Prelude Therapeutics Presents New Data from SMARCA Degrader Portfolio at the 36th EORTC-NCI-AACR Symposium
Prelude Therapeutics presented interim data from its ongoing Phase 1 trial of PRT3789, a SMARCA2 degrader for cancer patients with SMARCA4 mutations. Of 65 patients treated, the drug showed promising results with 4 confirmed partial responses among 26 evaluable NSCLC or esophageal patients with Class 1 mutations. Higher doses demonstrated deeper SMARCA2 degradation, with 2 of 9 NSCLC patients showing confirmed responses at doses of 283mg or higher.
The drug was generally well-tolerated, with mostly mild to moderate adverse events. Initial combination study with docetaxel showed an acceptable safety profile. The company also presented first preclinical proof-of-concept data from their novel SMARCA2/4 dual degrader payload program.
Prelude Therapeutics ha presentato dati interim del suo studio di Fase 1 in corso su PRT3789, un degradatore di SMARCA2 per pazienti oncologici con mutazioni di SMARCA4. Dei 65 pazienti trattati, il farmaco ha mostrato risultati promettenti con 4 risposte parziali confermate tra 26 pazienti con NSCLC o esofago valutabili con mutazioni di Classe 1. Le dosi più elevate hanno dimostrato una degradazione più profonda di SMARCA2, con 2 dei 9 pazienti con NSCLC che hanno mostrato risposte confermate a dosi di 283mg o superiori.
Il farmaco è stato generalmente ben tollerato, con effetti avversi per lo più lievi o moderati. Il primo studio di combinazione con docetaxel ha mostrato un profilo di sicurezza accettabile. L'azienda ha inoltre presentato i primi dati preclinici di prova di concetto dal loro programma innovativo di payload duale degradatore SMARCA2/4.
Prelude Therapeutics presentó datos interinos de su ensayo en Fase 1 en curso de PRT3789, un degradador de SMARCA2 para pacientes con cáncer con mutaciones en SMARCA4. De 65 pacientes tratados, el fármaco mostró resultados prometedores con 4 respuestas parciales confirmadas entre 26 pacientes de NSCLC o esófago evaluables con mutaciones de Clase 1. Dosis más altas demostraron una degradación más profunda de SMARCA2, con 2 de 9 pacientes de NSCLC mostrando respuestas confirmadas a dosis de 283mg o superiores.
El fármaco fue generalmente bien tolerado, con eventos adversos en su mayoría leves a moderados. El primer estudio de combinación con docetaxel mostró un perfil de seguridad aceptable. La compañía también presentó los primeros datos preclínicos de prueba de concepto de su nuevo programa de cargador dual degradador de SMARCA2/4.
프렐류드 테라퓨틱스는 SMARCA4 변이를 가진 암 환자를 위한 SMARCA2 분해제인 PRT3789에 대한 진행 중인 1상 시험의 중간 데이터를 발표했습니다. 65명의 환자 중 26명의 유효한 NSCLC 또는 식도 환자에서 4건의 확인된 부분 반응을 포함하여 약물이 유망한 결과를 보였습니다. 고용량에서 SMARCA2 분해가 더 깊게 나타났습니다, 9명의 NSCLC 환자 중 2명은 283mg 이상의 용량에서 확인된 반응을 보였습니다.
이 약물은 일반적으로 잘 견뎌졌으며, 대부분 경미하거나 중간 정도의 부작용이 있었습니다. 도세탁셀과의 초기 병용 연구는 허용 가능한 안전성 프로파일을 보여주었습니다. 이 회사는 또한 그들의 새로운 SMARCA2/4 이중 분해제 플로우드 프로그램에 대한 첫 번째 전임상 개념 증명 데이터를 발표했습니다.
Prelude Therapeutics a présenté des données intermédiaires de son essai de Phase 1 en cours sur PRT3789, un dégradateur de SMARCA2 destiné aux patients atteints de cancer avec des mutations SMARCA4. Parmi 65 patients traités, le médicament a montré des résultats prometteurs avec 4 réponses partielles confirmées parmi 26 patients atteints de NSCLC ou de l'œsophage ayant des mutations de classe 1. Des doses plus élevées ont démontré une dégradation plus profonde de SMARCA2, 2 des 9 patients atteints de NSCLC montrant des réponses confirmées à des doses de 283mg ou plus.
Le médicament a été généralement bien toléré, avec des événements indésirables principalement légers à modérés. La première étude de combinaison avec le docetaxel a montré un profil de sécurité acceptable. L'entreprise a également présenté les premières données précliniques de preuve de concept de son nouveau programme de charge utile dégradateur SMARCA2/4 dual.
Prelude Therapeutics hat Zwischeninformationen zu seiner laufenden Phase-1-Studie zu PRT3789, einem SMARCA2-Degrader für Krebspatienten mit SMARCA4-Mutationen, präsentiert. Von 65 behandelten Patienten zeigte das Medikament vielversprechende Ergebnisse mit 4 bestätigten partialen Ansprechen unter 26 bewertbaren NSCLC- oder Speiseröhrepatienten mit Mutationen der Klasse 1. Höhere Dosen zeigten eine tiefere SMARCA2-Abbau, wobei 2 von 9 NSCLC-Patienten bei Dosen von 283 mg oder mehr bestätigte Ansprechen zeigten.
Das Medikament wurde allgemein gut vertragen, mit überwiegend milden bis moderaten unerwünschten Ereignissen. Die erste Kombinationstudie mit Docetaxel zeigte ein akzeptables Sicherheitsprofil. Das Unternehmen präsentierte auch die ersten präklinischen Machbarkeitsdaten aus ihrem neuartigen Programm für duale Degrader Payload von SMARCA2/4.
