Adrug thought to modulate mitochondrial damage in amyotrophic lateral sclerosis (ALS) appears to slow the disease process, according to a two-part study in 100 patients with the fatal motor neuron disease.
The results from the phase 2 study — a reduction in functional decline and a significant drop in the death rate in those on the highest dose of the drug, dexpramipexole — has led Biogen-Idec to sponsor a phase 3 trial that will enroll 930 patients.
The findings, which were originally reported at the 2010 AAN annual meeting in Toronto, were published in the Nov. 20 online edition of Nature Medicine.
“We are very excited,” said study leader Merit Cudkowicz, MD, the Julianne Dorn Professor of Neurology at Harvard Medical School, director of the Neurology Clinical Trials Unit and co-director of the Neuromuscular Division at Massachusetts General Hospital. “In the ALS world, we have not had anything that works like this drug.”
Dr. Cudkowicz and her colleagues designed the two-part safety and tolerability study by initially testing three dosages — 50 mg, 150 mg, and 300 mg — against a placebo for 12 weeks. After a one-month washout, the ALS patients were re-randomized to the lowest dosage, 50 mg, or the highest dose of 300 mg, for an additional 24 weeks. During the study, clinicians at 20 medical centers across the country closely monitored patients, and the investigators were able to show a dose-dependent dip in the slope of the decline on the ALS functional rating scale.
The functional changes were repeated during the longer study and the investigators were also able to compare the number of deaths in each of the two arms. There were fewer deaths in the group taking the highest 300 mg dose.
The investigators considered that the patients failed to respond to the treatment if there was a six-point or greater drop in the functional ALS score from the baseline assessment to the end of the first 12-week study. There were 9 patients (33 percent) on the placebo dose who met this definition; 8 patients (15 percent) on the 50 mg; four patients (15 percent) on 150 mg and two patients (8 percent) on 300 mg (p=0.01).
The investigators tested a range of motor parameters and showed that fine motor function improved most on the highest dose of the drug. The treatment group slope estimates of ALS functional rating scores from the linear mixed-effects model at week 24 of active treatment were −1.28 for the 50-mg group (95% CI: −1.56 to −1.01) and −1.02 for the 300-mg group (95% CI: −1.29 to −0.75), a treatment group difference of 0.26 (95% CI: −0.12 to 0.64). This was an attenuation of 20.5 percent in the rate of decline in ALS functional rating scores for the 300-mg group relative to the 50-mg group over 24 weeks of active treatment
(p = 0.177).
The investigators concluded that the drug was safe and well tolerated.
“These phase 2 data are as compelling as anything we have seen to date in ALS,” said Jeremy Shefner, MD, PhD, professor and chair of neurology at SUNY Upstate Medical University and director of the Clinical Neurophysiology Laboratory and the MDA/ALS Research and Treatment Center at University Hospital in Syracuse, was also an author of the Nature Medicine report. He said that the mechanism of the drug's action is not yet known, though “it likely exerts some neuroprotective effects via mitochon-dria membrane stabilization, or other mechanisms that may reflect a reduction of oxidative stress.”
He added that the fact that “the trends towards reduced progression crossed multiple outcomes and two ran-domizations are both very encouraging.”
James Bennett, MD, PhD, chair of the department of neurology at Virginia Commonwealth University, was the first to identify dexpramipexole's ability to protect brain cells from dying. He began testing the drug on patients during his tenure at the University of Virginia. Knopp Biosciences took over the development and testing of the drug.
Dr. Bennett was not involved in the design or implementation of the current study, although he maintains a financial interest in the commercial development of the drug.
“Obviously, I think it has great potential for treating diseases where there is evidence of mitochondrial oxidative stress participating in pathogenesis. This would include ALS, Alzheimer's and Parkinson's,” said Dr. Bennett.
The drug is concentrated from blood to brain and can be concentrated many more times into mitochondria, explained Dr. Bennett. “This occurs because the drug has a positive charge and the interior of mitochondria is negatively charged. The drug is capable of helping to inactivate free radicals of oxygen and nitrogen. These free radicals are being formed all the time, but in diseases there is evidence that they are excessively formed and likely participate in damaging mitochondria and neurons.”
There may be additional mechanisms of action that involve improving the efficiency of mitochondrial energy production, he added.
Of the new findings in Nature Medicine, he said: “I am impressed by the findings, which most importantly showed a dose-related slowing of disease. That is very important.”
But Stanley H. Appel, MD, chair of the department of neurology at the Methodist Hospital in Houston and director of the Methodist Neurological Institute, provided a note of caution. He agreed that the drug shows promise but it will require the power of a large double-blind study to prove that it really offers a benefit for patients.
Dr. Appel said that while the preliminary findings look good, a definitive double-blind placebo controlled trial will be needed to see whether in fact patients on the medicine do better than those on a placebo dose. “We don't know whether this drug will be important for ALS without this information,” he said. “But even if it helps a little bit, it will be beneficial. There has been so little to offer our ALS patients as they courageously battle their disease that it is always exciting when a potentially new therapy might be on the horizon.”
“Dexpramipexole certainly has this potential based on the Nature Medicine report,” he added. “It appears to be safe and well-tolerated as an oral medication. And the statistical analysis of the part 2 study suggests that patients receiving 300mg ‘significantly' benefited both in change from baseline and mortality compared to patients receiving 50mg.”
However, he added, the “numbers of patients (48 at 50mg/day;44 at 300mg/day) were extremely limited. ALS is well accepted as a heterogeneous disease, and imputing efficacy based on such a small study is premature. The authors claim that using patients from a 12-week multi-dose study of part 1 had no carry over into their part 2 study after the four-week washout. However, that is an assumption, and not proven.”
As in all studies conducted with a relatively limited number of patients, he explained, there is heavy reliance on multiple statistical analyses. “I am not a statistician, but I'm still concerned when the significance is listed as p=0.046 (in the abstract) and yet in the Fig 2 as p=0.07.”
“I'm in total agreement that the pilot data on dexpramipexole is encouraging and determination of efficacy needs to be based on a well-designed double-blind, placebo-controlled phase 3 study.”
“There is nothing for ALS patients, and it will really be exciting when results come from the phase 3 study. But the most important question is: does it work?”