Prescription Medical Food for Alzheimer's: A Novel Approach to Neurologic Disease

Although there are several drugs approved for the treatment of Alzheimer’s disease (AD), pharmacotherapy generally can delay but not prevent disease progression and cannot reverse symptoms. Therefore, patients, caregivers and physicians continue to seek interventions that can provide additional benefits to patients with AD and potentially contribute to maintenance or improvement of quality of life. Axona® (caprylic triglyceride, Accera) is a prescription medical food, regulated by the FDA, intended for the clinical dietary management of the metabolic processes associated with mild to moderate AD. Importantly, both prescribers and patients must distinguish between prescription medical foods and other types of ingested products that purport to assist AD patients. Additionally, an understanding of the action of the food and its potential benefits is imperative.

Prescription Medical Foods

The Orphan Drug Act & Amendments of 1988 defined a medical food as a product intended for the dietary management of a specific disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, have been established by medical evaluation. All medical food ingredients must have generally recognized as safe (GRAS) status—a status given to dozens of foods, from basil to wild cherry bark—or must be approved food additives. Importantly, though, a medical food is intended for a patient under medical supervision, and is usually only sold under prescription.

It must be noted that medical foods, dietary supplements and prescription drugs are not interchangeable, but the FDA regulates all three categories. Prescription drugs undergo intensive clinical study and are meant in most cases to treat or prevent a specific disease. Medical foods, meanwhile, must be based on medical evaluation and recognized scientific principles, to meet the nutritional needs or metabolic imbalance of a specific “diseased patient population” before they can be marketed.

Supplements are intended for normal, healthy adults. Unlike supplements, medical foods are most often available by prescription only and must be administered under medical supervision.

A Medical Food in AD

Axona is the only prescription medical food studied in mild to moderate AD (Phase 2a/2b trials) that addresses diminished cerebral glucose metabolism (DCGM) by providing ketone bodies that serve as alternative energy for neurons.

Glucose is the primary energy source for neurons. If the supply of glucose is interrupted, or if cerebral glucose metabolism becomes flawed, neuronal function may be jeopardized.¹ Studies have found approximately a 24 percent reduction in glucose use in AD brains and have shown that DCGM may begin decades before the onset of symptoms.^2,3,4 Thus, DCGM or glucose hypometabolism, appears to be an important feature of AD.

DCGM in AD is progressive and fairly region-specific. It is most detectable in the posterior parietotemporal regions and cingulate, as well as in prefrontal cortices. This has led to the hypothesis that neurons in the AD brain do not use glucose efficiently.^5,6 Although glucose is the brain’s primary energy source, neurons can utilize an alternative energy source, in the form of ketone bodies In fact, under normal circumstances, the healthy brain utilizes both glucose and ketone bodies.⁵ Ketone bodies (mainly in the form of b-hydroxybutryate) can provide up to 60 percent of the energy requirements provided by glucose. Ketone supplementation therapy therefore targets the DCGM hypothesis, which is not currently addressed by other AD therapies.

Understanding Ketone bodies

Ketogenic diets leading to ketosis have been used to treat several neurologic conditions such as epileptic encephalopathy, Lennox-Gastaut syndrome, and glucose transport deficiency.^7,8,9

Several studies in the literature address dietary ketosis and its effect on memory. Krikorian, et al. studied 23 adults (mean age 70.1±6.2y, mean education 15.3±2.8y) with mild cognitive impairment on either a very-low-carbohydrate diet (five-10 percent carbs) vs. a 50 percent carbohydrate diet, for six weeks. The inclusion criteria consisted of adults who had experienced age-related memory decline, such as forgetfulness and prospective memory lapses, with inefficiencies in everyday activities but no substantial functional decline. They reported an improvement in verbal memory following a low carb/pro-ketotic diet.¹⁰

Findings were promising but preliminary. Furthermore, a strict diet may not be ideal in a population living with cognitive impairment and potential deficits in activities of daily living. Thus, no specific diet has been promulgated to address DCGM in AD. This led researchers to seek new methods to study and potentially treat DCGM with effective delivery of ketone bodies.

The initial pilot study to test the ketone hypothesis¹¹ involved 20 subjects with AD (15) or MCI (five) who consumed a drink containing emulsified medium chain triglycerides (MCT) or placebo. MCTs are unique fats that stimulate ketosis without the need for dietary change. Significant increases in levels of the ketone body beta-hydroxybutyrate were observed 90 minutes after treatment when cognitive tests were administered. On cognitive testing, MCT administration improved performance on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) for APOE4(-) subjects, but not for APOE4(+) subjects. Higher ketone values were associated with greater improvement in paragraph recall with MCT treatment, relative to placebo across all subjects.

In a follow-up study, the oral ketogenic compound, AC-1202 (now known as Axona), “significantly elevated a serum ketone body (beta-hydroxybutyrate) two hours after administration when compared to placebo.”¹² For the study, 152 outpatients with probable mild-to-moderate AD were recruited in 23 sites within the US. Patients were allowed to continue on stable concomitant AD treatments, and about 80 percent of the participants were on one or more approved AD medications. One half dose of matching placebo or AC-1202 was administered QD for the first week; then the dose was increased to the full amount for the remaining 11 weeks. AC-1202 was compared to placebo in numerous population groups, including: intention-to-treat (ITT), per protocol, and dosage compliant groups.

