공시 • Oct 24
Prelude Therapeutics Incorporated Presents New Data from SMARCA Degrader Portfolio at the 36th EORTC-NCI-AACR Symposium
Prelude Therapeutics Incorporated announced the presentation of additional data from its ongoing Phase 1 open-label, dose-escalation trial of PRT3789, a first-in-class, highly selective SMARCA2 degrader designed to treat cancer patients with a SMARCA4 mutation. The data were presented at a plenary session of the 36th Annual EORTC-NCI-AACR Symposium in Barcelona, Spain. The study investigators reported, as of September 23, 2024 (the Cutoff Date), additional follow up data on 65 patients that were enrolled, treated, and safety evaluable. PRT3789 was generally well-tolerated through 8 dosing cohorts. The majority of adverse events reported by investigators have been mild to moderate. Overall, of the 26 advanced, heavily pre-treated NSCLC or esophageal patients with Class 1 (loss of function) mutations evaluable for efficacy, now with additional follow up, RECIST partial responses (PRs) were confirmed in 4 patients, including 2 of 9 NSCLC patients with confirmed PRs at doses of 283 mg or higher. As anticipated, higher doses are resulting in deeper and more sustained SMARCA2 degradation in PBMCs. Additional patients demonstrated clinical benefit as measured by prolonged stable disease (SD) including one patient on treatment for more than a year. PRT3789 Interim Phase 1 Results PRT3789 is currently being evaluated in an ongoing dose-escalation Phase 1 trial in heavily pre-treated patients with advanced solid tumors harboring any SMARCA4 mutation who have relapsed/refractory disease. Sixty-five patients with advanced cancer were treated once weekly via intravenous infusion at eight dose levels (24 mg, 48 mg, 80 mg, 120 mg, 160 mg, 212 mg, 283 mg, 376 mg), and follow up data reported through to September 23, 2024. The median age of these patients was 62 and the median number of prior treatments was 3 (ranging from 1-10). 34 patients (52.3%) presented with a Class 1 (loss of function) SMARCA4 mutation, while 24 patients (36.9%) presented with a Class 2 (missense, VUS) SMARCA4 mutation and 7 (10.8%) had a loss of SMARCA4 protein. Initial Safety Data PRT3789 was generally well-tolerated. Treatment emergent adverse events of any grade observed to date consisted of nausea (26.2%), fatigue (21.5%), anemia (20.0%), decreased appetite (20.0%), abdominal pain (18.5%), and constipation (18.5%). No dose limiting toxicities were observed and no study drug-related serious adverse events were reported. Pharmacokinetic (PK) and Pharmacodynamic (PD) Data Preliminary PK data was available from 24 mg to 376 mg dose cohorts. A general trend of increases in exposure (Cmax, AUC) with dose was observed. Mean concentrations were observed above SMARCA2 plasma DC50 (21 nM) for approximately 8 hours at the 376 mg dose. No accumulation was observed with repeat dose administration, consistent with the half-life and once-weekly administration. PD effect (as measured by SMARCA2 protein levels in peripheral blood mononuclear cells) observed was more prolonged than PK half-life. Higher dose levels, above 212 mg, demonstrated a deeper, more consistent, and more prolonged PD effect. SMARCA2 degradation was observed in both peripheral blood mononuclear cells (PBMC) and in available tumor tissue as shown through biopsy. Analysis of Initial Clinical Activity Of the 26 advanced NSCLC or esophageal patients with Class 1 (loss of function) mutations who were evaluable for efficacy, RECIST confirmed partial responses (PRs) were observed in 4 patients (2 esophageal, 2 NSCLC), including 2 of 9 NSCLC patients with confirmed PRs at doses of 283 mg or higher. Tumor shrinkage was observed in patients with both Class 1 and Class 2 SMARCA4 mutations. Additional patients on-study demonstrated clinical benefit as measured by prolonged SD, including one advanced NSCLC patient who remains stable and on study having been treated for more than 1 year. Initial observations of safety from evaluable patients in the PRT3789 plus docetaxel combination dose escalation arm of the trial were also presented. To date, PRT3789 in combination with docetaxel demonstrated an acceptable safety profile, with no dose limiting toxicities or study drug serious adverse events reported. The Selective SMARCA2 Degrader, PRT3789, Counteracts the Protective Cellular Stress Response to Chemotherapy and Enhances the Efficacy of Standard of Care Chemotherapeutic Agents in SMARCA4 Mutant NSCLC Models The combination of PRT3789 with standard of care NSCLC chemotherapy agents significantly enhances anti-tumor activity in preclinical models of SMARCA4-mutated NSCLC. Downregulation of dominant gene pathways by PRT3789, specifically counters docetaxel-induced upregulation of the E2F and G2/M pathways, resulting in a more comprehensive cell cycle blockade and increased apoptosis in SMARCA4-mutated cells. This synergistic activity was observed with both Class I (loss of function) mutations and Class II (missense) mutations. Discovery of First-in-Class Precision Antibody Drug Conjugates with a Potent SMARCA 2/4 Dual Degrader Payloads that Safely Achieve Maximal and Tumor Specific Degradation and Efficacy in Mouse Models PRP0004 is a potent SMARCA2/4 dual degrader that robustly inhibits cancer cell growth and induces cell death. Conjugation of PRP0004 to clinically-validated antibodies yielded novel degrader antibody conjugates (DACs), which demonstrated potent and antigen-selective internalization and SMARCA2 and SMARCA4 degradation in cell lines derived from multiple cancers. Prostate cancer cell lines were among the most sensitive to the PRP0004 degrader payload. PRP0004 downregulated multiple drivers of prostate cancer cell growth and survival and resulted in cell death, rationalizing the use of PSMA-targeting antibodies for initial proof-of-concept studies in preclinical models. As expected, dosing with PRP0004 on its own was highly efficacious in prostate cancer xenografts but displayed a narrow therapeutic window. However, when delivered as a payload on anti-PSMA antibodies, the anti-PSMA SMARCA2/4 DACs demonstrate robust SMARCA2 and SMARCA4 degradation and antigen-dependent efficacy in xenograft models while being well-tolerated. These data highlight the potential of this first-in-class precision ADC approach utilizing a highly potent SMARCA2/4 dual degrader payload to achieve maximal target degradation in tumors while sparing healthy tissues. This strategy has the potential to significantly expand the reach of Prelude’s novel SMARCA degraders to treating patients without SMARCA4 mutations.