Zentalis Pharmaceuticals Shares Updated Clinical Data Demonstrating Meaningful Azenosertib Activity in Cyclin E1+, Platinum-Resistant Ovarian Cancer
Zentalis Pharmaceuticals (NASDAQ: ZNTL) has presented updated clinical data for azenosertib in treating Cyclin E1+ platinum-resistant ovarian cancer (PROC). The DENALI Part 1b study showed an Objective Response Rate (ORR) of approximately 35% in response-evaluable patients.
Key findings include a median duration of response of approximately 5.5 months, with patients continuing therapy. The safety profile remains well-characterized across over 350 patients treated at clinically active monotherapy doses, with no new safety concerns identified.
The company has aligned with FDA on the design of DENALI Part 2 study, expected to begin in 1H 2025, with topline data anticipated by year-end 2026. The study could potentially support accelerated approval, subject to FDA review. Notably, approximately 50% of PROC patients are Cyclin E1+, representing a substantial therapeutic and commercial opportunity.
Zentalis Pharmaceuticals (NASDAQ: ZNTL) ha presentato dati clinici aggiornati riguardanti azenosertib nel trattamento del cancro ovarico resistente al platino Cyclin E1+. Lo studio DENALI Parte 1b ha mostrato un tasso di risposta obiettiva (ORR) di circa il 35% nei pazienti valutabili per la risposta.
I risultati chiave includono una durata mediana della risposta di circa 5,5 mesi, con i pazienti che continuano la terapia. Il profilo di sicurezza rimane ben caratterizzato in oltre 350 pazienti trattati con dosi attive in monoterapia, senza nuove preoccupazioni di sicurezza identificate.
L'azienda ha allineato il design dello studio DENALI Parte 2 con la FDA, previsto per iniziare nel primo semestre del 2025, con i dati principali attesi entro la fine del 2026. Lo studio potrebbe potenzialmente supportare un'approvazione accelerata, soggetta a revisione da parte della FDA. È interessante notare che circa il 50% dei pazienti PROC sono Cyclin E1+, rappresentando un'opportunità terapeutica e commerciale significativa.
Zentalis Pharmaceuticals (NASDAQ: ZNTL) ha presentado datos clínicos actualizados para azenosertib en el tratamiento del cáncer de ovario resistente al platino Cyclin E1+. El estudio DENALI Parte 1b mostró una tasa de respuesta objetiva (ORR) de aproximadamente el 35% en pacientes evaluables para la respuesta.
Los hallazgos clave incluyen una duración mediana de respuesta de aproximadamente 5.5 meses, con pacientes continuando la terapia. El perfil de seguridad se mantiene bien caracterizado en más de 350 pacientes tratados con dosis monoterapéuticas activas, sin nuevas preocupaciones de seguridad identificadas.
La compañía ha alineado con la FDA el diseño del estudio DENALI Parte 2, que se espera comience en el primer semestre de 2025, con datos principales anticipados para finales de 2026. El estudio podría potencialmente apoyar una aprobación acelerada, sujeta a revisión de la FDA. Cabe destacar que aproximadamente el 50% de los pacientes PROC son Cyclin E1+, representando una oportunidad terapéutica y comercial considerable.
젠탈리스 제약 (NASDAQ: ZNTL)은 사이클린 E1+ 플래티넘 저항성 난소암 (PROC) 치료를 위한 아제노세르티브의 업데이트된 임상 데이터를 발표했습니다. DENALI Part 1b 연구에서 반응 평가가 가능한 환자들의 객관적 반응률(ORR)은 약 35%로 나타났습니다.
핵심 발견은 응답의 중간 지속 기간이 약 5.5개월이라는 점이며, 환자들이 치료를 지속하고 있습니다. 안전성 프로필은 임상적으로 활성화된 단독 요법 용량에서 350명 이상의 환자에 대해 잘 특성화되어 있으며, 새로운 안전성 우려 사항이 확인되지 않았습니다.
