Axona

Forms And Strengths

Axona is available in individual packets of 40 grams of powder containing 20 grams caprylic triglycerides. Commercial product is supplied in a carton containing 30 packets.

Storage And Handling

Axona is supplied as a powder in individual packets of 40 grams (containing 20 grams MCTs). Axona should be added to 4 to 8 ounces (118 to 236 milliliters) of water or other liquids as preferred, and shaken or blended until fully mixed. Reconstituted product may be refrigerated and stored for up to 24 hours. Refrigerated product should be re-blended and thoroughly mixed prior to consumption.

Axona should be stored at room temperature, 15°C-30°C (59°F-86°F), sealed, and protected from light and moisture.

REFERENCES

1. Hoyer S. Oxidative energy metabolism in Alzheimer brain. Studies in early-onset and late-onset cases. Mol Chem Neuropathol. 1992;16(3):207-224.

2. Small GW, Ercoli LM, Silverman DH, et al. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc Natl Acad Sci USA. 2000;97(11):6037-6042.

3. Henderson ST. Ketone bodies as a therapeutic for Alzheimer's disease. Neurotherapeutics. 2008;5(3):470-480.

4. Costantini LC, Barr LJ, Vogel JL, Henderson ST. Hypometabolism as a therapeutic target in Alzheimer's disease. BMC Neuroscience. 2008;9(suppl 2):S16.

5. Parsons MW, Gold PE. Glucose enhancement of memory in elderly humans: an inverted-U dose-response curve. Neurobiol Aging. 1992;13(3):401-404.

6. Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J. Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans. Diabetes. 1994;43(11):1311-1317.

7. Hasselbalch SG, Madsen PL, Hageman LP, et al. Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia. Am J Physiol. 1996;270(5 Pt 1):E746-E751.

8. Izumi Y, Ishii K, Katsuki H, Benz AM, Zorumski CF. b-Hydroxybutyrate fuels synaptic function during development. Histological and physiological evidence in rat hippocampal slices. J Clin Invest. 1998;101(5):1121-1132.

9. Gasior M, Rogawski MA, Hartman AL. Neuroprotective and disease-modifying effects of the ketogenic diet. Behav Pharmacol. 2006;17(5-6):431-439.

10. Van der Auwera I, Wera S, Van Leuven F, Henderson ST. A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer's disease. Nutr Metab (Lond). 2005;2:28.

Manufactured for: Accera, Inc.380 Interlocken Crescent, Suite 780, Broomfield, CO 80021, USA. 1-877-649-0004. Revised: Aug 2015

Clinical Study Experience

Thus far, a total of 197 subjects have received Axona in one of 3 clinical trials. Because clinical studies are conducted under varying conditions, AE rates cannot be directly compared to rates in clinical studies of other compounds, and may not reflect the rates observed in practice.

The first clinical trial was a randomized, placebo-controlled, crossover-design study to measure the potential therapeutic effects on memory of a single administration of Axona (40-80 grams of MCTs) in 20 patients between the ages of 55-85 years old and diagnosed with probable AD (n = 15) or mild cognitive impairment (MCI) (n = 5).12 Two subjects experienced AEs primarily associated with the GI system, including nausea, abdominal discomfort, and diarrhea.

The second clinical study was a double-blind (DB), randomized, 90-day, placebo-controlled study performed at multiple US clinical centers in a population of 152 patients with mild to moderate AD.13 In addition, subjects completing the 90-day trial were permitted to enroll in an optional 6-month, open-label (OL) extension study. Patients received 10 grams of caprylic triglyceride per day on days 1-7 and 20 grams of caprylic triglyceride per day on days 8-90. Seventy-six percent of Axona subjects (compared with 62% of placebo subjects) experienced at least one AE during the course of the study, the majority of which were mild to moderate in severity. The most frequently reported AEs involved the GI system, in which 48.8% of Axona and 27.3% of placebo subjects experienced one or more AEs. The primary GI AEs occurring more frequently in the Axona than in the placebo group consisted of: diarrhea (24.4% vs 13.6%), flatulence (17.4% vs 7.6%), and dyspepsia (9.3% vs 4.5%). AEs reported among the 49 subjects in the OL phase of the study were consistent with those observed in the DB phase.

The following table presents the number and percentage of AD patients in the DB AD study who developed the most commonly reported AEs (occurring more frequently in Axona than in placebo subjects and in at least 3% of patients receiving Axona).

