FDA Grants MM-398 NDA Priority Review for Advanced Pancreatic Cancer

Robert Mulroy, president and CEO at Merrimack

Robert Mulroy

The FDA has granted a priority review designation to a new drug application (NDA) for MM-398 (nal-IRI) in combination with 5-fluorouracil (5-FU) and leucovorin as a treatment for patients with metastatic pancreatic cancer following a gemcitabine-based regimen. Under this expedited review program, the FDA has promised to make a decision on the NDA by October 24, 2015.

"The rapid timeline associated with priority review designation brings Merrimack closer to our goal of making MM-398 available to patients with pancreatic cancer who have been previously treated with gemcitabine and are in significant need of treatment options," Robert Mulroy, president and CEO at Merrimack, said in a statement. "We look forward to working with the FDA as they review the application over the next several months."

In the NAPOLI-1 trial, 417 patients with gemcitabine-refractory metastatic pancreatic cancer were randomized to MM-398 monotherapy, 5-FU with leucovorin (control), or MM-398 plus 5-FU and leucovorin. Altogether, 61% of patients had cancer in the head of the pancreas and 68% had liver metastases. Per standard irinotecan protocols, dexamethasone and a 5-HT3 antagonist could be administered in the combination arms.

Intravenous MM-398 was administered at 120 mg/m²every 3 weeks in the single-agent arm. In the control, 5-FU was administered at 2000 mg/m²with racemic leucovorin at 200 mg/m²every 4 weeks followed by 2 weeks of rest. In the combination arm, MM-398 was administered at 80 mg/m2 prior to 5-FU at 2400 mg/m2 and racemic leucovorin at 400 mg/m²every 2 weeks.

Patients in the combination arm had a median OS of 6.1 months versus 4.2 months with 5-FU and leucovorin alone (HR = 0.67; 95% CI, 0.49-0.92;P= .012). The median PFS was 3.1 months for the combination compared with 1.5 months with the control (HR = 0.56; 95% CI, 0.41-0.75;P= .0001).

The ORR was 16% versus 1% (P<.001) and CA19-9 levels were decreased by &ge;50% in 36% versus 12% of patients in the combination and control arms, respectively.

MM-398 monotherapy did not demonstrate superior efficacy compared with 5-FU and leucovorin. Moreover, in some cases, MM-398 alone was associated with more side effects than the drug in combination.

The rates of diarrhea were 12.8% versus 21.1% and the rates of vomiting were 11.1% versus 13.6% for the combination and single-agent MM-398 arms, respectively. Additionally, febrile neutropenia occurred in 1.7% of patients in the combination arm compared with 4.1% with MM-398 monotherapy and not at all with 5-FU/leucovorin alone.

The most commonly reported grade 3/4 adverse events with MM-398 plus 5-FU/leucovorin were neutrophil count decrease (23.1%), fatigue (13.7%), diarrhea (12.8%), and vomiting (11.1%). Investigator assessed neutropenia occurred in 14.5% of patients receiving the MM-398 combination, whereas neutrophil count decrease was reported in the lab reports for 10.3% of patients.

The new drug application for MM-398 was submitted on a rolling basis, as part of a fast track designation granted to the medication in November 2014. Additionally, both the FDA and European Medicines Agency (EMA) have granted the therapy an orphan drug designation. The EMA has also accepted a marketing authorization application for MM-398, marking the beginning of the approval process.

In September 2014, Merrimack and Baxter entered into an agreement to develop and commercialize MM-398, with Merrimack retaining all rights to market the drug within the United States. In Taiwan, PharmaEngine controls commercialization rights for the drug.

"The acceptance of our marketing authorization application for review by the EMA is a positive indicator of the promise of this treatment to address a significant unmet need for patients with metastatic pancreatic cancer and the support for innovative new options," David Meek, head of Oncology at Baxalta, said in a statement. "We are actively advancing our plans to introduce nal-IRI following approval and look forward to extending the utility of the treatment to patients around the world."

Outside of the NAPOLI-1 trial, MM-398 has been explored been explored in a limited number of clinical trials. A phase I study is looking into the drug in combination with cyclophosphamide for pediatric patients with solid tumors. Additionally, a pilot study is exploring MM-398 biodistribution and the feasibility of ferumoxytol as a tumor-imaging agent (NCT01770353). Early results from this pilot study have shown promise for this approach.