회사는 2025년 상반기에 시작될 예정인 DENALI Part 2 연구 설계에 대해 FDA와 협의했으며, 2026년 연말까지 주요 데이터가 예상됩니다. 이 연구는 FDA 검토에 따라 가속 승인을 지원할 수 있습니다. 주목할 점은 PROC 환자의 약 50%가 사이클린 E1+라는 것이며, 이는 상당한 치료적 및 상업적 기회를 나타냅니다.
Zentalis Pharmaceuticals (NASDAQ: ZNTL) a présenté des données cliniques actualisées concernant l'azenosertib dans le traitement du cancer de l'ovaire résistant au platine Cyclin E1+. L'étude DENALI Partie 1b a montré un taux de réponse objective (ORR) d'environ 35% chez les patients évaluables.
Les résultats clés incluent une durée médiane de réponse d'environ 5,5 mois, les patients poursuivant leur traitement. Le profil de sécurité reste bien caractérisé chez plus de 350 patients traités à des doses monothérapeutiques cliniquement actives, sans nouvelles préoccupations de sécurité identifiées.
La société s'est alignée avec la FDA sur le design de l'étude DENALI Partie 2, qui devrait commencer au premier semestre 2025, avec des données principales attendues d'ici la fin 2026. L'étude pourrait potentiellement soutenir une approbation accélérée, sous réserve d'une révision par la FDA. Il est à noter qu'environ 50% des patients PROC sont Cyclin E1+, représentant une opportunité thérapeutique et commerciale substantielle.
Zentalis Pharmaceuticals (NASDAQ: ZNTL) hat aktualisierte klinische Daten zu Azenosertib zur Behandlung von Cyclin E1+ platinresistentem Eierstockkrebs (PROC) präsentiert. Die DENALI Teil 1b-Studie zeigte eine objektive Ansprechrate (ORR) von etwa 35% bei den auswertbaren Patienten.
Wichtige Ergebnisse umfassen eine mediant Dauer der Ansprechrate von etwa 5,5 Monaten, während die Patienten die Therapie fortsetzen. Das Sicherheitsprofil bleibt gut charakterisiert über mehr als 350 Patienten, die mit klinisch aktiven Monotherapie-Dosen behandelt wurden, ohne dass neue Sicherheitsbedenken identifiziert wurden.
Das Unternehmen hat sich mit der FDA auf das Design der DENALI Teil 2-Studie geeinigt, die voraussichtlich im ersten Halbjahr 2025 beginnen wird, wobei die Hauptdaten bis Ende 2026 erwartet werden. Die Studie könnte möglicherweise eine beschleunigte Zulassung unterstützen, vorbehaltlich einer FDA-Überprüfung. Bemerkenswert ist, dass etwa 50% der PROC-Patienten Cyclin E1+ sind, was eine erhebliche therapeutische und kommerzielle Chance darstellt.
- 35% Objective Response Rate in DENALI Part 1b study for Cyclin E1+ PROC patients
- 5.5 months median duration of response, still maturing
- FDA alignment on DENALI Part 2 study design, potentially supporting accelerated approval
- Large market opportunity with 50% of PROC patients being Cyclin E1+
- Cash runway extended into late 2027, beyond anticipated DENALI Part 2 data readout
- Two Grade 5 (fatal) treatment-related events reported in DENALI study
- Combination with niraparib discontinued due to inability to reach efficacious exposures
- Colorectal cancer study discontinued due to resource prioritization
Insights
The clinical data for azenosertib represents a potentially significant advancement in treating Cyclin E1+ platinum-resistant ovarian cancer. The consistent ~
The biomarker strategy targeting Cyclin E1+ tumors, which represent approximately
The safety profile demonstrates important advantages over traditional chemotherapy, with notably low rates of Grade 3+ gastrointestinal and hematological toxicities. The
The FDA-aligned DENALI Part 2 study design, incorporating both dose-confirmation (Part 2a) and potential registration (Part 2b) components, appears well-constructed to support accelerated approval. The timeline to topline data by end of 2026, combined with the company's cash runway extension into late 2027, positions Zentalis favorably for potential commercialization.
