Switch from Every Two Weeks to Every Four Weeks Administration Schedule of AOP2014, an Innovative Pegylated Interferon Alpha, in Polycythemia Very Patients Allows Maintaining of Efficacy with Improved Toxicity Profile in Phase I/II Study

Background AOP2014 is a next generation long-acting pegylated IFN-alpha-2b, consisting predominantly of only one isoform, as opposed to other commercially available pegylated interferons. Due to this property, reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with Polycythemia Vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development.

Study design This phase I/II single arm dose escalation study with cohort extension included 51 patients with PV who could be either cytoreduction therapy naive or pre-treated. AOP2014 was administered subcutaneously in a dose range of 50-540 mcg every two weeks. Main objectives were to define the maximum tolerated dose as well as observe the long term safety and efficacy in terms of normalization of blood parameters and molecular abnormalities (results were already presented at the ASH 2013 annual meeting by Gisslinger et al). The option to switch to an "once every four weeks" schedule has been implemented by the amended protocol for patients who responded well to the treatment and participated in the study for longer than one year. The dose of the study drug had to remain unchanged after the switch, resulting in a decrease (by approx. the half) of the overall exposure to the drug. Outcomes of this switch are presented here.

Results Patients (period A, median exposure duration 34 weeks, mean monthly dose 484 mcg) were dosed every two weeks based on the Phase II dosing rules prior having switch option. 33 patients (period B, median exposure duration 12 weeks, mean monthly dose 413 mcg) were dosed every two weeks beyond the first year and, showing benefit from treatment, have been assessed as eligible for switch. 28 patients (period C, median exposure duration 42 weeks) were then switched to once every four weeks schedule (mean monthly dose 221 mcg). Blood parameters were normalized and remained stable following one year of treatment and could be maintained after the switch (hematocrit, median,% - period A: 43, period B: 43, period C: 42; WBC, median, G/l - period A: 6.1, period B: 5.9, period C: 5.7; platelets, median, G/l - period A: 246, period B: 211, period C: 204). Spleen length stayed stable within the normal range following the switch in the majority of patients either (mean, in cm – period A: 11.4, period B: 8.3, period C: 10.3). Complete response as best individual response could be maintained in 42% from the period A, 55% in the period B and 67% of the period C patients, while for the partial hematological responders the results were 60%, 71% and 67%, respectively. Molecular response improved continuously over time, being maintained at the best individual level in 31% of period A patients, compared to 42% of period B and 75% of period C patients. Decrease of application frequency and total dose exposure led to decrease of the occurrence of all/drug related AEs (measured as mean count of adverse events [AE] per patient week exposure) to 0.17/0.09 (arm A) from 0.3/0.09 (arm B) and 0.08/0.03 (arm C).

Conclusions This explorative data from endpoints pre-defined in the prospective study demonstrate the feasibility to further reduce the frequency of AOP2014 administration to once every four weeks in responding patients, previously treated every two weeks. Reduced injection frequency is not associated with a lack of- response, but clearly improves tolerability. Finally, continuous reduction of the JAK2 allelic burden indicates that duration of interferon exposure rather than dose of interferon is an important variable inducing molecular responses. The here presented findings support the idea that interferon alpha effects in PV are pleiotropic, such as induction of immune-surveillance, which is continuously maintained at lower AOP2014 levels.