FDA Grants Orphan Drug Status to Verastem's Avutometinib and Defactinib for Pancreatic Cancer

Verastem Oncology, a biopharmaceutical firm listed on Nasdaq as VSTM, recently revealed that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to its drug avutometinib, a RAF/MEK clamp, when used in conjunction with defactinib, a selective FAK inhibitor, for the treatment of pancreatic cancer. This recognition underscores the significant unmet medical needs of patients suffering from this aggressive form of cancer.

At the ASCO 2024 Annual Meeting, Verastem shared encouraging initial interim results from the ongoing RAMP 205 trial. This study is evaluating the combination of avutometinib and defactinib with standard chemotherapy—gemcitabine and nab-paclitaxel—in treating first-line metastatic pancreatic cancer. Dan Paterson, President and CEO of Verastem Oncology, emphasized that the FDA's ODD highlights the potential for this combination therapy to offer an innovative treatment approach for pancreatic cancer patients.

The interim results presented at the ASCO meeting in June 2024 indicated promising safety and efficacy outcomes. As of May 14, 2024, a total of 41 patients had been treated across four different dose cohort regimens. Notably, in the dose level 1 cohort, 83% of patients achieved a confirmed partial response with at least six months of follow-up. While one dose-limiting toxicity (DLT) was observed in this cohort, it was cleared for further testing after additional patients were enrolled. Out of the 26 patients who underwent their first scan while on treatment, 21 showed a reduction in the target lesion diameters.

The FDA's Orphan Drug Designation is targeted at investigational treatments for diseases affecting fewer than 200,000 people in the U.S. This designation offers various incentives to drug developers, including tax credits for clinical trials, waivers on certain FDA fees, and seven years of market exclusivity upon approval.

Pancreatic cancer ranks as the third leading cause of cancer-related deaths in the United States and the seventh worldwide. Metastatic pancreatic cancer, which is defined as stage IV, indicates the spread of cancer to other organs. Each year, over 30,000 new cases are diagnosed in the U.S., with a grim five-year survival rate of just 3%. Globally, more than 240,000 cases are diagnosed annually, and over 90% of these cancers possess a KRAS mutation. Standard treatments typically include surgery, chemotherapy, radiation, or a combination of these methods.

The RAMP 205 study is a multicenter, open-label, single-arm Phase 1b/2a trial designed to assess the safety, tolerability, and efficacy of avutometinib and defactinib in combination with standard chemotherapy. The study's first part evaluates different dose and schedule combinations to recommend a Phase 2 dose for further expansion. This study is supported by a PanCAN Therapeutic Accelerator Award.

Avutometinib works as a RAF/MEK clamp that forms inactive complexes with MEK and RAF proteins, potentially offering a more comprehensive and lasting anti-tumor response by maximally inhibiting the RAS/MAPK pathway. This mechanism is distinct from current MEK-only inhibitors, which do not prevent RAF from activating MEK. The FDA has also granted Breakthrough Therapy Designation to the avutometinib and defactinib combination for treating recurrent low-grade serous ovarian cancer (LGSOC).

Verastem Oncology continues to explore the potential of avutometinib in various RAS/MAPK-driven tumors through its RAMP program, including ongoing trials like RAMP 301 and RAMP 201 for recurrent LGSOC. The company has initiated a rolling New Drug Application (NDA) for this combination and expects to complete it by late 2024, with a potential FDA decision in early 2025.

Furthermore, Verastem has established collaborations with Amgen and Mirati to evaluate their drugs, LUMAKRAS™ and KRAZATI™, in combination with avutometinib for treating KRAS G12C mutant non-small cell lung cancer (NSCLC). The RAMP 205 trial for first-line metastatic pancreatic cancer is also supported by the PanCAN Therapeutic Accelerator Award.

Verastem Oncology remains dedicated to developing and commercializing new cancer treatments, focusing on therapies that inhibit critical signaling pathways in cancer cells.