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Prelude Therapeutics Collaborates With Merck to Evaluate PRT3789 in Combination With KEYTRUDA

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Prelude Therapeutics has announced a new clinical trial collaboration and supply agreement with Merck to evaluate PRT3789 in combination with KEYTRUDA (pembrolizumab). Under the terms of the new agreement, a Phase II clinical study will commence to evaluate the combination. Merck will provide KEYTRUDA to Prelude, which will be the sponsor of the Phase II trial.1

PRT3789 is Prelude’s investigational, highly selective, first-in-class SMARCA2 degrader while Merck’s KEYTRUDA is an anti-PD-1 therapy.

“We are excited for this opportunity to work together with Merck on this study combining our novel, highly selective SMARCA2 degrader with KEYTRUDA,” Prelude’s President and Chief Medical Officer Jane Huang, MD said in a press release. “Through this collaboration of potentially complementary mechanisms, we may have the potential to positively impact clinical outcomes in patients harboring a SMARCA4 mutation, who have previously been known to have limited treatment options.”

The SMARCA2 degrader, PRT3789, received Investigational New Drug (IND) clearance from the FDA in October 2022. The clearance allowed Prelude to proceed with a Phase I study (NCT05639751) of PRT3789 in patients with advanced solid tumors in a biomarker selected SMARCA4 mutated population.2

“Preclinical models with SMARCA4 deletions demonstrated that selective degradation of SMARCA2 with our potent and highly selective molecule PRT3789, resulted in significant anti-tumor activity at well tolerated doses,” Peggy Scherle, PhD, chief scientific officer of Prelude said in an earlier press release. “Historically, structural similarities between members of the SMARCA family have made it challenging to selectively inhibit SMARCA2. Based on the breadth and depth of Prelude’s discovery engine expertise however, we have found an innovative solution by leveraging the emerging technology of targeted protein degradation to achieve exceptional selectivity for SMARCA2 over SMARCA4.”

Huang added: “Clearance of the IND for PRT3789 represents a major milestone for Prelude Therapeutics, as we advance our first-in-class SMARCA2 protein degrader from discovery to the clinic. There is a significant need for treatment options for patients with cancers carrying genetic alterations in SMARCA4 (BRG1) because these patients do not generally present with other targetable oncogenic drivers. While the field is evolving around SMARCA mutations, early observations indicate that patients with SMARCA mutations have aggressive disease with an urgent need for more therapies. Patients with specific SMARCA4 loss of function mutations can be easily identified with standard next generation sequencing panels and understanding how to best identify the patients who will benefit the most from PRT3789 will be investigated in the Phase I study.”

The Phase I clinical trial of PRT3789 is an open-label, multi-center, dose-escalation, first in human study. In addition to evaluating the SMARCA2 degrader as a monotherapy, the study has an arm evaluating PRT3789 in combination with docetaxel.3

According to Prelude, enrollment for the Phase I study of PRT3789 remains on track. The company expects to conclude monotherapy dose escalation mid-2024 and identify the recommended Phase II dose. In addition, enrollment of patients into back-fill cohorts enriched for non-small cell lung cancer (NSCLC) and SMARCA4 loss-of-function mutations is ongoing.

References

1. PRELUDE THERAPEUTICS ANNOUNCES CLINICAL COLLABORATION WITH MERCK TO EVALUATE PRT3789 IN COMBINATION WITH KEYTRUDA® (PEMBROLIZUMAB) IN PATIENTS WITH SMARCA4-MUTATED CANCERS. News release. Prelude Therapeutics. July 9, 2024. Accessed July 10, 2024. https://investors.preludetx.com/news-releases/news-release-details/prelude-therapeutics-announces-clinical-collaboration-merck

2. PRELUDE THERAPEUTICS RECEIVES FDA CLEARANCE OF IND FOR PRT3789, A POTENT AND SELECTIVE FIRST-IN-CLASS SMARCA2 PROTEIN DEGRADER. News release. Prelude Therapeutics. October 18, 2022. Accessed July 10, 2024. https://investors.preludetx.com/news-releases/news-release-details/prelude-therapeutics-receives-fda-clearance-ind-prt3789-potent

3. PRT3789 Monotherapy and in Combo w/​Docetaxel in Participants w/​Advanced or Metastatic Solid Tumors w/​SMARCA4 Mutation. ClinicalTrials.gov. Accessed July 10, 2024. https://clinicaltrials.gov/study/NCT05639751