MEK1

THURSDAY, Sept. 12, 2024 -- An ingredient in the hair dye a French woman used caused her to develop a vision-robbing retinopathy , researchers report. When she switched to a dye without these ingredients, called aromatic amines, her vision troubles resolved, according to a team led by Dr. Nicolas Chirpaz , an ophthalmologist at Edouard Herriot Hospital, in Lyon. Such cases could be rare, the researchers said, but spreading awareness of the danger "may allow prompt consideration to remove exposure to such hair dye" so eyes aren't permanently damaged, Chirpaz and colleagues said. They published their case report Sept. 12 in the journal JAMA Ophthalmology . As the French team noted, this isn't the first time hair dye has been linked to retinopathy: Three prior cases were reported in 2022 among "middle-aged women following exposure to hair dyes containing aromatic amines." In the latest case, a 61-year-old woman with no prior history of vision trouble came to doctors with progressively blurry vision in both eyes "a few days after dyeing her hair with hair dye containing aromatic amines," Chirpaz' group said. The aromatic amine in the dye used in this case was para-phenylenediamine. Upon examination, the woman was found to have multiple retinal detachments that resembled the damage that can occur in retinopathies that are tied to certain enzymes found in the eye, called MEK1 or MEK2. The woman's eyes also displayed an unhealthy "thickening of the neurosensory retina," the French team found. Tests were conducted to rule out a host of possible causes, including infections and even cancer. In the end, retinal damage caused by the ingredient in hair dye was "diagnosed based on the temporal association between symptoms and hair dye exposure," the team said. The woman soon switched her brand of hair dye, and her vision returned to 20/20 within a month. "Four years later, the patient reported using aromatic amines–free hair dye and has not experienced any recurrence," the study authors said. Chirpaz' team believes that aromatic amine chemicals such as para-phenylenediamine "disrupt" a neurochemical pathway that's essential to the health of what are known as retinal pigment epithelial cells. Cases of "retinopathy associated with the use of hair dye aromatic amines [RAHDAA]" remain rare, but doctors should be on the alert to the possibility when people show up with any retinopathy that doesn't have an easy explanation, the French team said. Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

iStock, Nomadsoul1 Recursion’s oral drug candidate for cerebral cavernous malformation showed no improvements in patient- or physician-reported outcomes at 12 months. The biotech will engage with the FDA to determine the need for an additional study. Recursion on Tuesday released topline data from its Phase II SYCAMORE trial, showing that its drug candidate REC-994 is largely safe to use in patients with cerebral cavernous malformation—though its efficacy pro much to be desired. After 12 months of treatment, both 200-mg and 400-mg doses of REC-994 showed similar adverse event profiles to placebo, indicating that the investigational treatment is largely safe and tolerable for patients with cerebral cavernous malformation (CCM). However, SYCAMORE’s efficacy data were less promising. Magnetic resonance imaging showed a “trend toward reduced lesion volume” in patients who were given the higher, 400-mg dose of REC-994, compared with placebo. These trends improved over time, though Recursion reported no improvements in patient- or physician-reported outcomes at 12 months. Recursion Chief R&D and Commercial Officer Najat Khan in a statement said the biotech is “encouraged” by these findings, which make REC-994 “the first investigational therapy to demonstrate safety” in CCM, while also demonstrating “promising trends in exploratory efficacy endpoints.” “These results provide critical insights that will inform our next study design, including exploring study duration, higher doses, and a larger cohort of patients,” Khan said, noting that Tuesday’s readout “represents an early proof-of-platform milestone” for the biotech. Recursion is seeking a meeting with the FDA “as soon as practical” to determine the way forward for REC-994, including an additional clinical trial, according to the company. The biotech will also present findings from SYCAMORE at an upcoming scientific congress and will submit them for publication in a peer-reviewed journal. CCM is a rare neurovascular disease characterized by malformations of the spinal cord and the brain, often involving abnormally enlarged capillary cavities. The condition affects around 360,000 symptomatic patients, who are at heightened risk of seizures, headaches and progressive neurological deficits, as well as potentially fatal hemorrhagic strokes. There are currently no pharmacologic treatments for CCM. REC-994, an orally available small molecule superoxide scavenger, was discovered using Recursion’s AI-powered drug discovery platform, which leverages “one of the world’s largest proprietary biological and chemical datasets,” according to the biotech’s website . The platform then makes use of machine-learning algorithms to produce an extensive searchable list of interactions from this database. Recursion is also developing REC-2282, another orally available drug candidate that can penetrate the central nervous system, for the treatment of NF2-mutated meningiomas, and REC-4481, a non-ATP-competitive blocker of MEK1 and MEK 2 for familial adenomatous polyposis.

