Final Results from the Phase 3 Traial Areta Comparing a Novel, Extended-Release Anagrelide Formulation to Placebo in Essential Thrombocythemia Patients with Defined Risk Status

Background: Anagrelide hydrochloride (ana), is a well-known compound used to selectively normalize platelet counts (plc) by inhibiting megakaryocyte development and maturation. Common side-effects of licensed formulations may be largely due to peak plasma concentrations of ana and its 3OH-metabolite, whereas efficacy is proportional to the Area under the curve (AUC). A novel extended-release formulation (ana retard, AR) has superior pharmacokinetics (Petrides 2015) and has been demonstrated to be equally effective as the licensed formulation (Gisslinger 2016). Here, we investigate a "treat-early" concept in non-high risk ET patients.

Study design:AR was compared to placebo in a phase 3, randomized, parallel group, multicenter, subject- and sponsor-blinded trial in patients diagnosed with ET according WHO 2008 and a defined risk status including JAK2 mutation, protein C/S or antithrombin III deficiency, factor V Leiden or prothrombin mutation, cardiovascular risk factors. The primary endpoint was time to first ET-related event adjudicated by a blinded expert panel, or progressive thrombocytosis (plc≥1000G/L or plc increase >300G/L within 3 months) requiring medical intervention. Secondary endpoints included plc response and change of risk status.

Results: 146 patients were randomized and dosed (all Caucasian, mean age 43 years, 74% females), and 112 completed the first year with drop-out rates of 22% in AR and 25% in placebo. Only 49% of placebo patients vs. 74% of AR patients consented to enter the extension phase. Consequently, over the entire study duration, median exposure times differed significantly with 123 weeks for AR and 62 weeks for placebo. The primary endpoint was met in all analysis sets, with p<0,0008 and 13 vs. 26 ET related events and/or progressive thrombocytosis in the ITT analysis. The progression to high-risk status was 11,7% for AR vs. 26,1% for placebo (p<0,005). AR proofed highly efficacious in normalizing plc: within 2 weeks of therapy mean baseline plc of around 750G/L were consistently below 400G/L (83% complete, 12% partial responders). The maintenance dose was the highest tolerated dose able to maintain plc in range; for 73% of AR patients this was achieved with a single 2mg tablet given once-daily. Remaining patients received doses up to 4 tablets per day. AR showed an acceptable safety profile consistent with the SmPC of licensed ana formulations.

Conclusions: Long term treatment of ET patients with defined risk status, using this novel modified-release anagrelide formulation proofed well tolerable, normalized plc in a vast majority, significantly reduced progression to high-risk status and most importantly was associated with significantly less clinical ET related events. These data have important implications for the optimal management of ET and support a "treat-early" approach.

References

Results of a phase I, single dose, randomized, 3-way crossover study, to assess the bioavailability of a novel anagrelide extended release (ER) formulation in comparison to a commercially available anagrelide reference product (CARP) in healthy volunteers, Petrides P, Zagrijtschuk O, Klade C, DGHO, 2015

Phase 3 trial TEAM-ET in 106 high-risk Essential Thrombocythemia patients, demonstrating non-inferiority of Anagrelide Retard, a novel, extended-release anagrelide formulation, to the licensed comparator

Gisslinger H, Radinoff A, Karyagina E,Kyrcz-Krzemień S, Abdulkadyrov K, Gerbutavicius R,Melikyan A, Burgstaller S, Hus M, Kłoczko J, Yablokova V, Tzvetkov N, Całbecka M, Shneyder T, Warzocha K, Jurgutis M, Kaplanov K, Hodisch J, Klade C, Buxhofer-Ausch V, European School of Hematology EHA 21^st Congress, 2016