- 4 confirmed partial responses observed in 26 evaluable NSCLC/esophageal patients
- Higher doses (>283mg) showing improved clinical responses
- Generally well-tolerated safety profile with no dose-limiting toxicities
- One patient maintaining stable disease for over one year
- Successful demonstration of SMARCA2 degradation in both blood and tumor tissue
- response rate in evaluated patient population (4 out of 26)
- Requires high doses for optimal clinical effect
- Multiple adverse events reported including nausea (26.2%), fatigue (21.5%), and anemia (20%)
Insights
The interim Phase 1 data for PRT3789 shows promising clinical activity in NSCLC patients with SMARCA4 mutations. The confirmed partial responses in
The pharmacodynamic data revealing deeper and more sustained SMARCA2 degradation at higher doses correlates with improved clinical responses, suggesting dose-dependent activity. The combination study with docetaxel showing acceptable safety expands potential therapeutic applications. The novel degrader antibody conjugate program could significantly broaden the addressable patient population beyond SMARCA4-mutated cancers.
– Interim data from ongoing trial of PRT3789 showed additional clinical activity at higher doses in patients with non-small cell lung cancer (NSCLC)
– First safety data presented from combination study of PRT3789 and docetaxel demonstrated an acceptable safety profile
– First preclinical proof-of-concept data presented from precision antibody drug conjugate program deploying a novel SMARCA2/4 dual degrader payload
WILMINGTON, Del., Oct. 24, 2024 (GLOBE NEWSWIRE) -- Prelude Therapeutics Incorporated (Nasdaq: PRLD) (“Prelude” or the “Company”), a clinical-stage precision oncology company, today 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.
“We, along with our study investigators, are encouraged by the promising activity shown to date by PRT3789 in this novel first-in-class mechanism for patients who have limited treatment options,” stated Jane Huang, M.D., President and Chief Medical Officer of Prelude. “We look forward to further characterizing and understanding the full potential of PRT3789 through ongoing monotherapy dose escalation and in combination studies with both docetaxel and pembrolizumab.”
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 (
Initial Safety Data
PRT3789 was generally well-tolerated. Treatment emergent adverse events of any grade observed to date consisted of nausea (
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.
Additional SMARCA Degrader Presentations
The Company also provided two poster presentations at the conference.
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.
“Preclinical data presented today with our novel approach to develop degrader antibody conjugates by using potent dual degraders of SMARCA2 and 4 as payloads offers first proof-of-concept of effectively and safely targeting an important mechanism to treat cancers beyond those with SMARCA4 mutations” stated Peggy Scherle, Ph.D., Chief Scientific Officer of Prelude.
All of the above noted presentations can be found at Publications - Prelude Therapeutics (preludetx.com).
About PRT3789-01
PRT3789 is a first-in-class, potent and highly selective SMARCA2 degrader, in Phase 1 clinical development in SMARCA4-mutated patients. Enrollment remains on track, and the Company expects to conclude monotherapy dose escalation by year end 2024 and identify the biologically active dose to advance for future registrational trials. In addition, enrollment of patients into back-fill cohorts enriched for NSCLC and SMARCA4 loss-of-function mutations at higher dose levels is ongoing. The objective is to assess clinical activity in a more homogeneous group of patients with high unmet need to support planned discussions with regulatory agencies. A maximum tolerated dose has not yet been identified. Dose escalation continues, now in the 10th dosing cohort (665 mg IV once weekly).
About Prelude Therapeutics
Prelude Therapeutics is a leading precision oncology company developing innovative medicines in areas of high unmet need for cancer patients. Our pipeline is comprised of several novel drug candidates including first-in-class, highly selective IV and oral SMARCA2 degraders, and a potentially best-in-class CDK9 inhibitor. We are also leveraging our expertise in targeted protein degradation to discover, develop and commercialize next generation degrader antibody conjugates (Precision ADCs) with partners. We are on a mission to extend the promise of precision medicine to every cancer patient in need. For more information, visit preludetx.com.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated discovery, preclinical and clinical development activities for Prelude’s product candidates, the potential safety, efficacy, benefits and addressable market for Prelude’s product candidates, and clinical trial results for Prelude’s product candidates. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The words “believes,” “anticipates,” “estimates,” “plans,” “expects,” “intends,” “may,” “could,” “should,” “potential,” “likely,” “projects,” “continue,” “will,” “schedule,” and “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements are predictions based on the Company’s current expectations and projections about future events and various assumptions. Although Prelude believes that the expectations reflected in such forward-looking statements are reasonable, Prelude cannot guarantee future events, results, actions, levels of activity, performance or achievements, and the timing and results of biotechnology development and potential regulatory approval is inherently uncertain. Forward-looking statements are subject to risks and uncertainties that may cause Prelude's actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to Prelude's ability to advance its product candidates, the receipt and timing of potential regulatory designations, approvals and commercialization of product candidates, clinical trial sites and our ability to enroll eligible patients, supply chain and manufacturing facilities, Prelude’s ability to maintain and recognize the benefits of certain designations received by product candidates, the timing and results of preclinical and clinical trials, Prelude's ability to fund development activities and achieve development goals, Prelude's ability to protect intellectual property, and other risks and uncertainties described under the heading "Risk Factors" in Prelude’s Annual Report on Form 10-K for the year ended December 31, 2023, its Quarterly Reports on Form 10-Q and other documents that Prelude files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and Prelude undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof, except as may be required by law.
Investor Contact:
Robert A. Doody Jr.
Senior Vice President, Investor Relations
484.639.7235
rdoody@preludetx.com
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