FDA offers support for Takeda's potential cytomegalovirus drug ahead of adcomm
After almost two decades of discussions with FDA regarding the development of Takeda’s potential drug for post-transplant cytomegalovirus (CMV), which it bought in its acquisition of Shire in 2019, the agency seems to be offering positive marks for the drug’s safety and efficacy profile ahead of Thursday’s adcomm.
According to FDA’s briefing documents released ahead of the meeting, maribavir proved safe across multiple studies and statistically superior to investigator-assigned treatment (IAT) in a Phase III trial, which Takeda announced earlier this year.
FDA’s concerns about discontinuations in the IAT arm of the trial also did not overshadow that statistical success.
While FDA noted the Phase III results “appeared to be driven by treatment discontinuation in the IAT group (discontinuation was considered treatment failure in the primary analysis),” several sensitivity analyses of the primary endpoint “showed that maribavir remained statistically superior to IAT for the primary endpoint, and thus the treatment effect remains robust.”
In additional important subgroup analyses, FDA said maribavir remained superior to IAT for the primary endpoint with the exception of the “refractory” subgroup and for the subgroup of patients with CMV disease.
But FDA noted that one of its “major concerns” in the trial “was the potential for bias due to the open-label design of the trial. Although bias is suggested by the demonstration of more discontinuations in the IAT arm than in the maribavir arm, bias cannot be definitively demonstrated or ruled out, particularly because of the known safety profile of the drugs in the IAT arm.”
And overall, the agency said maribavir “provides some advantages over currently available therapies, i.e., it appears to have a better safety profile, with taste disturbance being the most common adverse reaction associated with its use. In these trials, most subjects did not discontinue maribavir due to taste disturbance or other adverse reactions. Additionally, maribavir is available as an oral tablet (as is valganciclovir), providing ease of administration.”
Adcomm members will vote on two questions on whether the overall benefit-risk assessment is favorable for maribavir to treat transplant recipients with CMV infection and disease, with one question asking if that risk-benefit profile is still favorable with or without those with genotypic resistance to other antivirals, including ganciclovir, valganciclovir, foscarnet or cidofovir.
If approved, Takeda’s maribavir could be the first drug specifically approved for treatment of post-transplant CMV infection, which FDA says is one of the most common infectious complications in post-transplant recipients. FDA also noted that the available CMV antiviral drugs, including ganciclovir, valganciclovir, foscarnet and cidofovir, all have significant toxicities.
An approval would also cap a long and rocky history for the drug, which has changed hands several times over the last two decades through positive and negative trials.
GlaxoSmithKline first synthesized the drug 20 years ago and did some early clinical work, before licensing it to the rare disease and infectious disease-focused biotech ViroPharma.
ViroPharma then took it through Phase II, then missed the primary endpoint in a Phase III study in 2009. Maribavir failed to prevent CMV infections better than placebo in patients receiving bone marrow transplants. ViroPharma suggested a higher dose might lead to a better response, but ended up passing the candidate to Shire during a $4.2 billion buyout in 2013.
Shire ran with ViroPharma’s idea, increasing the dose in various pharmacokinetic and efficacy studies, and in 2016, a Phase II study showed that it helped clear infections. The FDA commended the results with a breakthrough designation in 2018. And the following year, Takeda completed its acquisition of Shire for $62 billion.