SpringWorks Therapeutics Announces Publication of the Pivotal Phase 2b ReNeu Trial Evaluating Mirdametinib in Adults and Children with NF1-PN in the Journal of Clinical Oncology
SpringWorks Therapeutics announced the publication of pivotal Phase 2b ReNeu trial results for mirdametinib in the Journal of Clinical Oncology. The trial evaluated the MEK inhibitor in adults and children with NF1-PN, demonstrating significant confirmed objective response rates of 41% in adults and 52% in children. The study showed deep and durable tumor volume reductions, with median best percentage changes of -41% in adults and -42% in children. Patients experienced early and sustained improvements in pain and quality of life. The treatment was generally well-tolerated, with mostly Grade 1 or 2 adverse events. The FDA's PDUFA action date is set for February 28, 2025.
SpringWorks Therapeutics ha annunciato la pubblicazione dei risultati decisivi del trial di Fase 2b ReNeu per mirdametinib nel Journal of Clinical Oncology. Lo studio ha valutato l'inibitore MEK in adulti e bambini con NF1-PN, dimostrando tassi di risposta obiettiva confermata significativi del 41% negli adulti e del 52% nei bambini. La ricerca ha evidenziato riduzioni profonde e durevoli del volume tumorale, con variazioni percentuali medie migliori del -41% negli adulti e del -42% nei bambini. I pazienti hanno sperimentato miglioramenti precoci e sostenuti nel dolore e nella qualità della vita. Il trattamento è stato generalmente ben tollerato, con la maggior parte degli eventi avversi classificati come di Grado 1 o 2. La data di azione PDUFA della FDA è fissata per 28 febbraio 2025.
SpringWorks Therapeutics anunció la publicación de los resultados decisivos del ensayo de Fase 2b ReNeu para mirdametinib en el Journal of Clinical Oncology. El ensayo evaluó el inhibidor de MEK en adultos y niños con NF1-PN, demostrando tasas significativas de respuesta objetiva confirmada del 41% en adultos y del 52% en niños. El estudio mostró reducciones profundas y duraderas en el volumen tumoral, con cambios porcentuales medianos mejores del -41% en adultos y del -42% en niños. Los pacientes experimentaron mejoras tempranas y sostenidas en el dolor y la calidad de vida. El tratamiento fue generalmente bien tolerado, con la mayoría de los eventos adversos siendo de Grado 1 o 2. La fecha de acción PDUFA de la FDA está programada para el 28 de febrero de 2025.
SpringWorks Therapeutics는 mirdametinib의 2상 ReNeu 시험 결과를 Journal of Clinical Oncology에 발표했다고 발표했습니다. 이 시험은 NF1-PN이 있는 성인 및 아동에서 MEK 억제제를 평가했으며, 성인에서는 41%, 아동에서는 52%의 유의적인 확정 객관적 반응률을 보여주었습니다. 연구는 깊고 지속적인 종양 볼륨 감소를 보여주었으며, 성인에서는 -41%, 아동에서는 -42%의 중앙 최상의 백분율 변화가 나타났습니다. 환자들은 통증과 삶의 질에서 조기 및 지속적인 향상을 경험했습니다. 치료는 전반적으로 잘 견뎌졌으며, 대부분은 1도 또는 2도의 부작용이었습니다. FDA의 PDUFA 조치 날짜는 2025년 2월 28일로 설정되어 있습니다.
SpringWorks Therapeutics a annoncé la publication des résultats décisifs de l'essai de Phase 2b ReNeu pour mirdametinib dans le Journal of Clinical Oncology. L'essai a évalué l'inhibiteur MEK chez des adultes et des enfants atteints de NF1-PN, démontrant des taux de réponse objective confirmée significatifs de 41 % chez les adultes et de 52 % chez les enfants. L'étude a montré des réductions profondes et durables du volume tumoral, avec des changements de pourcentage médians de -41 % chez les adultes et de -42 % chez les enfants. Les patients ont constaté des améliorations précoces et durables de la douleur et de la qualité de vie. Le traitement a généralement été bien toléré, avec principalement des événements indésirables de Grade 1 ou 2. La date d'action PDUFA de la FDA est fixée au 28 février 2025.
