South Side facility working on treatment for Lou Gehrig's disease

It is clear to Neil Alexander that his amyotrophic lateral sclerosis is progressing.

In the little more than two years that have passed since the 48-year-old was diagnosed with the disease more commonly known as ALS or Lou Gehrig's, his hands have weakened, his lung capacity has declined and he is beginning to have difficulty with his speech.

Over the past few months, his legs have gotten "significantly weaker," so that he now walks with a limp, has trouble using stairs and has fallen several times, he said. He knows the fatal disease is progressing through his body, but for more than a year, he believes the progression slowed.

The reason, he thinks, is dexpramipexole.

From October 2011 through January 2013, Mr. Alexander was one of nearly 1,000 ALS patients enrolled in a late-stage clinical trial of dexpramipexole, a compound investigated in earlier trials by the South Side's Knopp Biosciences.

Biogen Idec, the Weston, Mass.-based company that ran the latest trial, announced in January it was discontinuing development of the drug, stating that the trial showed dexpramipexole to be ineffective in treating ALS. "The evidence for us is unequivocal," said Biogen spokesman Dan McIntyre.

Living with Lou Gehrig's disease

  • This is one in an occasional series of stories profiling Neil Alexander of O'Hara, who was diagnosed in 2011 with ALS, also known as Lou Gehrig's disease.

Here in Pittsburgh, however, Knopp wants to continue exploring the drug. The company believes its analysis of the Biogen results shows some ALS patients may indeed benefit from dexpramipexole, often referred to simply as dex.

Into this disagreement about dex enters Mr. Alexander, an O'Hara lawyer and financial services executive. He believes dex slowed the progression of his ALS, and now, two years into a disease that on average leads to death three to five years after diagnosis -- and with a wife and two children ages 11 and 9 -- he is racing against time to get back on it.

ALS, a disease that is devastating for patients, has been difficult for researchers as well.

Its causes are unknown, and an effective treatment remains elusive. About 30,000 people in the United States have ALS, which attacks the body's motor neurons, eventually causing a person to lose control of muscle movement. Paralysis and difficulty swallowing and breathing follow.

Rilutek, or riluzole, is the only available drug treatment for ALS. Approved by the FDA in 2005, it extends survival by two or three months. The worldwide search for a better or additional treatment has continued, including at Knopp.

Researchers at Knopp, formed in 2004 to discover possible treatments for ALS, have long been interested in dex, a compound identified by a University of Virginia researcher that may work by increasing the efficiency of mitochondria, which produce energy in the body's cells.

The company licensed the drug in 2006. Its Phase I trial, to determine the drug's safety in humans, and a two-part Phase II trial, to determine its safety in about 100 ALS patients, were both successful.

Phase II, completed in late 2009, also showed that dex had positive effects in preserving function and extending survival in ALS patients. And, in a finding that caught the attention of many ALS researchers, the trial indicated that patients who received a higher dosage of the drug did better.

It was "very promising," said Michael Bozik, president and CEO of Knopp. Biogen Idec agreed. In August 2010, the two companies announced they were entering a licensing agreement so Biogen could further develop dex.

Enrollment in the Phase III study dubbed "EMPOWER" started in March 2011, with 943 ALS patients at 81 sites in 11 countries eventually joining the placebo-controlled study for at least a year. One of those patients was Mr. Alexander, founder with his wife, Suzanne, of, a fund of The Pittsburgh Foundation.

The trial was designed to determine, among other endpoints, whether the drug was effective in slowing function loss and extending survival. But on Jan. 3, Biogen Idec announced that the Phase III trial had failed to reach any of its endpoints. Subsequent analysis showed the same lack of benefit in more than 40 patient subgroups, said Mr. McIntyre of Biogen. "There was absolutely no benefit to anybody at all," he said.

In its initial news release, and in subsequent publications, presentations and interviews by its business and medical leaders, Biogen reiterated its disappointment in the results, stating that although it would continue to research ALS and potential treatments, it planned to discontinue development of dex in ALS.