In each of the population groups, researchers noted, “a significant difference … between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45: 1.9 point difference, p = 0.0235 in intention-to-treat; 2.53 point difference, p = 0.0324 in per protocol; 2.6 point difference, p = 0.0215 in dosage compliant.”¹² The investigators found that APOE4(-) individuals had a significant difference between AC-1202 and placebo in cognitive performance on day 45 and day 90. Other findings included:

• ITT population: The 55 APOE4(-) participants had a significant 4.77 point difference in mean change from baseline in ADAS-Cog scores at Day 45 and a 3.36 point difference at Day 90 compared to placebo.
• Per protocol population: APOE4(-) participants receiving AC-1202 (N = 37) differed from placebo by 5.73 points at Day 45 and by 4.39 points at Day 90.
• Dosage compliant population: APOE4(-) participants receiving AC-1202 differed from placebo by 6.26 points at Day 45 (N = 38) and 5.33 points at Day 90 (N = 35). Furthermore, a significant pharmacologic response was observed between serum beta-hydroxybutyrate levels and change in ADAS-Cog scores in E4(-) subjects at Day 90.

Measuring Effectiveness

Treatment responses with medical foods, as with other prescription medications for AD, can be challenging to measure, and early in the course of therapy may be subtle. In addition, potential benefits have to be weighed against side effects. Identifying proper candidates for treatment, establishing appropriate expectations, and tracking responses are important.

To chart a patient’s progress on Axona, neurologists can take several steps to ensure proper record keeping:

• Establish a baseline cognitive performance before initiating treatment. This should include caregiver reports of patient function, attention and concentration.
• Assess several cognitive domains (e.g., memory, language, construction) as was done in the clinical trial using the ADAS-Cof
• Ensure the patient is dose-compliant for 90 days before attempting to assess response
• Titrate up to and maintain the full therapeutic dose of 40 grams/day, if tolerated over a seven day period
• Re-assess cognitive domains measured at baseline on follow-up visit(s)

The most frequently reported side effects associated with Axona were GI upset, flatulence, and diarrhea. The risk for these seems to increase when treatment is initiated at the full 40g daily dose. Conversely, these side effects can be minimized or avoided through titrated dosing, and consuming Axona following a full meal. Physicians should prescribe Axona 40g daily after the patient completes the Graduated Dosing Plan (See table). Axona—properly mixed—should be sipped slowly after a meal (breakfast or lunch) over a 20-30 minute period. If GI symptoms develop, patients should discontinue Axona use until symptoms resolve (generally within two to three days) and restart at a lower dose.

Patients allergic to milk or soy should not take Axona; it contains casein and lecithin. Axona should be used with caution in patients at risk for high blood ketone levels, including people with poorly-controlled diabetes and a history of alcohol abuse.

Adverse events associated with Axona (GI symptoms) may be due to rapid hydrolysis of MCTs in the gut and the resultant accumulation of high concentration of medium-chain fatty acids in the small intestine. As such, Axona should be used with caution in patients with a history of GI upset. Further, there may be increased risk when using Axona in patients with a history of GI bleeding and/or certain GI conditions, such as inflammatory bowel disease, irritable bowel syndrome, diverticular disease, chronic gastritis, and gastroesophageal reflux disease.

Fainting and dizziness have been infrequently reported (in <1 in 500 patients filling prescriptions for Axona), principally among patients with a history of bradycardia or hypotension, or among patients taking medications that may induce these effects (eg, antihypertensives and cholinesterase inhibitors). It is important to emphasize the need of taking Axona following a meal, especially for patients who may be at risk for development of these symptoms.

Mild increases in blood urea nitrogen (BUN), creatinine or uric acid can be observed, though these increases rarely exceed 1.5 times normal. Elevated triglyceride values were observed in some subjects who presented with probable metabolic syndrome, meaning these levels should be periodically monitored in patients who meet at least three of the following five criteria indicative of metabolic syndrome: Elevated waist circumference (≥40 inches in men, ≥35 inches in women), hypertension (≥130/85 mm Hg), hypertriglyceridemia (≥150 mg/dL), reduced fasting high-density lipoprotein cholesterol (<40 mg/dL in men, <50 mg/dL in women), and fasting glucose (≥100 mg/dL).

An Adjunctive Intervention

Subjects enrolled in the Axona clinical trial who were receiving commonly prescribed medications for AD were allowed to remain on these medications as long as they had been receiving stable doses for at least three months and remained on stable doses throughout the course of the study. Approximately 80 percent of the patients in this trial were receiving one or more medications for AD (AChE inhibitors and NMDA receptor antagonists), with a higher proportion of subjects within the placebo group receiving these medications compared with the Axona group. While data are limited, based on the Phase IIb trial, Axona may be administered concurrently with other AD medications, without the need to alter doses.

Conclusion

For the treating physician, there has been little new to offer the Alzheimer patient. The last new compound approved for Alzheimer’s disease was in 2003, although doses at higher formulation of previous approved medications have become available. Recently, a series of candidate treatments for AD have failed to reach their primary endpoints in phase III trials, leaving the physician with few options. Medical foods offer a growing category of options for disease management of AD. However, due to the lack of a formal FDA review of products available without prescriptions, such products should be critically viewed in the absence of Type I medical evidence. Axona, a medical food prescribed under the supervision of a physician, offers clinicians an additional option for treating patients with mild to moderate AD in conjunction with pharmacologic and nonpharmacologic approaches.

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