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GH not beneficial for treatment of ALS
No difference between IGF-1 vs. placebo.
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Insulin-like growth factor type 1 provided no benefit for patients with amyotrophic lateral sclerosis. Results from the two-year study, published in Neurology, demonstrated no effect of IGF-1 on slowing the progression of weakness in the disease.
“There is an outcry from the ALS community to get an answer whether this drug works or does not work,” Eric J. Sorenson, MD, section head and associate professor of Neurology at Mayo Clinic, Rochester, told Endocrine Today.
“The current treatment options for ALS are inadequate, and more effective treatments are vitally needed,” he said in a press release.
Two previous, shorter studies using IGF-1 to treat ALS had conflicting results. Results of a study conducted in North America showed that the drug was beneficial; however, results of another study conducted in Europe showed no benefit.
Two-year study
Researchers of the phase-3, randomized, double-blind, placebo-controlled study enrolled 330 patients with ALS at 20 medical centers. They randomly assigned patients to receive 0.05 mg/kg body weight of human recombinant IGF-1 given subcutaneously twice daily or placebo.
After two years of treatment, the researchers reported no difference between treatment groups in the primary outcome measure — change in manual muscle testing score (0.44 U per month with IGF-1 vs. 0.39 U per month with placebo; P=.529). A secondary outcome measure — rate of change in functional rating scale — was also similar between treatment groups (2.5 U per month with IGF-1 vs. 2.2 U per month with placebo; P=.321). The researchers also reported no difference in tracheostomy-free survival, another secondary outcome measure.
Area under the curve analysis yielded no significant difference in rate of progression for muscle weakness (P=.455) or functional rating (P=.314) between patients who received IGF-1 or placebo.
“We found that there was absolutely no difference between the placebo and treated groups for any of the three outcome measures we instituted; in fact, they were essentially identical,” Sorenson said.
The most commonly reported adverse event was thrombotic events, with overall thrombotic events more common among patients who received IGF-1 compared with placebo (11 vs. 9; P=.087). However, serious thrombotic events — combined deep vein thrombosis and pulmonary embolism — were similar between treatment groups. Additionally, patients assigned to IGF-1 experienced significantly more hypoglycemic events (21 vs. 9; P=.034).
“There is still a great deal of evidence that IGF-1 as a growth factor has some effect on the neurons. The question now is if we give the drug subcutaneously, as we did in this study, is it getting to where we need it to get?” Sorenson said. “People still haven’t given up hope on this drug but are now looking at alternative delivery platforms.” – by Katie Kalvaitis
Neurology. 2008;71:1770-1775.
ALS is a progressively debilitating, usually fatal disease characterized by muscle wasting. Growth hormone deficiency has been found to be common in ALS. The mechanism of diminished GH secretion in ALS is unclear, but has been hypothesized to be due to altered neurons in the hypothalamus, including microglia or acetylcholine-secreting neurons, due to the underlying disease. Measurements of IGF-1 values have shown variable results, with normal values seen in some studies. Because in vitro and in vivo models of IGF-1 have suggested that IGF-1 may delay motor neuron death, and both GH and IGF-1 can improve body composition, use of growth factors including IGF-1 have been hypothesized for this disease. Studies with GH or IGF-1 have shown no or inconsistent effects on muscle function in ALS subjects.
This study was well-performed, well-powered and the groups were properly balanced at baseline. The dose of IGF-1 used in this study was reasonable; this dose has been sufficient to affect bone parameters in certain disorders, though inconsistent in its effects on body composition in other sarcopenic states.
Nevertheless, this study did not demonstrate any benefit with regard to muscle function/tone or on survival. In addition, there was a nonsignificant trend for more thromboembolic events in the IGF-1 group, and there were significantly more hypoglycemic reactions in the treated group. Despite the fact that this population is in great need of therapies that can reverse the neurodegenerative process, it does not appear, based on studies to date, that the potential or theoretical benefits of IGF-1 outweigh the risks in this population.
– Laurence Katznelson, MD
Associate Professor of Neurosurgery and Medicine, Medical Director of the Pituitary Center
and Director of the Endocrinology Fellowship Training Program, Stanford University School of Medicine