Regulatory Decision Summary for Livtencity

The purpose of this New Drug Submission (NDS) application was to obtain market authorization for Livtencity (maribavir) for the treatment of patients with post-transplant cytomegalovirus (CMV) infection/disease who are refractory and/or resistant to one or more prior antiviral therapies. Upon review, Livtencity was approved for the indication of the treatment of adults with post-transplant cytomegalovirus (CMV) infection/disease who are refractory (with or without genotypic resistance) to one or more prior antiviral therapies. This submission was for a new indication and was filed and approved under the Priority Review Policy Guidance.

The Canadian regulatory decision on the review of Livtencity was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) were used as added reference.

The human cytomegalovirus (HCMV) is a member of the betaherpesvirinea subfamily of enveloped, double-stranded DNA viruses. Like other herpes viruses, CMV establishes latency after the primary infection and persists for the life of the individual. CMV infection is common and usually asymptomatic in healthy individuals. It is estimated that 40 to 90% of the population worldwide had a CMV infection at some time in their life. CMV infection is an important cause of complication post-transplantation in recipients of hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT) and is often associated with increased morbidity and mortality. High CMV viral load is associated with end-organ disease including: gastroenteritis, pneumonia, hepatitis, retinitis, and encephalitis. Management of post-transplant CMV infection/disease involves the off-label use of anti-CMV agents. The use of these antivirals is limited by their toxicities. Development of resistance is also an issue with the current available anti-CMV agents. Ganciclovir, valganciclovir, foscarnet, and cidofovir all target the UL54 viral DNA polymerase making them susceptible to the development of cross-resistance. There were no approved therapies available for the treatment of adults with post-transplant cytomegalovirus (CMV) infection/disease who were refractory (with or without genotypic resistance) to one or more prior antiviral therapies, highlighting an unmet medical need for this population. Livtencity (maribavir) was considered a first-in-class drug. It is an orally bioavailable benzimidazole riboside antiviral drug with activity against HCMV.

Livtencity was evaluated in a pivotal Phase 3, multi-centre, randomized, open-label, active-controlled superiority study (Study 303) to assess the efficacy and safety of Livtencity treatment compared to investigator assigned treatment (IAT) in 352 HSCT and SOT recipients with CMV infections that were refractory to treatment with ganciclovir, valganciclovir, foscarnet, or cidofovir, including CMV infections with or without confirmed resistance to 1 or more anti-CMV agents. Patients where stratified by transplant type (HSCT or SOT) and screening viral load and then randomized in a 2:1 allocation ratio to receive Livtencity 400 mg twice daily (n = 117) or IAT (ganciclovir, valganciclovir, foscarnet, or cidofovir) (n = 235) for an 8-week treatment period and a 12-week follow-up phase. The primary efficacy endpoint was confirmed CMV viremia clearance (plasma CMV DNA concentration below the lower limit of quantification (<LLOQ; i.e., <137 IU/mL) at Week 8. The key secondary endpoint was CMV viremia clearance and CMV infection symptom control at the end of Study Week 8 with maintenance of this treatment effect through Study Week 16.

The pivotal trial (Study 303) met its primary endpoint and showed that Livtencity was superior to IAT (56% versus (vs) 24%, respectively, p<0.001). The key secondary endpoint, a combined endpoint of maintenance of undetectable CMV DNA levels through week 16 and control of CMV symptoms (in those that were symptomatic with CMV disease), showed statistical superiority of Livtencity over IAT (19% vs. 10% achieved both CMV viremia clearance and CMV infection symptom control in the Livtencity and IAT group, respectively (p = 0.013). The overall lower response rates seen for the secondary endpoint is to be expected, given the latent nature of the CMV virus. The treatment effect was consistent across key subgroups (i.e., transplant type, baseline CMV DNA viral load, genotypic resistance to other anti-CMV agents, CMV syndrome/disease at baseline, and age) highlighting the generalizability of the study outcomes. The one exception was for the renal transplant subgroup which had a very small number of patients; thus, these results should be interpreted with caution.

Approximately 50% (65/131) of patients in the Livtencity group and 39% (11/28) of patients in the IAT group who achieved CMV DNA level < LLOQ experienced virologic recurrence during the follow-up period. Most of the recurrences, 89%, (58/65) in the Livtencity group and 100% (11/11) (in IAT group) occurred within 4 weeks after study drug discontinuation; and the median time to recurrence after CMV DNA level < LLOQ were both 15 days in the Livtencity group (range 7, 71) and IAT group (range 7, 29). The clinical course for patients that develop viral recurrence following treatment with Livtencity remains uncertain.

