Plexiform Neurofibroma

-- Tunlametinib is poised to be a potential best-in-class MEK inhibitor based on positive data from the pivotal Phase 2 study SHANGHAI, March 18, 2024 /PRNewswire/ -- KeChow Pharma, a commercial-stage pharmaceutical company focused on developing and commercializing differentiated small molecule therapeutics for cancer, today announced that the China National Medical Products Administration (NMPA) has approved tunlametinib (HL-085) for the treatment of patients with NRAS mutated advanced melanoma who were previously treated with PD-1/PD-L1. This is the first approved targeted therapy for this patient population and the first product originated from KeChow's in-house research and development activities since the company's inception. The new drug application (NDA) of tunlametinib was previously granted priority review by the Center for Drug Evaluation (CDE) of the NMPA. The approval was based on the results of a multicenter, single-arm, phase II, pivotal registrational study which conducted in 100 patients in China (NCT 05217303). Clinical efficacy data of tunlametinib in China, as assessed by independent radiological review committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, include an overall response rate (ORR) of 35.8%, median progression free survival (PFS) of 4.2 months, and disease control rate (DCR) of 72.6%. Subgroup analysis showed that in patients who had previously received immunotherapy, the ORR was 40.6%. The most common treatment-related skin event was rash (53%), followed by dermatitis acneiform (24%). The most common grade ≥3 TRAE in this study was blood creatine phosphokinase increased (38.0%), which was mostly asymptomatic and manageable with dose modification [1]. "We are excited and proud of this major milestone for KeChow. Tunlametinib, approved in China, is the first internally designed and developed molecule by KeChow team ." said Dr. Hongqi Tian, Founder, Chief Executive Officer and Chairman of KeChow. "The approval of tunlametinib is an important milestone to provide new treatment option for Chinese patients with NRAS-mutated advanced melanoma who previously received PD-1/PD-L1. We would like to express our sincere gratitude to the clinicians and patients who participated in our trials, and we thank the health authorities for their strong support. We are committed to making tunlametinib available in China as soon as possible to serve this patient population." "We own the worldwide rights to tunlametinib. KeChow has a comprehensive clinical development plan to evaluate tunlametinib as a monotherapy and in combination with other standard of care therapies to treat multiple cancers including melanoma, neurofibromatosis type 1–related plexiform neurofibromas, colorectal cancer, and non-small cell lung cancer in China," said Dr. Hongqi Tian. "We look forward to expanding the product potential of tunlametinib through establishing partnerships on a worldwide basis." Melanoma is one of the most common cutaneous cancers. There are an estimated 20,000 newly diagnosed melanoma patients in China each year [2]. NRAS mutations accounted for 10.4~12.6% of melanoma patients in China [3], and 15-25% globally [4-7]. NRAS-mutated melanoma is more aggressive and associated with poorer outcomes [8-11]. There were no approved targeted therapies for patients with NRAS-mutant melanoma. Tunlametinib is the first small molecule drug approved for this indication. About tunlametinib Tunlametinib is a small molecule inhibitor of Mitogen-activated protein kinase kinase (MEK) discovered and developed by KeChow. Tunlametinib targets the Mitogen-activated protein kinase (MAPK)/extracellular regulated protein kinases (ERK) signaling pathway (also known as RAS/RAF/MEK/ERK signaling pathway) by inhibiting the activity of MEK kinase, blocking downstream signaling pathways, inhibiting the growth and proliferation of tumor cell. MAPK/ERK signaling pathway plays a critical role in cancer cell proliferation and apoptosis. Aberrant activation of this signaling pathway has been implicated in more than one-third of all malignancies. Compared to other approved MEK inhibitors, tunlametinib demonstrated stronger target inhibition and improved pharmacokinetic properties. About KeChow Pharma Shanghai KeChow Pharma, Inc. is a commercial-stage pharmaceutical company focusing on differentiated small molecule therapeutics for cancer. The company was founded by Dr. Hongqi Tian in 2014, and is headquartered in Shanghai Zhangjiang Pharmaceutical Valley. Since its inception, KeChow is committed to accelerate the discovery, development and commercialization of novel small molecule therapeutics through scientific innovation and by leveraging extensive pharmaceutical expertise from the management team. The company has a science driven corporate culture and is specialized in the development of best-in-class innovative therapeutics to address unmet medical needs of patients around the world. References SOURCE Shanghai KeChow Pharma, Inc

Chinese biotech KeChow Pharma has secured approval from the country's drug regulator for tunlametinib (HL-085), an oral MEK inhibitor indicated for patients with NRAS-mutated advanced melanoma previously treated with PD-1/PD-L1 immune checkpoint inhibitors.The company noted Monday that its drug, developed entirely in-house by KeChow, becomes the first approved targeted therapy for this patient population. Melanoma harbouring NRAS mutations represents approximately 10-12% of melanoma patients in China and is characterised by more aggressive disease and poorer outcomes, it added.The approval was based on positive data from a pivotal single-arm Phase II study involving 100 patients in China. KeChow said the trial demonstrated an overall response rate (ORR) of 35.8%, with median progression-free survival of 4.2 months. In a subset of patients previously treated with immunotherapy, the ORR increased to 40.6%.Side effects include rash and dermatitis acneiform. The most common Grade ≥3 treatment-related adverse event was increased blood creatine phosphokinase, which occurred at a rate of 38%, and was mostly asymptomatic and manageable with dose modification, according to the company.KeChow owns worldwide rights to tunlametinib and has a clinical development plan evaluating it, both as a monotherapy and in combination regimens, across multiple cancer types such as melanoma, neurofibromatosis type 1–related plexiform neurofibromas, colorectal cancer, and non-small-cell lung cancer in China, CEO Hongqi Tian said.The company is also looking to expand the product by "establishing partnerships on a worldwide basis," the executive added.

