Lou Gehrig’s disease is a rare but devastating illness with no satisfactory treatments and a typical survival period of only about five years after diagnosis. But precisely because it’s so dire, drug developers have been scrambling in recent years to test the possibilities of new treatments for the neurodegenerative disease, whose formal name is amyotrophic lateral sclerosis.
Now experts in the ALS field are eagerly anticipating clinical trial updates over the next year or so from large companies and small ones, including two in the Bay area: Cytokinetics (NASDAQ: CYTK) of South San Francisco and Neuraltus in Palo Alto.
Drug developers see an unmet need among patients with Lou Gehrig’s disease—a commonly used term for ALS that refers to one of its most prominent victims, the legendary New York Yankees batter who died in 1941. Only about 30,000 Americans are living with ALS in a given year, and about 5,600 are diagnosed annually. That limits the market size for any new treatment, but the FDA offers incentives to drugmakers who tackle orphan diseases that affect fewer than 200,000 people in the United States.
Both Cytokinetics and Neuraltus have recently moved forward with plans for a new round of clinical testing on their experimental ALS drugs. Both companies detected encouraging signs of possible benefits of their drugs in earlier trials. But both small companies need to conduct larger trials to see if those benefits can meet the standard of statistical significance. Neither drug is an attempted cure for ALS, whose cause is not fully understood. But the companies hope to delay its debilitating effects—a steady decline in nearly every aspect of normal physical functioning, from speaking and swallowing to walking and breathing.
“It’s the most horrible disease I think I’ve encountered,’’ says industry veteran Robert Blum, the CEO of Cytokinetics. Patients lose the ability to move while their thinking ability is left intact. “They become prisoners in their own bodies.’’
Because the deterioration is rapid enough to be noticeable from one month to the next, researchers can gauge whether some drugs are making a difference by testing them over a relatively short period of time. Short trials cut down the expense of developing a new drug—an important consideration when financing is tight.
In late October, Cytokinetics opened its Phase IIb trial of tirasemtiv, an agent designed to increase the response of skeletal muscles to nerve impulses like those sent by a person’s brain to lift an arm. Trial subjects will receive the drug for three months. Blum says he expects to have data by the end of 2013. “We believe, based on the mechanism of action, that three months is ample to show an effect,’’ Blum says.
At present, the drug used by about half of ALS patients in the United States is Sanofi-Aventis’s riluzole (Rilutek), which was approved by the FDA in 1995. The drug improves survival times by a few months. But new discoveries about genes associated with ALS have stimulated a search for medicines with greater benefits, says Steve Perrin, CEO of the ALS Therapy Development Institute, a non-profit biotechnology research center in Cambridge, MA, that collaborates with drug companies on ALS studies.
“That has enhanced our knowledge of what might be the druggable targets,’’ Perrin says. His institute collaborates with drug companies on ALS studies.
US sales of riluzole have been estimated at $40 to $50 million. But Perrin says the US market could approach $1 billion for a new drug that could substantially delay the loss of muscle function in ALS patients, or improve survival times. Judging from pricing patterns seen in new drugs for multiple sclerosis, Perrin says, an effective ALS drug might command about $50,000 for a year of treatment.
Among the most-watched of the ALS drug development programs, the first peek at data is expected by early 2013 from Weston, MA-based Biogen Idec, which has completed a 900-patient Phase III trial of its drug dexpramipexole. In a Phase II trial, there were signs that the experimental drug could slow the decline of function and extend survival. Dexpramipexole is designed to bolster the efficiency of the energy-manufacturing units called mitochondria in motor neurons. Biogen Idec licensed the compound from Knopp Biosciences of Pittsburgh, PA.
Perrin says the prospects of other ALS contenders such as Cytokinetics won’t be dimmed if Biogen Idec announces favorable Phase III data on dexpramipexole. ALS is a complex disease that is probably caused by multiple factors, and the various drug candidates work through different mechanisms, he says. Just as in multiple sclerosis, there could be a market for a number of new drugs for ALS, Perrin says.
“I would imagine that one drug isn’t going to solve all of it,’’ Perrin says.
