Prelude Therapeutics Unveils SMARCA Degrader Data at 36th EORTC-NCI-AACR Symposium

Prelude Therapeutics Incorporated, a clinical-stage precision oncology company, has released important new data from its ongoing Phase 1 trial of PRT3789. This first-in-class, highly selective SMARCA2 degrader targets cancer patients with a SMARCA4 mutation. The data were revealed at the 36th Annual EORTC-NCI-AACR Symposium in Barcelona, Spain.

As of September 23, 2024, the trial involved 65 patients with advanced solid tumors, including non-small cell lung cancer (NSCLC) and esophageal cancer. These patients had previously undergone extensive treatments. The majority of the adverse events reported were mild to moderate, and PRT3789 was well-tolerated across the eight dosing cohorts.

Notably, out of 26 patients with Class 1 (loss of function) mutations who were evaluated for efficacy, partial responses were confirmed in four patients, including two NSCLC patients at doses of 283 mg or higher. Higher doses of PRT3789 resulted in more profound and sustained SMARCA2 degradation. Additionally, some patients experienced prolonged stable disease, with one particular patient remaining on treatment for over a year.

Jane Huang, M.D., President and Chief Medical Officer of Prelude, expressed optimism about the promising activity demonstrated by PRT3789 for patients with limited treatment options. She highlighted their commitment to further characterizing the potential of PRT3789 through ongoing monotherapy dose escalation and combination studies with docetaxel and pembrolizumab.

In the trial, PRT3789 was administered through weekly intravenous infusions at doses ranging from 24 mg to 376 mg. The study's median patient age was 62, with a median of three prior treatments. Among the participants, 52.3% had Class 1 SMARCA4 mutations, 36.9% had Class 2 (missense, VUS) mutations, and 10.8% exhibited a loss of SMARCA4 protein.

PRT3789 demonstrated good tolerability, with common treatment-emergent adverse events including nausea, fatigue, anemia, decreased appetite, abdominal pain, and constipation. Importantly, no dose-limiting toxicities or study drug-related serious adverse events were observed. Preliminary pharmacokinetic data showed a trend of increased exposure with higher doses, and pharmacodynamic effects indicated more prolonged SMARCA2 degradation at doses above 212 mg.

The initial clinical activity analysis revealed partial responses in 4 out of 26 advanced NSCLC or esophageal cancer patients with Class 1 mutations. Tumor shrinkage was observed in patients with both Class 1 and Class 2 mutations. One advanced NSCLC patient maintained stable disease for over a year while on study treatment.

Preliminary safety data from the combination arm of the trial involving PRT3789 and docetaxel showed an acceptable safety profile, with no dose-limiting toxicities or serious adverse events reported.

In addition to these clinical findings, Prelude presented preclinical data on a novel precision antibody drug conjugate program utilizing a SMARCA2/4 dual degrader payload. This approach demonstrated significant anti-tumor activity in SMARCA4-mutated NSCLC models when combined with standard chemotherapy agents. Furthermore, PRP0004, a potent SMARCA2/4 dual degrader, displayed promising results in prostate cancer xenografts, especially when delivered as a payload on anti-PSMA antibodies.

Peggy Scherle, Ph.D., Chief Scientific Officer of Prelude, highlighted the potential of this novel approach to significantly expand the application of Prelude’s SMARCA degraders beyond cancers with SMARCA4 mutations. This strategy aims to deliver targeted degradation while sparing healthy tissues, thus offering a promising new avenue for cancer treatment.

PRT3789 remains in Phase 1 clinical development, with enrollment on track. Prelude plans to conclude monotherapy dose escalation by the end of 2024 and identify a biologically active dose for future registrational trials. The company is also enrolling patients into back-fill cohorts to assess clinical activity in a more homogeneous group with high unmet medical needs.

Prelude Therapeutics is dedicated to developing innovative precision oncology treatments, with a pipeline that includes first-in-class SMARCA2 degraders and a potentially best-in-class CDK9 inhibitor. The company leverages its expertise in targeted protein degradation to create next-generation degrader antibody conjugates in partnership with other entities, aiming to extend the benefits of precision medicine to all cancer patients in need.