From a commercial perspective, azenosertib's potential in Cyclin E1+ PROC represents a significant market opportunity. With approximately 20,000 new cases of ovarian cancer annually in the US and roughly
The company's strategic decision to focus resources on PROC while discontinuing the colorectal cancer program demonstrates disciplined capital allocation. The extended cash runway into late 2027 provides a strong financial foundation, eliminating near-term funding concerns and spanning beyond the critical DENALI Part 2 readout.
The clear regulatory pathway with potential accelerated approval significantly de-risks the development program. The biomarker-driven approach not only increases probability of technical success but also supports favorable reimbursement dynamics. This positions Zentalis for either independent commercialization or attractive partnership opportunities with larger oncology players.
Results from DENALI Part 1b show an Objective Response Rate (ORR) of ~
Across monotherapy cohorts in key clinical studies, well-characterized safety and tolerability profile shows no new safety signals
Company aligned with FDA on seamless study design for DENALI Part 2 in patients with Cyclin E1+ PROC; study expected to begin 1H 2025
Topline data from registration-intent DENALI Part 2 anticipated by year end 2026
Management to host conference call today at 8:00 am ET
SAN DIEGO, Jan. 29, 2025 (GLOBE NEWSWIRE) -- Zentalis® Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company discovering and developing clinically differentiated small molecule therapeutics targeting fundamental biological pathways of cancers, today presented updated azenosertib monotherapy clinical data from its ZN-c3-001, MAMMOTH and DENALI studies and shared details on future clinical development and potential registration plans for patients with Cyclin E1+ platinum-resistant ovarian cancer (PROC). Results from the combination cohorts of MAMMOTH and from the ZN-c3-016 study in colorectal cancer were also disclosed today.
"We are excited to outline a clear path for Zentalis to bring azenosertib to patients with Cyclin E1+ PROC,” said Ingmar Bruns, M.D., Chief Medical Officer. “In a patient population with a clear unmet medical need, the monotherapy data showed a meaningful and consistent improvement in responses as compared to historical data from current monotherapy chemo standard of care, across multiple studies, in heavily-pretreated patients at the 400mg QD 5:2 intermittent dose. The results demonstrate a median duration of response of approximately 5.5 months that continues to mature with patients remaining on therapy. In addition, with over 350 patients treated at clinically active monotherapy doses (total daily dose ≥ 300mg) across our studies, we have observed a well-characterized safety profile and no new safety signals since our last report. Our data have also confirmed Cyclin E1 overexpression as a predictor of sensitivity to azenosertib monotherapy in PROC, and we intend to pursue further development in this patient population.”
“We are very pleased with the azenosertib results obtained to date and believe we have a clear path to advancing this product candidate to patients,” said Julie Eastland, Chief Executive Officer. “Notably, approximately
The Company plans to present the following at the corporate event:
DENALI Part 2 Study Design
The Company has aligned with the U.S. Food and Drug Administration (FDA) on the design of its DENALI Part 2 study in patients with Cyclin E1+ PROC, which allows for seamless enrollment across Parts 2a and 2b: Part 2a is designed to confirm the primary dose-of-interest, 400mg QD 5:2 (intermittent daily dosing on a five days on, two days off schedule), with a target enrollment of approximately 30 patients at each of two dose levels: 400mg QD 5:2 and 300mg QD 5:2. Part 2b is designed to enroll approximately 70 patients at a single dose, the selection of which will be informed by the Part 2a results, with the final Part 2b dose selection and endpoints subject to FDA feedback. The Company plans to initiate enrollment of DENALI Part 2 in the first half of 2025 and to disclose topline data from DENALI Part 2 by year end 2026. DENALI Part 2, if successful, has the potential to support an accelerated approval, subject to FDA review.
Azenosertib Clinical Results
ZN-c3-001
ZN-c3-001 is a Phase 1, dose-escalation study that evaluated azenosertib monotherapy in solid tumors across continuous and intermittent dosing schedules.
