Epizyme has been pursuing a novel target in multiple myeloma, and now it has reported positive data from mouse studies for a potential first-in-class therapy.
The drug, dubbed EPZ-719, targets the enzyme SETD2, which the company's scientists believe helps support a cancer-causing mutation that’s found in about 15% of multiple myeloma cases. EPZ-719 significantly inhibited tumor growth in mice with or without the driver mutation, according to data presented at the European Hematology Association virtual congress.
With the positive early results, Epizyme is now aiming to file for an investigational new drug application soon and to start a first-in-human clinical trial by year-end, Epizyme’s chief scientific officer, Jeff Kutok, M.D., Ph.D., said via email.
Epizyme’s initial insight into the potential value of SETD2 inhibition came from research into multiple myeloma that's caused by a specific genetic mutation. That mutation involves an unusual rearrangement of specific regions on chromosomes 4 and 14. The chromosomal abnormality is responsible for about 15% to 20% of multiple myeloma cases and is associated with poor patient prognosis, Kutok explained.
This mutation drives overexpression of the MMSET gene. MMSET, like SETD2, causes epigenetic changes that play key roles in gene expression and transcriptional regulation as well as DNA damage repair and RNA splicing regulation, Kutok said.
Previous research has focused on high MMSET expression, but the target had been considered to be undruggable. So Epizyme decided to turn to SETD2, given its role immediately downstream of MMSET.
Epizyme tested EPZ-719 in mice bearing myeloma tumors with the mutation. The drug safely induced strong tumor growth inhibition of up to 95%, according to Kutok. Tumor regressions were observed in mice that got the drug at the top three doses tested.
What’s more, the team also reported anti-tumor effects in two mouse models of myeloma without the mutation. The drug produced maximum tumor growth inhibition of 79% in one type and 92% in the other at a high dose.
The myeloma field has innovated several important new drug classes in recent years, including CD38 inhibitors and anti-BCMA drugs. Johnson & Johnson, developer of the Legend Biotech-partnered BCMA CAR-T therapy cilta-cel, recently reported positive phase 1 data for two bispecific antibodies in heavily pre-treated myeloma patients. One drug, teclistamab, a BCMAxCD3 bispecific, shrank tumors in 65% of patients; the other, talquetamab, which targets CD3 and GPRC5D, triggered a response in 70% of patients.
Epizyme entered the commercial stage last year with first-in-class EZH2 inhibitor Tazverik, or tazemetostat, now approved in epithelioid sarcoma and relapsed or refractory follicular lymphoma. However, the drug’s launch performance has been lagging, in part because of COVID-19 restrictions.
The new Epizyme findings support targeting SETD2 for multiple myeloma, Kutok said. “We believe it could present a promising potential therapeutic option … either as a monotherapy or in combination with approved standard of care and/or investigational therapies,” he said.