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FDA Accepts New Drug Application for Propylene Glycol-Free Melphalan

Approval decision set for October

A new drug application for Captisol-enabled (propylene glycol-free) melphalan (CE-melphalan) has been accepted by the FDA. Spectrum Pharmaceuticals is seeking approval for the drug’s use as a high-dose conditioning treatment prior to autologous hematopoietic (progenitor) stem-cell transplantation (AHCT) in patients with multiple myeloma (MM). Spectrum is also seeking approval for the palliative treatment of patients with MM for whom oral therapy is not appropriate.

The FDA has assigned a Prescription Drug User Fee Act (PDUFA) action date of October 23, 2015.

CE-melphalan is a new intravenous formulation of melphalan being investigated for the MM transplant setting, for which it was granted an “orphan drug” designation by the FDA. This formulation eliminates the need to use propylene glycol-containing custom diluent, which has been reported to cause renal and cardiac adverse effects, which in turn limit the ability to deliver higher doses of therapeutic compounds. The use of the Captisol technology to reformulate melphalan also improves its stability and is expected to allow slower infusion rates and longer administration durations, potentially enabling clinicians to achieve a higher dose intensity for pre-transplant chemotherapy, according to Spectrum.

Captisol (Ligand Pharmaceuticals) is a chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. The technology has been used in six FDA-approved products, including carfilzomib (Kyprolis, Onyx Pharmaceuticals), amiodarone (Nexterone, Baxter International), and posaconazole (Noxafil, Merck). More than 30 other Captisol-enabled products are currently in clinical development.

CE-melphalan was evaluated in a pivotal phase II trial. The study’s primary objective was to determine the safety and toxicity profiles of CE-melphalan in MM patients receiving 200 mg/m2 as myeloablative therapy prior to AHCT. Secondary objectives evaluated the efficacy of CE-melphalan in this patient population, as measured by the MM response rate (according to International Myeloma Working Group criteria), and the rates of myeloablation and engraftment.

The study results supported the safety and efficacy of CE-melphalan as a high-dose conditioning treatment prior to AHCT in patients with MM. CE-melphalan led to successful myeloablation and subsequent engraftment in all of the MM patients studied, with no mortality or unexpected transplant-related toxicity. Overall, 95% of the subjects (n = 61) responded to high-dose CE-melphalan, and very good partial responses or better were achieved by 67% of a subgroup of high-risk patients (15%).

There were no deaths by day 100, and the most common grade-3 or grade-4 toxicities consisted of hematologic adverse events (i.e., neutropenia, leukopenia, lymphopenia, thrombocytopenia, and anemia). The most frequent non-hematologic adverse events included diarrhea, nausea, and fatigue. Importantly, the incidence of severe (grade-3 or grade-4) mucositis was low (10%).

Source: Spectrum Pharmaceuticals; March 9, 2105.

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