Question marks over AbbVie/Roche’s venetoclax after safety scare

AbbVie and Roche have stopped recruiting patients for all multiple myeloma trials involving the drug venetoclax after a higher proportion of deaths was observed in patients receiving it than in a trial’s control arm.

AbbVie, which is developing the drug in partnership with Roche, said the partial clinical hold follows a review of data from the ongoing phase 3 BELLINI trial, in relapsed/refractory multiple myeloma.

Following a ruling from the FDA, no new patients will be enrolled in any studies of venetoclax for multiple myeloma until a further analysis of the data is completed.

This action does not impact any of the approved indications for venetoclax, such as chronic lymphocytic leukaemia (CLL) or acute myeloid leukaemia (AML), and is limited to investigational clinical trials in multiple myeloma.

AbbVie said it “remains confident in the benefit/risk profile of venetoclax in those approved indications.”

The response from the medical establishment on twitter was largely supportive, as data from the same trial seems to support its efficacy in multiple myeloma.

Whether the drug can now become deemed marketable in the new indication will likely rely on the companies finding a suitable work-around in the clinic to find a way to reduce risk of infection, which seems to be the root cause of the problems identified in the trial.

The FDA made the call based on results from the trial testing venetoclax combined with bortezomib and dexamethasone, compared with placebo and dexamethasone in relapsed/refractory disease.

BELLINI had already met its primary endpoint of progression-free survival and demonstrated statistically significant improvements in response rate, and very good partial or better response in the venetoclax arm compared with the control arm.

But in a preplanned analysis, in the venetoclax arm 41 out of 194 (21.1%) deaths were observed, among which 13 (6.7%) were treatment emergent.

Of the 13 treatment-emergent deaths, eight were attributed by the investigator to an event of infection, and more than half were in the setting of refractory or progressive disease.

In the placebo arm 11 out of 97 (11.3%) deaths were observed, among which, 1 (1.0%) was treatment emergent (occurred less than 30 days after last dose of study drug).

Incidence of severe toxicity was high in both arms (86.5% vs. 87.5%) and serious adverse events was similar in both arms, affecting around half of patients.

Branded as Venclexta in the US and Venclyxto in Europe, the drug is being developed by AbbVie and Roche and is jointly marketed by AbbVie and Roche’s Genentech unit in the US, and by AbbVie outside of the US.

In the US it is already approved in certain chronic lymphocytic leukaemia or small lymphocytic leukaemia patients, and in combination with chemotherapy in certain acute myeloid leukaemia patients.

The drug is predicted to generate sales of several billion dollars a year if approved in further indications – but this safety scare naturally raises question marks about how much further the drug can go.

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