FDA Accepts sNDA for Avatrombopag in ITP

The FDA has accepted a supplemental new drug application (sNDA) for review for avatrombopag (Doptelet) as a treatment for patients with chronic immune thrombocytopenia (ITP) who have had an inadequate response to prior treatment, according to Dova Pharmaceuticals, the developer of the second-generation, oral thrombopoietin receptor agonist.¹

The application for avatrombopag was based on findings from the phase III Amendment 02 trial, which met its primary and first secondary efficacy endpoints—number of weeks with a platelet count ≥50 x 10⁹/L in the absence of rescue therapy and the proportion of patients with platelet counts ≥50 × 10⁹/L on day 8, respectively—with high statistical significance (P <.0001). Under the Prescription Drug User Fee Act, the FDA will render a decision on the application by June 30, 2019.

“Chronic ITP affects approximately 60,000 adults in the United States and despite the currently available therapies, which include 2 other thrombopoietin receptor agonists, there remains an important unmet need,” Lee F. Allen, MD, PhD, chief medical officer of Dova, said in a statement. “Acceptance of this sNDA is another significant milestone for Dova, and an important step towards addressing this underserved patient population and expanding the applications for Doptelet as a treatment for thrombocytopenia.”

Results from the Amendment 02 trial were published in the British Journal of Hematology in September 2018.² In the study, investigators aimed to demonstrate that the efficacy of avatrombopag plus standard of care was superior to placebo plus standard of care for adult patients with ITP who had received at least 1 previous ITP treatment, as measured by cumulative number of weeks of platelet response over 6 months with once-daily treatment.

The trial, which was conducted from February 6, 2012, to April 9, 2015, included a core study and an extension phase. Forty-nine of the 100 patients who were screened by investigators met the eligibility criteria for the trial. These patients were randomized to either receive avatrombopag (n = 32) or placebo (n = 17).

For the core study, the duration of exposure was longer in the avatrombopag arm, with 26/32 (81.3%) of the patients receiving the avatrombopag over 18 weeks, 17/32 (53.1%) over 26 weeks, and 2/32 (6.3%) over 30 weeks. Only 3/17 (17.6%) of patients in the placebo arm were exposed to study medication over 18 weeks, and only 1 patient was exposed for longer than 26 weeks. In the combined core study and extension, the mean duration of exposure to avatrombopag was 43.9 weeks, with the longest exposure to the medication being 75.7 weeks.

Data showed that avatrombopag was superior to placebo in the cumulative number of weeks of platelet response with a significantly longer duration of a platelet count ≥50 × 10⁹/l in the absence of rescue therapy versus placebo (median: 12.4 vs. 0.0 weeks; mean: 12.0 vs. 0.1 weeks; P < .0001). Additionally, a greater platelet response rate was observed for patients who received avatrombopag at day 8 versus those who received placebo (21/32; 65.6% and 0/17, 0.0%, respectively; P <.0001).

Results also showed that 5 of the 15 patients who were on concomitant ITP medication in the avatrombopag arm reduced their use of this medication from baseline, while none of the 8 patients who received placebo were able to do so (33.3% vs. 0%, respectively; 95% CI, 9.48-57.19). However, this was not found to be statistically significant due to the small number of patients who had been using concomitant ITP medications at baseline.

Four patients in the avatrombopag arm experienced grade 3 treatment-emergent adverse events (TEAEs), such as epistaxis, petechiae, headache, and platelet count reduction. Two grade 4 TEAEs were also reported in the core study; one patient experienced a cerebrovascular accident who discontinued study treatment and the other experienced worsening ITP not deemed to be associated with the mediation. The most commonly reported TEAEs in the avatrombopag arm were headache, contusion, upper respiratory tract infection, arthralgia, epistaxis, fatigue, gingival bleeding and petechiae.

Avatrombopag was deemed to be well tolerated with a safety profile comparable with placebo when adjusted for treatment exposure. The safety data yielded in the trial proved consistent with phase II studies and 6-month studies that evaluated other thrombopoietin receptor agonists, with headaches being the most frequently reported AE.

Avatrombopag was initially approved by the FDA as a treatment for thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure.

References

1. Dova Pharmaceuticals, Inc. Dova Pharmaceuticals announces FDA acceptance of supplemental new drug application for DOPTELET (avatrombopag) for the treatment of chronic immune thrombocytopenia (ITP). Published November 5, 2018. https://bit.ly/2D5WejX. Accessed November 8, 2018.
2. Jurczak W, Chonjnowski K, Mayer J, et al. Phase 3 randomization study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia [published online September 7, 2018]. Br J Haematol. doi: 10.1111/bjh.15573.