Dabrafenib Mesylate

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.”

According to Lutris’ CEO, approximately 75% of cancer patients taking EGFR inhibitors develop some form of acneiform rash. Credit: sruilk via Getty Images. Lutris Pharma has secured a US Food and Drug Administration (FDA) orphan drug designation for its BRAF inhibitor LUT014, an investigational treatment for epidermal growth factor receptor (EGFR) inhibitor-induced acneiform rash. EGFR inhibitors are used as cancer treatments, however dermatological side effects such as acneiform lesions, a skin condition that appears as small red bumps or pustules on the skin, seen with the treatment affect a patient’s quality of life. Approximately 75% of cancer patients taking EGFR inhibitors develop some form of an acneiform rash, according to Lutris’ CEO Noa Shelach. The candidate is currently being investigated in a Phase II clinical trial (NCT04759664), where 117 colorectal cancer patients with acneiform lesions receive either one of two strengths of LUT014 gel once a day for four weeks, or a placebo. EGFR, found on cell surfaces including skin, regulates crucial cell functions such as growth and differentiation. It is overexpressed in cancer cells, so EGFR inhibitors prevent cancer cells from receiving the signals needed for growth and division, inhibiting tumour growth and progression. See Also: Market cap upturn for top 20 biopharma companies with obesity drug successes in 2023 LUT014 is a BRAF inhibitor that is applied topically on the skin. BRAF, a protein translated from the BRA gene, is part of the EGFR signalling pathway. LUT014 helps to shrink tumours with mutated BRAF proteins while promoting cell growth in normal cells, helpful for conditions such as an acneiform rash. In the announcement accompanying the orphan drug designation, Shelach said: “Receipt of orphan drug designation for LUT014 is strategically important for Lutris, as it reflects the significant unmet need for patients treated with EGFR inhibitors. “The [orphan drug designation] also qualifies us for incentives including tax credits for qualified clinical trials, exemption from user fees and potentially seven years of marketing exclusivity for LUT014, should it gain approval for the treatment of EGFRI inhibitor acneiform rash.” In March 2023, the FDA approved Novartis’ Tafinlar and Mekinist BRAF/MEK inhibitor combination therapy to treat BRAF V600E low-grade glioma in paediatric patients starting at one year of age. Findings from the Phase II/III TADPOLE trial listed acneiform rash as one of the most common adverse reactions observed.