Its efficacy is unknown; it is untested in clinical trials, untried in mouse models, and, for the most part, unapproved by the Food and Drug Administration. But that hasn’t stopped some patients with amyotrophic lateral sclerosis from trying Iplex. The drug garnered attention this week with a front-page story in last Sunday’s New York Times that chronicled a mother’s efforts to obtain Iplex for her son. The FDA is allowing a few patients to request compassionate use of the medication. Iplex, which was briefly available off-label for ALS, has since been pulled from the market in a patent dispute. It is currently available to Italian citizens with ALS.
Iplex is a complex of two recombinant human proteins: insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3). It is FDA-approved to treat short stature caused by IGF-1 deficiency in children. Scientists have long been eyeing IGF-1, known to have neuroprotective properties (for review, see Sullivan et al., 2008), as a potential ALS therapeutic. In vitro, it promotes axon outgrowth in corticospinal motor neurons (zdinler and Macklis, 2006); in a mouse model of ALS, the growth factor delayed disease and prolonged survival (Nagano et al., 2005). But in clinical trials, subcutaneous IGF-1 injections have been a bit of a bust, with a handful of studies showing little or no effect (see ARF related news story and Sorenson et al., 2008). It is unknown how much, if indeed any, recombinant IGF-1 was able to cross the blood-brain barrier to reach motor neurons in those trials. Another approach under development is viral delivery of the IGF-1 gene; this prolongs survival in mouse models (Dodge et al., 2008).
Iplex is kind of an IGF-1 me-too, said Jeffrey Rothstein of the Johns Hopkins University in Baltimore, Maryland. In the body, the majority of IGF-1 is bound to a binding protein, not free; in theory, the addition of the binding protein might give the growth factor better access to dying motor neurons. It’s a scientifically interesting idea, Rothstein said, but added that at this point there is not enough evidence to warrant human trials.
The FDA has released data on more than 100 Italian patients using Iplex. Among 24 people who took Iplex for a year, the average pre-treatment score on the ALS Functional Rating Scale was 30.2 7.9, and the average score after 12 months was 25.2 7.8. John McCarty, director of therapeutic investigations for the ALS Therapy Development Institute, discussed Iplex in an Institute webinar April 8. My interpretation of the data is that it is not strongly consistent with a high degree of efficacy, he said then. The Italian data do indicate that the drug is fairly safe; just five patients out of 110 discontinued treatment because of problems possibly related to Iplex.
The FDA reports that Insmed, the Richmond, Virginia-based company that makes Iplex, will conduct a clinical trial on Iplex for ALS. Until more data come out, Iplex remains an intriguing idea with next to no evidence to back it up.
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