The casualties in the Clostridium difficile vaccine race are starting to pile up. Having been vaulted to the front of the queue by Sanofi’s failure, Pfizer has now missed the primary endpoint in its phase 3 trial.
Pfizer is yet to give up on the candidate, leading its press release with details of secondary endpoints and burying the primary endpoint miss in the fourth bullet point. But the inability of its vaccine candidate PF-06425090 to stop primary C. difficile infection (CDI) in a phase 3 trial of 17,500 adults aged 50 years and older leaves significant doubts about the future of the program.
"With what also appears to be a reasonable safety profile, we believe there may still be a role for the vaccine in high-risk patients. However, we think it is unlikely the product has the potential to reach peak commercial sales of >$1Bn as management had previously hoped," analysts at Mizuho Securities wrote in a note to investors.
The clinical trial set out to show whether giving adults a vaccine composed of genetically modified toxins A and B from C. difficile reduces CDI. After the second dose, efficacy against the first primary episode of CDI stood at 28.6%. Giving a third dose raised the efficacy to 31%. The figures caused the trial to miss its primary efficacy endpoints. There were 17 CDI cases in the vaccine arm versus 25 in the placebo cohort.
Pfizer had planned to accrue 66 CDI cases within two years of the primary vaccination series. However, Pfizer said the study, which got underway in March 2017, was affected by the pandemic, leading the FDA to clear the company to perform the final analysis on 42 cases within four years.
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In the absence of the hoped-for primary endpoint hit, Pfizer looked to secondary endpoints for evidence of the efficacy of PF-06425090. Pfizer saw zero cases of medically attended CDI in the PF-06425090 arm compared to 11 cases in the placebo cohort. The company latched on to the reduced median and mean durations of CDI in the vaccine group as further evidence of efficacy.
The question now is whether the secondary endpoints, coupled with a clean safety profile, are enough to save PF-06425090 from the scrapheap. Pfizer is evaluating the next steps in coordination with regulatory agencies.
"Today's news will likely lead to an even greater focus on what the company will do with its 'COVID cash' from sales of Comirnaty and Paxlovid to boost its growth outlook for the 2025-2030 time period," the Mizuho analysts wrote.
If Pfizer drops PF-06425090, it will leave Valneva’s stalled VLA84 as the leading prospect. VLA84 is ready for phase 3, but Valneva stopped work after phase 2. Valneva has left the door open to reactivating and partnering the program, but it is questionable whether Pfizer’s data support that action. While VLA84 has some differences to candidates developed by Pfizer and Sanofi, it shares the central idea of using versions of the A and B toxin subunits to prevent CDI.
Further back, GlaxoSmithKline is closing in on the completion of a phase 1 clinical trial of its challenger, a recombinant protein vaccine based on the F2 antigen that it is studying with its AS01B adjuvant.