Drug development doesn’t get much more depressing than the so-far futile search for a lasting treatment for amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease. More than 20 experimental drugs have failed in clinical trials, the most recent being Biogen Idec’s (NASDAQ: BIIB) closely watched dexpramipexole. Dex, as it is often called, made it all the way to a 943-patient, Phase III trial, one of the largest clinical trials yet in this disease, but still did not show any benefit for patients, and Weston, MA-based Biogen announced last week that it will drop all development of the drug.
So what lessons, if any, do all these flame-outs hold for the handful of drugs still in development against this deadly disease? Steve Perrin, CEO of the nonprofit ALS Therapy Development Institute in Cambridge, MA, has one suggestion, but it won’t be of much comfort to companies struggling to finance and recruit patients for clinical tests for this rare and deadly disease. Nor is it likely to get Big Pharma companies to reach into their deep pockets and fund drug development for a disease that seems to produce nothing but heartache. Perrin posits that mid-stage Phase 2 trials must be larger, and longer, than they are now if companies want to determine the best way forward in a Phase 3 trial.
“All of the drugs that have failed recently in Phase 3 looked promising at Phase 2. Dex slowed down the disease in over 30 percent of the patients in the Phase 2b trial,” Perrin told me in a phone interview. “The lesson here is that we need to change the design in Phase 2,” especially if companies plan to test the drug in different doses. There were only 102 patients in Biogen Idec’s Phase 2 trial; dividing a group this small into two or three subgroups means the cohorts “are just not big enough to reach significant conclusion about the data,” Perrin said.
The problem is, ALS affects a mere five out of every 100,000 people worldwide, and there are only 30,000 people living with the
disease in the U.S., making it exceedingly difficult to recruit enough patients to enroll in a large Phase 2 trial—especially if multiple companies are chasing after those same patients for their trials. Currently there are at least five drugs in Phase 2 trials for ALS; if each enrolled a few hundred patients, the available pool could quickly be depleted.
There is also a good news/bad news development in the treatment of the disease—steady improvement in the standard of care means that trial participants on placebo are doing better than expected, raising the bar for experimental drugs. “We have seen dramatic incremental improvements in patient care that have slowed down the disease in the last five years,” Perrin said. That means multi-year clinical trials may find that the level of improvement required by the time testing ends is higher than when the trial began.
That may have been part of the problem for olesoxime, developed by France’s Trophos. Trophos reported in December 2011 that olesoxime failed to show clinically significant improvement over a placebo in a Phase 3 trial of 512 patients in advanced stages of the disease. At this year’s Annual Symposium on Amyotrophic Later Sclerosis/Motor Neuron Disease, held in Chicago Dec. 5-7, the Parisian doctor who presented the results of the unsuccessful olesoxime study said that almost 70 percent of patients on placebo during the trial survived 18 months, compared with a 50 percent survival rate for patients in a 1996 ALS study, according to a report in the Alzheimer’s Research Forum.
The need for better treatments could not be more dire. ALS, often called Lou Gehrig’s disease after the revered New York Yankees first baseman who died from it in 1941, is a progressive neurological disease which attacks nerve cells that control muscle movement. Patients typically die within a few years of diagnosis. There is no known cause or cure, and the only drug on the market, Sanofi’s (NYSE: SNY) riluzole (Rilutek), was approved by the FDA seven years ago, and improves survival times by just a few months.
As for the other drugs in clinical trials, progress is a bit of a one step forward, two steps back dance. Neuraltus Pharmaceuticals of Palo Alto, CA, reported in October that its NP001, a drug that prompts certain immune system cells to protect rather than attack the central nervous system, failed to meet its clinical endpoints in a 136-patient Phase 2 trial. Nevertheless, the company said it will move the drug into a Phase 3 trial because an analysis after the trial ended revealed better results when the outcomes were combined with historical data of an unspecified number of patients on placebo—a very unusual type of data analysis for clinical trials.
Perrin said he wasn’t keen about the design of the NP001 Phase 2 trial, but he still agrees with the decision to keep testing the drug: “NP001 needs another shot with a larger trial. I wouldn’t throw it out.” He is more enthusiastic about tirasemtiv, an experimental drug from Cytokinetics (NASDAQ: CYTK) of South San Francisco, CA, that is meant to boost muscle strength by amplifying the response of muscles to nerve signals. As Xconomy reported in November, Cytokinetics started enrolling approximately 400 patients in a Phase 2b trial for the drug in October. “They are doing the right type of trial,” Perrin enthused. “This drug looks pretty exciting.”
Meanwhile, Perrin worries that the Biogen Idec failure will be a setback for the whole field of ALS research. He realizes that a larger Phase 2 trial would not likely have saved the drug, “but we would have known earlier that this wasn’t the right one. A lot of patient and financial resources were wasted.” The setback with dexpramipexole “is certainly not going to help drug development [for ALS]. If it were successful I think investment in the disease would have gone up.” Instead, he fears pharmaceutical companies will shy away from ALS because they will figure it doesn’t make sense to pour money into such a risky target.
But Biogen Idec isn’t quite ready to throw in the towel. At the JP Morgan Healthcare Conference in San Francisco on Monday, CEO George Scangos told investors that the failure of dexpramipexole “has not dampened our determination to do something about this disease. We continue to work on the biology to come forward with rationally designed compounds.” He highlighted the company’s $10 million investment in a research collaboration searching for new disease targets.
Perrin’s ALS Institute also continues to explore other approaches, and on January 8 announced a collaboration with to-BBB, a Dutch company, to develop potential treatments that can cross the blood-brain barrier, which can block drugs from reaching the brain.
Desperate patients can only hope that some of this research finally pays off.