Regulatory Decision Summary for Revolade

Clinical benefit for Revolade in the treatment of pediatric (≥1 years to <18 years) chronic immune thrombocytopenia purpura (cITP) to increase platelet counts in patients who have had an insufficient response to corticosteroids or immunoglobulins was primarily demonstrated in Study TRA115450 (PETIT2), a Phase III double-blind, randomized, placebo-controlled study to investigate the efficacy, safety and tolerability of eltrombopag.

The primary efficacy endpoint was a sustained platelet response, defined as the proportion of subjects achieving platelet counts ≥50 x 10⁹ /L for at least 6 out of 8 weeks (in the absence of rescue therapy), between Weeks 5 to 12 of randomized treatment. Overall, this was achieved by 40% versus 3%, eltrombopag versus placebo, respectively. The response was statistically significant and consistent across all age cohorts. During the first 12 weeks of randomized treatment, the median of the maximum duration for which a platelet count ≥50 x 10⁹/L was continuously maintained was 3 weeks for eltrombopag compared with 0 weeks for placebo. During the same period, the proportion achieving at least one platelet count >50 x 10⁹/L was 75% versus 21%, eltrombopag versus placebo, respectively. The achievement of platelet response with eltrombopag was associated with a decreased need for rescue treatment, decreased severity and incidence of bleeding, and reduction or discontinuation of baseline ITP medications.

Overall, treatment with eltrombopag was well tolerated and the safety profile was favourable. Adverse events (AEs) were manageable with appropriate safety monitoring and intervention as needed. The most common AEs (≥10%) with a higher incidence for eltrombopag versus placebo were nasopharyngitis, rhinitis, cough, and upper respiratory tract infection. Common AEs (≥3%) with a higher incidence for eltrombopag versus placebo included abdominal pain, aspartate aminotransferase (AST) increased, pyrexia, alanine aminotransferase (ALT) increased, decreased appetite, diarrhea, oropharyngeal pain, rash, toothache, and vitamin D deficiency. Two cataract events were observed in eltrombopag subjects concurrently using corticosteroids.

Based on pharmacokinetics, efficacy and safety data, effective eltrombopag dosing in pediatric cITP patients was established. Individualization of dosing regimen based on each patients platelet counts is required.

The powder for oral suspension (PfOS) formulation of Revolade was withdrawn by Novartis. As such, Revolade will only be marketed as tablets. While the pivotal safety and efficacy data for subjects 1-5 years of age who were administered the PfOS formulation in pediatric clinical trials remained relevant to the benefit-risk analysis, with withdrawal of this formulation, the ability to swallow tablets whole became an important prerequisite for the safe administration to any patient, regardless of age. These concerns were mitigated via labelling.

Based on the data reviewed, the benefit-risk assessment for Revolade for the treatment of pediatric cITP to increase platelet counts in pediatric patients who have had an insufficient response to corticosteroids or immunoglobulins was considered to be positive. Of note, the long-term efficacy and safety of eltrombopag have not been established in pediatric ITP patients. As the overall safety profile in pediatric subjects was similar to the safety profile in adults, no changes to current risk management strategies were needed.