ASH 2024 preview – best of the rest

Away from the big-ticket items of multiple myeloma therapies, menin inhibition and novel anti-CD19 approaches, this year's ASH conference offers several presentations that, while perhaps falling under the radar, should still generate interest.

One area is myelofibrosis and Incyte's BET inhibitor; a similar approach from MorphoSys impressed sufficiently last year to secure a Novartis buyout that's since turned sour. Attention could also fall on CD123, a target that's still in play in AML despite numerous clinical setbacks, as well as on a long-awaited update on the anti-ROR1 ADC Merck & Co gained in its $2.8bn buyout of VelosBio.

The ROR1 ADC, zilovertamab vedotin, has led a somewhat low-key existence since the Merck buy-out, at a time when other attempts to hit ROR1, notably from Lyell, Boehringer Ingelheim and Oncternal, have foundered. But the ASH data could raise hopes among players like Ipsen that have, against the odds, kept faith with this target.

Zilo-V is in several phase 2 studies, one of which, Waveline-007, concerns first-line DLBCL in combination with R-CHP. Here, according to the ASH abstract, the project has produced a complete response rate of 94% across all doses, and 100% at the recommended phase 2 dose of 1.75mg/kg.

ApexOnco separately previewed ASH presentations from Arcellx, and those concerning menin inhibitors, anti-CD19 approaches, other multiple myeloma therapeutics, BTK inhibition/degradation, and late-breakers.

Buyout trigger

At last year's ASH MorphoSys succeeded in stoking investor interest in its BET inhibitor pelabresib, despite its first-line myelofibrosis study, Manifest-2, failing on a key metric. The data were enough to attract a €2.7bn buyout from Novartis, but fears proved to be well founded when the Swiss group recently revealed an extensive filing delay.

Incyte, as maker of the first-line standard of care Jakafi, is motivated to defend its position through an in-house BET inhibitor, INCB057643, though at ASH this will feature in a relapsed rather than front-line setting. Separately, Bristol Myers Squibb recently discontinued its BET inhibitor ezobresib.

Other approaches to treating myelofibrosis include Chia Tai's JAK/ROCK inhibitor rovadicitinib and Sumitomo's PIM1 kinase inhibitor nuvisertib. The latter is the only clinical PIM1 inhibitor in clinical development (OncologyPipeline reveals one other industry asset, Biolexis's BLX-0631, in preclinical trials), but both concern Jakafi-relapsed myelofibrosis.

Selected ASH 2024 presentations

Meanwhile, in the loosely related space of myelodysplastic syndromes, which is mechanistically linked to AML, Novartis's will have data on DFV890, one of the industry's four clinical-stage NLRP2 inhibitors. However, the abstract only reveals biomarker data.

CD123 is a target that's been extensively studied here, but has become linked to significant off-tumour toxicities. Xencor's anti-CD123 T-cell engager vibecotamab will have clinical data at ASH, even though this project is no longer listed in the pipeline, having been dropped by its licensee Johnson & Johnson some time ago.

Affimed specialises in NK cell engagers that use CD16A as the anchor, and an anti-CD123 iteration, AFM28, will feature at ASH. While this has previously been highlighted as causing no dose-limiting toxicities at initial dosing, the ASH abstract reports one DLT at 200mg, with the patient dying after possibly related pneumonitis.

Other clinical-stage discontinuations with this mechanism include the Car-T projects JEZ567 (Novartis) and UCART123, which Cellectis quietly deprioritised earlier this month.

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