Perrin’s institute is helping Novartis in studies of an ALS drug candidate, fingolimod (Gilenya), and he anticipates data on that drug in mid-2013. The drug is already approved to treat multiple sclerosis. The compound works by curbing the activities of immune system cells that can cause nerve damage, according to PubMed Health. Fingolimod, an oral capsule, may substantially slow the heartbeat, so patients take it in a medical facility where they can be observed for at least six hours.
Cytokinetics is pinning its hopes on observations from two Phase II trials whose main purpose was to establish safe dosing procedures for tirasemtiv. But the results, reported in April, also suggested that tirasemtiv might slow the decline of physical functioning and preserve the capacity to breathe. An analysis of the trial results also hinted that at the higher doses tested, 250 mg and 375 mg daily, some subjects might get a bit better than they were before treatment began.
If that pattern proves to be statistically significant in the ongoing Phase IIb trial in 400 subjects, Cytokinetics may seek FDA approval based solely on that new data, Blum says.
“If at the end of three months, patients are doing better than their baseline, we think that would make a compelling case for single study approval,” Blum says.
ALS patients usually decline at a rate of about 0.92 points per month on a 48-point scale used in an evaluation tool called the ALSFRS-R, or ALS Functional Rating Scale, revised form. The scale assesses changes in 12 major areas of activity, including ease of walking and speaking. After three months without treatment, a typical patient’s score would decline by 2.7 points, Blum says. Cytokinetics is hoping to reduce that number.
In the Phase IIb trial, the tirasemtiv dose will be gradually elevated to 500 mg a day for subjects who are not in the control group given a placebo. The daily amount of tirasemtiv will be split into two doses of 250 mg to minimize the dizziness some trial subjects have experienced in their first week taking the drug, Blum says.
Cytokinetics, which finished the third quarter with $81.2 million in cash and cash equivalents, can fund the $30 million Phase 11b trial itself, according to the public company’s statements. In June, Cytokinetics raised $60 million through sales of common stock, convertible shares and warrants.
But the South San Francisco company, founded in 1997, is looking for a partner for tirasemtiv and its entire program in skeletal muscle activation. That drug mechanism could prove useful in maladies in addition to ALS, such as the muscle weakening that comes with aging, AIDS, cancer, and muscular dystrophy, Blum says.
Cytokinetics’ share price dropped below the Nasdaq exchange’s minimum of $1 this year, triggering a June warning that the stock might be delisted if the price doesn’t come back into compliance by Dec. 17.
Neuraltus, a private company that began operations in 2009, intends to begin a Phase III trial of its ALS drug candidate by the second half of 2013. But it must find a partner, says CEO John Walker.
Neuraltus sees promise in its investigational drug NP001 based on the results of a Phase II trial in 136 subjects with ALS. A study analysis released Oct. 29 showed signs that the compound might slow or even halt the progression of ALS. That intriguing trend did not meet the standard of statistical significance, says Dr. Gil Block, chief medical officer of Neuraltus.
But a post-hoc analysis that included historical control data, and meetings with the FDA, encouraged the company to plan for a Phase III trial.
After six months of treatment with 2 mg of NP001 per kilogram of body weight, 27 percent of subjects either improved or did not decline on the ALSFRS-R scale, the post-hoc analysis of the Phase II trial indicated. By comparison, no decline was seen in 19 percent of subjects who received 1 mg of NP001 per kilogram, and in 11 percent of subjects receiving a placebo, Block said. NP001 is a small molecule given intravenously.
Walker says Neuraltus has recently started discussions with potential partners. The CEO says a partner willing to invest in the NP001 program could find out within six months whether the drug’s promising pattern will hold up and produce a marketable product. If the data were very strong, he says, the single Phase III trial might form the basis for a New Drug Application to the FDA by the end of 2015.
NP001 is designed to stop a cascade of damage to neurons caused when immune system cells called macrophages shift from their normal role and begin releasing toxic compounds. Block says the drug, which can moderate the body’s inflammatory response, has potential in disorders in addition to ALS.
Perrin says the increased research activity in ALS seems likely to turn up some new answers.
“For anyone working in the ALS field, it’s a real time of hope and promise,’’ says Perrin. “I wouldn’t have said that five or ten years ago.’’