Accera, a Broomfield, Colo.-based biotechnology company, discussed plans this week to commercialize a first-in-class medical food product to treat Alzheimer’s disease, called Ketasyn, that is particularly effective in patients with polymorphisms in their APOE genes and insulin-degrading enzymes.
Following initial clinical trial results, the company has concluded that the disease “may effectively be thought of and treated as diabetes of the brain.”
In a statement, Accera cited recent research from Brown University that challenges conventional wisdom that Alzheimer’s disease is caused by the accumulation of amyloid beta plaques in the brain. Specifically, the Brown study found that insulin resistance in murine brains “gives rise to some of the behavioral and pathological symptoms” of Alzheimer’s disease.
Alzheimer’s disease “may therefore be thought of as brain-specific ‘type 3 diabetes,’ an idea that is further supported by brain images of AD patients showing decreased glucose metabolism,” the company said.
Food for Thought
Type 2 diabetes is marked by insulin resistance and the resulting inability to absorb glucose. Studies have also shown that the brain cells of Alzheimer’s patients become resistant to insulin, and the resulting lack of glucose to the brain can cause memory loss, impaired cognition, and brain shrinkage.
Ketasyn, also known as AC-1202, is an orally administered liquid compound that provides glucose-deprived brain cells an alternative energy source, according to Accera.
According to the company, the liver converts Ketasyn into ketone bodies that the “brain cells can use for energy even when their ability to metabolize glucose is impaired.”
In a study conducted with the University of Washington in 2002, Accera researchers used gene sequencing to determine Ketasyn’s efficacy in a subgroup of patients lacking the APOE4 genotype. APOE4(-) patients comprise approximately 50 percent of the Alzheimer’s population.
Accera validated this initial study in a Phase IIb trial, a prospective study of 152 patients that looked at how individuals without the APOE4 genotype and 10 other polymorphisms responded to the drug. In this study, researchers determined that patients with variations in IDE, which occurs in 95 percent of Alzheimer’s patients, also responded particularly well to Ketasyn.
The study also confirmed Ketasyn’s safety and efficacy as measured by an improvement in ADAS-Cog scores, the US Food and Drug Administration’s gold standard for measuring efficacy in cognition and short-term memory.
“When we looked at the combination of APOE4(-) and IDE, we saw an enormous jump in response,” Accera CEO Steve Orndorff told Pharmacogenomics Reporter this week. “So, those patients who had these markers saw better than a five-point improvement in ADAS-Cog scores. Those patients with those two polymorphisms represented almost 40 percent of patients in the study.”
According to Orndorff, a five-point improvement in ADAS-Cog scores is a 50 percent improvement in efficacy over Alzheimer’s drugs like Pfizer’s Aricept, which improves scores by as much as 2.5 points.
These studies further confirmed Accera’s approach to treating Alzheimer’s as a form of “type 3 diabetes.” According to the company, other studies showed that Alzheimer’s patients lacking the APOE4 genotype respond positively to insulin-sensitizing drugs and to direct exposure to insulin, while patients expressing the APOE4 genotype showed little or no response.
Accera plans to initiate a Phase III multi-center clinical trial in early 2008 to study the effects of Ketasyn in APOE4(-) patients with mild-to-moderate Alzheimer’s disease. The study, which is slated to end in early 2010, will use the ADAS-Cog index to asses the drug’s safety and efficacy, as well as determine the role of insulin regulation in Alzheimer’s disease.
In the summer of 2008, Accera plans to submit an application for Ketasyn to the Center for Food Safety and Applied Nutrition, one of six FDA centers responsible for regulating medical food products (see sidebar).
Despite Ketasyn’s promising efficacy in patients who are APOE4(-) and have polymorphisms in IDE, the company plans to market the product in the general Alzheimer’s population.
“AD may therefore be thought of as brain-specific ‘type 3 diabetes,’ an idea that is further supported by brain images of AD patients showing decreased glucose metabolism.”
While Accera considered putting information in Ketasyn’s label restricting its use in the genetically-targeted population, the company decided against doing so after an open label extension of its Phase IIb study revealed that APOE4(+) patients eventually responded to the product.
“We think that there is still room for improvement for our product so that we can address both the APOE4(+) and APOE4(-)” populations, Orndorff said.
Although Accera is not required to submit materials regarding Ketasyn to the FDA’s Center for Drug Evaluation and Research, Orndorff said that the company will still turn in materials to that division of the agency to “maintain transparency.”
According to the company, Ketasyn differs from other marketed drugs for AD by allowing doctors to treat Alzheimer’s disease earlier. Currently, the company said there are no marketed medical food products for AD, and marketed AD drugs target production and clearance of amyloid beta plaques.
With Ketasyn, Accera is trying to treat Alzheimer’s earlier by targeting an earlier event.
“Declines in glucose use are visible decades before there is extensive amyloid deposition and decades before clinical signs of dementia are evident,” Samuel Henderson, Accera’s executive director of research, said in a statement. “We hope that our early intervention in this process will have a significant impact on the disease.”
Accera has other small-molecule compounds in its product pipeline for various neurodegenerative diseases including Parkinson’s disease and Huntington’s disease, for which the company is conducting genomic studies.