Six international clinical trials assessing the PI3K inhibitor Zydelig (Gilead’s idelalisib) in combination with other agents were stopped on March 14, 2016, following reports of an increased rate of serious adverse events, including deaths. Both the FDA and the EMA have since issued statements, warning health care professionals of these serious adverse events.
Zydelig, Gilead’s first venture into the oncology space, is currently FDA- and EMA-approved for the treatment of:
- Relapsed CLL, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate due to other comorbidities.
- Relapsed or refractory FL patients who have received at least two prior therapies.
- U.S. only: Relapsed SLL patients who have received at least two prior therapies.
- Europe only: in combination with rituximab, for treatment-naive CLL patients harboring del(17p)/TP53 mutations, who are unsuitable for chemo-immunotherapy.
Following the news, the EMA has updated its European Public Assessment Report for Zydelig, specifying the following1:
- Zydelig can be prescribed to CLL patients who have received at least one prior therapy. Patients harboring del(17p) should not start Zydelig therapy, but those who had already initiated Zydelig as first-line treatment can continue it.
- Close monitoring of absolute neutrophil counts should be done at least weekly, to prevent high-grade neutropenia. Treatment should be withheld in patients at risk of developing neutropenia.
- As serious and fatal infections have occurred with Zydelig, including opportunistic infections such as Pneumocystis jirovecii and cytomegalovirus, prophylaxis for these infections should be administered throughout treatment. Treatment with Zydelig should be discontinued if there is evidence of infection of viraemia.
- Patients should be monitored for respiratory symptoms.
Worldwide sales of Zydelig reached $132 million in 20152, and Gilead had been steering Zydelig’s development towards multi-drug combinations—the standard of care in CLL—in an attempt to expand the drug’s label and boost its revenue. Decision Resources Group estimated that by 2024, G7 sales of Zydelig in first-line CLL were to reach $1.4 billion, mainly attributed to these combinatorial approaches.
Two of the halted studies were Phase III combination trials targeting previously-untreated CLL patients. One study was assessing Zydelig in combination with bendamustine/rituximab, and one in combination with Roche’s Gazyva/Gazyvaro, and represented means of expanding Zydelig’s label in the lucrative first-line CLL setting. Experts interviewed prior to the stopping of the trials were optimistic about the potential of Zydelig combinations, which were meant to boost the drug’s response rates; however, they were wary of the Zydelig-related toxicity, especially pneumonitis and gastrointestinal toxicity. Indeed, the drug carries a black box warning for fatal or serious hepatic toxicity, severe diarrhea, colitis, pneumonitis, and intestinal perforation, and it is subject to a REMS program imposed by the FDA.
While it is yet unclear exactly which Zydelig trials are set to continue, the gap left in the market should Zydelig’s further development in CLL be permanently halted will be significant. The news is also likely to have a two-pronged effect—it may negatively impact physician confidence in PI3K inhibitors, thus affecting second-generation agents like Bayer’s copanlisib and AbbVie/Infinity’s duvelisib; it may also negatively impact other drugs that were being tested in combination with Zydelig and that were to receive a boost upon regulatory approval of such combinations (e.g., Gazyva/Gazyvaro and Novartis’ Arzerra). However, if the toxicity seen with Zydelig is not a class effect, second-generation PI3K inhibitors may benefit from Zydelig’s woes, but this benefit may be minimal in the first-line CLL population because of significant competition from J&J/AbbVie’s well-established blockbuster Imbruvica (approved for use in first-line CLL patients on March 4, 2016).
Zydelig’s future in the CLL space has suffered a massive blow, and its development as part of combination regimens, in the largest CLL population is facing an uphill battle and an uncertain future.
2. Gilead Sciences 2015 Form 10-K