Low-key Astra hold puts spotlight on Novartis and Servier

A low-key US clinical hold yesterday suggests more problems for the MCL-1 inhibitor drug class. The phase 1 trial of AZD5991, Astrazeneca’s inhibitor of this anti-apoptosis regulator, has been put on hold after "asymptomatic elevation in cardiovascular laboratory parameters" was seen in a patient treated in combination with Venclexta, a spokesperson said. Though the elevation resolved, the issue is relevant because two years ago Amgen halted its rival anti-MCL-1 agent AMG 397 after seeing cardiac toxicity. Astra stressed that the patient had other co-morbidities, but nevertheless it is impossible to ignore the possibility of a class effect. The companies most invested in MCL-1 inhibition are probably Novartis and Servier, which have a joint project, MIK665, in phase 1/2. New clinical entrants since Evaluate Vantage last analysed the space include projects from Abbvie – though this too has now been scrapped – Prelude Therapeutics and Gilead, while the private group Anji has a preclinical asset. Amgen, meanwhile, has canned AMG 397, though it insists that this was for “strategic” and not “safety” concerns; its second MCL-1 inhibitor, AMG 176, is in two phase 1 trials, one of which is still suspended for lack of safety.

Selected MCL-1 inhibitors
Project Company Trial Note
Phase 1/2
MIK665/S64315 Novartis/Servier (ex Vernalis) NCT04629443 Azacitidine combo in AML
NCT03672695 Venclexta combo in AML
NCT04702425 VOB560 (Bcl2 inhibitor) combo
Phase 1
AMG 176 Amgen/Beigene NCT02675452 Earlier voluntarily halted, now enrolling again
NCT03797261 Venclexta combo, trial suspended for lack of safety in Sep 2019
AMG 397 Amgen/Beigene NCT03465540 Put on hold for cardiac tox; now terminated
AZD5991 Astrazeneca NCT03218683 Trial put on hold after cardiovascular parameter elevations with Venclexta combo
ABBV-467 Abbvie NCT04178902 Trial terminated for "strategic considerations"
PRT1419 Prelude Therapeutics NCT04543305 Started Sep 2020
GS-9716 Gilead Sciences NCT05006794 Started Sep 2021
ANJ810 Anji Pharmaceuticals –  – 
Source: Evaluate Pharma & clinicaltrials.gov.

This story was updated to add comment from Astrazeneca.

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