The safety analysis from the pivotal trial (Study 303) included 350 patients that were randomized and treated with Livtencity (n = 234) or Investigator Assigned Treatment (IAT) consisting of monotherapy or dual therapy with ganciclovir, valganciclovir, foscarnet, or cidofovir (n = 116) for an 8-week treatment phase following a diagnosis of resistant/refractory CMV. Adverse events were collected during the treatment phase and follow-up phase through Study Week 20. The mean exposures (SD) for Livtencity and IAT were 48.6 (13.82) and 31.2 (16.91) days, respectively. Livtencity treated patients received a maximum of 60 days.

The most commonly reported adverse reactions occurring in at least 1% of patients in the Livtencity group, were: taste disturbance (44.8%), nausea (8.5%), vomiting (7.7%), immunosuppressant drug concentration level increased (6.4%), diarrhea (3.8%), abdominal pain (2.1%), neutropenia (1.7%), acute kidney injury (1.7%), anemia (1.3%), and decreased appetite (1.3%). The most commonly reported serious adverse reactions were acute kidney injury (1.3%), and nausea, fatigue, immunosuppressant drug concentration level increase, and pyrexia, treatment failure, hepatic failure, gastroenteritis, hepatic enzyme increase, vomiting occurring at < 1%.

Serious adverse reactions occurred less frequently in the Livtencity group than in the IAT group (5.1% and 14.7%, respectively). No patients in the Livtencity group experienced serious, drug related neutropenia or febrile neutropenia. In contrast, in patients treated with ganciclovir/valganciclovir, 7.1% of patients had serious related febrile neutropenia. In addition, 1% of patients in the Livtencity group and 11% in the foscarnet group experienced serious related renal disorders (acute kidney injury and renal impairment). Adverse reactions led to discontinuation in 1.7% of the IAT group compared to 1.3% in the Livtencity group.

Virologic failure due to resistance occurred during and after treatment with Livtencity. Virologic recurrence during the post-treatment period usually occurred within 4-8 weeks after treatment discontinuation. Some maribavir pUL97 resistance-associated substitutions confer cross-resistance to ganciclovir and valganciclovir. It is recommended to monitor CMV DNA levels and check for Livtencity resistance if the patient is not responding to treatment or has a recurrence.

Livtencity is eliminated primarily via biliary excretion in rats and monkeys, with some evidence of enterohepatic recirculation. The pharmacodynamics (PD) studies and pharmacokinetics (PK) profile of maribavir as evaluated in mice, rats and monkeys appear to support the oral use of maribavir.

The non-clinical toxicology studies were adequate with respect to the therapeutic use of maribavir and applicable regulatory guidelines. Key toxicities were reversible upon discontinuation of treatment. Livtencity had no effects on male or female fertility or reproductive performance in rats and had no teratogenic effect in pregnant rats. Reduced embryofetal survival and increased pre- and post-implantation losses were observed in rats. Based on this evidence, the Product Monograph states that Livtencity is not recommended during pregnancy and in women of childbearing potential not using contraception.

No dose adjustment are required for patients with mild, moderate or severe renal impairment and mild or moderate hepatic impairment. Co-administration with strong CYP3A4 inducers are not recommended. Livtencity increases exposure of drugs that rely on BCRP for elimination. Livtencity increases exposure of drugs that are substrate of P-gp. Livtencity has the potential to increase the drug concentrations of immunosuppressant drugs that are CYP3A4 and/or P-glycoprotein (P-gp) substrates where minimal concentration changes may lead to serious adverse events. Frequent monitoring of immunosuppressant drug levels throughout treatment with Livtencity is recommended. Co-administration of Livtencity with ganciclovir or valganciclovir is contraindicated. Livtencity may antagonize the antiviral effect of ganciclovir and valganciclovir by inhibiting human CMV UL97 serine/threonine kinase, which is required for activation/phosphorylation of ganciclovir and valganciclovir.

The oral administration of a single 400 mg dose of a developmental formulation of maribavir with a moderate-fat meal decreased AUC_0-t and C_max of maribavir by 14% and 28%, respectively, in healthy patients. There was insufficient data to support the administration with crushed tablets in water via nasogastric or orogastric tube; thus, this was removed from the label.

A Risk Management Plan (RMP) for Livtencity was submitted by Takeda Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product.

Overall, Livtencity showed substantial evidence in support of a clinical benefit compared to IAT in the treatment of transplant patients with resistant/refractory CMV infection. Efficacy may be driven in large part by increased tolerability, however given the known toxicities of the current agents, a more tolerable and effective agent provides more options for patients. On the basis of the information reviewed, Livtencity presents an acceptable and manageable safety profile in consideration of the intended population. Based on the benefit-harm-uncertainty profile of the product, it is recommended that Livtencity be granted authorization.

The Canadian regulatory decision on the review of Livtencity was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) were used as added reference.

For further details about Livtencity, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.