limiting toxicities or serious adverse events related to the study drug were reported. Dose escalation is ongoing, and a maximum tolerated dose has not yet been identified.

In terms of efficacy, among the 26 evaluable patients with advanced non-small cell lung cancer (NSCLC) or esophageal cancer, seven showed tumor shrinkage. Three of these patients had confirmed partial responses. Additionally, some patients experienced prolonged stable disease, with one patient remaining on treatment for over a year.

Dr. Robin Guo from Memorial Sloan Kettering Cancer Center remarked that the observations of durable stable disease and tumor regressions are promising, especially given the aggressive nature of cancers with SMARCA4 mutations. Dr. Jane Huang, President and Chief Medical Officer of Prelude, highlighted the initial proof of concept that selective SMARCA2 degradation can be effective against certain SMARCA4 mutated cancers.

The ongoing Phase 1 trial evaluates PRT3789 in patients with solid tumors harboring any SMARCA4 mutation. As of the data cutoff, 65 patients, with a median age of 62 and a median of three prior treatments, were treated at eight dose levels ranging from 24 mg to 376 mg once weekly. The majority of adverse events reported were mild to moderate, with nausea being the most common. No dose-limiting toxicities were observed.

Preliminary pharmacokinetic (PK) data showed a dose-dependent increase in drug exposure with no accumulation observed on repeat dosing. Pharmacodynamic (PD) effects included a prolonged inhibition of SMARCA2, demonstrating the high selectivity of PRT3789.

Efficacy analysis revealed that among 46 evaluable patients, seven experienced tumor shrinkage, including three confirmed partial responses in advanced NSCLC and esophageal cancer patients. Tumor shrinkage was observed in patients with both Class 1 and Class 2 SMARCA4 mutations. However, no tumor shrinkage was seen in patients with other tumor types at the doses studied to date.

Prelude Therapeutics plans to continue dose escalation and identify a biologically active dose by year-end. The company also aims to advance monotherapy and combination studies with docetaxel to establish PRT3789 as a new treatment option for aggressive cancers with SMARCA4 mutations.

PRT3789 is a first-in-class, highly selective SMARCA2 degrader, currently in Phase 1 clinical development for patients with SMARCA4 mutations. The trial aims to establish the safety, tolerability, and efficacy of PRT3789 as both a monotherapy and in combination with docetaxel, to determine the appropriate dose for future clinical trials.

Prelude Therapeutics is committed to delivering innovative cancer treatments. Their pipeline includes novel drug candidates such as SMARCA2 degraders and a potentially best-in-class CDK9 inhibitor. The company leverages its expertise in targeted protein degradation to develop next-generation therapies aimed at addressing high unmet needs in oncology.