Earlier this year, Shire announced the FDA had granted Breakthrough Therapy Designation to maribavir, its phase III investigational drug for the treatment of cytomegalovirus (CMV) infections that are resistant or refractory to prior therapy. The announcement came on the heels of the recent approval of Merck’s Prevymis (letermovir), a first-in-class inhibitor of the CMV terminase complex used for CMV prophylaxis in transplant patients. If approved, maribavir will join Prevymis in boosting a CMV therapeutics landscape that is poised for resurgence after almost two decades of relative stasis.

CMV is a globally ubiquitous pathogen of the herpesvirus family that infects a majority of individuals by adulthood, typically producing mild symptoms, or none at all. However, infection or reactivation of latent CMV in individuals with weakened immune systems can lead to severe complications, including end-stage organ disease and invasive CMV disease. Patients undergoing solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) are particularly vulnerable to CMV infections due to concurrent immunosuppression therapy. Over 50 percent of SOT patients show evidence of CMV infection, and without intervention 10–50 percent of those patients develop symptomatic illness that can culminate in graft rejection or even death.

Clinical Progression of Maribavir Previously Stalled

The mainstays of antiviral therapy for CMV are ganciclovir and valganciclovir, nucleoside analogues with well-established activity against CMV DNA replication. However, the utility of these drugs is limited by severe hematopoietic and renal toxicities, particularly when used for extended periods as prophylaxis. Moreover, patients who develop antiviral resistance are left with limited alternatives. In the absence of an approved CMV vaccine, there is a pressing need for new treatment strategies for CMV infections employing less-toxic antiviral mechanisms.

Maribavir was developed as a novel anti-CMV drug that acts by disrupting viral DNA packaging and viral egress rather than DNA replication. Clinical progression of maribavir stalled after a Phase III trial failed to prevent CMV infections in high-risk liver transplant patients, but later analysis identified flaws in the study’s selected dosage (100mg taken orally twice-daily) and primary endpoint (CMV disease). A subsequent Phase II trial using higher dosages (400–1,200mg taken orally twice-daily) found that maribavir effectively eliminated plasma CMV DNA in SOT and HSCT patients who were resistant or refractory to standard therapy. Notably, no myelosuppression or other major toxicities were observed with maribavir therapy.

Maribavir Well-Placed to Tackle Unmet Need

An ongoing Phase III, multicenter, randomized trial is now evaluating the safety and efficacy of maribavir (400mg taken orally twice-daily) in transplant recipients. Focusing on subsets of vulnerable individuals, the trial will compare maribavir to investigator-assigned anti-CMV therapy in patients who are resistant or refractory to at least one existing treatment, with a primary endpoint of CMV viremia clearance (plasma CMV DNA concentration <137 IU/mL).

GlobalData anticipates that maribavir will be well-positioned to address the unmet need of treating relapsed or resistant CMV infections, given that the alternative newcomer, Prevymis, is currently only approved for CMV preventative therapy in HSCT patients. From a drug development perspective, the Breakthrough Therapy Designation of maribavir is welcome news in an otherwise uncertain period for Shire, which recently announced plans to restructure into two operational divisions covering neuroscience and rare diseases. Besides potentially bolstering Shire’s portfolio, maribavir may serve as an attractive asset to shop if the company elects to fully divest from the infectious diseases space as part of its corporate bifurcation process.

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