Phase 1 Study Results of a Novel Controlled-Release Formulation of Anagrelide (GALE-401) for the Treatment of Thrombocytosis

Introduction: Despite recent advances in the diagnosis and management of myeloproliferative neoplasms (MPNs), treatment of essential thrombocythemia (ET) has remained largely unchanged since the introduction of anagrelide in the US during 1997. Anagrelide is indicated for the treatment of thrombocythemia, to reduce the elevated platelet count and risk of thrombosis, and to ameliorate symptoms including thrombohemorrhagic events. The primary pharmacological effect of anagrelide is inhibition of megakaryocyte hypermaturation leading to reduced platelet production. Anagrelide also inhibits cyclic AMP phosphodiesterase III (PDE3), and common drug related adverse events (AEs; e.g., headache, palpitations, fluid retention, nausea and diarrhea) are believed to be due to this mechanism. Although initiating treatment at low doses and slowly increasing the dose to reach a target decreased platelet count may mitigate AEs, over 20% of patients still withdraw from treatment due to poor tolerability. As the currently marketed anagrelide product is an immediate release (IR) formulation with peak plasma concentrations (C_max) that may exceed that needed for platelet reduction and cause unwanted PDE3 inhibition and AEs, an alternate formulation that modifies this pharmacokinetic (PK) profile may improve patient tolerability, adherence and treatment outcomes. This has led to the development and study of a controlled-release (CR) formulation of anagrelide (GALE-401).

Methods: 98 healthy adult subjects were enrolled among 5 Phase 1 clinical trials of anagrelide CR, including 12 placebo-control subjects and 86 subjects who received single or multiple doses ranging from 0.2 to 0.6 mg twice daily (b.i.d.) for up to 41 days. The trials included an open-label, single dose developmental study; two placebo-controlled multiple dose ranging studies; a food effect study; and a comparative crossover PK study vs. IR reference product. Safety parameters included routine laboratory, ECG, and clinical evaluations. PK was assessed by measurements of plasma anagrelide and its active metabolite using a validated HPLC-MS/MS method. Pharmacodynamic activity was assessed by daily platelet count determinations in the multiple dosing studies.

Results: Single doses of anagrelide CR were well tolerated, and the only drug-related AE reported in 2 or more subjects was headache. In the b.i.d. dose-ranging studies, the frequency and severity of AEs were similar between anagrelide CR and placebo groups, with the exception of decreased platelet counts in subjects receiving anagrelide CR. All AEs were transient, mild or moderate in severity, and no severe or serious AEs were reported.

Anagrelide CR demonstrated dose proportional PK characteristics. Following a single 0.5 mg dose in the fasted state, the mean time to maximum plasma concentration (T_max) and terminal elimination half-life (t_1/2) were 2.0±1.5 hrs and 10.4±9.3 hrs (mean ± SD), respectively; in contrast, T_max and t_1/2 following IR was 1.0±0.9 hrs and 1.4±0.2 hrs, respectively. C_max and total plasma exposure (AUC_0-inf) with anagrelide CR were reduced to 26% and 59% of IR, respectively. However, steady-state PK following 6 daily 0.5 mg b.i.d. doses of anagrelide CR or IR showed similar AUC_0-inf values, while C_max with anagrelide CR remained nearly unchanged (29%). Plasma exposure was higher when anagrelide CR was administered in the fed state, as demonstrated by the ratio of least-squares mean values for C_max and AUC_0-t, which were increased by 100% and 60%, respectively.

The platelet lowering effect of anagrelide CR was evident in the 2 multiple dose ranging studies. In a placebo-controlled study of 0.2 to 0.6 mg b.i.d. dosing for up to 21 days, a dose-related decrease in platelet counts was observed, and the 0.6 mg cohort was halted early due to excessive platelet reductions. Anagrelide CR did not have a relevant impact on platelet function as assessed by template bleeding time.

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Conclusion: Anagrelide CR is a promising, novel formulation of anagrelide that exhibited the desired PK profile of a significantly reduced C_max, while maintaining plasma exposure to induce platelet count reductions. The product was well tolerated with an AE profile that was not distinguishable from placebo. These data support the importance of an ongoing Phase 2 study in patients with MPN-related thrombocytosis, including ET.