Subcutaneous IGF-1 is not beneficial in 2-year ALS trial

Abstract

Background Previous human clinical trials of insulin-like growth factor type I (IGF-1) in amyotrophic lateral sclerosis (ALS) have been inconsistent. This phase III, randomized, double-blind, placebo-controlled study was undertaken to address whether IGF-1 benefited patients with ALS. Methods A total of 330 patients from 20 medical centers were randomized to receive 0.05 mg/kg body weight of human recombinant IGF-1 given subcutaneously twice daily or placebo for 2 years. The primary outcome measure was change in their manual muscle testing score. Secondary outcome measures included tracheostomy-free survival and rate of change in the revised ALS functional rating scale. Intention to treat analysis was used. Results There was no difference between treatment groups in the primary or secondary outcome measures after the 2-year treatment period. Conclusions Insulin-like growth factor type I does not provide benefit for patients with amyotrophic lateral sclerosis.

αCAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice

“…IGF‐1 is known to have a neurotrophic effect on motor neurons 30. To date IGF‐1 ‐based therapies have little beneficial effect upon systemic or intrathecal administration in ALS patients 19, 20, 21. The poor outcomes of these studies may possibly be due to low availability of IGF‐1 as free IGF‐1 is reduced while IGF‐1 R expression is upregulated in both the CNS and muscle of ALS patients 31, 32.…”

“…In recent years, many studies have focused on gene delivery of growth factors to the central nervous system (CNS) in order to slow disease progression in animal models of ALS utilizing the intramuscular,10, 11, 12, 13 intracerebral,14, 15 intracerebroventricular16, and intraspinal17, 18 routes of administration. Despite the encouraging results of these studies, subcutaneous delivery of recombinant human insulin‐like growth factor 1 IGF‐1 ( rhIGF‐1) in ALS patients had little effect in 3 clinical trials 19, 20, 21. Each of these approaches has its own limitations which may negate achieving efficacy in ALS patients.…”

Gene Therapy for the Nervous System: Challenges and New Strategies

“…Thus, for example, AAV vectors injected into brains to deliver NGF in Alzheimer's disease [248], neurturin or glia cell-derived neurotrophic factor (GDNF) in Parkinson's disease [249,250], and insulin-like growth factor I in ALS [251] have proven safe, but with no demonstrable benefit. This apparent lack of benefit may relate to the late stage of the diseases at the time of treatment, the progressive nature of the diseases and/or the inability to quantitate minor benefit with lack of a robust biomarker [201].…”

Review of Phase II and Phase III clinical trials for Duchenne muscular dystrophy

“…There have been several treatment trials using free IGF-1 therapy in amyotrophic lateral sclerosis (ALS) [68][69][70] and one trial of free IGF-1 complexed with IGF-1 binding protein-3 in myotonic dystrophy [71]. ALS trials failed to show a clear beneficial result but demonstrated safety of IGF-1 in these patients.…”