ASH 2023 – a new EZ battle shapes up

EZH2 inhibitors have seen some success, but several companies are hoping to improve on their efficacy with a dual approach targeting EZH1 and 2. Two such groups, Daiichi Sankyo and Haihe Biopharma, presented data at ASH on Saturday in peripheral T-cell lymphoma (PTCL), allowing a handy cross-trial comparison of the agents in question.

Daiichi's valemetostat is further ahead, having already been approved in Japan in a related disease, but Haihe's HH2853 looks like it might have an efficacy edge – with the caveat that data with the latter came from a small Chinese trial, versus Daiichi’s much larger global phase 2 study.

EZH2 is overexpressed in PTCL, hence the investigation of these projects for this use. It's hoped that EZH1/2 inhibitors could be more potent than EZH2 blockers such as Ipsen's Tazverik, which is FDA-approved for epithelioid sarcoma and follicular lymphoma. 

PTCL race

Daiichi’s valemetostat was approved in Japan in 2022 for adult T-cell leukaemia/lymphoma, where it is branded Ezharmia. 

In PTCL, the drug is being tested in the global phase 2 Valentine-PTCL01 study;  data were presented at ASH on Saturday came from 133 patients. Meanwhile, the conference saw data from 37 patients in a Chinese phase 1 study of Haihe’s HH2853.

Both trials enrolled patients with a median of two prior lines of therapy, so overall response rates of 44-65% look respectable, and in line with results with Dizal's JAK1 inhibitor golidocitinib in PTCL, also presented at ASH.

Cross-trial comparison of EZH1/2 inhibitors at ASH 2023

Source: ASH 2023.

On the face of it HH2853 looks slightly better than valemetostat, but as usual cross-trial comparisons should be treated with caution, especially given the relative sizes of the two studies, and the fact that both are uncontrolled.

Rates of severe treatment-related adverse events and discontinuations could be something to keep an eye on in future, with thrombocytopenia, anaemia and diarrhoea seen. There was also one treatment-related death with HH2853, in a patient who previously had thrombocytopenia rated grade 4.

Daiichi is planning a supplemental filing for valemetostat in Japan by the end of this fiscal year, while a phase 2 single-arm study of HH2853 in PTCL is ongoing.

PTCL is a rare and aggressive group of blood cancers that account for around 10% of non-Hodgkin’s lymphomas in western countries, rising to 20% in Asia. There is no standard therapy; common treatments include chemo and radiotherapy, and progression-free survival with current approaches is around three to four months.

As well as PTCL, valemetostat trials are under way in various indications including B-cell lymphoma and head and neck cancer.

EZH1/2 inhibitors in development

Source: OncologyPipeline.