The FDA granted Shire’s Phase III-stage drug maribavir (SHP620) Breakthrough Therapy Designation for treating cytomegalovirus (CMV) infection and related disease in transplant patients who are resistant or refractory to previous therapy. Maribavir is a benzimidazole riboside compound, which is designed to target the key CMV UL97 protein kinase enzyme and so block viral DNA replication and encapsidation, which prevents viral capsid release from the nucleus of infected cells. The drug is being tested in patients who have CMV infection following hematopoietic stem cell or solid organ transplantation.

Breakthrough Therapy Designation status for maribavir was granted based on the data from two Phase II studies. In one study involving 120 CMV-infected patients aged 12 years or more, 67% of participants treated with varying doses of maribavir for up to 24 weeks had no detectable levels of the virus in their blood plasma within six weeks of starting treatment. The most commonly reported treatment-related adverse event (AE) was taste disturbance, although other treatment-emergent AEs reported in 5% or more of the study participants receiving any dose of maribavir included nausea, increased levels of immunosuppressant drugs, CMV infection, diarrhea, rash, vomiting, anemia, and pruritis (itch).

Listing CMV as one of the reported treatment-emergent adverse events (TEAEs) was curious, as pre-existing CMV infection was a condition of enrollment into the clinical trial—meaning all of the patients would be expected to already have CMV. When GEN asked Shire about this, Jaren Madden Herron, head of R&D communications at Shire in Cambridge, U.K., explained there are a few instances in which an investigator would decide to report CMV infection as a TEAE: if viral load increased despite treatment (i.e., a non-responder), if a patient was asymptomatic and then symptoms later developed after treatment, or if clearance of the virus was followed by subsequent recurrence.

Herron adds, “The patients in the Phase II study, with advanced resistant/refractory infections, represent the most difficult-to-treat population. Therefore, CMV infection as a TEAE is not unexpected.”

CMV is a common virus that Shire suggests infects more than half of the U.S. population by the age of 40 years. While the vast majority of infected individuals display no signs or symptoms, in people with compromised immunity, CMV infection can cause serious tissue-invasive disease and potentially be fatal.

The FDA and the European Commission have previously granted maribavir orphan drug designation for treating clinically significant CMV viremia and disease in at-risk patients and for treating CMV disease in patients with impaired cell mediated immunity, respectively. Andreas Busch, Ph.D., Shire’s global head of R&D, said the firm was “eager to work with the FDA” as maribavir development continued. “Maribavir has the potential to address critical medical needs for transplant patients who are refractory or resistant to currently available antiviral therapies, and I’m proud of the innovation and hard work that made this Breakthrough Designation Therapy milestone a reality.”

Shire reported data from the Phase II maribavir study back in October 2016. The trial enrolled patients who were undergoing hematopoietic stem cell transplant or solid organ transplant and who were resistant or refractory to valganciclovir or foscarnet therapy. Shire is carrying out two large randomized Phase III maribavir studies. Study SHP620-303 is designed as a randomized trial to compare 8 weeks of maribavir therapy with investigator’s choice anti-CMV therapy in otherwise treatment-resistant/refractory transplant patients. Initiated in December 2016, the study aims to enroll 351 patients aged 12 years and over and is scheduled to end in December 2019.

The second, double-blind Phase III study, SHP620-302, was started in April 2017, and is comparing maribavir with oral valganciclovir therapy for 8 weeks in hematopoietic stem cell transplant patients aged 16 years and over who have asymptomatic CMV infection. The study plans to enroll 550 participants, and is scheduled to end in August 2019. 

FDA grants Breakthrough Therapy Designation to treatments for serious conditions when preliminary clinical evidence indicates that the drug may demonstrate clinically significant benefits compared with existing therapies. The agency then provides guidance and support for the development program, although there is no guarantee of ultimate regulatory approval. 

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