Daiichi Sankyo Company, Limited announced that it has submitted a New Drug Application (NDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW) for valemetostat, a potential first-in-class dual inhibitor of EZH1 and EZH2, for the treatment of patients with relapsed/refractory adult T-cell leukaemia/lymphoma (ATL).

ATL is a rare and aggressive type of peripheral T-cell lymphoma that occurs with greater frequency in parts of Japan and other regions.  Patients with ATL face a poor prognosis with current therapies.  Nearly 90% of patients relapse after completing intensive first-line treatment, at which point there are few options available.

The Japan NDA submission of valemetostat is based on pivotal phase 2 study results in Japanese patients with three aggressive subtypes of relapsed/refractory ATL, recently presented at the 2021 American Society of Haematology (ASH) Annual Meeting. Valemetostat previously received Orphan Drug designation (ODD) from the Japan MHLW for treatment of patients with relapsed/refractory ATL.

“Valemetostat would potentially be the first dual inhibitor of EZH1 and EZH2 to be approved anywhere in the world and could provide a new type of targeted therapy option for patients with relapsed/refractory ATL, which represents one of the most significant unmet medical needs in Japan,” said Wataru Takasaki, PhD, executive officer, head of R&D Division in Japan, Daiichi Sankyo. “Valemetostat is the fifth innovative oncology medicine from our pipeline to be submitted for regulatory approval in Japan in the past three years.”

Adult T-cell leukaemia/lymphoma (ATL) is a rare and aggressive type of peripheral T-cell lymphoma (PTCL) that is caused by human T-cell lymphotropic virus type 1 (HTLV-1). More than 3,000 new cases of ATL are diagnosed each year worldwide.  ATL occurs with greater frequency in regions where the HTLV-1 virus is endemic including southwest Japan, Central and South America and central Australia. Cases are also observed in North America and Europe, and incidence of ATL is rising in non-endemic areas. In Japan, there are approximately 1,000 new ATL cases and over 1,000 deaths due to ATL annually.

ATL has the poorest prognosis compared to other types of PTCL, with a five-year overall survival rate of about 14%.  A median survival time of approximately eight months (252 days) was reported for patients in Japan with the most common acute ATL subtype.

Treatment of ATL is based on subtype and consists primarily of intensive multi-drug chemotherapy regimens. Nearly 90% of patients relapse after completing intensive first-line treatment, at which point there are few options available. Additional therapies are needed to improve the prognosis of ATL in Japan and worldwide.

Valemetostat is a potential first-in-class dual inhibitor of EZH1 and EZH2 currently in clinical development in the Alpha portfolio of Daiichi Sankyo. A potent and selective small molecule inhibitor, valemetostat is designed to counter epigenetic dysregulation by targeting both the EZH1 and EZH2 enzymes.

The valemetostat development program includes VALENTINE-PTCL01, a global pivotal phase 2 trial in patients with relapsed/refractory PTCL and ATL; a pivotal phase 2 trial in patients with relapsed or refractory ATL in Japan; and, a phase 1 study in patients with relapsed/refractory NHL in the US and Japan. Valemetostat received ODD from the US Food & Drug Administration for the treatment of PTCL in December 2021, ODD from the Japan MHLW for the treatment of relapsed/refractory ATL in November 2021 and SAKIGAKE Designation from the Japan MHLW for the treatment of adult patients with relapsed/refractory PTCL in April 2019.

Valemetostat is an investigational medicine that has not been approved for any indication in any country. Safety and efficacy have not been established. About the Pivotal phase 2 Study The pivotal, open-label, multi-center, single-arm phase 2 study evaluated efficacy and safety of valemetostat (200 mg dose daily) as monotherapy in patients with relapsed/refractory ATL who were previously treated with mogamulizumab or at least one systemic chemotherapy in case of intolerance/ contraindication for mogamulizumab and with no history of allogenic hematopoietic stem cell transplant.

The primary endpoint is objective response rate (ORR) assessed by independent efficacy assessment committee. Secondary endpoints include investigator-assessed ORR, best response in tumour lesions, complete remission rate, tumour control rate, time to response, duration of response, progression-free survival, overall survival and safety. A total of 25 patients were enrolled in the study in Japan.