ZN-c3-001 is fully enrolled (n=274). As of the December 2, 2024 data cutoff, results from ZN-c3-001 showed encouraging ORR and median duration of response (mDOR) at a total daily dose level ≥ 300mg in patients with Cyclin E1+ PROC who were dosed at an intermittent schedule (n=23). In these patients, an ORR of
In the ZN-c3-001 study, as of the December 2, 2024 data cutoff, azenosertib was shown to be tolerable at a total daily dose level ≥ 300mg (n=193) across all tumor types and regardless of biomarker status, with no Grade 3+ gastrointestinal treatment-related adverse events (TRAEs) observed and low rates of Grade 3+ hematological toxicity, with the majority of hematological toxicity events being Grade 3. There was also a low rate of TRAEs leading to discontinuation (n=10,
MAMMOTH (ZN-c3-006)
MAMMOTH is a multi-arm study that evaluated azenosertib monotherapy and in combination with niraparib in patients with PARP-inhibitor resistant ovarian cancer.
MAMMOTH is fully enrolled. In the monotherapy arm of the study (n=61), patients who were PARPi refractory were treated with azenosertib at the 300mg QD 5:2 or 400mg QD 5:2. As of the December 2, 2024 data cutoff, among Cyclin E1+ patients treated at the primary dose-of-interest, 400mg QD 5:2 (n=16), an ORR of
As of the December 2, 2024 data cutoff, in the monotherapy arm of the MAMMOTH study at both 300mg QD 5:2 and 400mg QD 5:2 regardless of biomarker status, similar rates of treatment-related serious adverse events (SAEs) were observed across dose levels. There was a low rate of treatment-related Grade 3+ hematological toxicity with the majority being Grade 3 events. There was a low rate of TRAEs leading to treatment discontinuation
In the combination arms of the study, where azenosertib was dosed on a concurrent or alternating schedule with niraparib, although no new safety signals were observed, efficacious exposures of azenosertib were not reached, and the Company is not proceeding further with development of the combination with niraparib.
DENALI (ZN-c3-005) Part 1b
DENALI Part 1b is a single-arm study that evaluated azenosertib monotherapy at the 400mg QD 5:2 dose in patients with PROC (n=102). Tissue collection for biomarker assessment was mandated in the study and upon a retrospective analysis, approximately
As of the December 2, 2024 data cutoff, in patients with Cyclin E1+ PROC tumors who were response-evaluable (patients who had at least one scan after receiving azenosertib), an ORR of
As of the December 2, 2024 data cutoff, a safety and tolerability profile broadly consistent with ZN-c3-001 and MAMMOTH monotherapy was observed. There were two previously reported treatment-related Grade 5 events in the study (n=2,
ZN-c3-016
ZN-c3-016 is a Phase 1/2 study that evaluated azenosertib in combination with encorafenib and cetuximab in patients with metastatic BRAF V600E mutant colorectal cancer in collaboration with Pfizer.
The dose-finding phase of the ZN-c3-016 study is fully enrolled (n= 44). 34 patients were BRAF-inhibitor naïve and 10 had previously been treated with a BRAF-inhibitor. Topline results as of the November 25, 2024 data cutoff can be found in the appendix of the presentation. While the results in BRAF inhibitor naïve patients were encouraging, the Company decided not to advance into the dose expansion phase of the study due to resource prioritization and an evolving treatment landscape.
Corporate Event Details
On January 29, 2025, at 8:00am ET Zentalis will host a virtual corporate event to present data from its studies of azenosertib and provide a regulatory update. Access to a live webcast of this event, as well as an archived recording, will be available under the “Events & Presentations” tab on the Investors & Media section of the Company’s website. Analysts who wish to join the teleconference and participate in Q&A should register here.
About Azenosertib
Azenosertib is a novel, selective, and orally bioavailable inhibitor of WEE1 currently being evaluated as a monotherapy and combination clinical studies in ovarian cancer and additional tumor types. WEE1 acts as a master regulator of the G1-S and G2-M cell cycle checkpoints, through negative regulation of both CDK1 and CDK2, to prevent replication of cells with damaged DNA. By inhibiting WEE1, azenosertib enables cell cycle progression, despite high levels of DNA damage, thereby resulting in the accumulation of DNA damage and leading to mitotic catastrophe and cancer cell death.
