Developing an effective treatment for Alzheimer’s disease has been a particularly elusive goal in drug development over the past decade and a half. No new drug for the neurodegenerative disease has been approved in the U.S. since 2003, and there are currently only five treatment options on the market.
“You have got the perfect storm – massive area of need, huge prevalence, and no new drugs. So it is a perfect storm for patients,” said Charles Stacey, CEO of Colorado-based biotech Accera, Inc.
Accera is one of three companies set to report Phase 3 data on drugs for Alzheimer’s disease later this year.
Stacey believes Accera’s unusual approach to addressing the cognitive and functional declines characteristic of Alzheimer’s could give it a chance to break the uninspiring trend of drug development in the space.
But Accera’s past attempt to market an earlier formulation of its now-drug candidate as a medical food ran into criticism, and the company eventually stopped marketing the product, casting some doubt on whether Accera can prove the efficacy of its new formulation.
Unlike most previous efforts by other companies, Accera is not targeting amyloid plaques—clumps of protein which build up outside nerve cells in the brain and are thought to be associated with the development of Alzheimer’s.
“We address a different mechanism in Alzheimer’s disease which has to do with the metabolic dysfunction of the brain,” said Stacey, speaking to BioPharma Dive at the 2016 BIO International Convention in San Francisco.
Stacey explained how AC-1204 targets the underlying metabolic deficit in the brains of Alzheimer’s patients, which are unable to properly metabolize glucose for fuel.
The human body typically relies on glucose as an energy source. But when glucose isn’t available in sufficient quantities, the body can also use fat reserves, breaking down those reserves into an alternate energy source called ketone bodies.
AC-1204 helps boost production of ketone bodies, which can be used by the brain as energy. For some people, however, high levels of ketone bodies can be harmful.
“All we are doing is leveraging what is physiological. This happens naturally but we are just helping that process. The idea is if you can restore metabolism, you can restore function and prevent the ultimate disease,” Stacey said.
Medical food to new drug?
Accera previously marketed Axona, a “medical food” similar in method of action to AC-1204 but with different components, as a treatment for Alzheimer’s. Medical foods do not require approval from the FDA, and are intended to be used for dietary management of a patient under the supervision of a physician.
Data from a Phase 2B trial of this earlier formulation showed improvement in patients with mild-to-moderate Alzheimer’s who did not have a specific gene known as APO-E4. Among those patients, Accera found Axona led to a 3.36-point difference in ADAS-cog score at 90 days, compared to patients taking a placebo. A larger 4.77-point difference had been seen at 45 days, according to the product insert for Axona.
ADAS-cog is a standard metric for evaluating cognition in Alzheimer’s patients, and a two- to four-point change is typically considered clinically meaningful.
While that difference in ADAS-cog score was statistically significant, there were only 55 patients tested who did not have the APO-E4 gene in the study, potentially limiting the relevance of the findings for a broader patient population.
Across all 152 patients in that trial, the difference in ADAS-cog score between the Axona group and placebo group was not statistically significant.
Stacey said the decision to initially market its product as a medical food was an attempt to reach patients sooner. But pursuing a new drug approval was always the ultimate goal, Stacey said.
In late 2013, however, Accera ran into trouble with the FDA, who issued a warning letter to the company over Axona’s classification as a medical food. In the letter, the FDA said Axona was “misbranded,” determining the product did meet the definition for medical foods.
“There are no distinctive nutritional requirements or unique nutrient needs for individuals with mild to moderate Alzheimer’s disease,” the FDA said.
The Alzheimer’s Association has also expressed concern about medical foods as a treatment for the disease, particularly as the lack of FDA approval means the data supporting such products has not undergone regulatory scrutiny.
A challenging pivot
After working in an advisory role as a board member, Stacey moved into the permanent CEO role last June and has overseen Accera’s shift in strategy towards pursuing a new drug approval.
Stacey said AC-1204, while sharing the same method of action as Axona, is different enough to clear the standard for an investigational new drug.
And in May, Accera completed enrollment in its Phase 3 study of AC-1204. It expects to read-out topline data in December. A second pivotal phase 3 study is tentatively planned for next year, mimicking the first phase 3 trial in size and endpoints but taking place internationally rather than solely in the U.S.
These trials are bigger—the current one has 414 patients enrolled—and look at patients who don’t have that EPO-A4 gene. Demonstrating a similar reduction in ADAS-cog score as seen in the earlier Phase 2 trial could give Accera’s prospects a significant boost, and better legitimize its unique approach.
Accera’s transition hasn’t come without costs, though. The company dropped staff after it stopped marketing Axona, going from over 100 employees to under 20. Stacey plans to double that number over the next 12 months and has moved the company to Boulder, Colorado to better take advantage of the life-sciences hub there.
Competition from Tau, Lilly
Accera could find itself with some new competitors by December, however.
TauRx, a spinoff from the University of Aberdeen based in Singapore, plans to announce data from its Phase 3 trial on July 27th at the Alzheimer's Association International Conference. The company has been tight-lipped about its drug, called LMTX, but raised $135 million in an equity financing last year.
And Eli Lilly could also report Phase 3 data on its Alzheimer’s drug, solanezumab, after a long and arduous development process. The trial will be unblinded sometime in the fourth quarter, and top line results will be reported after a database lock, according to the company.
Earlier this year, Lilly announced it changed the endpoints for the study, saying it would now only look at the drug’s effect on cognition. The move was particularly unusual as regulators will likely want to see both cognition and function studied as co-primary endpoints for mild Alzheimer’s disease.
Lilly is also working with AstraZeneca to advance their BACE inhibitor AZD3293 into Phase 3 trials for Alzheimer’s, after positive safety data was reported in April.
Stacey estimates there are a total of 11 drugs currently in development for Alzheimer’s.
However, even if Accera has some company, Stacey believes AC-1204 is a complementary product that can work with other drugs.
Stacey said Accera has ambitions beyond Alzheimer’s and envisioned the company could pursue other neurological conditions with a metabolic component, such as Parkinson’s disease. But before it can get there, Accera will have to clear one of the highest hurdles in drug development by proving AC-1204 can be an effective treatment for Alzheimer’s.
While its unique approach could be an advantage by side-stepping previous pitfalls, the high failure rate and challenging biology of the disease suggest a slam-dunk case for approval will be hard to come by.