Pimasertib hydrochloride

First and only FDA-approved type II RAF inhibitor for patients with relapsed or refractory pLGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation RAPNO LGG overall response rate (ORR) of 51% Day One receives rare pediatric disease priority review voucher Conference call and webcast to be April 24, 8:30 a.m. Eastern Time April 23, 2024 -- Day One Biopharmaceuticals, Inc. (Nasdaq: DAWN) (“Day One” or the “Company”), a commercial-stage biopharmaceutical company dedicated to developing and commercializing targeted therapies for people of all ages with life-threatening diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved OJEMDA (tovorafenib), a type II RAF inhibitor, for the treatment of patients 6 months of age and older with relapsed or refractory pLGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. This indication is approved under accelerated approval based on response rate and duration of response. With the approval, Day One received a rare pediatric disease priority review voucher from the FDA. “OJEMDA ushers in a new day for children living with relapsed or refractory pLGG, and we are pleased that we can deliver a new medicine for these patients in desperate need of new treatment options. Moreover, OJEMDA is the first and only FDA-approved medicine for children with BRAF fusions or rearrangements, which are the most common molecular alteration in pLGG,” said Jeremy Bender, Ph.D., chief executive officer of Day One. “We are very proud that our first approved medicine addresses this serious and life-threatening disease of childhood and adolescence. We are grateful to the pLGG community, including patients and their families, study investigators, non-profit organizations, and advocacy groups, for their collaboration and support as we strive to close the innovation gap for children with cancer awaiting new treatments.” pLGG is the most common brain tumor diagnosed in children, with patients suffering profound tumor- and treatment-associated morbidities that can impact their life trajectory. BRAF is the most commonly altered gene in pLGG, with up to 75 percent of children having a BRAF alteration. Until now, there had been no medicines approved for patients with pLGG driven by BRAF fusions. “pLGG is a chronic and relentless cancer that can devastate children and their families, often stealing their vision, balance and speech,” said Dr. Sabine Mueller, pediatric neuro-oncologist, University of California San Francisco Benioff Children’s Hospitals. “The goal of pLGG treatment is to stabilize or shrink the tumor without further disrupting the child’s and family’s life. Historically, there has been no standard of care for children with pLGG who have relapsed. We are excited to welcome a new targeted treatment option with once-weekly oral dosing designed specifically for these kids and their families.” OJEMDA is the only systemic therapy for pLGG that offers once-weekly dosing, with or without food, as a tablet or oral suspension. The accelerated approval of OJEMDA is based on data from the Company’s pivotal open-label Phase 2 FIREFLY-1 trial, which enrolled a total of 137 relapsed or refractory BRAF-altered pLGG patients across two study arms. Arm 1, which accrued 77 patients, was used for the efficacy analyses. Arm 2 provided additional safety data from an incremental 60 patients and was initiated to enable access to tovorafenib once Arm 1 had fully accrued. Details of this trial were presented in November 2023 at the Society for Neuro-Oncology meeting through two oral plenary presentations and in parallel through a publication in Nature Medicine. The approval of OJEMDA was based, in part, on the major efficacy outcome measure of overall response rate (ORR), defined as the proportion of patients with complete response (CR), partial response (PR), or minor response (MR) by independent review based on Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO LGG). “This is a tremendous moment not only for Day One, but also for the broader pediatric brain tumor community. Thanks to the close collaboration between RAPNO and Response Assessment for Neuro-Oncology (RANO) working groups and the patients and families impacted by a pLGG diagnosis, the way we think about measuring response and the goals of therapy for this unique patient population truly evolved,” said Dr. Samuel Blackman, co-founder and head of research and development at Day One. “As a pediatric neuro-oncologist, the approval of OJEMDA is a dream realized.” A best ORR of 51% (95% CI: 40 - 63), which included 28% PRs and 11% MRs. The ORR for OJEMDA was 52% among the 64 patients with BRAF fusions or rearrangements and 50% for the 12 patients with a BRAF V600 mutation. The ORR was 49% among the 45 patients who had received a prior MAPK-targeted therapy, and 55% among the 31 patients who had not received a prior MAPK-targeted therapy. As of the June 5, 2023 data cutoff, the median duration of response by RAPNO LGG was 13.8 months (95% CI: 11.3, not estimable). In addition, 66% of patients remained on study and continue on treatment as of this date. The median time to response, following initiation of treatment, with OJEMDA was 5.3 months (range 1.6, 11.2). Based on RANO LGG criteria, the ORR was 53% [95% CI: (41, 64)]. The safety of OJEMDA was evaluated in 137 patients with relapsed or refractory pLGG, with the majority of adverse events being Grade 1 or Grade 2. The most common side effects were rash, hair color changes, tiredness, viral infection, vomiting, headache, fever, dry skin, constipation, nausea, acne and upper respiratory tract infection. “This is an exciting moment for children and families living with pLGG who previously had few