A placebo‐controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis

Abstract

Preclinical investigations indicated that recombinant human ciliary neurotrophic factor (rhCNTF) may have potential as therapy for amyotrophic lateral sclerosis (ALS). We evaluated the safety and efficacy of rhCNTF in a prospective, double-blind, placebo-controlled trial in 570 patients with ALS. Patients were randomized to receive 0.5, 2, or 5 micrograms/kg/day rhCNTF, or placebo, for 6 months. The primary efficacy end point was the change from baseline to the last on-treatment value of a combination megascore for limb strength (maximum voluntary isometric contraction) and pulmonary function. Secondary end points included individual arm and leg megascores, pulmonary function tests, an activities-of-daily-living outcome measure, and survival. The four treatment groups were similar at baseline with respect to age, sex, disease duration, and muscle strength values. At all doses tested, rhCNTF had no beneficial effect on the primary or secondary end points. Certain adverse events, as follows, appeared to be dose related: injection site reactions, cough, asthenia, nausea, anorexia, weight loss, and increased salivation. There was an increased number of deaths at the highest dose level. rhCNTF had no beneficial effect on any measure of ALS progression. There were increased adverse events in the 5 micrograms/kg group and increased deaths.

Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein

“…Brain-derived neurotrophic factor in ALS patients had no effect on survival but exhibited a statistically significant benefit for those ALS patients with early respiratory impairment and altered bowel function (70). Ciliary neurotrophic factor exhibited mostly negative effects in ALS patients (71).…”

Continued Administration of Ciliary Neurotrophic Factor Protects Mice from Inflammatory Pathology in Experimental Autoimmune Encephalomyelitis

“…50 So far, side effects of CNTF such as fever, malaise, and weight loss as well as the most likely poor ability of CNTF to cross the intact BBB have limited the success of clinical studies in amyotrophic lateral sclerosis patients who were given CNTF because of its known neuroprotective effect. 28,31,32 More promising results were obtained when CNTF was administered to the CNS by intrathecal injections or implantation of encapsulated transfected cells into the ventricular system. 34,36,37,81,82 Recent progress on human CNTF biochemistry indicated that this cytokine can use soluble or membrane-bound IL-6R␣ as a substitute to CNTFR␣ to activate the receptor signaling subunits, gp130 and LIFR␤.…”

“…28 -30 CNTF was administered systemically to patients with amyotrophic lateral sclerosis, but no beneficial effect was detected. 28,31,32 The lack of therapeutic efficiency could be linked to the poor ability of CNTF to pass the bloodbrain barrier (BBB). 33 More promising preclinical or clinical results have been obtained with CNTF targeted to the CNS by intrathecal injection or implantation of encapsulated transfected cells.…”

Antiapoptotic activity maintenance of Brain Derived Neurotrophic Factor and the C fragment of the tetanus toxin genetic fusion protein

“…In vitro studies demonstrated that several neurotrophic factors delay motorneuron degeneration [3][4][5][6]. However, clinical trials using subcutaneous and intrathecal neurotrophic factors caused several side effects such as weight loss, fever, cough, fatigue and behavioural changes [7][8][9][10][11][12].…”