Trophos identified olesoxime in a screen for drugs that would support neurons stressed by the absence of trophic factors (Bordet et al., 2007). Olesoxime binds to the mitochondrial voltage-dependent anion channel (VDAC) and translocator protein (18 kDa). Both are involved in the mitochondrial permeability transition pore, which functions in metabolite uptake and oxidative stress, said chief scientific officer Rebecca Pruss. She believes that olesoxime somehow modulates those processes, but the precise mechanisms remain murky. Several lines of evidence point to mitochondria, and their role in cell death, as important participants in the demise of ALS-afflicted motor neurons (reviewed in Martin, 2010). In their earlier 2007 study, Pruss and colleagues reported that olesoxime delayed disease onset in ALS model mice—although it did not slow the disease process once the mice started to show symptoms.

“I am saddened by the result, but not too surprised to find out the biology of the disease is much more complicated than scientists tend to perceive (and perhaps more complicated than we can even comprehend),” wrote Lee Martin of Johns Hopkins University, who was not involved in the study, in an e-mail to ARF. Beyond mitochondria, there are several other possible disease mechanisms to consider, he told ARF. Alzheimer’s researchers may find this setback feels familiar: In 2010 they discovered that Dimebon, another proposed mitochondrial modulator thought to interact with the permeability transition pore, was ineffective in Phase 3 after showing apparent promise in a smaller trial (see ARF related news story; ARF news story; and Bachurin et al., 2003).

The double-blind, placebo-controlled olesoxime trial included 512 people with ALS who were already taking riluzole, the only approved drug for the disease. Riluzole extends the life of people with ALS by a few months. The desired endpoint in the Trophos trial was a 12 percent increase in the number of subjects surviving after 18 months of treatment, said chief medical officer Jean-Louis Abitbol. The researchers also evaluated participants with the 48-point ALS Functional Rating Scale. People taking olesoxime plus riluzole maintained scores a point or two higher than those taking riluzole plus a placebo, but the difference is of “doubtful clinical significance,” Abitbol said.

The Trophos team suspects timing was a factor in the drug’s failure. ALS symptoms do not appear until many motor neurons are already dead, and it can take a year beyond that point to diagnose the disease and make a person eligible for a clinical trial. In the Trophos study, participants had received an ALS diagnosis six months to three years before enrolling. “It may just be too late,” Marron said.

Another possible problem, Martin noted, is bioavailability: The drug would have to travel from the digestive system, across the blood-brain barrier, into the motor neurons to mitochondria. It is an important issue, agreed Pruss, who told ARF in an e-mail that Trophos carefully measured brain uptake in preclinical models. VDAC is found not only on mitochondria, but also on the plasma membrane (Yu et al., 1995), and it could perhaps sequester olesoxime at the neuron’s exterior, Martin speculated.

Given these disappointing results, should ALS researchers turn away from mitochondria in favor of other potential therapeutic targets? Not based on this study alone, Martin said. Lucie Bruijn of the ALA Association agreed in an e-mail to ARF, noting that there is an ongoing trial of dexpramipexole, another mitochondrial modulator (see ARF related news story on Cudkowicz et al., 2011). However, Martin noted there are plenty of other possible drug targets to consider.

The Trophos team believes that olesoxime may work on more slowly progressing diseases. They are currently testing the drug in a Phase 2 study for spinal muscular atrophy types II and III, with results due in the second half of 2013. Trophos is also raising funds for a Phase 2 trial in progressive multiple sclerosis, Marron said. In addition, the company continues to pursue the drug’s mechanism of action. They found it promotes microtubule polymerization and acts on Fas death receptors, Pruss said. At the 2011 Society for Neuroscience meeting in Washington, DC, she presented a poster on olesoxime’s ability to dampen glial activation in ALS mice. These pleiotropic effects may make interpretation of preclinical and clinical data even more difficult.—Amber Dance.