Summary: Results of a clinical trial of Axona show the medical food may be an effective treatment for people with mild to moderate Alzheimer’s, at least for those who don’t have the APOE4 genetic variation. Accera is planning a larger trial to confirm these results.
The company is also planning an imaging study to try to prove that treatment with Axona changes the metabolism of certain areas of the brain, and that those changes are linked with improvements in cognition. If successful, Accera could be among the first to show that changes to a “biomarker” reflect real changes in memory and thinking.
I’ve written before about Accera’s Axona, a medical food available by prescription for people diagnosed with mild to moderate Alzheimer’s. The theory behind Axona is that if brain cells aren’t getting or using enough glucose, you can substitute ketone bodies for glucose. A ketone body is a substance created when fats are broken down in the body. Axona increases the level of ketone bodies in the blood, and in theory, provides an alternate fuel for brain cells.
Last week, I talked with Steve Orndorff, President and CEO of Accera, to get an update on his company’s product. Data from an initial trial of Axona have now been published, and the results are encouraging enough for Accera to plan a larger clinical trial, he says.
At the end of the three month trial there was a modest, but statistically significant difference on ADAS-Cog test scores (3.36 points out of 70) between those taking Axona and those receiving placebo, but only for trial participants who did not have the APOE4 genetic variation.
Not As Effective for Those with the APOE4 Genetic Variation
For the three month trial period, there was no difference in scores of the treatment group versus the placebo group for participants with the APOE4 variation. Does this mean that people should be tested for the variation before a doctor prescribes Axona for them? Not necessarily, Dr. Orndorff says. Unpublished results of a six month open label extension show that APOE4 positive participants who took Axona for the full nine months stabilized their ADAS-Cog scores, instead of showing the expected decline. [APOE4 negative participants continue to improve.] “Based on that observation, there is the potential that E4 positives might eventually respond to Axona,” he says. “But this is just a hypothesis. So we put full data for both E4 positives and negatives in Axona’s package insert and encourage physicians to decide on a case by case basis.”
More Study Needed
Dr. Orndorff says he views the trial as comparable to early Phase 2 clinical trials of other Alzheimer’s treatments, especially early Aricept studies, in terms of measuring safety and efficacy. The Axona results on the ADAS-Cog for all APOE4-negative participants are actually a little better than those in some cholinesterase inhibitor trials.
However, as with many recent Alzheimer’s trials, the actual numbers involved are small when you start looking at sub-groups. With smaller sub-groups, there is greater variability (and so less reliability) because a small number of extreme results can greatly affect the average result. In this trial, 55 participants were APOE4 negative, and of those 29 received Axona and 26 received the placebo. An analysis after the trial showed APOE4-negative participants who were able to take Axona exactly as instructed may have improved even more over the placebo group, but there were only sixteen people in this sub-group.
Still, the results are encouraging, Dr. Orndorff says. “While many would view these sample sizes as small, the data was statistically significant nonetheless. Even though the N sizes [number of participants] were small, there was a strong signal with this product. But it bears more study, and certainly bears more longitudinal study.”
This trial was also meant to test the safety of Axona. Early in the study, “gastrointestinal events” were reported more frequently among those taking Axona than among those on placebo, with almost 10 percent of those taking Axona reporting severe diarrhea. This went down to three percent when participants were told to mix Axona or the placebo with Ensure (a nutritional shake), rather than water, milk or juice. A few participants taking Axona had increased signs of kidney problems in blood tests. The Nutrition and Metabolism journal article about the study notes that these may have been due to dehydration or to health problems unrelated to Axona.
Larger Clinical Trial Planned
Based on the results of this study, Accera is planning a larger clinical trial to test Axona’s safety and efficacy in people who do not have the APOE4 genetic variation. Accera executives hope the data confirms the positive comments they’ve received from patients and doctors. “We’ve had anecdotal reports from patients and physicians that it makes a significant difference in the quality of life for some patients -- head and shoulders above what is reported for current Alzheimer’s disease drugs,” Dr. Orndorff says. “It reinforces our belief that we’re on to something that could make a difference for patients.”
Positive comments or not, Axona faces the same challenge as other potential treatments: the large Phase 3 trial needed to confirm that the treatment is effective will be lengthy and expensive. This is where “biomarkers” (physical or biochemical characteristics that are signs of disease) come in.
Scientists worldwide are working towards the ambitious goal of being able to use Alzheimer’s biomarkers as indications of problems in the brain before symptoms appear. In addition, they hope to be able to use biomarkers as “surrogate outcome measures.” This means they want to prove that a treatment that changes a biomarker is actually treating or preventing disease [see my previous post on “preclinical Alzheimer’s” and biomarkers]. Then, at least in theory, they can substitute that biomarker for cognitive tests as proof that a treatment works. If they achieve this goal, it could greatly change how Alzheimer’s is diagnosed and treated. It could also reduce the cost and length of clinical trials by screening for participants most likely to benefit from a potential treatment, and perhaps by eliminating the need to run a trial long enough so the placebo group has a clear decline. Various biomarkers have been proposed, but at this point, none have been validated.Accera is moving forward with its own biomarker study. “We want to demonstrate through imaging and other measures of brain metabolism that ketones are used in these areas of the brain, and that usage of ketones is linked to cognitive function,” Dr. Orndorff says. The company should be able to report results of this study in nine to twelve months. If successful, Accera could be among the first to show that changes to a biomarker reflect real changes in memory and thinking.