BioPharma

The Phase 3 Alzheimer’s company few have heard of

Accera will soon deliver Phase 3 data on Alzheimer’s disease, so why has nobody heard of them?

Testing for ketone bodies

A ketone strip used to measure levels of ketone bodies in the patient’s system

In a field dominated by Big Pharma and clinical trials that cost tens of millions of dollars, one small private company has made it all the way to Phase 3 trials in pursuit of an Alzheimer’s therapy.

The company is Accera. Based in Boulder, Colorado, its approach is so painstakingly simple that the industry has largely overlooked its lead compound, AC-1204.

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The company had two lucky breaks, which, ironically have in some ways backfired in terms of awareness and credibility.

The first is that its active compound didn’t require lengthy clinical trials. As a result, many wrote it off as an unproven alternative therapy. The second is that Accera has now received hundreds of millions of dollars from Nestlé. It hasn’t had to raise money from investors, but that’s how many companies drive name recognition.

In January, MedCity News sat down with Accera CEO Charles Stacey to learn more about the science, its strategy and whether the company has a patent estate that could theoretically guard future success.

The approach
There are two major schools of thought when it comes to Alzheimer’s etiology; that either amyloid beta and/or tau tangles are responsible for the neurodegeneration that eats away at patients’ memories and selves.

But optimism is waning in those fields, as each and every drug based on that science has failed. There hasn’t been a successful Phase 3 clinical trial in Alzheimer’s disease in 15 years, Stacey noted. The most recent, Eli Lilly’s Solanezumab, failed to show efficacy in a late-stage trial last November, crushing hope once again.

“We know that amyloid is part and parcel of the disease; but is it a cause, is it an effect?” Stacey said. “If it is a cause, how far down the disease cascade is it?”

Accera approaches Alzheimer’s as a metabolic condition, following literature that shows metabolic deficits arise in the brains of Alzheimer’s patients some 20-30 years before symptoms arrive. If the cells are unable to process glucose they are effectively starved, leading to cell death and potentially triggering amyloid-beta deposits, Stacey explained.

It’s a plausible theory, said Andrew Budson, a professor of neurology at Boston University, an Alzheimer’s clinician and author of an upcoming book about the disease. But there are many others areas to investigate.

Recent research has suggested, for example, that the amyloid build-up could be the brain’s response to an infection. Others have dubbed the disease ‘type 3 diabetes,’ suggesting the metabolic deficits in the brain are the result of an insulin deficiency or resistance.

“It’s reasonable, but I wouldn’t believe it until I saw data,” Budson said of Accera’s metabolic approach.

Stacey hopes to deliver that data through two Phase 3 trials of AC-1204. The compound stimulates production of ketone bodies, an alternative fuel source that can be used by the brain when glucose aren’t available — or when they can’t be metabolized.

Ketone bodies are naturally produced in the liver when glucose are in short supply, such as after periods of fasting or if an individual adhere’s to an extremely low carbohydrate, low protein diet.

The ketogenic diet has been around since the 1920s as a clinically-validated therapy for pediatric epilepsy that cannot be controlled with drugs. More recently, it has become popular as a diet for weight loss and increased energy and focus.

“So our technology hypothesis is very simple, which is ‘Alzheimer’s patients can’t use glucose but maybe they can use ketone bodies, so can we provide them with an exogenous source of ketone bodies?’” Stacey said.

Many organizations, patients and families are already experimenting with a ketogenic diet as a way to control symptoms, (a quick Google search underscores how established that community is).

The problem with the ketogenic diet is that it’s very hard to adhere to. The menu is built around oils and fats; protein and carbohydrates are severely limited as the body can convert them into glucose.

It’s hard for healthy people to stick with. It’s not a nice proposition for an elderly patient with Alzheimer’s.

That’s where Accera comes in. The active compound in AC-1204 is derived from palm kernels. It contains medium chain triglycerides (MCTs), which stimulate ketone production in the liver without requiring glucose restriction. Coconut oil has the same effect, on a much smaller scale.

Crucially, if the therapy does work, Accera has a patent estate that covers the use of MCTs for the treatment of Alzheimer’s disease and a handful of other conditions. That should prevent a competitor from quickly rolling out an alternative ketogenic compound if the Phase 3 data proves successful.

The strategy

Accera has taken an unusual path-to-market, to say the least.

Its first product, Axona, was a generally recognized as safe (GRAS) medical food that was tested in Phase 2 trials. Accera commercialized the formulation as a powdered shake and began selling it in 2010.

The company chose to make it prescription-only to position it as a medical food, not an alternative therapy. That approach didn’t really work as planned. Without data, neurologists —including Budson — wouldn’t prescribe it.

“So we made a decision in 2014 that actually commercialization as a medical food wasn’t the path forward,” Stacey said. “It wasn’t making the most of a very exciting drug.”

Stacey was hired as the new CEO and a new development team was built to begin advancing the formulation as an investigational new drug (IND). The existing product was withdrawn from the market, with a few exceptions for existing patients.

Accera tweaked the formulation for the new clinical trials creating AC-1204. It is still sold as a packaged shake as the required dose is approximately 20 grams — far too much to fit into a capsule.

After re-engaging the FDA, Accera designed two sequential Phase 3 trials to determine the drug’s efficacy. The first has enrolled approximately 400 patients, who will be followed for 6 months. An open-label extension study will then run for a further 6 months to gauge response durability.

The trial is significantly smaller than standard Phase 3 Alzheimer’s trials, which often include over 1,000 patients. Accera can stay small, Stacey said, because the effect the company is targeting is substantial.

“In our Phase 2b program we showed almost a three and a half point change in the ADAS-COG score,” Stacey said. “That’s on top of the standard of care.”

Axovant, which is also in Phase 3 trials for Alzheimer’s, is pursuing a 1.5 point improvement on the ADAS-cog scale (Alzheimer’s Disease Assessment Scale – Cognitive Subscale).

That’s still very worthwhile and the two therapies could potentially work together — if both are approved. The point is that it’s too soon to write Ac-1204 off as a medical food with minimal benefits. However it gets there, a clinically-significant improvement for Alzheimer’s patients is desperately needed.

Accera expects to announce data from its first Phase 3 trial in March. All going well, a second pivotal trial would follow shortly after.

Photo: Andrew Brookes, Getty Images