treatment options if their disease progressed,” said Courtney Davies, president and chief executive officer of the Pediatric Brain Tumor Foundation. “The approval of OJEMDA is a testament to the power of community and industry collaboration to address a critical unmet need for children whose day-to-day living and long-term health outcomes are significantly impacted by pLGG. The potential benefit that a new treatment option provides children living with this disease and their families is crucial. There is so much to celebrate here.” The Company continues its commitment to the pLGG community with the Phase 3 FIREFLY-2/LOGGIC randomized clinical trial evaluating tovorafenib as a potential front-line therapy compared to chemotherapy in patients aged 6 months to 25 years with pLGG, which it believes will satisfy certain post-marketing requirements to the FDA. This study is currently enrolling patients in the United States, Canada, Europe, Australia, and Asia. Day One Biopharmaceuticals is dedicated to helping patients with pLGG access OJEMDA and supporting their families throughout the treatment journey. As part of this commitment, we are pleased to announce EveryDay Support From Day One™, a comprehensive program that offers personalized services for eligible patients and their care teams, including insurance coverage support, financial assistance options, shipping medication to patients' homes, and educational resources. Caregivers and healthcare providers can visit www.everydaysupport.com or call a patient navigator at 855-DAY1-BIO (855-329-1246) for more information. OJEMDA (tovorafenib) is a Type II RAF kinase inhibitor of mutant BRAF V600, wild-type BRAF, and wild-type CRAF kinases. OJEMDA is indicated for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). Tovorafenib is under evaluation as a therapy for patients with pLGG requiring front-line treatment (Phase 3 FIREFLY-2/LOGGIC). It is also being studied in combination with the MEK inhibitor pimasertib for adolescent and adult patient populations with recurrent or progressive solid tumors with MAPK pathway alterations (FIRELIGHT-1). Tovorafenib was granted Breakthrough Therapy and Rare Pediatric Disease designations by the FDA for the treatment of patients with pLGG harboring an activating RAF alteration, and it was evaluated by the FDA under priority review. Tovorafenib has also received Orphan Drug designation from the FDA for the treatment of malignant glioma and from the European Commission for the treatment of glioma. Pediatric low-grade glioma (pLGG) is the most common brain tumor with an estimated incidence of 1,100 children per year who are eligible for front-line systemic therapy. BRAF is the gene most commonly altered in pLGG, of which there are two primary types of BRAF alterations – a BRAF gene fusion and a BRAF point mutation. In children with BRAF-altered pLGG, approximately 80 percent have BRAF fusions or rearrangements, while the remaining 20 percent have a V600 mutation. Pediatric low-grade gliomas can be chronic and relentless, with patients suffering profound side effects from both the tumor and the treatment, which may include chemotherapy and radiation. These side effects can impact their life over the long term, and may include muscle weakness, loss of vision, and difficulty speaking. This type of tumor has a high risk of progression, and many children with pLGG require long-term treatment. While most children with pLGG survive their cancer, children who do not achieve a complete resection following surgery may face years of increasingly aggressive treatment. FIREFLY-1 is evaluating OJEMDA™ (tovorafenib) as once-weekly monotherapy in patients aged 6 months to 25 years with relapsed or progressive pLGG harboring a known activating BRAF alteration. The trial is being conducted in collaboration with the Pacific Pediatric Neuro-Oncology Consortium (PNOC). The primary endpoint is overall response rate (ORR), defined as the proportion of patients with confirmed response based upon Response Assessment for Neuro-Oncology High-Grade Glioma (RANO HGG) criteria. Secondary and exploratory endpoints include the overall response rate based on Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO LGG) criteria, Response Assessment for Neuro-Oncology Low-Grade Glioma (RANO LGG) criteria and volumetric analyses, progression-free survival, safety, functional outcomes, and quality of life measures. RANO HGG, RANO LGG and RAPNO LGG are assessed by blinded independent central review. Additional information about FIREFLY-1 may be found at ClinicalTrials.gov, using Identifier NCT04775485. The Pacific Pediatric Neuro-Oncology Consortium (PNOC) is an international consortium with study sites within the United States, Canada, Europe and Australia dedicated to bringing new therapies to children and young adults with brain tumors. Day One Biopharmaceuticals is a commercial-stage biopharmaceutical company that believes when it comes to pediatric cancer, we can do better. The Company was founded to address a critical unmet need: the dire lack of therapeutic development in pediatric cancer. Inspired by “The Day One Talk” that physicians have with patients and their families about an initial cancer diagnosis and treatment plan, Day One aims to re-envision cancer drug development and redefine what’s possible for all people living with cancer—regardless of age—starting from Day One. Day One partners with leading clinical oncologists, families, and scientists to identify, acquire, and develop important targeted cancer treatments. The Company’s pipeline includes tovorafenib (OJEMDA™) and pimasertib. The content above comes from the network. if any infringement, please contact us to modify.

