Development of melflufen
In the late-1990s, a group of Swedish researchers based at the Karolinska Institute developed a series of cancer fighting molecules given the series name J1 to J6 that built on research into alkylating agents undertaken by Italian scientists in the 1970s. The ‘J’ recognized the contribution of one of the lead researchers, Dr Joachim Gullbo of Uppsala University, Sweden.
The molecule ‘J1’ was identified as having the most potential to deliver higher levels of cancer fighting alkylating agents to cancer cells and and is now called melflufen.
Pre-clinical research showed melflufen delivered significantly lower rates of tumour growth when compared to alkylating agents commonly used in cancer treatment. The overrepresentation of certain enzymes in cancer cells, including a family of enzymes known as peptidases, was identified early as the reason for melflufens ability to rapidly increase the presence of cancer fighting molecules in cancer cells.
Clinical Development Phases for Treatment of Late-stage Multiple Myeloma
Given the history of using alkylators in treating multiple myeloma, it was decided that the clinical development phase for melflufen would focus on patients with late-stage multiple myeloma.
A Phase 2 clinical trial was undertaken with the aim of studying the efficacy and safety of melflufen in late-stage relapsed and refractory multiple myeloma patients. This study was conducted with the support of seven collaborating institutions (in the US and Europe), including Harvard University’s Dana-Farber Cancer Institute.
Results from the Phase 2 study showed that 48% of patients were progression-free of their cancer at six months and 13.7% at twelve months. The Phase 2 study also showed a median survival time of 20.7 months for patients being treated with melflufen. This contrasts with data from other studies on the current standard of care, pomalidomide, where the median survival time is 12.4 months.
The Phase 2 study results also showed that when compared to available data on standard of care, melflufen demonstrated a significantly lower incidence of those side effects that substantially reduce the day-to-day quality of life in late-stage relapsed and refractory multiple myeloma patients.
Results of the Phase 2 clinical study were presented to the US FDA in July 2016. Additional melflufen clinical data was presented at the European Hematology Association conference in Stockholm, Sweden, in June 2018.
In the course of 2015, melflufen received Orphan Drug Status in both the US and Europe.
The regulatory path ahead
The initiated filing process in the US for accelerated approval for melflufen for the treatment of RRMM patients with triple-class refractory disease based on data from the ongoing pivotal phase 2-study called HORIZON. It is the first step in building a potential label for melflufen within myeloma. A potential accelerated approval results in a regulatory approval that later needs to be confirmed with clinical data from a randomized trial. Both OCEAN and LIGHTHOUSE can independently act as confirmatory trials for a potential accelerated approval. Additionally, both OCEAN and LIGHTHOUSE – assuming positive outcome from the trials – can result in broadening of the label into less advanced RRMM patient populations (both trials) as well as in combination with daratumumab (LIGHTHOUSE).
Oncopeptides has collaborated with leading experts and held discussions with governing medical agencies and professional bodies in the US and Europe to create the development program for melflufen in RRMM. Upon receiving approval of the phase 3 OCEAN study design through the FDA Special Protocol Assessment in August 2016, detailed preparations commenced for the development program of melflufen. The program aims to fully characterize melflufen in the treatment of RRMM and thereby maximize the product candidate’s market potential.
The OCEAN phase 3 trial is expected to lay the foundation for an application for melflufen late 2020. The application can act as a confirmatory trial after a potential accelerated approval – including label extension into RRMM patients with only single class refractory disease (compared to the potential accelerated approval for the treatment of RRMM patients with triple-class refractory disease) – as well as act as an independent application for market authorization across markets.
Further Indications for melflufen
Beyond the treatment of relapsed and refractory multiple myeloma, pre-clinical studies suggest that melflufen may also be effective in a wide range of cancer indications. Oncopeptides is currently investigating the possibility of clinical studies in the high-dose setting in conjunction with bone marrow transplantation in multiple myeloma patients, also in the treatment of amyloidosis and of non-Hodgkin’s lymphoma. All these indications are examples of where alkylating agents are currently used, and where melflufen may show enhased efficacy and/or safety.