Regulatory Decision Summary for Tavalisse

The assessment of efficacy and safety of fostamatinib was based on two phase 3, 24-week placebo-controlled studies with identical design (studies 047 and 048) in 101 fostamatinib-treated and 49 placebo-treated adults with chronic (93%) or persistent (7%) immune thrombocytopenic purpura (ITP) and insufficient response to previous treatments.

Subjects in the placebo-controlled trials who completed 24 weeks or discontinued ≥ week 12, due to lack of response, could transition to the ongoing phase 3 open-label extension study (049), in which the primary objective was long-term safety, with efficacy assessed as secondary objective; 79 fostamatinib-treated and 44 placebo-treated patients crossed over to fostamatinib in the extension study. A total of 146 subjects were exposed to fostamatinib across phase 3 studies (44 received fostamatinib after receiving placebo) with a median duration of exposure of 179 days (8 to 712 days), 98 subjects treated for ≥24 weeks and 58 subjects for ≥48 weeks.

The primary efficacy endpoint of a stable platelet response (platelet count of at least 50,000/microliter (µL) or increased by at least 20,000/µL if baseline platelet count <15,000/µL on at least 4 of the last 6 visits between weeks 14 and 24) was met by 17.6% (9/51) of the fostamatinib group in study 047 (p-value (p) = 0.03) and 18.0% (9/50) of the fostamatinib group and 4.2% of the placebo group in study 048, not reaching statistical significance (p = 0.15). In subjects with a stable platelet response, an initial response was observed within 6 weeks of treatment for 12 of the 18 responders and within 12 weeks for all responders. The identification of non-responders within 12 weeks of use and subsequent discontinuation of therapy prevents unnecessary exposure. In the extension study, the difference in stable platelet response (platelet count ≥50,000/µL within 12 weeks of beginning treatment) between placebo crossover and placebo-treated subjects was of 20.5%. Among the 28 subjects who achieved stable response in the phase 3 trials, 18 subjects maintained the platelet count of at least 50,000/µL for 12 months or longer.

Overall, the data does not allow for clear conclusions regarding the prevention of bleeding or reduction of concomitant ITP therapy. Nevertheless, although there was no difference in overall bleeding events between groups, no bleeding-related serious adverse events occurred in stable responders compared with 7% in non responders and 10% in the placebo group.

The safety profile was primarily based on data from 102 fostamatinib-treated and 48 placebo-treated ITP patients in the placebo-controlled studies, and the 44 placebo-treated patients who received fostamatinib in the extension trial.

The most common adverse reactions associated with fostamatinib in the placebo-controlled studies were diarrhea, hypertension, nausea, epistaxis, dizziness, alanine aminotransferase (ALT) increased, asparate aminotransferase (AST) increased, abdominal pain, neutropenia, and rash. Serious adverse drug reactions in the fostamatinib-treated patients included febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis (1% each). Severe adverse reactions included dyspnea, hypertension (2% each), neutropenia, chest pain, diarrhea, dizziness, pneumonia, syncope and hypoxia (all 1%). Overall, 20% of fostamatinib-treated patients required either an increase in antihypertensive medications and/or a new antihypertensive medication for hypertension-related events, and patients with pre-existing hypertension were more susceptible to the hypertensive effects of fostamatinib. Fostamatinib may have played a role in fatal events of sepsis and pneumonia. The incidence of adverse reactions was higher in subjects ≥65 years of age, including serious adverse reactions and those leading to discontinuation.

Many AEs were identified with monitoring and manageable with anti-diarrheal or antihypertensive therapy and dose reduction, interruption or discontinuation.

The safety profile of fostamatinib in the placebo-controlled studies was consistent with safety in the overall fostamatinib exposure period and previous findings in other indications; however long-term safety in ITP patients is limited by the number of patients completing ≥24 weeks.

Non-clinical studies revealed effects on reproduction and fetal development including skeletal abnormalities and effect on bone growth and remodeling, with potential risk in children and young adults with incomplete epiphyseal fusion, in patients with fractures or osteoporosis, and if used during pregnancy.

Pharmacokinetic data concluded that concomitant use of a strong cytochrome P450 (CYP) 3A inducer should be avoided and Tavalisse dose should be reduced when concomitantly taken with a strong CYP3A inhibitor.

Risk mitigation measures include close monitoring of complete blood counts, liver function tests and blood pressure, dose modification schedules for management of important safety risks, a warning related to potential effects on bone metabolism and a contraindication for use in pregnancy, a statement that fostamatinib is not indicated in children and young adults who have not reached skeletal maturity, monitoring of patients with fractures or osteoporosis and discontinuation of breast-feeding during treatment.

A Risk Management Plan (RMP) was deemed acceptable, with revisions to the proposed pharmacovigilance plan. The benefit-harm-uncertainty profile of Tavalisse is considered favorable for treatment of thrombocytopenia in adult patients with chronic ITP who have had an insufficient response to other treatments, a subpopulation in which even a modest efficacy is beneficial given the limited treatment options left.