About Zentalis Pharmaceuticals
Zentalis® Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company developing azenosertib (ZN-c3), a potentially first-in-class and best-in-class WEE1 inhibitor for patients with Cyclin E1+ platinum-resistant ovarian cancer (PROC). Azenosertib is being evaluated as a monotherapy and in combination across multiple tumor types in clinical trials and has broad franchise potential. In clinical trials, azenosertib has been well tolerated and has demonstrated anti-tumor activity as a single agent across multiple tumor types. The Company is also leveraging its extensive experience and capabilities to translate its science to advance research on additional areas of opportunity for azenosertib outside PROC. Zentalis has operations in San Diego.
For more information, please visit www.zentalis.com. Follow Zentalis on X/Twitter at @ZentalisP and on LinkedIn at www.linkedin.com/company/zentalis-pharmaceuticals.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, as amended. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, but not limited to, statements regarding the potential of azenosertib; our plans to hold a corporate event and present clinical data and provide a development and regulatory update, including the timing and content thereof; our anticipated milestones and the timing thereof, including the anticipated timing of initiation of clinical trials and timing of clinical data disclosures; the potential to advance research on additional areas of opportunity for azenosertib outside PROC; our anticipated cash runway; the potential for azenosertib to be first-in-class and best-in-class; the broad franchise potential of azenosertib; the potential of azenosertib to address an unmet need in patients with Cyclin E1+ PROC and our plans to pursue further development in this patient population; our belief that we have a clear path to advance azenosertib to patients; the planned design of our clinical trials, including target enrollment numbers; the potential for Cyclin E1 to serve as a predictor for sensitivity to azenosertib; the therapeutic and commercial opportunity for azenosertib; the potential for DENALI Part 2 to support an accelerated approval for azenosertib; our positioning to execute; and our planned clinical development strategy and regulatory strategy for azenosertib and the timing thereof, including plans for registration-intent studies and the potential for accelerated approval. The terms “anticipated,” “ahead,” “believe,” “design,” “excited,” “expect,” “further,” “future,” “goal,” “intent,” “opportunity,” “path,” “plan,” “potential,” "promising,” “target,” and “will” and similar references are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our limited operating history, which may make it difficult to evaluate our current business and predict our future success and viability; we have and expect to continue to incur significant losses; our need for additional funding, which may not be available; our plans, including the costs thereof, of development of companion diagnostics; our substantial dependence on the success of our lead product candidate, azenosertib; the outcome of preclinical testing and early trials may not be predictive of the success of later clinical trials; failure to identify additional product candidates and develop or commercialize marketable products; potential unforeseen events during clinical trials could cause delays or other adverse consequences; risks relating to the regulatory approval process or ongoing regulatory obligations; failure to obtain U.S. or international marketing approval; our product candidates may cause serious adverse side effects; inability to maintain our collaborations, or the failure of these collaborations; our reliance on third parties; effects of significant competition; the possibility of system failures or security breaches; risks relating to intellectual property; our ability to attract, retain and motivate qualified personnel, and risks relating to management transitions; significant costs as a result of operating as a public company; and the other important factors discussed under the caption “Risk Factors” in our most recently filed periodic report on Form 10-K or 10-Q and subsequent filings with the U.S. Securities and Exchange Commission (SEC) and our other filings with the SEC. Any such forward-looking statements represent management’s estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change.
Statements such as “compared to historical data” indicate that no head-to-head clinical trial has been conducted evaluating azenosertib against the indicated therapies. Notable differences exist between the Company’s trial designs, conditions under study and subject characteristics as compared to the evaluated third party results and caution should be exercised when comparing data across these studies.
ZENTALIS® and its associated logo are trademarks of Zentalis and/or its affiliates. All website addresses and other links in this press release are for information only and are not intended to be an active link or to incorporate any website or other information into this press release.
Contact:
Elizabeth Pingpank Hickin
ehickin@zentalis.com
860-463-0469
FAQ
What was the ORR for azenosertib in Cyclin E1+ PROC patients in the DENALI Part 1b study?
When will Zentalis (ZNTL) begin the DENALI Part 2 study?
What is the expected timeline for ZNTL's DENALI Part 2 topline data?
What percentage of PROC patients are Cyclin E1+ according to Zentalis's data?
What is the median duration of response for azenosertib in the latest data?