Day One Biopharmaceuticals’ Ojemda is approved by the FDA as the first drug for a common type of childhood brain tumors with a BRAF fusion or rearrangement. Another drug is in town for common pediatric brain tumors. Compared with an incumbent offering from Novartis, the newcomer boasts an FDA approval covering a broader patient population. The FDA on Tuesday handed out an accelerated approval to Day One Biopharmaceuticals’ Ojemda, also known as tovorafenib, as a treatment for patients 6 months of age and older with certain relapsed or refractory pediatric low-grade glioma (pLGG). The nod sanctions the type 2 RAF inhibitor to be used in tumors with a BRAF fusion or rearrangement, or BRAF V600 mutation. The go-ahead puts Ojemda toe to toe with Novartis’ Tafinlar-Mekinist combo, which, thanks to an FDA approval last year, is allowed in pLGG but only for cases with BRAF V600 mutations. Ojemda ushers in a new day as the first FDA-approved medicine to treat pLGG marked by BRAF fusions, and it’s also Day One’s first commercial product, CEO Jeremy Bender, Ph.D., said in a statement Tuesday. BRAF gene fusions are much more prevalent than BRAF V600 mutations, Day One’s head of R&D, Samuel Blackman, M.D., Ph.D., told Fierce Pharma in an interview ahead of the FDA approval.  PLGG is the most common form of childhood brain tumor. As the most prevalent type of pLGG, BRAF alterations make up about 1,100 new diagnoses in the U.S. each year out of 1,500 total cases. Among the BRAF alterations, about 80% have a gene rearrangement, while the rest 20% have a V600 mutation. About a third of pLGG patients can undergo complete tumor resection, after which 90% of children don’t need any additional therapy. And for the majority of kids for whom surgery alone can’t tackle the disease, that’s where Ojemda comes in. This translates into about 2,000 to 3,000 pLGG patients who needs systemic therapy at any given time in the relapse setting, Blackman said. Based on the broad patient population and the lack of a boxed warning on the label, analysts at JPMorgan pegged Ojemda could reach around $750 million in peak sales, which they noted is slightly ahead of Wall Street’s consensus estimates, according to a Tuesday note. With the approval, Day One gained a rare pediatric disease priority review voucher, although the company has not specified whether it will monetize the regulatory fast pass. Priority review vouchers, which can speed up the FDA’s review of drugs, are typically sold for around $100 million these days. Ojemda proved its case in the phase 2 FIREFLY-1 trial. Among 76 efficacy-evaluable patients, Ojemda’s best overall response rate clocked in at 51%, which means the drug successfully shrank tumors in those patients at any time from treatment start. The response rates were 52% and 50% for patients with BRAF fusions and V600 mutations, respectively. Even among those who received a targeted therapy along the MAPK pathway—including traditional BRAF-MEK inhibitors such as the Tafinlar-Mekinist duo—Ojemda triggered a response in 49% of patients. The duration of response, based on a pLGG-specific assessment, was 13.8 months at the median for Ojemda. Back in March 2023, Tafinlar and Mekinist got its FDA go-ahead based on an overall response rate of 47% in BRAF V600 mutation pLGG as well as a 69% reduction in the risk of disease progression or death compared with chemotherapy. Tafinlar belongs to what’s known as type 1 BRAF inhibitors, which specifically block the V600 form of the protein mutation. That design means those drugs may enhance cancer signaling and fuel tumor growth in BRAF fusion cases, Blackman explained. And Mekinist is added to reduce this damaging “paradoxical activation effect” while also adding to the regimen’s efficacy, Blackman explained. In contrast, Ojemda’s mechanism allows it to inhibit the fusions and V600 without causing the toxic activation seen in type 1 BRAF inhibitors, he added. Another advantage of Ojemda is that it’s given once weekly, whereas Tafinlar is dosed twice a day. Under the accelerated approval pathway, Day One is on the hook to provide confirmatory evidence to prove Ojemda’s clinical benefit. The company is conducting the phase 3 FIREFLY-2 randomized trial pitting Ojemda against chemotherapy as a first-line therapy in patients aged 6 months to 25 years. The trial kicked off last year and is still enrolling patients. Day One decided to again use Ojemda as a monotherapy rather than combining it with chemotherapy because it believes chemo doesn’t add benefits for patients, Blackman said. Instead, chemo comes with toxicity and more cumbersome infusions. “We designed this trial with the pediatric oncology community to specifically address the question, ‘can an oral targeted therapy be as good as or ideally better than chemotherapy?’ because chemotherapy has a lot of burdens for patients and for families in the short term and in the long term,” Blackman said. But when it comes to other solid tumors, Day One is exploring pairing Ojemda with its in-house MEK inhibitor candidate, pimasertib, in adult patients with various types of aberrations along the MAPK pathway, not just BRAF. “At the end of the day, for V600 colorectal cancer, for V600-mutant melanoma, there’s obviously so many type 1 RAF inhibitors out there that are approved for these indications,” Blackman said. “The places that aren’t approved—the fusions—they’re just too small in the adult population.”