Efficacy and Safety Of AOP2014/P1101, a Novel, Investigational Mono-Pegylated Proline-Interferon Alpha-2b, In Patients With Polycythemia Vera (PV): Update On 51 Patients From The Ongoing Phase I/II Peginvera Study
Authors: Gisslinger Heinz , Buxhofer-Ausch Veronika , Thaler Josef , Schloegl Ernst , Gastl Guenther A. , Wolf Dominik , Kralovics Robert , Gisslinger Bettina , Lechner Daniel , Strecker Karin , Egle Alexander , Melchardt Thomas , Burgstaller Sonja , Willenbacher Ella , Zoerer Michael , Zahriychuk Oleh , Klade Christoph , Greil Richard 
Published: October 2019

Abstract

Background
AOP2014/P1101 is a novel, investigational mono-pegylated proline-interferon alpha-2b. In contrast to other pegylated IFNs, AOP2014/P1101 consists of one predominant isoform. AOP2014/P1101 has Orphan Drug Designation in EU and USA for treatment of patients with PV.

Study design
Long term efficacy and safety data are being collected in the follow-up extension stage of the study (collecting the data of both Phase I and Phase II portions of the study), after the maximum tolerated dose (MTD) of AOP2014, administered subcutaneously every 14 days, has been defined earlier. Patients with confirmed PV diagnosis, age ≥18 years, both naïve and cytoreduction pre-treated were eligible. After establishing the MTD, an extended cohort of 25 additional patients has been planned to be recruited. Complete hematological response (CR) is defined by Hct<45%, platelet count≤400*109/L, WBC count≤10 *109/L, normal spleen size by sonography, and absence of thromboembolic events. Partial response (PR) is defined as haematocrit <45% without phlebotomy but with persistent splenomegaly or elevated (>400*109/L) platelet count, or reduction of phlebotomy requirements by at least 50%. Complete molecular response has been defined as reduction of any molecular abnormality to undetectable levels; partial molecular response as: reduction ≥ 50% in patients with < 50% mutant allele burden, or a reduction ≥ 25% in patients with > 50% mutant allele burden.

Results
Study completed recruitment late 2012, after inclusion of 51 patients. Data on treatment by March, 31, 2013, are covered by the current analysis. Median time from diagnosis to inclusion was 2 years (Q1-Q3: 1.0-6.0). 20 patients (39%) were pre-treated with HU prior to study entry. Median number of phlebotomies in the past 3 months prior to inclusion was 1 (range 0–8), a total of 31 patients (61%) were regularly phlebotomized at least once in three months prior to study entry. 11 patients (22%) had a history of thrombotic complications. Median Hct at baseline was 43% (Q1-Q3: 41-44). Median WBC and platelet counts were 11.1*109/l (Q1-Q3: 9.3–13.6) and 415*109/l(Q1-Q3: 316-583), respectively. 17 of 46 (67%) evaluable patients had spleen >12cm in length at baseline (by ultrasound). Median JAK2 allelic burden at baseline was 48% (Q1-Q3: 29-71). The median reported treatment duration is 345 days, 25 patients completed were followed up for at least one year. After six months of treatment (35 evaluable patients), 60% of patients had hematological response (9 CRs, 26%; 12 PR, 34%). At one year (25 evaluable patients), 9 patients (36%) had CR and 10 (40%) had PR, resulting in an ORR of 76%. At 18 months (n=19), there were 9 CRs (47%) and 8 PRs (42%), resulting in an ORR of 89%. At months 6, 12 and 18; 6 (19%), 1 (4%) and 1 (5%) patients were still in need of phlebotomy, respectively. The percentage of patients with enlarged spleen (>12cm in length) decreased to 56% at the end of the first treatment year. Mean JAK2 allelic burden dropped to 44% at both 6 months (7/29% mPRs) and 12 months (6/22%), while at 18 month the mean value was 25% (2 of 3 evaluable patients were in PR); decrease of allelic burden was more profound in the arm of HU naïve patients. 645 adverse events (AE) were reported in 48 (94%) patients, half of them (296; 46%) were drug-related and 26 (4%) serious. The following AEs were reported in >20% of the patients: pruritus, headache, fatigue, arthralgia, diarrhea and vertigo. AE related patient discontinuation occurred in 10 (20%) patients; two patients left the study due to administrative reasons; violation of eligibility criteria, lack of efficacy and administrative reasons led to withdrawal in one case per category, respectively. 87 events (13%) mandated dose reduction or delay.

Conclusions
The more convenient, every 14 days treatment schedule is feasible and effective. Efficacy and safety profile remain in line with expectations from other (pegylated) interferons. ORR of >80% with cumulative CRs 45-50%, accompanied by phlebotomy independence, normalization of hematological parameters and spleen size reduction in majority of patients has been observed. Significant and sustained JAK2 allelic burden decrease, starting from week 28 of treatment, was seen. The results support further development of AOP2014/P1101 in PV; accordingly, a phase III clinical study (PROUD-PV) is starting to recruit patients in Q4 2013.

Disclosures:
Gisslinger: AOP Orphan Pharmaceuticals AG: Research Funding. Buxhofer-Ausch:AOP Orphan Pharmaceuticals AG: Research Funding. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding. Schloegl:AOP Orphan Pharmaceuticals AG: Research Funding. Gastl:AOP Orphan Pharmaceuticals AG: Research Funding. Wolf:AOP Orphan Pharmaceuticals AG: Research Funding. Kralovics:AOP Orphan Pharmaceuticals AG: Research Funding. Gisslinger:AOP Orphan Pharmaceuticals AG: Research Funding. Lechner:AOP Orphan Pharmaceuticals AG: Research Funding. Strecker:AOP Orphan Pharmaceuticals AG: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Melchardt:AOP Orphan Pharmaceuticals AG: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals AG: Research Funding. Willenbacher:AOP Orphan Pharmaceuticals AG: Research Funding. Zoerer:AOP Orphan Pharmaceuticals AG: Employment. Zahriychuk:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment. Greil:AOP Orphan Pharmaceuticals AG: Research Funding.