Regulatory Decision Summary for Shingrix

Currently, Shingrix is indicated in adults ≥50 YOA, with no contraindication for use in immunocompromised (IC) subjects. The risk of HZ is increased in adults ≥18 YOA who are immunodeficient or immunosuppressed due to disease or therapy. IC patients who develop HZ are more likely to experience complicated clinical outcomes. Moreover, live, attenuated varicella-zoster virus (VZV) vaccines are contra-indicated in adults with immunosuppression or immunodeficiency due to the risk of vaccine-associated disease, including disseminated disease. Therefore, an unmet medical need exists for IC individuals 18-49 YOA.

The authorization was based on 6 clinical studies in which subjects ≥18 YOA in 5 IC conditions received Shingrix HZ subunit (HZ/su) in a 2-dose schedule. Each of these five IC populations represents a distinct population with different profiles of disease risk. For all studies, HZ/su was administered intramuscularly with a one- to two-month interval between the first and second dose. The efficacy in IC subjects was assessed in 1 pivotal study in autologous HCT (auHCT) and in post-hoc analysis of another clinical study in hematologic malignancies. Safety and immunogenicity in IC subjects were evaluated in 1 pivotal, 3 new non-pivotal studies, and 2 non-pivotal studies submitted as part of the original New Drug Submission (NDS).

Efficacy in autologous hematopoietic stem cell transplant (auHSCT) subjects ≥18 YOA was 68.17% (median follow-up time of 21 months) and 76.15% in the first 12 months after transplant, when the risk of HZ is the highest. Post-hoc analysis of efficacy was found to be 87.20% in patients with hematologic malignancies assessed after administering Shingrix during or shortly after chemotherapy, when the risk of HZ is the greatest. The other trials demonstrated immunogenicity in three other populations (solid organ tumor subjects, renal transplant subjects, and human immunodeficiency (HIV) positive subjects) and provide substantial supportive evidence of effectiveness of vaccination in a diverse population of IC adults.

The 6 clinical studies also evaluated the safety and reactogenicity in adults ≥18 YOA with 5 different IC conditions. Post-vaccination safety assessment methodology was similar across all six studies, enabling pooling across studies to assess for the occurrence of uncommon adverse events. In general, overall proportions of unsolicited adverse events (AEs), serious adverse events (SAEs), and potential immune mediated disorders (pIMDs) were reported at similar rates in both HZ/su and Placebo groups.

Similar to the older adult population, the majority of IC subjects in the HZ/su group experienced local and/or general reactogenicity of short duration. Overall, the frequency and severity of solicited local and general symptoms did not differ between the first and the second dose of HZ/su across the studies. Most solicited local and general symptoms were mild-to-moderate in severity and transient in nature with median durations being at most 4 days for injection site and systemic reactions. Severe reactogenicity also commonly occurred and within the IC population, reactogenicity was higher in the younger age stratum. The most frequently reported solicited local and general symptoms in IC adults in the HZ/su group across studies were pain at the injection site, fatigue and myalgia as reported in previous studies with Shingrix in adults ≥50 YOA in the initial NDS. Overall, SAEs, deaths, and pIMDs were reported in similar proportions of subjects in HZ/su and placebo groups during select time periods evaluated.

The new indication includes women of child-bearing potential. Pregnancy was an exclusion criteria for all the studies however, a few pregnancies did occur. The number of subjects with pregnancy outcomes is too low to draw any conclusions on risks to women of child-bearing potential regarding pregnancy outcomes.

In consideration of broad use of HZ/su for the prevention of HZ in all IC adults at increased risk of HZ, it is acknowledged that IC populations are heterogeneous and HZ/su has not been evaluated in all IC populations, for all safety outcomes, or at the many potential timepoints relative to administration of immunosuppressive therapies. The safety database submitted for subjects 18-49 YOA in the supportive trials was small, which limits the ability to fully characterize risk. However, safety data accrued from multiple IC populations, support a favorable risk-benefit profile of HZ/su for use in a broad population of IC adults.