A Potential New Weapon Against Alzheimer’s Disease

BOSTON—Providing glucose-deprived neurons with an alternative energy source may improve memory and cognitive function in patients with Alzheimer’s disease, according to findings presented at the 59th Annual Meeting of the American Academy of Neurology.

Reduced cerebral glucose metabolism occurs early in the course of Alzheimer’s disease, before symptoms and neuropathology. While neurons affected by this metabolic dysfunction can no longer use glucose, they can use ketone bodies as an energy source.

Therefore, researchers have developed a novel compound, ­AC-1202 (Ketasyn), which is meta­bolized to the ketone body b-­hydroxy­butyrate and is used by neurons in areas of the brain that are most affected by metabolic dysfunction.

THE CANINE MODEL

A preclinical study demonstrated improved memory following treatment with AC-1203, the veterinary version of AC-1202, in an aged canine model. According to the researchers, 8- to 11-year-old dogs show Alzheimer’s disease–like symptoms, such as hypometabolism, mitochondrial deficits, cognitive and behavioral changes, and neuropathology. Results of the trial revealed that, following administration of 1 or 2 g/kg of AC-1203 daily for 180 days, the dogs showed elevated serum ketone levels, improved learning and memory on a variety of cognitive battery tests, and increased daytime activities—typically, older dogs sleep during the day and wander at night.

“So then we moved on to our first clinical study,” said lead researcher Lauren C. Costantini, PhD. In this phase IIa, double-blind, single-dose, crossover study, AC-1202 was administered orally to 20 patients with mild to moderate Alzheimer’s disease. Results showed mild gastrointestinal adverse events; elevated serum ketone levels; and significantly improved Alzheimer Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) scores in apolipoprotein (APOE) e4–negative patients relative to e4–positive patients. In addition, b-hydroxybutyrate serum levels correlated with improved memory.

THE HUMAN MODEL

In the current phase IIb study, which was a randomized, double-blind, placebo-controlled, parallel, multicenter trial, 152 patients with mild to moderate Alzheimer’s disease received either AC-1202 (20 g orally) or placebo for 90 days, followed by a two-week washout period. At this time, patients were given the option to enter an open-label six-month extension study.

Participants were assessed at the time of screening and at baseline, as well as at days 45, 90, and 104 (during washout). Primary outcome measures included a change at day 90 from the baseline score  on the ADAS-Cog, as well as on day 90 on the Alzheimer’s Disease Cooperative Study–Clinician’s Global Impression of Change (CGIC).

Baseline characteristics were similar between the patients who received placebo and those who received AC-1202, with comparable ages, male to female ratios, and body weight. Mini-Mental State Examination scores ranged from 14 to 24 (average, 19.5). About half of the patients were positive for the APOE e4 allele. Approximately 80% of the patients were taking approved Alzheimer’s disease medications, which were maintained throughout the study.

The researchers used data from the intention-to-treat population of 140 patients, which revealed that AC-1202 showed a trend toward improved ADAS-Cog scores versus placebo at day 90 (0.26 vs 1.93, respectively). When patients were stratified by e4 variant, a significant treatment effect of AC-1202 was observed. At day 90, APOE e4–negative patients taking AC-1202 significantly improved in ADAS-Cog scores, compared with those taking placebo­ (-1.75 vs 1.61, respectively). Furthermore, APOE e4–negative patients showed a significant treatment effect in ADAS-Cog scores at day 45, compared with those who received placebo (-1.72 vs 3.05, respectively). Dr. Costantini reported a significant inverse correlation between plasma b-hydroxybutyrate levels and ADAS-Cog scores in APOE e4–negative patients. However, no difference was seen in ADAS-Cog scores between APOE e4–positive patients treated with AC-1202 or placebo. Furthermore, no significant difference in CGIC scores was observed between the two treatment groups, regardless of genotype.

THE POSSIBILITIES

Overall, AC-1202 appeared to be well tolerated. Most adverse events were mild to moderate, and the most common were gastrointestinal related—diarrhea, flatulence, dyspepsia, and nausea. These adverse events were similar to those associated with currently approved Alzheimer’s disease medications. Eight serious adverse events were seen in the AC-1202 group, while three were seen in the placebo group. The investigators noted that one serious adverse event was possibly related to the study medication. There was one death; however, the patient had a history of irritable bowel syndrome and multiple cardiac conditions, and the researchers concluded that her death was not related to the study medication.

Dr. Costantini concluded that AC-1202 could provide added benefit to patients with the APOE e4 allele who receive the current standard of care drugs. “The profound effect we see in the population without the APOE e4 risk factor supports the findings of an earlier study linking efficacy to a certain pharmacogenomic profile,” she said. “It also provides further ­evidence of the link between Alzheimer’s disease and glucose metabolism.” She also suggested that AC-1202 might provide a new approach to treating other neurodegenerative disorders characterized by neuronal hypometabolism.        

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