March 04, 2024 -- SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, announced today that the Company has initiated a rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for mirdametinib, an investigational MEK inhibitor, in pediatric and adult patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN). “There is tremendous potential for mirdametinib to address the substantial needs that exist for children and adults with NF1-PN, and the initiation of our rolling NDA submission brings us one step closer toward our goal of providing these patients with a best-in-class therapy that could make a significant impact on their lives,” said Saqib Islam, Chief Executive Officer of SpringWorks. “We are excited to advance the regulatory filing for our second product and look forward to working closely with the FDA on their review of our application.” The NDA submission includes data from the Phase 2b ReNeu trial, a multi-center, open-label study that opened across 50 sites in the U.S. and enrolled 114 patients across two cohorts (pediatric and adult). The primary endpoint was confirmed objective response rate (ORR), defined as ≥ 20% reduction in target tumor volume as measured by MRI and assessed by Blinded Independent Central Review (BICR). As of the data cutoff date of September 20, 2023, the BICR-confirmed objective response rate was 52% in pediatric patients and 41% in adult patients. Mirdametinib treatment showed deep and durable responses and demonstrated significant improvements in key secondary patient-reported outcome measures. Pediatric and adult patients in the ReNeu trial experienced statistically significant improvements from baseline in pain, quality of life, and physical function, as assessed across multiple patient-reported outcome tools. Mirdametinib was generally well tolerated in the trial, with the majority of adverse events (AEs) being Grade 1 or Grade 2. The most frequently reported AEs were rash, diarrhea, and vomiting in the pediatric cohort and rash, diarrhea, and nausea in the adult cohort. The FDA and the European Commission have 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. In July 2023, the FDA granted mirdametinib Rare Pediatric Disease designation for the treatment of NF1, which provides eligibility for a priority review voucher upon FDA approval. SpringWorks expects to complete the NDA submission in the second quarter of 2024. About the ReNeu Trial ReNeu (NCT03962543) is an ongoing, multi-center, open-label Phase 2b trial evaluating the efficacy, safety, and tolerability of mirdametinib in patients two years of age and older with an inoperable NF1-associated PN causing significant morbidity. The study 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 is administered orally in a 3-week on, 1-week off dosing schedule and has a pediatric formulation (dispersible tablet) for patients who cannot swallow a pill. The primary endpoint of the ReNeu trial is confirmed objective response rate defined as ≥ 20% reduction in target tumor volume as measured by MRI and assessed by BICR. Secondary endpoints include safety and tolerability, duration of response, and changes from baseline in patient reported outcomes. 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.3,4 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 eight to 15-year mean reduction in their life expectancy compared to the general population.2 NF1 patients have approximately a 30-50% lifetime risk of developing plexiform neurofibromas, or PN, which are tumors that grow in an infiltrative pattern along the peripheral nerve sheath and that can cause severe disfigurement, pain and functional impairment; in rare cases, NF1-PN may be fatal.6,7 Patients with NF1-PN can also experience additional manifestations, including neurocognitive deficits and developmental delays. NF1-PNs are most often diagnosed in the first two decades of life.9 These tumors can be aggressive and are associated with clinically significant morbidities; typically, they grow more rapidly during childhood.10,11 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.12 MEK inhibitors have emerged as a validated class of treatment for NF1-PN.13 Mirdametinib is a potent, oral, 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 that plays a central role in multiple oncology and rare disease indications when genetically altered. The U.S. Food and Drug Administration (FDA) and the European Commission granted Orphan Drug designation for mirdametinib for the treatment of NF1, and the FDA granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity. 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. 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. Published 2023 Sep 14. 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. Journal of Clinical Oncology. 2021;JCO.20.02220.doi.org/10. 1200/JCO.20.02220. Prada: 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: Miller DT, et al. Health Supervision for Children With Neurofibromatosis Type 1. Pediatrics. 2019;143(5):e20190660. Ferner R. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. The Lancet Neurology. 2007;6(4):340-351. doi:10.1016/s1474-4422(07)70075-3. Prada C, Rangwala F, Martin L, et al. Pediatric Plexiform Neurofibromas: Impact on Morbidity and Mortality in Neurofibromatosis Type 1. J Pediatr. 2012;160(3):461-467. doi:10.1016/j.jpeds.2011.08.051. 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. The Lancet Neurology. 2007;6(4):340-351. doi:10.1016/s1474-4422(07)70075-3. The content above comes from the network. if any infringement, please contact us to modify.