Pharmacokinetics and Pharmacodynamics of Peginterferon Beta-1a in Patients with Relapsing-Remitting Multiple Sclerosis: Data from the Pivotal Phase 3 ADVANCE Study (P3.194)

OBJECTIVE: To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS). BACKGROUND: At Year 1 of the ongoing Phase 3 ADVANCE study, peginterferon beta-1a (a pegylated interferon beta-1a in clinical development; 125 µg subcutaneous every 2 [Q2W] or 4 [Q4W] weeks) significantly improved primary and secondary clinical and magnetic resonance imaging (MRI) endpoints versus placebo in RRMS patients, with a safety profile that was consistent with other beta interferons. Q2W dosing provided numerically greater reductions relative to placebo versus Q4W across relapse and MRI endpoints. In previous Phase 1 studies, compared with non-pegylated interferon beta-1a, peginterferon beta-1a had a longer half-life (t 1/2 ) and greater exposure (peak serum concentration [C max ] and area under the curve [AUC]), supporting the contention that pegylation of interferon beta-1a would allow for less frequent dosing. DESIGN/METHODS: Patients (n=1512) with RRMS were randomized (1:1:1) and received double-blind placebo or peginterferon beta-1a 125 µg Q2W or Q4W. Intensive blood samples for PK and PD (neopterin elevation) analyses were collected from 25 patients (Q2W: n=12; Q4W: n=13) pre-dosing and at intervals over 240 hours post-dosing at Weeks 4 and 24. Intensive PK and PD data were analyzed using non-compartmental-analysis. RESULTS: The PK profile of peginterferon beta-1a 125 µg did not change over time or across the two dosing regimens. No accumulation was observed. C max was reached 1-1.5 days post-dosing, with a mono-phasic decline, and a median t 1/2 of approximately 2-3 days. Neopterin concentrations peaked at approximately 3 days post-dosing for both Q2W and Q4W, and were sustained for 10-14 days following each dose. CONCLUSIONS: Peginterferon beta-1a Q2W provided an approximate 2-fold cumulative AUC over a month relative to the Q4W regimen, with a similar C max . Neopterin elevations sustained for approximately 2 weeks post-dosing. Both PK and PD results supported the enhanced efficacy seen with peginterferon beta-1a Q2W in patients with RRMS. Study Sponsored by: Biogen Idec Inc. Disclosure: Dr. Hu has received personal compensation for activities with Biogen Idec as an employee. Dr. Hu holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Hu was involved as an investigator. Dr. Cui has received personal compensation for activities with Biogen Idec as an employee. Dr. Cui holds stock and/or stock options in Biogen Idec. Dr. White has received personal compensation for activities with Biogen Idec as an employee, and ExL Pharma as a speaker. Dr. White holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. White was involved as an investigator. Dr. Zhu has received personal compensation for activities with Biogen Idec as an employee. Dr. Zhu holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Zhu was involved as an investigator. Dr. Zhu holds stock and/or stock options in Elan. Dr. Deykin has received personal compensation for activities with Biogen Idec as an employee. Dr. Deykin holds stock and/or stock options in Biogen Idec. Dr. Nestorov has received personal compensation for activities with Biogen Idec. Dr. Nesterov holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Nesterov was involved as an investigator. Dr. Hung has received personal compensation for activities with Biogen Idec. Dr. Hung holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Hung was involved as an investigator.