Takeda’s Maribavir Post-Transplant CMV Indication Should Not Be Limited By Resistance, US Panel Says
Executive Summary
Advisory committee unanimously endorses novel antiviral for treatment of post-transplant patients with refractory/resistant cytomegalovirus infection, and in the process rejects US FDA’s proposal to distinguish target population based upon genetic resistance.
Takeda Pharmaceutical Co. Ltd.’s maribavir appears on track for a broad treatment indication in post-transplant patients with refractory/resistant cytomegalovirus infection following an unanimous US Food and Drug Administration panel endorsement of the candidate and rejection of the agency’s proposal to distinguish the targeted population based upon evidence of genetic resistance.
In separate 17-0 votes, the Antimicrobial Drugs Advisory Committee on 7 October said the overall benefit-risk assessment was favorable for maribavir’s use for post-transplant patients with CMV infection and disease refractory to treatment, with and without genotypic resistance to other drugs commonly used to treat the indication.
The committee’s slam dunk recommendation for approval was driven by a raft of considerations.
Maribavir was statistically superior to conventional therapy in clearing CMV infection in a population of patients with refractory/resistant disease, and numerous sensitivity and subgroup analyses supported the primary efficacy results.
The drug appears to have a less toxic profile relative to other drugs used for CMV, and it comes in an oral formulation. There also is high unmet need in this patient population given the lack of approved therapeutics for treatment of CMV infection or disease in transplant patients.
The strong endorsement came despite panelists’ own reservations about the pivotal study design, including potential bias resulting from the open-label nature and a longer duration of treatment with comparator therapies than is typically used in clinical practice.
Nevertheless, committee members generally agreed the Phase III study (SHP620-303) was the best that could be done under the circumstances given the challenging patient population, maribavir’s taste disturbance effect that makes it difficult to blind, and the mix of oral and intravenous conventional therapies used in the comparator arm.
“In the field of CMV treatment, it’s been many, many years since a new product, especially one that can be delivered by oral administration, has come to FDA review,” said David Hardy, an infectious disease scientific and medical consultant and adjunct clinical professor at the Keck School of Medicine at the University of Southern California. “I believe this is an advance, but certainly an incremental advance, for a very high-need patient population.”
Issues For Discussion
The new drug application for maribavir, a first-in-class benzimidazole riboside cytomegalovirus pUL97 protein kinase inhibitor, is undergoing a priority review at the FDA, with a user fee date believed to be on or before 21 November.
Takeda is seeking approval for the treatment of adults with post-transplant CMV infection and/or disease, including infections that are resistant and/or refractory to ganciclovir, valganciclovir, cidofovir or foscarnet – all drugs that are used off-label to treat post-transplant CMV infections.
However, at the meeting’s outset, Debra Birnkrant, director of the FDA’s Division of Antivirals, said discussion would focus on a narrower indication – for a population that is refractory, with or without genotypic resistance – because results from an ongoing Phase III, noninferiority trial of maribavir and valganciclovir for treatment of hematopoietic stem cell transplant recipients with asymptomatic CMV viremia are not yet available.
In briefing documents for the meeting, the FDA said the results from SHP620-303 showed maribavir was statistically superior to conventional therapy in clearing CMV infection in a population of patients that were phenotypically resistant, some of whom also had genotypic resistance. However, in a subgroup analysis maribavir was not superior to conventional therapy for those without genotypic resistance, although there was a trend favoring maribavir. (Also see "Takeda’s Maribavir For Post-Transplant Cytomegalovirus Might See Split Panel Vote" - Pink Sheet, 5 Oct, 2021.)
The FDA’s review also raised concerns that the beneficial effect seen with maribavir in the Phase III study was driven by adverse event-related drug discontinuations in the conventional therapy arm, and the agency noted the proportion of virologic failures in both arms was similar.
Continuum Of Disease
Experts appearing on behalf of Takeda said that in clinical practice, resistant/refractory disease is viewed as continuum, rather than a clear separation.
After resistant/refractory disease is identified as likely, it can take several weeks to get back the results of resistance genotyping, and appropriate treatment must be initiated in the meantime, said Takeda expert Camille Kotton, clinical director of transplant and immunocompromised host infectious diseases at Massachusetts General Hospital. “It would be heartbreaking if we sort of divided this into resistant disease only but not management of refractory patients because we really think of this as sort of one in the same process.”
In addition, there are issues with currently available diagnostics, she said, adding that many refractory patients may have resistance that is not yet diagnosable.
Several panelists agreed with Kotton’s comments.
“Given the way that patients present in clinic, refractory disease with or without resistance is a distinction without a difference.” – VA White River Junction Medical Center’s Richard Murphy
Ghady Haidar, director of research for bone marrow transplant and hematologic malignancy infectious diseases at University of Pittsburgh, said the distinction between resistance and refractory “is a little arbitrary.”
“It’s a continuum of conditions and the point that [Kotton] made about having to wait for the genotype to come back is actually crucial,” Haidar said. “It does take a very long time for us to get a genotype back, and these patients typically can’t wait the many weeks we have to wait for the reference lab to tell us what the genotype is.”
“Given the way that patients present in clinic, refractory disease with or without resistance is a distinction without a difference,” said Richard Murphy, an infectious disease specialist at VA White River Junction Medical Center. “Since it’s not something that’s clear up front, it wouldn’t make sense to make that distinction in the approval to me and may actually result in harm if patients are not given a more active therapy while waiting for resistance results.”
“The pragmatics of care make this distinction untenable,” said panel chairman Lindsey Baden, director of clinical research in the division of infectious disease at Brigham and Women’s Hospital.
Phase IV Studies
Despite their overwhelming endorsement for approval, panelists identified several gaps in the existing data that should be filled in postapproval.
There “needs to be further clarification of where it works, where it works best,” and resistance patterns in postmarketing studies, Hardy said.
Panelists also pushed for more research on the drug’s efficacy and safety in minorities and women, citing a lack of diversity in the pivotal Phase III trial. Study 303 randomized a total of 352 subjects, most of whom were male (61%), white (76%) and not Hispanic or Latino (83%).
Numerous committee members cited the need for research on pediatric use. Panel member George Siberry, a medical officer in the US Agency for International Development’s Office of HIV/AIDS, urged the agency to allow use of maribavir in older adolescents, requesting it not set an “artificially low” minimum of 18 years of age for the drug’s indication.
Among the risk monitoring and labeling recommendations, panelists suggested a need for therapeutic drug monitoring in light of possible drug-drug interactions and anticipated off-label use, such as for prophylaxis, in the real world, as well as monitoring of hematological and renal parameters at baseline and throughout treatment.