SpringWorks Therapeutics hat die Veröffentlichung der entscheidenden Ergebnisse der Phase-2b-Studie ReNeu für mirdametinib im Journal of Clinical Oncology bekannt gegeben. Die Studie bewertete den MEK-Inhibitor bei Erwachsenen und Kindern mit NF1-PN und zeigte signifikante bestätigte objektive Ansprechquoten von 41 % bei Erwachsenen und 52 % bei Kindern. Die Studie zeigte tiefe und dauerhafte Tumorvolumenverringerungen, mit medianen besten prozentualen Veränderungen von -41 % bei Erwachsenen und -42 % bei Kindern. Die Patienten erlebten frühe und nachhaltige Verbesserungen bei Schmerzen und Lebensqualität. Die Behandlung wurde allgemein gut vertragen, mit überwiegend Grad 1 oder 2 Nebenwirkungen. Das PDUFA-Aktionsdatum der FDA ist auf den 28. Februar 2025 festgelegt.
- High objective response rates: 41% in adults and 52% in children
- Significant tumor volume reductions: -41% in adults and -42% in children
- Durable responses in 96% of adults and 100% of children
- FDA review ongoing with PDUFA date set
- New tablet formulation shows high acceptability for patients with swallowing difficulties
- 22% of adults discontinued treatment due to adverse events
- 9% of children discontinued treatment due to adverse events
- High rate of treatment-related adverse events, including dermatitis acneiform affecting 78% of adults
Insights
The Phase 2b ReNeu trial results for mirdametinib demonstrate compelling clinical evidence for NF1-PN treatment. Key highlights include confirmed objective response rates of 41% in adults and 52% in children, with remarkable durability - 96% of adult responders and 100% of pediatric responders maintaining their responses. The median tumor volume reductions of
Most noteworthy is the sustained efficacy, with 75% of adults and 76% of children maintaining responses beyond 12 months. The tablet's oral suspension formulation addresses a critical need for patients with swallowing difficulties. The safety profile appears manageable, with mostly Grade 1-2 adverse events, though the
– Mirdametinib treatment demonstrated significant confirmed objective response rates and a manageable safety profile in adults and children with NF1-PN –
– Patients achieved deep and durable reductions in tumor volume and early, sustained and clinically meaningful improvements in pain and health-related quality of life –
– New Drug and Marketing Authorization Applications under review; U.S. PDUFA action date set for February 28, 2025 –
STAMFORD, Conn., Nov. 11, 2024 (GLOBE NEWSWIRE) -- SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, today announced that data from the pivotal, Phase 2b ReNeu trial of mirdametinib, an investigational MEK inhibitor, in adult and pediatric patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN), were published online in the Journal of Clinical Oncology (JCO). Data from ReNeu, which is a multi-center, single arm trial, were previously presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. The JCO e-publication can be accessed at the following link: https://ascopubs.org/doi/pdf/10.1200/JCO.24.01034.
“Plexiform neurofibromas can cause extreme pain, disfigurement, compression of internal organs, and impaired physical function. There is a substantial unmet need for a highly effective and well tolerated systemic therapy for these patients,” said Christopher Moertel, M.D., Medical Director, Pediatric Neuro-Oncology and Neurofibromatosis Programs and Kenneth and Betty Jayne Dahlberg Professor of Pediatrics, University of Minnesota and lead author of the JCO publication. “The deep tumor volume reductions and significant improvements in pain and other quality of life measures that we saw in the ReNeu trial, as well as having a formulation option for young children or those who have difficulty swallowing, underscore the potential for mirdametinib to be a valuable new treatment option for adults and children with NF1-PN.”
As of the data cutoff of September 20, 2023, the ReNeu trial met its primary endpoint of confirmed objective response rate (ORR), as assessed by blinded independent central review. During the 24-cycle treatment phase (approximately 22 months), the ORR was
Tumor volume reductions were deep and durable during the course of the study. The median best percentage change in target PN volume was –
Mirdametinib was generally well tolerated in the ReNeu trial, with the majority of adverse events (AEs) being Grade 1 or 2. The most commonly reported treatment-related adverse events (TRAEs) occurring in >
“ReNeu is the largest multicenter trial conducted to date in patients with NF1-PN and we are very pleased that the JCO publication will serve as an important resource to further disseminate the robust efficacy and safety data of mirdametinib to the broader scientific and clinical community,” said Jim Cassidy, M.D., Ph.D., Chief Medical Officer, SpringWorks Therapeutics. “We look forward to continuing to work with the FDA and EMA as they review our applications and are excited by the opportunity to make a meaningful impact on this underserved patient community.”
