Therapeutic Angiogenesis With Intramuscular NV1FGF Improves Amputation-free Survival in Patients With Critical Limb Ischemia

Abstract

This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.2 mg/ml on days 1, 15, 30, and 45 (total 16 mg: 4 x 4 mg). The primary end point was occurrence of complete healing of at least one ulcer in the treated limb at week 25. Secondary end points included ankle brachial index (ABI), amputation, and death. There were 107 patients eligible for evaluation. Improvements in ulcer healing were similar for use of NV1FGF (19.6%) and placebo (14.3%; P = 0.514). However, the use of NV1FGF significantly reduced (by twofold) the risk of all amputations [hazard ratio (HR) 0.498; P = 0.015] and major amputations (HR 0.371; P = 0.015). Furthermore, there was a trend for reduced risk of death with the use of NV1FGF (HR 0.460; P = 0.105). The adverse event incidence was high, and similar between the groups. In patients with CLI, plasmid-based NV1FGF gene transfer was well tolerated, and resulted in a significantly reduced risk of major amputation when compared with placebo.

Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia

“…The calculation of sample size for the combined event rate (amputation and death) was based on the TALISMAN PM201 study 16 in which a hazard ratio (HR) of 0·558 was recorded. With the assumption of a combined event rate (major amputation or death) at 1 year of at least 35% in the placebo group, a fi xed HR of 0·56, a fi xed patient follow-up of 12 months, and a drop-out rate of 5%, a sample size of 490 patients (245 patients in each treatment group) would give a minimum power of 90% to show a 44% reduction in events with NV1FGF compared with placebo, with a twosided log-rank test at a 5% signifi cance level.…”

“…15 In the phase 2 TALISMAN trial, 16 administration of NV1FGF (4 mg every 2 weeks) showed a similar improvement in ulcer healing (the primary endpoint) to that of placebo, but a 62·9% reduction of the risk of major amputation (p=0·015) and a 56% reduction of the risk of major amputation or death (p=0·009) at 12 months as compared with placebo.…”

“…Other secondary endpoints were: (1) all amputations, including all minor and major amputations on the treated leg; (2) skin lesion status (worsened, unchanged, improved, fully healed lesion); (3) pain intensity as assessed at rest (VAS Scale); 17 (4) functionality and general health assessmentambulatory function and residential status for patients according to the Deneuville questionnaire, 15 and overall quality of life as assessed with the EuroQoL questionnaire; 16 (5) admittance to hospital for amputations because of critical limb ischaemia, prespecifi ed events related to critical limb ischaemia (worsening or increase of ulcers, pain related to peripheral artery disease, necrosis or gangrene, complication caused by amputation of lower limb, infection of skin [ulcer or postamputation wound site], osteomyelitis, procedure related to the ischaemia [eg, revascularisation], wound care [debridement or dressing]), or further diagnostic procedures; and (6) ankle brachial index and toe brachial index.…”

“…Our search identifi ed two meta-analyses and three systematic reviews. 11,16,[19][20][21][22] Additionally, we identifi ed one report in press about the use of gene therapy in claudication.…”

Emerging hurdles in stem cell therapy for peripheral vascular disease

“…While repeated administration of the angiogenic gene may increase the chances of success as demonstrated by a recent study treating CLI patients with FGF-1 [5], the current thought is that use of a combination of growth factors, or "master switches" (e.g. hypoxia-inducible factor (HIF)-1α), may be better strategies for successful revascularization [6] due to the molecular complexity of angiogenesis and vasculogenesis.…”