Study Finds Extended-Release Anagrelide Noninferior to Reference Product in ET

Sir Heinz Gisslinger, MD

Heinz Gisslinger, MD

A new phase III trial has demonstrated that a novel extended-release formulation of anagrelide (Thromboreductin) is noninferior to immediate-release anagrelide in reducing platelet counts in patients with essential thrombocythemia (ET).

“Even in pretreated patients, platelet counts decreased after [trial] inclusion, indicating the strict requirements of the trial and the efficacy of both trial drugs,” the authors, led by Heinz Gisslinger, MD, of the Medical University of Vienna, wrote in theBritish Journal of Haematology.“The use of extended release formulations may offer an important advantage by reducing the dosing frequency and the total number of pills patients have to take.”

This randomized, double-blind trial was conducted at 18 centers in 5 European countries. It compared the efficacy, safety, and tolerability of both versions of anagrelide in anagrelide-naïve and anagrelide-experienced patients with ET who needed cytoreductive therapy. The individual dose was identified during a 6- to 12-week titration period, which lasted until 2 consecutive platelet counts were stable. Efficacy was assessed during a 4-week maintenance period. The end of study and safety follow-up visit was 28 days after the end of the maintenance period.

The primary endpoint was the mean platelet count during the maintenance period (3 consecutive measurements, day 0, 14, and 28). Secondary endpoints included the tolerability and safety of the trial drugs and patients’ platelet response status.

The investigators defined 10 dose levels ranging from 0.5 to 5 mg for the immediate-release drug and from 1 to 10 mg for the prolonged-release version, based on their relative bioavailability. Anagrelide-naïve patients received 1 mg or 2 mg as an initial dose, depending on whether they were randomized to the immediate-release or prolonged-release group. Pretreated patients continued with their existing dose or its extended-release equivalent.

Any necessary dosing adjustments were made weekly according to platelet response, with a target of 150-400 x 10⁹/L). Titration was adjusted weekly if needed in 0.5 mg steps in the control group and 1.0 mg steps in the experimental group. The investigators used placebo capsules as needed to maintain blinding.

Of 112 patients who were screened, 54 were randomized to receive extended-release anagrelide and 52 were randomized to receive the existing drug. Of these, 43 extended-release group and 48 immediate-release group patients completed the trial.

The mean screening platelet counts were 822 x 10⁹/L (95% confidence interval [CI], 707-936 x 10⁹/L) for the extended-release group and 797 x 10⁹/L (95% CI, 708-883 x 10⁹/L) for the reference product.

At the 3 assessed time points, mean platelet counts in the extended-release analysis set ranged between 308 and 322 x 10⁹/L. Mean platelet counts ranged between 330 and 348 x 10⁹/L in the immediate-release group. The point estimates for adjusted mean platelet counts in the maintenance period were 281 x 10⁹/L (95% CI, 254-311) for the experimental drug group and 305 x 10⁹/L (95% CI, 276-337) for the commercially available anagrelide group.

The platelet count ratio was 0.92 (95% CI, 0.817-1.037). The upper limit of the one-sided 97.5% CI was 1.037 and the primary endpoint of the trial achieved aP<0.0001. Gisslinger et al noted that cardiovascular medical history had no significant impact, and no significant cross effect between time and treatment was detected.

There was no difference between treatments regarding response rates. In an additional analysis, the authors compared the number of patients with platelet counts above or within the reference range of 370 x 10⁹/L at the end of treatment. &ldquo;More patients treated with [the prolonged-release drug] had platelet counts within the reference range of platelets, indicating more stable effects,&rdquo; they wrote. &ldquo;This effect was most pronounced in treatment-na&iuml;ve patients or patients pretreated with a platelet reduction different from anagrelide.&rdquo;

Gisslinger et al found that platelet counts decreased in most patients with prior anagrelide treatment during the trial. In the extended-release group, 6 of 7 pretreated patients saw platelet counts decrease by a mean 137 &plusmn; 126 x 10⁹/L (SD). In the immediate-release group, platelet counts dropped by a mean 111 &plusmn; 102 X 10⁹/L (SD) in 6 of 7 patients.

The number of days from randomization to starting maintenance therapy was consistent, with a median of 42.5 days for the extended-release group and 42 days for the immediate-release group.

Gastrointestinal adverse events (AEs) occurred more frequently in the experimental group (47 vs 24,P= 0.048). Otherwise, the occurrence and the distribution of AEs throughout both treatment groups were similar. Investigators reported 40 cardiac AEs in 19 extended-release group patients, while they documented 65 cardiac AEs in 26 patients in the immediate-release group.

Other expected AEs were comparable between the 2 groups, including headache, dizziness, nausea, vomiting, and diarrhea. Patients in both groups experienced an almost identical number of ET-related AEs (24 extended-release vs 23 immediate-release). The investigators reported 10 patients with 18 serious AEs in the extended-release group but deemed only one, an episode of acute pancreatitis, to be related to the study drug. Neither of the 2 serious AEs in the immediate-release group were related to the study drug.

Gisslinger et al noted that their trial was not intended to prove superiority, only noninferiority and safety. &ldquo;Due to the short exposure of only 4 weeks after the titration period, the expected advantages in tolerability of the novel anagrelide could not be assessed in this trial,&rdquo; they wrote. &ldquo;Moreover, this trial was not powered to compare safety or tolerability between both groups. Furthermore, dosing schedules and the double-blind character of the trial made pharmacokinetic analysis difficult.&rdquo;

Reference:

Gisslinger H, Buxhofer-Ausch V, Hodisch J, et al. A phase III randomized, multicentre, double blind, active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia — the TEAM-ET 2.0 trial.Brit J Haem2019. [Epub ahead of print.]