Results of an International Postmarketing Surveillance Study of pl-VEGF165 Safety and Efficacy in 210 Patients with Peripheral Arterial Disease

Abstract

Introduction: The effective treatment of chronic lower limb ischemia is one of the most challenging issues confronting vascular surgeons. Current pharmacological therapies play an auxiliary role and cannot prevent disease progression, and new treatment methods are needed. pl-VEGF165, a gene therapy drug, was approved in Russia for the treatment of atherosclerotic peripheral arterial disease (PAD) after clinical studies in 2011. The study drug is an original gene construction in which pl-VEGF165 1.2 mg is the active substance.

Objective: This postmarketing surveillance study was undertaken to evaluate the safety (identification of uncommon side effects) and efficacy of gene therapy in patients in routine clinical practice.

Methods: In total, 210 patients with stage II-III chronic limb ischemia (according to the Fontaine classification modified by AV Pokrovsky) in 33 healthcare facilities in Russia and the Ukraine were enrolled in the study. The control group (n = 60) received conservative therapy without prostaglandins and prostacyclins, and the treatment group (n = 150) received treatment with pl-VEGF165 as two intramuscular injections for a total dose of 2.4 mg. Pain-free walking distance (PWD) (the primary efficacy criterion for Fontaine stages II-III), blood flow linear velocity (BFLV), and ankle-brachial index (ABI) were monitored for 6 months. The safety of pl-VEGF165 gene transfer in terms of the trial protocol was initially evaluated 6 months after the start of the study; adverse events (AEs) and serious adverse events (SAEs) were recorded during both routine visits and unscheduled requests for medical care.

Results: Overall, PWD increased by 177%, from 100.3 ± 6.9 to 277.1 ± 16.2 m (p = 0.0001), in the treatment group, whereas the mean value was unchanged in the control group (p = 0.218). Both BFLV and ABI values increased by 24% (p = 0.0001) in the treatment group but decreased in the control group. The greatest therapeutic effect was observed for stage III disease: PWD increased by 683% (p = 0.0001). No angiogenic therapy-related AEs or side effects were recorded, and target limb salvage was 96 and 97% in the treatment and control groups, respectively. The results obtained in this study are not significantly different from those observed in the phase IIb/III registration clinical study completed in 2011.

Conclusion: pl-VEGF165 intramuscular gene transfer is an effective treatment for moderate to severe claudication due to chronic lower limb ischemia in routine clinical practice. ClinicalTrials.gov identifier: NCT02369809.

Conflict of interest statement

Funding

This study was funded by the Human Stem Cells Institute OJSC, Moscow, Russia.

Conflict of interest

A Isaev, I Bozo, R Deev, and I Plaksa are employees of the OJSC Human Stem Cells Institute. A Isaev holds shares in the Human Stem Cells Institute OJSC.

Figures

Fig. 1

Design of the postmarketing surveillance study. ABI ankle-brachial index, BFLV blood flow linear velocity, PWD pain-free walk distance

Fig. 2

Proportion of the treatment group patients with a pain-free walk distance increase extent depending on the initial disease stage: red indicates an increase of >100%; blue indicates an increase of 50–100%; purple indicates an increase from 30 to 50%; green indicates an increase <30%; yellow indicates no increase; brown indicates negative dynamics