Merck & Co. is putting the prevailing theory on the cause of Alzheimer’s to a test with two studies in thousands of people that may, once and for all, determine whether the amyloid tangles that grow in the brain spur the disease or are simply an outgrowth.
What it finds will be closely watched by its competitors, including Indianapolis-based Eli Lilly and Co.
Merck’s experimental drug, called MK-8931, reduces amyloid, a hallmark sign of the illness, by as much as 90 percent, an unprecedented effect. The new trials, announced this week following a three-month review in 200 patients, seek to enroll more than 3,000 people and will run from 18 months to two years.
If successful, the trials would reverse an unrelentingly negative trend. Since 1998, there have been more than 100 attempts to develop an Alzheimer’s treatment, and all have failed. Such a product may generate as much as $5 billion annually for Whitehouse Station, N.J.-based Merck, according to analysts, a boon for a company in the midst of eliminating one-fifth of its workers.
“Now we can get an answer on the amyloid hypothesis,” Darryle Schoepp, Merck’s vice president of neuroscience, said. “We will have the data that will tell one way or the other” whether slashing amyloid levels will slow the disease itself.
The allure of the Merck drug is clear. People with naturally elevated levels of amyloid, a protein that occurs in the body, are at much higher risk, research has shown. A genetic study from Iceland last year found those with a mutation that blocks the BACE enzyme, the target of Merck’s MK-8931, appear to be protected from the disease.
Works like scissors
BACE is an enzyme that works like scissors to release the sticky amyloid and create the characteristic plaques that build up in the brains of Alzheimer’s patients. Merck announced Dec. 10 that it will start approval studies of its BACE inhibitor.
“The rationale for this drug is about as good as it gets,” said Samuel Gandy, director of Mount Sinai Center for Cognitive Health in New York. “In the lab, BACE inhibitors have been among the most potent compounds for reducing the production of amyloid, thereby preventing formation of the nerve-cell- killing form.”
While Merck is moving forward with final trials, safety issues this year derailed similar drugs Lilly and Roche Holding AG of Basel, Switzerland. Those drugmakers have turned to different anti-amyloid therapies as they compete with Merck to become the first company with a treatment for the neurodegenerative disease.
History of setbacks
The history of Alzheimer’s treatment efforts tempers any excitement. Last year featured setbacks from the world’s biggest pharmaceutical companies, including Pfizer Inc. and Johnson & Johnson. Sanofi CEO Chris Viehbacher said his company won’t pursue therapies because the science isn’t advanced enough to justify the risks and cost to develop a drug.
More than 5 million Americans suffer with Alzheimer’s disease, and the number is expected to triple by 2050. The only drugs approved for the condition ease symptoms for a few months while the debilitating brain disease rampages on. Still, they generate more than $5 billion annually.
U.S. President Barack Obama and United Kingdom Prime Minister David Cameron have increased funding from their governments for research into the brain with the hope of finding an Alzheimer’s cure.
$1.3 billion to develop
Drugs usually need three phases of clinical trials to gain U.S. approval. Each study in the final stage for Alzheimer’s takes at least 18 months and costs $50 million to $100 million. The cost of finding a new medicine may top $1.3 billion, with the complexities of Alzheimer’s drug development pushing it to the high end of the range, according to industry research.
The earlier drug setbacks have caused some scientists and doctors to doubt a fundamental theory of Alzheimer’s: that amyloid plaque found in patients’ brains causes the disease. Others have argued the treatments tried weren’t strong enough or were given too late, once the plaque was present and the damage had been done. Merck’s studies are designed to resolve those issues.
“Amyloid-reducing drugs have failed so far, so this like others might only be useful for prevention and not for those who already have Alzheimer’s disease,” Gandy said. “That is yet to be seen.”
Lilly is taking the prevention approach with solanezumab after the experimental medicine failed to slow the condition in more advanced patients.
Success would be a boost for Merck, once known for its ambitious research. The company is firing 20 percent of its workers as it grapples with declining sales and faces setbacks to its drugs for heart disease, surgery, and osteoporosis. Chris Schott, a New York-based analyst for JPMorgan Chase & Co., estimates MK-8931 may generate in excess of $5 billion annually in peak sales, though he doesn’t include it in his models through 2020 because of the risk.
Moving the therapy into final-stage studies shows the scientific community and Merck remain committed to finding treatments for the disease, said Maria Carrillo, vice president of medical and scientific relations at the Chicago-based Alzheimer’s Association. MK-8931 is a new strategic approach to the disease and the company is targeting patients at an earlier stage, before the condition is diagnosed and when it may be more tractable, she said.
“We don’t have any way to treat or prevent this disease, which is one of the nation’s top 10 killers,” Carrillo said. “This shows it’s necessary to keep the research funded so we continue to have a pipeline and will see products become available.’”
The decision to continue MK-8931’s development after the safety review is an “incremental positive,” particularly after Lilly terminated a similar program, Schott wrote.
Alzheimer’s disease is definitively diagnosed only during an autopsy, based on finding the amyloid plaques in the brain. The first 18-month study of MK-8931 dubbed Epoch will look at as many as 1,960 patients with mild to moderate disease, a group that already has significant plaque buildup. The second two-year study called Apecs will be done in 1,500 patients at an earlier stage, with mild cognitive impairment and memory difficulties.
There’s no way around the large and expensive studies to get the answers when it comes to Alzheimer’s disease, Merck’s Schoepp said. There aren’t any early markers of response, such as a shrinking tumor or falling blood pressure levels, to suggest a treatment is working, he said.
“You have to have a lot of faith you’re testing something that has validity,” Schoepp said. “The field needs to develop tools so you can do small studies earlier that get an answer.”
The potential benefit to the health-care system would be enormous if the drug just delayed the relentless decline from the disease. The cost of caring for people with dementia is already $109 billion a year, topping heart disease and cancer, according to a study published in April in the New England Journal of Medicine.
The odds aren’t in Merck’s favor. More than a decade ago Elan Corp. halted a study that stimulated antibodies to attack amyloid plaque after the therapy caused brain inflammation. The shot cleared the plaque, though it didn’t slow the disease.
While early data for MK-8931 suggests it is safer than rivals, other concerns may crop up during the larger tests, said Mark Schoenebaum, an analyst with International Strategy & Investment Group LLC. The drug also has to prove it works.
“We know from prior data that Merck’s BACE inhibitor profoundly lowers amyloid beta levels, but the expert community is split on whether or not that will matter for patients,” he said. “From a stock perspective, there is virtually nothing in Merck models for this molecule.”
Company executives are aware of the challenges.
“At some point in this business, you have to be going for game-changing therapies,” CEO Kenneth Frazier said in May. “We know that we’re studying a compound and we’re also trying to prove a fundamental hypothesis at the same time. That makes you really try to be reserved a little bit, but I’ve got to tell you, behind all of those sort of intellectual comments is a very visceral excitement that this could be the kind of compound that changes the world.”