ALS Alert Newsletter | January

Targeting Mitochondria in ALS Treatments

Despite varying success, researchers believe mitochondria remain a good drug target.

Bullseye? Scientists hope that targeting mitochondria will lead to new ALS treatments.

On November 20, a group of researchers led by Merit Cudkowicz, a Harvard University neurologist and co-chair of the Northeast ALS Consortium (NEALS), announced promising results in a small Phase II trial of the drug dexpramipexole. Scientists believe that the drug helps to delay clinical deterioration in ALS by preventing damage to the mitochondria in motor neurons. Damaged mitochondria mean that motor neurons don’t have the energy to function properly, which may cause their decline over time.

Merit Cudkowicz

"In the mouse model of ALS, one of the first signs of disease is swelling of the mitochondria and damage to them, even before the mice get sick," Cudkowicz said. "Researchers think, at least in the mouse model, that mutant SOD1 is actually clumping at the mitochondria, directly causing their damage." Human ALS studies (even in patients without SOD1 mutations) also indicate mitochondrial damage, Cudkowicz noted, which led researchers to believe that preventing this damage may help slow the progress of ALS.

On the heels of these results came an announcement about an ALS drug trial of olexisome by the French pharmaceutical company Trophos that also targeted mitochondria. Unlike dexpramipexole, however, olexisome did not appear to be effective in slowing the advance of ALS. Although olexisome did not have the same initial success as dexpramipexole, researchers remain optimistic that targeting mitochondria will help improve the lives of those with ALS.

When good mitochondria go bad.

Although no one knows for sure exactly what causes motor neurons to stop functioning correctly in ALS, damage to the energy-producing mitochondria in the cell appears to be one major pathway involved in this disease. A portion of SOD1 is located in the membrane surrounding the mitochondria, and mutant SOD1 proteins, identified in ALS patients, are known to clump together with mitochondria proteins to finally impair normal mitochondrial function.

Recent imaging studies in mouse models of ALS, in which the mice were engineered to have an SOD1 mutation, have identified physical changes to the mitochondria in motor neurons. A team of researchers that included Packard scientists and collaborators from P2ALS (a collaboration between the Packard Center and Project ALS) found that the mitochondria did not move along the axon freely in the ALS mice, and that the mitochondria became smaller and more spherical. Seeing as these changes happened before the mice began to show clinical signs of illness, the researchers believe that these changes lead to ALS symptoms rather than being caused by them.

The links between ALS and mitochondrial dysfunction seem pretty clear. Scientists working to develop new therapies for the disease believe that preventing mitochondrial damage may help slow the progression of disease. Packard scientists and other researchers around the world have been looking for compounds that might target mitochondria. Two of these compounds, olexisome and dexpramipexole, were recently evaluated in Phase II clinical trials.

About the drugs.

When researchers first tested olexisome in the lab, they found that it helped protect motor neurons grown in culture. Next, researchers tested the compound in mice, and also found that it appeared to protect motor neurons and slow the progression of ALS. With these promising lab results in hand, Trophos began human trials of olexisome. In an 18-month randomized control trial, researchers randomized 512 ALS patients from across Europe to receive a single daily 330 mg oral dose of olexisome or placebo. The patients had been diagnosed with ALS between 6 and 36 months before the start of the study.

Although the researchers found that olexisome is safe and well-tolerated, it didn't significantly extend patients' lives. In a press release from December 13, 2011, Damian Marron, CEO of Trophos, said, "The results of this study in ALS are disappointing, above all for the ALS community, who urgently require new therapies that can prolong survival and improve function. We are genuinely proud to have worked closely with this community and our international partners in the MitoTarget project on this important and very well run study."

Trophos is continuing to test the efficacy of olexisome in other neurological disorders like multiple sclerosis and spinal muscular atrophy.

Just a few days before the results of the Trophos study was released, Cudkowicz and colleagues published a paper in Nature Medicine announcing that their mitochondrial-targeted compound, dexpramipexole, did slow the progress of ALS. Dexpramipexole is the mirror image of pramipexole, which researchers had been testing to treat tremors and other symptoms of Parkinson's disease. Low levels of the neurotransmitter dopamine have been linked to Parkinson’s disease, and pramipexole works by simulating the effects of dopamine. But scientists noted that pramipexole had a secondary effect: it appeared to be neuroprotective. Maybe, they thought, dexpramipexole (the mirror image of pramipexole) would have these same neuroprotective effects without such strong effects on the dopamine system.

It did. Cudkowicz and colleagues from Knopp Biosciences, who had licensed dexpramipexole from its original developers, recently completed a small Phase II clinical trial to assess the safety and tolerability of dexpramipexole in patients recently diagnosed with ALS. The study had two parts – in the first part of the study, 102 patients whose ALS symptoms had begun within the last 24 months were randomized to receive placebo, 50, 150, or 300 mg dexpramipexole per day for twelve weeks. After the end of the first part, all study participants received placebo for four weeks. In the second part of the study, the remaining 92 subjects were re-randomized to receive either 150 or 300 mg dexpramipexole per day for 24 weeks.

Patients receiving dexpramipexole showed fewer declines on the ALS Functional Rating Scale-Revised than those receiving placebo. Higher doses of dexpramipexole were associated with significantly less decline than lower doses. Dexpramipexole was safe and well-tolerated. The most common side effect was a reduction in disease-fighting white blood cells.

"What's really driving interest in dexpramipexole is the human data. We showed a dose-dependent improvement in function and survival. The preclinical data did show some neuroprotection, but the driving force is the patient data," Cudkowicz said.

Currently Cudkowicz and colleagues have begun an international Phase III trial to measure the safety and efficacy of dexpramipexole in a larger group of ALS patients that is already fully enrolled. The study has finished recruiting, and researchers anticipate that the study will be complete by late 2012. Researchers hope to begin a second Phase III trial sometime in 2012, although enrollment information is not yet available.

What’s next?

With seemingly mixed results on ALS drugs that are supposed to improve mitochondrial function, it may seem that mitochondria aren’t the best targets for further drug research. But eliminating mitochondria as potential pharmaceutical targets would be premature. For one, the Trophos study of olexisome did not conduct a separate trial assessing the most effective dose of the drug, so scientists don't know if the patients received adequate amounts of olexisome. For another, many of the patients in the Trophos study were in much later stages of ALS, generally a year or two after diagnosis. Patients in the dexpramipexole study had only been experiencing symptoms for less than two years. Since ALS diagnosis is such a long, time-consuming process, treating the disease earlier in its course may be more beneficial. As well, the European patients in the Trophos study had been taking riluzole for some time, which may have masked the effects of olexisome, especially in a later stage of disease.

"The two drugs work on mitochondria in different ways. We know dexpramipexole works on mitochondria, but that doesn't mean it doesn't have other properties, and that's something that we're exploring: the full mechanism of action," Cudkowicz said. "The challenge in ALS trials is knowing if drugs hit their target and had the desired biological effect in humans. We don't know that for either drug because we don't have good biomarkers of mitochondrial dysfucntion in humans. So it is possible that the dosage in Trophos study was not the right dosage, or it could be that it truly failed and that any dosage of it would not work."

The Trophos study doesn't kill the idea of targeting mitochondria, Cudkowicz said. "Both drugs act differently on mitochondria so we can't lump all drugs that target mitochondria together- it is more complex," she said. On the whole, these two studies have opened up new avenues for research into potential ALS treatments.

–– Carrie Arnold