Two highly respected neurologists, both of whom direct MDA/ALS centers, can disagree — and they’ve done so in back-to-back opinion pieces in the November issue of Muscle & Nerve. The controversy is over whether or not to use drug "cocktails," combinations of pharmaceuticals, each of which hasn’t necessarily proven itself alone, in ALS clinical trials.
Jeffrey Rosenfeld, who directs the MDA/ALS Center at Carolinas Medical Center in Charlotte, N.C., is conducting such a multidrug trial. (It’s now closed to enrollment, with results expected this year.)
In his study, participants take eight drugs from five drug classes. There’s no placebo (inactive substance) group, but patients take the drugs using different delivery systems, such as from separate bottles or partitioned boxes.
The study’s purpose is to look at safety and the feasibility of giving people 32 pills a day, either by mouth or via a gastrostomy tube, Rosenfeld said, and not to measure efficacy.
No Straight Lines
Rosenfeld says multidrug combination trials are needed in ALS because the pathways that lead to the death of muscle-controlling nerve cells (motor neurons) are "very complex and not necessarily in straight lines."
He adds, "There’s more than one way for motor neurons to degenerate. If several mechanisms leading to cell death are in place concurrently, if you were to interrupt any one pathway, it’s still likely that there are other, parallel pathways by which cells could continue to die."
In addition, Rosenfeld notes, ALS is "perhaps not just one disease. We worry a lot about the fact that patients with different types of motor neuron disease may have different underlying physiology."
Aiming at multiple targets, he says, is necessary when you know there’s more than one involved and you don’t know which one is the most important in each patient.
"It’s reasonable to say that the chance of hitting meaningful targets certainly is greater when you intervene at multiple levels," he says. "It would be incredibly optimistic to think that any one drug would have a specific enough, potent enough benefit to create the kinds of treatment effects that we look for in available drug trials."
On the Other Hand…
On the other side of the drug cocktail question is Jeremy M. Shefner, director of the MDA/ALS Center at State University of New York Upstate Medical University in Syracuse.
"Scientifically it has no merit," Shefner says of current drug cocktail studies in ALS. Scientists can’t tell which drug was responsible for any benefit detected in such a study, although he admits that may not matter to everyone. Still, he says, "Patients want to know what works; they don’t generally want to take a zillion things."
Shefner says the question of whether ALS will ultimately be treated with combinations of drugs is entirely different from whether combinations of unproven drugs should be tested now.
"If you’re asking if it’s very likely that ALS will be treated by drug combinations, yes, of course, I’m a proponent of that," he says. "But if the question is whether people should take a bunch of things that show no efficacy in human beings" his answer is different. "You don’t just combine them," he says.
Shefner says that, although a justification for multiple drugs in ALS has sometimes been that such combinations are used in cancer treatment, he thinks this comparison has no meaning for the current state of affairs in ALS.
"We do treat cancer with multiple agents that have synergistic effects," he says, "and I suspect that we will be treating ALS with synergistic agents. But the way cancer drugs have evolved has never been to put drugs with unknown effects together. Individual drug activity has been demonstrated and then added to a previous treatment."
In his editorial, Shefner notes that combinations of drugs can expose patients to increased risks of side effects, the possibility that drugs will counteract and nullify each other’s effects, and increased costs for treatment.
For Rosenfeld, the possible benefits outweigh the risks. "It’s a little bit counterintuitive, the premise that underlies multidrug therapy, but it’s that drugs that individually do not show benefit might show benefit when you put them together."
Given the many disappointments in ALS clinical trials, it’s time, he says, to "think out of the box.