ASH 2025 preview – toxicity worries hit BeOne’s sonrotoclax

BeOne Medicines is heading towards a first FDA approval decision for its BCL2 inhibitor sonrotoclax in mantle cell lymphoma, but an ASH abstract suggests that toxicity might be an issue. In the phase 1/2 Celestial-201 trial, in post BTK-inhibitor patients, 13% of patients died from treatment-emergent adverse events.

Sonrotoclax features among ASH presentations outside the high-profile areas such as multiple myeloma and B-cell lymphomas. Elsewhere, Pfizer’s Adcetris follow-on PF-08046044 produced impressive early efficacy in various lymphomas, but dose-limiting toxicities add to questions about the project’s future. And Terns looks to have come out on top, for now, in a battle with Enliven over BCR-ABL inhibitors.

Seeing stars

BeOne believes that sonrotoclax is a more potent BCL2 inhibitor than Venclexta; however, that potency might come with a price. The uncontrolled Celestial-201 trial found a 53% ORR among 103 patients treated with sonrotoclax at 320mg, in line with a 50% ORR with Lilly’s non-covalent BTK inhibitor Jaypirca in post-BTKi MCL. Venclexta isn’t approved for MCL.

However, 37% of 115 patients getting sonrotoclax at 320mg had a serious treatment-emergent adverse events, the most common being pneumonia (7%). TEAEs led to treatment discontinuations in 14% and death in 13% of patients.

On Wednesday, BeOne said the FDA had accepted a filing for sonrotoclax in relapsed MCL, with priority review, making a decision likely before the end of May. As well as the confirmatory Celestial-RR MCL study, phase 3 trials of sonrotoclax are ongoing in chronic lymphocytic leukaemia, with data from the first-line Celestial-TNCLL expected next year. Investors might now keep a close eye on adverse events.

Adcetris follow-on

Pfizer recently discontinued one Adcetris follow-on, but is persevering with another, PF-08046044. The latter will feature at ASH, with data from a phase 1 trial in various relapsed/refractory lymphomas.

Among 42 evaluable patients receiving 0.6-3.2mg/kg the ORR was 74% – including a 76% ORR among 26 classical Hodgkin’s lymphoma patients. This looks similar to a 73% ORR with Adcetris in relapsed classical Hodgkin’s – impressive given that the PF-08046044 number encompasses various doses, and the fact that most patients had already received Adcetris and checkpoint inhibitors.

However, there were DLTs at 2.0mg/kg and 2.5mg/kg – and two more at a higher 4mg/kg dose. At ASH, investors will be hoping to see more information about responses at different dose levels.

There are already some doubts about PF-08046044, whose phase 1 trial, which began in May 2024, had once planned to enrol 210 patients; that target was cut to 46 last month, and currently stands at 57.

Best of the rest: selected ASH abstracts

Note: *by independent review & at 320mg dose; MMR=major molecular response; TR=treatment-related; TSS=total symptom score. Source: ASH.

Terns is one of several companies trying to improve on Novartis’s approved BCR-ABL inhibitor Scemblix, and ASH will feature data from the phase 1 Cardinal trial of TERN-701 in pretreated chronic-phase chronic myeloid leukaemia. 36% of patients in the study had received prior Scemblix.

The abstract notes that 64% of patients (14 of 22) achieved the primary endpoint, major molecular response (MMR) by 24 weeks. There was also a 60% MMR rate in prior Scemblix patients – but this is a cumulative number that includes patients in response at baseline.

Still, the numbers look better than those seen with TERN-701’s major competitor, Enliven Therapeutics’ ELVN-001. In that project’s phase 1 Enable trial 32% of patients (13 of 41) achieved MMR by 24 weeks. However, caveats about this cross-trial comparison include that more patients in Enable – 58% – had received prior Scemblix. 

Both projects look better than Scemblix, which produced a 25% cumulative MMR rate at 24 weeks in the Ascembl trial. Enliven has a market cap of $1.3bn while Terns, which has been climbing since the ASH abstracts were released, sits at $2.6bn.

Meanwhile, abstracts concerning Corvus’s ITK inhibitor soquelitinib and Cogent’s KIT inhibitor bezuclastinib could be placeholders, as they reprise previously reported data.

Finally, a phase 1/2 trial of Abcuro’s anti-KLRG1 MAb ulviprubart in T-cell large granular lymphocytic leukaemia began in 2022, but is only just yielding results. The ASH abstract only gives pharmacodynamic data, which are described as “variable”. Perhaps more details will come at the meeting, but there might not be much hope for this project. There are no other KLRG1-targeting MAbs in the clinic, according to OncologyPipeline.

ASH 2025 takes place in Orlando, Florida on 6-9 December.