Biologics, Drug Development, FDA

FDA review details suicides, cardio risks linked to Valeant’s $100M drug brodalumab

At one point not long ago, AstraZeneca execs thought their IL-17 psoriasis drug brodalumab could earn up to $1.5 billion in annual sales. But after Phase III, they offloaded it to Valeant for $100 million upfront plus milestones. And briefing documents filed by FDA insiders spell out the serious problem with suicides and suicidal thinking that caused both AstraZeneca and its partner Amgen to abandon the drug near the end of their extensive late-stage program.

The FDA review paints a picture of a drug plagued by two major safety issues and an application that was filed after the original partners decided to abruptly end the trials ahead of schedule, making its assessment considerably harder.

The FDA reviewers had this to say ahead of next week’s advisory panel:

The safety review of brodalumab presented challenges. Late into the clinical studies, a suicide signal emerged with 4 completed suicides occurring in the Phase 3 clinical trials. A total of 6 completed suicides in all brodalumab clinical trials were reported (4 in psoriasis, 1 in rheumatoid arthritis, and 1 in psoriatic arthritis); however, one suicide was later adjudicated as indeterminate due to possible accidental drug overdose. The Phase 3 clinical trials were terminated early by the sponsor, thereby preventing further assessment of safety. A comprehensive evaluation of suicidal ideation and behavior (SIB) was undertaken by both the product sponsor and the Agency and will be discussed at length during this Advisory Committee meeting.

The suicide issue was known but never detailed before. And Valeant also faces scrutiny for the drug’s potential to trigger cardiovascular events. The review continues:

It has been hypothesized that IL-17 receptor inhibition may lead to an increase in other cytokines involved in inflammation thereby resulting in an increase in MACE events.

Amgen was first out the door, abruptly departing their partnership with AstraZeneca after execs concluded that the drug had little commercial potential if it was linked to suicides. AstraZeneca insisted that it continued to see value in the program, though, then dumped it off to Valeant. At the time, Valeant was still in the market for bargain basement specials – the company also bought Provenge after it proved to be a commercial flop – ahead of its spectacular fall from grace recently, which has crushed its stock value.

That hasn’t stopped Valeant from pursuing an approval, though.

The FDA considers a number of potential steps Valeant could take to control the risk, but they don’t believe it’s possible to eliminate it.

Each option provides progressive levels of assurance that prescribers, pharmacists, and patients have been educated and understands the safe use conditions when taking this drug. However, no risk management strategy will completely eliminate the risk of SIB seen with brodalumab.

And that topic will dominate much of next week’s adcomm meeting.

Investigators did track positive efficacy data, but even if Valeant does overcome the safety issues and wins an approval, it will face off against a crowded field of rivals: Eli Lilly’s ixekizumab, approved in March as Taltz, Merck’s MK-3222 and J&J’s IL-23 inhibitor guselkumab. Novartis’ was first out into the market, with Cosentyx. Given Valeant’s tarnished rep, regulators are going to be particularly reluctant to OK a drug when better options are on the table.

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Sr. Manager, Regulatory Affairs, CMC
CytomX Therapeutics San Francisco, CA
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Catalytic Data Science Charleston, SC
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Flatiron Health New York City or San Francisco

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