At Knopp, and throughout the ALS community, the news came as a blow.

"It was devastating to think that our expectation that we might have a product to slow the progression had been set back significantly," said Thomas Petzinger Jr., Knopp's executive vice president for business development and public affairs. But the company was surprised and puzzled by the difference between the two studies, he said.

Knopp now believes that for a certain subgroup of patients -- those taking riluzole, the patients whose ALS was affecting more parts of their body at the start of the trial and those who likely had quickly progressing ALS -- dex's benefit was statistically significant.

Knopp's leadership wants to explore the hypotheses that dex might work for some ALS patients, that it could work better at a higher dose, and that dex may reduce the rate of creatinine loss in the blood. Creatinine is a waste product produced by the muscles, and since the muscles atrophy in ALS patients, Knopp believes the chemical may be useful as a biomarker, or measure of progression, in a disease for which there are currently no such markers.

There are other researchers who agree that dex is still worth exploring. Hiroshi Mitsumoto, director of the Eleanor and Lou Gehrig MDA/ALS Research Center at Columbia University in New York and an investigator in the EMPOWER study, said the benefit of a drug to a smaller subset of patients may have been diluted in a large study.

"Everyone was disappointed with dex, yet this is not the final answer. I think we should explore," he said.

Merit Cudkowicz, director of the MDA ALS Clinic at Massachusetts General Hospital and principal investigator for the EMPOWER study, said researchers should be cautious about interpreting trial results because "the more times you look, the more times you might find things by chance that aren't real." But, she said: "Given that it's such a serious illness, you never want to throw away a drug that might help even a small subset of patients."

Knopp wanted Biogen to continue exploring dex, and the two companies are currently engaged in litigation over what Knopp alleges was breach of contract and wrongful termination.

Next year, Knopp intends to resume its study of dex. The company is currently waiting for the necessary dex IND, which stands for investigational new drug. Biogen has said it is ready to transfer the IND, and Dr. Bozik expects to hold it by the end of the summer. Once Knopp holds the IND, Mr. Petzinger said, the company plans to provide dex to patients in the Phase III study who ask for it.

Mr. Alexander, however, decided he could not wait.

Although he is not part of the specific subset that Knopp has identified, Mr. Alexander believes that dex, which he learned he was taking the entire trial, was slowing down his ALS and that his ALS has worsened significantly since he stopped taking the drug. He cites his decline on a scale used to measure rate of function in ALS patients, the drop in his creatinine levels, as well as his own observations that his body is weakening, especially in his legs.

From the start, Mr. Alexander has been considered a "slower progresser" compared to the general ALS population, said David Lacomis, co-director of the Center for ALS Research at UPMC and the doctor who diagnosed him in 2011. His progression is still considered to be "relatively slow," he said.

As for whether dex was working for Mr. Alexander, Dr. Lacomis, who was an investigator in the EMPOWER study, said, "I cannot say for sure in him."

To get back on dex, Mr. Alexander applied for an individual IND through Biogen. But his request, and an appeal made to Biogen through Knopp, were denied.

Biogen's response to Mr. Alexander's request, the only one they received, was a "difficult decision," Mr. McIntyre said. But, he said, Biogen believes dex has "no chance of helping and it comes with a non-trivial risk of harm," including the unknown risks of increased exposure.

"As difficult as it is not to approve this in any individual instance, we considered the consequences for all those who might receive dexpramipexole and to the larger community living with ALS," he said.

Dr. Lacomis said Mr. Alexander has had no adverse side effects from dex. This month, Mr. Alexander found another way to get dex, or, rather, a close substitite, from a Madison, Wisc.-based group that has what is called a "compassionate use" IND for the drug.

The treatment costs more than $2,000 a month and, perhaps because it is a slightly different substance than dex, Mr. Alexander has so far had trouble tolerating it.

"My goal is to get back on dex as soon as possible," he said.

neigh_city - region - health

Kaitlynn Riely: or 412-263-1707. First Published July 24, 2013 9:15 PM


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