About the ReNeu Trial
ReNeu (NCT03962543) is an ongoing, multi-center, open-label, single arm, Phase 2b trial evaluating the efficacy, safety, and tolerability of mirdametinib in patients ≥2 years of age with an inoperable NF1-associated PN causing significant morbidity. The trial enrolled 114 patients to receive mirdametinib at a dose of 2 mg/m2 twice daily (maximum dose of 4 mg twice daily) without regard to food. Mirdametinib was administered orally in a 3-week on, 1-week off dosing schedule as either a capsule or tablet for oral suspension. The primary endpoint is confirmed objective response rate assessed by proportion of patients with a ≥
About NF1-PN
Neurofibromatosis type 1 (NF1) is a rare genetic disorder that arises from mutations in the NF1 gene, which encodes for neurofibromin, a key suppressor of the MAPK pathway.1,2 NF1 is the most common form of neurofibromatosis, with an estimated global birth incidence of approximately 1 in 2,500 individuals, and approximately 100,000 patients living with NF1 in the United States.3, The clinical course of NF1 is heterogeneous and manifests in a variety of symptoms across numerous organ systems, including abnormal pigmentation, skeletal deformities, tumor growth and neurological complications, such as cognitive impairment.5 Patients with NF1 have an 8 to 15-year mean reduction in their life expectancy compared to the general population.4
NF1 patients have approximately a 30
Surgical removal of these tumors is challenging due to the infiltrative tumor growth pattern along nerves and can lead to permanent nerve damage and disfigurement.10 MEK inhibitors have emerged as a validated class of treatment for NF1-PN.11
About Mirdametinib
Mirdametinib is a potent, oral, CNS-penetrant, allosteric small molecule MEK inhibitor in development as a monotherapy treatment for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) and low-grade glioma (LGG), and as a combination therapy for the treatment of several subsets of biomarker-defined metastatic solid tumors. Mirdametinib is an investigational drug for which safety and efficacy have not been established.
Mirdametinib is designed to inhibit MEK1 and MEK2, which occupy pivotal positions in the MAPK pathway. The MAPK pathway is a key signaling network that regulates cell growth and survival and plays a central role in multiple cancers and rare diseases when genetically altered.
The U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) for mirdametinib in adults and children with NF1-PN. The NDA was granted Priority Review designation and has been given a Prescription Drug User Fee Act (PDUFA) action date of February 28, 2025. The European Medicines Agency (EMA) has validated the Marketing Authorization Application (MAA) for mirdametinib for the treatment of adult and pediatric patients with NF1-PN.
In addition, the FDA and the European Commission previously granted Orphan Drug designation for mirdametinib for the treatment of NF1. The FDA has also granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity and Rare Pediatric Disease designation for the treatment of NF1.
About SpringWorks Therapeutics
SpringWorks is a commercial-stage biopharmaceutical company applying a precision medicine approach to developing and delivering life-changing medicines for people with severe rare diseases and cancer. OGSIVEO® (nirogacestat), approved in the United States for the treatment of adult patients with progressing desmoid tumors who require systemic treatment, is the Company’s first FDA-approved therapy. SpringWorks also has a diversified targeted therapy pipeline spanning solid tumors and hematological cancers, with programs ranging from preclinical development through advanced clinical trials. In addition to its wholly owned programs, SpringWorks has also entered into multiple collaborations with innovators in industry and academia to unlock the full potential for its portfolio and create more solutions for patients in need.
For more information, visit www.springworkstx.com and follow @SpringWorksTx on X (formerly Twitter), LinkedIn, and YouTube.