– PDUFA target action date of February 28, 2025 – – EU Marketing Authorization Application also validated by European Medicines Agency – Aug. 28, 2024 -- SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, announced today that the U.S. Food and Drug Administration (FDA) has accepted the Company’s New Drug Application (NDA) for mirdametinib, an investigational MEK inhibitor, for the treatment of adult and pediatric patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN). The NDA was granted Priority Review and has been given a Prescription Drug User Fee Act (PDUFA) action date of February 28, 2025. In addition, the FDA has stated that it is not currently planning to hold an advisory committee meeting to discuss the application. SpringWorks also announced today that 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. Mirdametinib has the potential to be the first approved therapy for the treatment of adult patients and a best-in-class therapy for children with NF1-PN. “These significant milestones bring us closer to our goal of delivering a transformative medicine to both adults and children with NF1-PN in the U.S. and Europe,” said Saqib Islam, Chief Executive Officer of SpringWorks. “People living with NF1-PN are in need of new advances and we look forward to working with the FDA and EMA during their review processes as we prepare to bring our second medicine to patients suffering from devastating diseases.” The FDA grants Priority Review to applications for medicines that offer, if approved, significant improvements over available options or that provide a treatment option where no adequate therapy currently exists. The FDA and the European Commission have 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. “Plexiform neurofibromas may sit next to or surround vital organs and can cause serious medical complications for patients. While progress has been made, there remains a pressing need for more treatment options, particularly for adults who currently have no approved therapy,” said Annette Bakker, Ph.D., Chief Executive Officer of the Children’s Tumor Foundation (CTF) and Board Chair of CTF Europe. “CTF is dedicated to deploying its time, talent and funding towards accelerating the development of new treatments. We congratulate our long-term partner SpringWorks on this important milestone and we are thrilled that patients in the United States and Europe could soon have a new therapy available to them. Both submissions include data from the pivotal Phase 2b ReNeu trial, which evaluated mirdametinib in patients ≥ 2 years of age with NF1-associated PN causing significant morbidity. Results were presented in an oral presentation at the 2024 American Society of Clinical Oncology Annual Meeting and demonstrated that mirdametinib treatment resulted in robust objective response rates confirmed by blinded independent central review, deep and durable responses, improvement in pain and health-related quality of life as well as a manageable safety profile across both the adult and pediatric cohorts.1 ReNeu (NCT03962543) is an ongoing, multi-center, open-label 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 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 was administered orally in a 3-week on, 1-week off dosing schedule as either a capsule or dispersible tablet. The primary endpoint is confirmed objective response rate assessed by proportion of patients with ≥ 20% reduction in target tumor volume on consecutive scans during the 24 cycle treatment phase, as measured by MRI and assessed by blinded independent central review. Secondary endpoints include safety and tolerability, duration of response, and changes in patient reported outcomes from baseline to Cycle 13. The treatment phase of the trial is complete and results were presented at the 2024 American Society of Clinical Oncology Annual Meeting. Patients who completed the treatment phase were eligible to continue receiving treatment in the optional long-term follow up portion of the study, which is ongoing. About NF1-PN Neurofibromatosis type 1 (NF1) is a rare genetic disorder that arises from loss-of-function variants in the NF1 gene, which encodes for neurofibromin, a key suppressor of the MAPK pathway.2,3 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.4,5 The clinical course of NF1 is heterogeneous and manifests as a variety of symptoms across numerous organ systems, including abnormal skin pigmentation, skeletal deformities, tumor growth, and neurological complications such as cognitive impairment.6 Patients with NF1 have an 8 to 15-year mean reduction in their life expectancy compared to the general population.3 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.7,8 NF1-PNs are most often diagnosed in the first two decades of life.7 These tumors can be aggressive and are associated with clinically significant morbidities; typically, they grow more rapidly during childhood.9,10 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.11 MEK inhibitors have emerged as a validated class of treatment for NF1-PN.12 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 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 and Rare Pediatric Disease designation for the treatment of NF1. 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 Moertel C, et al., ReNeu: A pivotal phase 2b trial of mirdametinib in children and adults with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN). Journal of Clinical Oncology 42, 3016-3016(2024). DOI:10.1200/JCO.2024.42.16_suppl.3016. The American Society of Clinical Oncology Abstract 3016. May 2024. 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. 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.