Bleximenib (JNJ-75276617) is a highly selective, orally bioavailable small molecule designed to target the interaction between the menin protein and histone-lysine N-methyltransferase 2A (KMT2A). Small-molecule inhibitors like Janssen’s bleximenib are under clinical investigation for treating leukemias with KMT2A and NPM1 alterations, addressing significant unmet medical needs.

Combining hypomethylating agents such as azacitidine and decitabine with venetoclax has significantly improved clinical outcomes for AML patients. This combination is now preferred as a frontline treatment for patients 75 years or older, or those with comorbidities preventing intensive induction chemotherapy.

Bleximenib has demonstrated the ability to inhibit HOX/Meis1 stemness genes and activate differentiation genes in leukemic cells with KMT2A or NPM1 alterations. An initial Phase Ib study evaluating Bleximenib in combination with venetoclax and azacitidine in relapsed/refractory KMT2A-altered and NPM1-mutated AML revealed an acceptable safety profile, with no dose-limiting toxicities. Additional findings presented at EHA 2024 supported these results.

The Phase Ib study demonstrated that bleximenib is compatible with standard doses of venetoclax and azacitidine in relapsed/refractory AML patients with KMT2A or NPM1 alterations. Preliminary results showed promising activity, with a 79% overall response rate (ORR) in the efficacy population and a 65% ORR among participants previously treated with venetoclax. The ORR for NPM1m and KMT2Ar AML groups was 90% (n=19/21) and 62% (n=8/13), respectively.

Bleximenib was well tolerated, with differentiation syndrome occurring in only 3% of patients and no related events of QT prolongation or tumor lysis syndrome (TLS). The ongoing Phase I dose escalation study aims to determine the recommended Phase II dose (RP2D). Additionally, the exploration of bleximenib in combination with AML-directed therapies continues, including both newly diagnosed fit and unfit AML participants, as well as doublet combinations with venetoclax or azacitidine.

KOL insights

“The KMT2A rearrangement is present in up to 15% of children and adults with acute leukemias and around 80% of infants with acute lymphocytic leukemia (ALL). The NPM1 mutation is more common, occurring in up to 30% of patients with acute myeloid leukemia (AML). People with these alterations tend to have very aggressive cancer.” – MD, United States.

Conclusion

KMT2A rearrangements, found in about 5% of adult de novo AML cases and more commonly in pediatric cases, are linked to poor prognosis and can occur in patients of all ages. NPM1 mutations are the most prevalent genetic alterations in AML. Both genetic changes can lead to the production of leukemia cells. Menin inhibitors, such as Janssen’s bleximenib, bind to menin and halt this process, restoring normal blood cell function.

Bleximenib is currently being investigated in a Phase I clinical trial, with results presented at EHA 2024 demonstrating its compatibility with standard doses of venetoclax and azacitidine in relapsed/refractory AML with KMT2A or NPM1 alterations. Preliminary findings revealed a high ORR in the efficacy population. The drug was well tolerated, with ongoing Phase I dose escalation studies aimed at determining the RP2D. Additionally, the exploration of bleximenib in combination with AML therapies is continuing in both newly diagnosed and relapsed patients. Given the positive results from the Phase I clinical study, the future of bleximenib looks promising.

Reports:

Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) Pipeline Insight, 2024 Relapsed/Refractory Acute Myeloid Leukemia Market Insights, Epidemiology, and Market Forecast-2032