Ezharmia (valemetostat)

P2, N=900, Not yet recruiting, Gustave Roussy, Cancer Campus, Grand Paris

Therapeutic targeting of H3K27me3 with EZH2-selective inhibitors such as tazemetostat has shown clinical benefit in lymphoma; however, their efficacy is limited by functional redundancy with EZH1. The dual EZH1/2 inhibitor valemetostat overcomes this limitation by reactivating tumor suppressor genes, achieving durable responses in ATL and peripheral T-cell lymphoma (PTCL). Nonetheless, therapeutic resistance can emerge through PRC2 gatekeeper mutations and compensatory DNA methylation. These findings underscore the value of targeting the dysregulated epigenome and support the continued clinical development of dual EZH1/2 inhibitors.

P1, N=60, Recruiting, Daiichi Sankyo | Not yet recruiting --> Recruiting

P2, N=155, Active, not recruiting, Daiichi Sankyo | Trial completion date: Sep 2025 --> Feb 2027

P1, N=60, Not yet recruiting, Daiichi Sankyo

The developed PBPK model was validated against clinical drug-drug interaction studies with a moderate CYP3A inhibitor (fluconazole), a strong CYP3A/P-gp dual inhibitor (itraconazole), and a strong CYP3A/P-gp dual inducer (rifampicin), indicating that the contributions of CYP3A and P-gp in the gut and liver to valemetostat PK were appropriately described in the PBPK model. The validated model was applied to assess the effect of either a CYP3A or a P-gp inhibitor, or a moderate CYP3A inducer on valemetostat PK. The PBPK model incorporating the contribution of CYP3A and P-gp in the gut and liver effectively estimated the effect of CYP3A/P-gp modulators on valemetostat PK and can be used to inform dose recommendations for valemetostat upon coadministration with other treatments.

Moreover, mutp53 was downregulated, p21 was upregulated, and CHK1 was reduced, increasing DNA damage and leading to a stronger impairment of pancreatic cancer cell survival compared with single-agent treatments. Our results reveal that combining epigenetic drugs such as Valemetostat and SAHA could be exploited to target mutp53 and improve the outcome of treatments for aggressive tumors harboring it, such as in pancreatic cancer.

P1/2, N=60, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Sep 2025 --> Sep 2027 | Trial primary completion date: Sep 2025 --> Sep 2027

No significant adverse effects of valemetostat were observed early after transplantation, in contrast to the increased incidence of severe GVHD and non-relapse mortality reported following allo-HCT after mogamulizumab therapy. These findings suggest that valemetostat is a promising option as a bridging therapy to allo-HCT for aggressive ATL.

The EZH2 histone methyltransferase inhibitors tazemetostat and valemetostat have recently received approval for clinical use in follicular lymphoma and adult T-cell leukemia/lymphoma, respectively. Mechanistically, EZH2 inhibition in B cells depletes the repressive histone modification H3K27me3 while concurrently enhancing the active histone modification H3K27ac, thereby selectively increasing transcriptional activity and facilitating chromosomal translocation formation in the presence of high AID activity or Ligase4 deficiency. These findings highlight the impact of drugs that induce epigenetic changes to influence chromosomal translocations and demonstrate the genetic safety of EZH2 inhibitors as monotherapy while highlighting the increased risk of genomic instability when used in cells prone to translocations, such as B cells with high AID levels or DNA-repair deficiency.

P1/2, N=45, Recruiting, University of Alabama at Birmingham | Not yet recruiting --> Recruiting

P1/2, N=438, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting | Trial completion date: Apr 2027 --> Feb 2028 | Trial primary completion date: Apr 2026 --> Apr 2027