Lilly stopped development of the pill in August after data showed it harmed patients instead of helping them. Even seven months after patients ceased the use of semagacestat, they still had more trouble with thinking, remembering and mental functioning than those who didn’t receive the medication, the Indianapolis-based company said today.
Semagacestat, which was in the last of three stages of testing usually needed for U.S. regulatory approval, was designed to block an enzyme called gamma secretase that’s tied to production of beta amyloid plaque, considered by researchers to be a main contributor to Alzheimer’s. The findings suggest Alzheimer’s research shouldn’t focus on the enzyme, said Eric Siemers, senior medical director for Alzheimer’s at Lilly.
Scientists should “very specifically target beta amyloid, and not target things like gamma secretase that do a lot of things besides having an effect on amyloid,” Siemers said in an interview at the at the Alzheimer’s Association International Conference in Paris, where the data was presented.
More insight on semagacestat may clarify whether other gamma secretase inhibitors, such as Bristol-Myers Squibb Co. (BMY)’s avagacestat, pose the same problem, said Marc Goodman, an analyst at UBS AG in New York.
“If you have a gamma secretase inhibitor, you need to think very carefully about these results,” Siemers said. He said he couldn’t comment on similar products in development, including the Bristol-Myers one, as he didn’t know them well enough. Not all gamma secretase blockers are alike, he said.
Lilly gathered information on the failed compound for 32 weeks after patients stopped taking the treatment.
“We wanted to understand what happened,” Siemers said. “Even though semagacestat didn’t work, we feel we moved the field forward in terms of our understanding of how you develop these compounds.”
The reasons for the failure may never be known, Siemers said. The dosing was right, he also said. Semagacestat had an effect on more than 50 proteins and the failure could have stemmed from an interaction with any one of them, he said.
About 36 million people worldwide suffer from the memory- robbing condition, according to the Alzheimer’s Association. By 2050, that number is expected to double. The disease, first described in 1906 by the German doctor Alois Alzheimer, destroys brain cells and makes it difficult for patients to think, remember and function. Current therapies, including Forest Laboratories Inc. (FRX)’s Namenda and Pfizer Inc. (PFE) and Eisai Co.’s Aricept, address only Alzheimer’s symptoms and don’t cure or slow it.
“If the semagacestat data points to a significant class effect, we would see risk to Bristol’s compound,” which is in mid-stage testing, Goodman wrote in a July 14 note to clients.
William Thies, chief medical and scientific officer at the Alzheimer’s Association, doesn’t think the Bristol-Myers drug will necessarily be affected by the findings.
“We don’t know yet” whether this will have an effect on similar products “but the Lilly compound was a very early gamma secretase inhibitor and you would think that new ones would be more selective,” Thies said in an interview after the presentation. “Typically, when new drug classes are opened up, the first agents tend to be dirty and we recognize side effects that we can attack by changing the molecule slightly.”
The data presented today is preliminary, Siemers said. Lilly still has to review all the information as well as data from another semagacestat trial, he said.
“They did a great thing in modifying the trial to follow up on patients,” James Vornov, a neurologist who heads the central nervous system therapeutic area at Parexel International Corp. (PRXL) in Waltham, Massachusetts, in an interview after the presentation. “The data beautifully shows you can measure the decline” in patients, he said.
“Unfortunately, the drug had an effect in the wrong direction, but you could clearly see the change in the direction and once a drug will go in the right direction, we will know,” Vornov said. Semagacestat data has “increased the anticipation” for results from other gamma secretase inhibitors as well as from other amyloid-targeting drugs, he said.
The setback hasn’t deterred Lilly from Alzheimer’s research, Siemers said.
“This is the first time that a compound, which is amyloid- related and designed to be disease-modifying, has had an effect on cognition,” he said. “We did get enough compound into the brain to have an effect. It tells us that our strategy, for how we developed it, is on the right track.”
Eli Lilly is running two final-stage trials of another Alzheimer’s treatment, solanezumab, which works against beta amyloid by trying to clear it through the bloodstream. The U.S. drugmaker needs new products to replace its schizophrenia treatment Zyprexa and other of its top-selling medicines facing generic competition.
The company expects late-stage results for solanezumab in the third quarter next year, Siemers said. Lilly has two other Alzheimer’s compounds in clinical development, including a so- called BACE inhibitor in early-phase testing which is “looking quite good” so far, “with robust reduction of beta amyloid” and “good” tolerability, he said. The drugmaker also has several projects in pre-clinical development, Siemers said.
“Even though as a company we’ve been fairly focused on beta amyloid, we also have very early work in tau,” Siemers said, referring to another protein found abundantly in abnormal form in the brains of patients with some dementias including Alzheimer’s.
“None of that is in the clinic yet, but we certainly have an interest” in tau research, Siemers said. “We haven’t put all our eggs in the amyloid basket.”
Recent study failures, including the semagacestat one, have called into question the leading Alzheimer’s discovery strategy being pursued by companies such as Lilly, Pfizer and Johnson & Johnson (JNJ): the theory that amyloid, sticky wads of protein accumulating in the brain are the driving force of the debilitating disease.
“My problem philosophically is that nobody knows how Alzheimer’s starts and progresses, therefore the chances of hitting on a drug are very slim,” Les Funtleyder, a portfolio manager and health-care strategist at Miller Tabak & Co. in New York, said in e-mailed comments. He has no estimate for Lilly’s solanezumab as he doesn’t think the treatment will be approved.
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