SpringWorks Forward-Looking Statements
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, relating to our business, operations, and financial conditions, including but not limited to current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our development and commercialization plans, our preclinical and clinical results, whether the preclinical and clinical results of the mirdametinib studies will meet the regulatory requirements for an approval by the FDA or by the EMA of mirdametinib for the treatment of pediatric and adult patients with NF1-PN, the potential for mirdametinib to become an important new treatment for patients with NF1-PN, our plans for seeking regulatory approval for and making mirdametinib available for NF1-PN patients, if approved, , as well as relating to other future conditions. Words such as, but not limited to, “look forward to,” “believe,” “expect,” “anticipate,” “estimate,” “intend,” “plan,” “would,” “should” and “could,” and similar expressions or words, identify forward-looking statements. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks relating to: (i) our limited experience as a commercial company, (ii) the success and timing of our product development activities, including the initiation and completion of our clinical trials, (iii) the fact that topline or interim data from clinical studies may not be predictive of the final or more detailed results of such study or the results of other ongoing or future studies, (iv) the timing of our planned regulatory submissions and interactions, including the timing and outcome of decisions made by the FDA, EMA, and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, (v) whether FDA, EMA, or other regulatory authorities will require additional information or further studies, or may fail or refuse to approve or may delay approval of our product candidates, (vi) our ability to obtain regulatory approval of any of our product candidates or maintain regulatory approvals granted for our products, (vii) our plans to research, discover and develop additional product candidates, (viii) our ability to enter into collaborations for the development of new product candidates and our ability to realize the benefits expected from such collaborations, (ix) our ability to maintain adequate patent protection and successfully enforce patent claims against third parties, (x) our ability to establish manufacturing capabilities, and our and our collaboration partners’ abilities to manufacture our product candidates and scale production, and (xii) our ability to meet any specific milestones set forth herein.
Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements.
For further information regarding the risks, uncertainties and other factors that may cause differences between SpringWorks’ expectations and actual results, you should review the “Risk Factors” in Item 1A of Part II of SpringWorks’ Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, as well as discussions of potential risks, uncertainties and other important factors in SpringWorks’ subsequent filings.
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References
- Yap YS, McPherson JR, Ong CK, et al. The NF1 gene revisited - from bench to bedside. Oncotarget. 2014;5(15):5873-5892. doi:10.18632/oncotarget.2194.
- Rasmussen S, Friedman J. NF1 Gene and Neurofibromatosis 1. Am J Epidemiol. 2000;151(1):33-40. doi:10.1093/oxfordjournals.aje.a010118.
- CTF: Children’s Tumor Foundation. New and Improved: The way to talk about NF. Press release. May 9, 2023. Accessed February 2, 2024.
- Lee: Lee TJ, et al. Incidence and prevalence of neurofibromatosis type 1 and 2: a systematic review and meta-analysis. Orphanet J Rare Dis. 2023;18(1):292. doi:10.1186/s13023-023-02911-2
- Weiss BD, Wolters PL, Plotkin SR, et al. NF106: A neurofibromatosis clinical trials consortium Phase II trial of the MEK inhibitor mirdametinib (PD-0325901) in adolescents and adults with NF1-related plexiform neurofibromas. J Clin Onc. 2021;JCO.20.02220.doi.org/10. 1200/JCO.20.02220.
- Prada CE, Rangwala FA, Martin LJ, et al. Pediatric plexiform neurofibromas: impact on morbidity and mortality in neurofibromatosis type 1. J Pediatr. 2012;160(3):461-467.
- Miller DT, et al. Health supervision for children with neurofibromatosis Type 1. Pediatrics. 2019;143(5):e20190660.
- Gross A, Singh G, Akshintala S, et al. Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1. Neuro Oncol. 2018;20(12):1643-1651. doi:10.1093/neuonc/noy067.
- Nguyen R, Dombi E, Widemann B, et al. Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1. Orphanet J Rare Dis. 2012;7(1):75. doi:10.1186/1750-1172-7-75.
- Needle M, Cnaan A, Dattilo J, et al. Prognostic signs in the surgical management of plexiform neurofibroma: The Children’s Hospital of Philadelphia experience, 1974-1994. J Pediatr. 1997;131(5):678-682. doi:10.1016/s0022-3476(97)70092-1.
- Ferner R. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol. 2007;6(4):340-351. doi:10.1016/s1474-4422(07)70075-3.
FAQ
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