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Prelude Therapeutics Cleared by FDA to Start Phase I Trial of SMARCA2 Degrader

NEW YORK – Prelude Therapeutics said Tuesday that the US Food and Drug Administration has cleared it to begin a Phase I trial of its selective SMARCA2 protein degrader PRT3789 in patients with advanced solid tumors with SMARCA4 mutations.

The SMARCA2 and SMARCA4 proteins, also known as BRM and BRG1, respectively, are involved in chromatin remodeling and repair. Cancer cells that have lost functionality of SMARCA4 due to mutations become heavily dependent on SMARCA2 for survival.

Prelude has hypothesized that targeting SMARCA2 will lead to a synthetic lethality effect in SMARCA4-mutated cancer cells while sparing healthy cells with wild-type SMARCA4. SMARCA4 is mutated in multiple cancers, including 10 to 12 percent of non-small cell lung cancers.

According to the firm, preclinical studies have shown selective degradation of SMARCA2 by PRT3789, leading to significant anti-tumor activity at doses that were well tolerated. The Phase I study will enroll patients with advanced solid tumors bearing relevant SMARCA4 alterations and will be enriched for patients with non-small cell lung cancer. The goal of the trial will be to evaluate safety and tolerability of the drug and establish a recommended Phase II dose.

In the trial, the Wilmington, Delaware-based company will also investigate the best way to test patients for SMARCA4 mutations. "There is a significant need for treatment options for patients with cancers carrying genetic alterations in SMARCA4 because these patients do not generally present with other targetable oncogenic drivers," Prelude President and Chief Medical Officer Jane Huang said in a statement.