ASH 2024 preview – menin inhibitors face off again

Menin inhibition will feature again at this year’s ASH meeting, although the leading contender, Syndax Pharmaceuticals, will have an uncharacteristically low-key presence. Instead the spotlight looks likely to fall on its rival Kura Oncology, which will have more data on its contender, ziftomenib, plus chemo, in first-line AML.

Meanwhile, Johnson & Johnson’s candidate bleximenib will also feature, and a new menin inhibitor has emerged: Sumitomo’s enzomenib.

Kura’s Komet trail

In January Kura released promising, but very early data with ziftomenib combinations from the Komet-007 trial. Notably the project, in combination with 7+3 chemotherapy in first-line AML, spurred complete responses in all five evaluable first-line patients, with full count recovery.

Now data among more patients detailed in an ASH abstract show this rate waning, though results still look respectable.

Ziftomenib’s evolving first-line dataset 

Notes: *CRc (CR or CR with partial or incomplete haematological recovery); **CR with full count recovery. Source: ASH abstract & company release.

However, it’s notable that the new figures concerned the less stringent endpoint of composite complete remission, defined in the abstract as CR or CR with partial or incomplete haematological recovery.

And another reason for pause could be a lack of dose response, with a 400mg once-daily dose underperforming 200mg, particularly among patients with KMT2A rearrangements – the genetic subtype in which Kura abandoned ziftomenib monotherapy in relapsed/refractory AML after seeing high rates of differentiation syndrome.

Results look better in the other subtype tested, those with NPM1 mutations.

The good news for Kura is that there have been no cases of side effects that have previously looked troublesome with menin inhibitors, namely differentiation syndrome or ziftomenib-associated QTc prolongation. With updated results set to be presented at the meeting, investors will hope the latest numbers hold up.

At ASH, Kura will also present a poster on a different Komet-007 cohort: ziftomenib plus Venclexta and azacitidine in relapsed/refractory AML.

Bleximenib & enzomenib

J&J’s JNJ-75276617, now known as bleximenib, burst onto the scene at ASH last year, and it will have another monotherapy update in relapsed disease this year – with response rates in the abstract looking similar to those reported in 2023, and 100mg twice daily now selected as the go-forward dose.

The project will also see chemo combo data in first-line AML at ASH, giving the chance for a cross-trial comparison against Komet-007, with the caveat that the bleximenib abstract uses a slightly different endpoint of complete response with partial haematological recovery (CRh).

Notable menin inhibitor presentations at ASH 2024

Notes: AML=acute myeloid leukaemia; CRc=composite complete remission (CR or CR with partial or incomplete haematological recovery); CRh=complete remission with partial haematological recovery; DS=differentiation syndrome. Source: ASH 2024 abstracts.

No differentiation syndrome or dose-limiting toxicities were seen with the bleximenib combo; there were two cases of grade 1 QTc prolongation, but these were not attributed to the drug.

Meanwhile, Sumitomo has joined the menin fray with enzomenib, and an ASH presentation will focus on a phase 1/2 trial testing monotherapy in relapsed/refractory acute leukaemia. Results look in line with what has been seen with the other menin inhibitors, raising the question of how Sumitomo, which is behind its bigger rivals, might compete.

The most advanced menin inhibitor is Syndax’s revumenib, which is awaiting an FDA approval decision in relapsed/refractory KMT2Ar acute leukaemia, based on a 23% CR/CRh rate seen in the Augment-101 trial among 57 patients.

More data from this trial will feature at ASH, showing this number holding up among 97 patients. Revumenib’s decision was delayed by three months, and investors will be hoping not to see anything sinister in terms of side effects. Cases of grade 3 or higher differentiation syndrome and QTc prolongation were seen in 15% and 13% of patients respectively – no worse than in previous updates.

ASH will take place on 7-10 December in San Diego.