AOP2014, a Novel Peg-Proline-Interferon Alpha-2b with Improved Pharmacokinetic Properties, Is Safe and Well Tolerated and Shows Promising Efficacy in Patients with Polycythemia Vera (PV)

Abstract 175

AOP2014 is a next generation long-acting pegylated IFNa-2b, consisting predominantly of only one isoform, as opposed to other commercially available pegylated interferons. AOP2014 has a distinct pharmacokinetic and pharmacodynamic profile which may potentially allow reduced dosing frequencies compared to other pegylated IFNs. This is being expected to result in improved tolerability, better compliance, and, finally, favorable long-term treatment outcomes. AOP2014 is a designated Orphan Drug in EU for treatment of patients with PV. The maximum tolerated dose (MTD), long term safety and efficacy of AOP2014, administered subcutaneously every 14 days, are the main objectives of the study. Patients with confirmed PV diagnosis, age equal or older 18 years, both naïve and cytoreduction pre-treated are eligible. After establishing the MTD, an extended cohort of 25 additional patients was planned to be recruited. European LeukemiaNet criteria were used for response assessment. 34 patients, treated by March 31, 2012 were included into this analysis: 25 in Phase I (dose-finding) and 9 in the Phase II (cohort extension). Median time from diagnosis was 24 months (range 0–180). 12 patients (35%) were HU pre-treated (mean past duration of HU pre-treatment 39 months, mean daily HU dose 950 mg). Median number of phlebotomies in the past 3 months prior to inclusion was 1 (range 0–8), a total of 21 patients (62%) were regularly phlebotomized at least once in three months prior to study entry. 11 patients (32%) had a history of thrombotic complications. Median Hct at baseline was 42% (range 36–51). Median WBC and platelet counts were 10.6*109/l (range 3.9–20.4) and 452*109/l (range 141–1019), respectively. 17 patients (50%) had splenomegaly at baseline. The median reported treatment duration was 41 weeks (range: 1 day – 80 weeks), 11 patients completed 1 year on treatment. Doses from 50 to 540 ug every two weeks were tested, 540 ug has been concluded as MTD as the highest tested dose, since no DLTs occurred in the study. The mean administered dose (both Phase I and II patients) was 287 ug. After 28 weeks of treatment (21 evaluable patients), 71% of patients had hematological response (7 CR, 33%; 8 PR, 38%), at week 36 (19 evaluable patients) 8 patients (42%) achieved a CR and 8 patients (42%) a PR, overall response rate (ORR, CR+PR) was 84%. At week 52 (1 year; 11 evaluable patients), 5 patients (46%) had CR and 5 (46%) PR, ORR was 91%; 8 (73%) patients presented with completely normalized blood values, all evaluable patients were phlebotomy free at this timepoint. 4 patients (of 12 evaluable for this measurement, 33%) had still enlarged spleen at week 52. At week 76, 2 evaluable patients were complete responders. At week 52, 1 patient (of 9 evaluable, 11%) developed partial molecular response, at week 68 3 patients (of 7 evaluable, 43%) had partial molecular response. One patient with allelic burden of 22% at baseline developed complete molecular response at week 36 (still ongoing). Mainly grade 1 and 2 adverse events were reported. A total of 358 adverse events occurred. 27 patients (79%) suffered from drug-related adverse events. 9 patients (26%) developed serious adverse events; 4 SAEs were considered to be treatment related. 5 patients (15%) discontinued their study participation prematurely, 3 of them due to adverse events (deterioration of underlying disease and two cases of depression). Acceptable tolerability and durable clinical benefits have been demonstrated in PV patients measured as overall response rate of above 90% with CRs of 46% at one year after treatment start. Phlebotomy independence and normalization of hematological parameters could be seen in most of the patients. The study continues to recruit and collect long term follow up information. Presented data support further development of AOP2014 in PV, a Phase III study is planned to start early 2013.