Adverse Events Reported in ≥ 3% of Axona Patients*

The third clinical study was a 14-day, open-label, randomized trial performed at 4 US clinical centers in 66 normal elderly volunteers. Three formulations of Axona were administered for 14 days either with a 7-day titration (7 days at 10 grams caprylic triglyceride followed by 7 days at 20 grams caprylic triglyceride) or without titration (14 days at 20 grams caprylic triglyceride). The original formulation utilized in the DB AD study was compared with 2 formulations that contained different ratios of proteins to carbohydrates. Subjects within each cohort experienced comparable frequencies of AEs, including those within the GI system. The most common AEs, consisting of nausea (19.7%), abdominal distension (16.7%), flatulence (15.2%), and diarrhea (13.6%), were generally transient in nature and resolved without treatment. In addition, 7 subjects developed clinically significant increases in triglyceride values after Axona administration. Six of these 7 subjects were identified as having probable metabolic syndrome. Of note, dietary restrictions were not imposed during this study, and neither the quantity nor the quality of food consumption was monitored. Therefore, although a causal relationship to Axona was not determined, triglyceride levels should be periodically monitored in patients receiving Axona who meet criteria indicative of metabolic syndrome.

In each of the 3 clinical studies, AEs occurring within the GI system were the most commonly experienced events, and in general, the most frequently reported AEs consisted of diarrhea, flatulence, and dyspepsia. Mild “queasiness” or nausea that was transient in nature was also occasionally reported, as were “bloating” and abdominal discomfort. In the DB AD study, the overall rate of severe GI events in Axona patients included diarrhea (5.8%), dyspepsia (2.3%), and flatulence (1.2%). In all but 2 cases, the diarrhea spontaneously resolved without treatment. The majority of GI events were mild to moderate in severity, and it was found that the severity of AEs could be reduced if Axona was taken with food. In the DB AD study, the incidence of severe diarrhea declined from 9.7% to 3.1% following a change in mixing instructions (blending the original formulation of Axona with a meal replacement drink such as Ensure® instead of water). The marketed formulation of Axona does not require mixing with Ensure (see “Clinical Studies” and “HOW SUPPLIED/Storage and Handling” below).

In the DB AD clinical study, mean values in BUN, uric acid, and creatinine increased from screening values in the Axona group; however, in 5 of 7 cases these laboratory increases did not exceed 1.5 x ULN. One subject with a recent history of renal failure requiring dialysis had an elevated BUN value that was 2.4 x ULN. Another patient who had been receiving long-term therapy with medications associated with elevated renal function test results (ie, an angiotension II receptor antagonist and furosemide) developed increased BUN and creatinine values up to 2.5 x ULN. The majority of subjects with significant renal function test abnormalities were also noted to have abnormal values at screening, were taking concomitant medications associated with elevated renal function test results, and had BUN/creatinine ratios > 15, indicative of dehydration. While the increases in these renal function tests appear to be related to either pre-existing conditions or to dehydration, a relation to Axona cannot be entirely ruled out.

In the DB AD study, a 93-year-old AD patient with a history of IBS and intermittent diarrhea, along with multiple cardiac abnormalities including left ventricular hypertrophy, expired due to a GI bleed following 28 days of Axona administration. Also in the DB AD study, an 87-year-old patient with a history of diverticulitis and stomach ulcer was found to have a guaiac-positive stool when hospitalized for pneumonia. This patient was discharged from hospital without sequelae. All of these events were likely to be related to the subjects' underlying comorbidities; however, the possibility that Axona may exacerbate pre-existing GI inflammatory processes should be considered.

Consistent with AEs reported during clinical trials, spontaneously reported AEs consisted primarily of abdominal discomfort, diarrhea, nausea, and dyspepsia. Fainting and dizziness were also reported in < 1 in 500 patients taking Axona (see “WARNINGS AND PRECAUTIONS”). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to exposure to the product.

Axona (caprylidene) is a medical food (see Section 11 "Description" below) containing a proprietary formulation of medium-chain triglycerides (MCTs), specifically caprylic triglyceride, for the clinical dietary management of the metabolic processes associated with mild to moderate Alzheimer�s disease (AD). Axona is taken orally once a day, and must be administered under physician supervision and dispensed by prescription.

Alzheimer's Disease as a Metabolic Deficiency

Under normal conditions, glucose is the primary energy source for the brain. Imaging studies have shown decreased utilization of glucose in the brains of AD patients early in the disease, before clinical signs of cognitive impairment occur. This decrease in glucose metabolism (hypometabolism) worsens as clinical symptoms develop and the disease progresses. 1,2 Hypometabolism may not be solely an artifact of cell atrophy since it occurs in asymptomatic patients at risk for AD, such as patients homozygous for the epsilon 4 variant of the apolipoprotein E gene (APOE4, a genetic risk factor for AD), as well as in familial forms of AD. Thus, AD is a disease with distinctive metabolic and nutritional requirements. 3,4

Given that hypometabolism is an early and progressive event in AD and may precipitate downstream pathological events, it is reasonable to target the improvement of neuronal energy states for the management of AD. Studies in animals and human subjects have shown that increasing blood glucose levels facilitates memory.5 However, due to the impracticality of maintaining chronically elevated glucose levels, a safer alternative is required. Ketone bodies provide an alternative energy substrate that can be utilized by the brain to improve cognition and memory.

Ketone bodies are naturally produced from fat stores as an alternative to glucose during periods of sustained hypoglycemia, such as during fasting or very low carbohydrate intake. In a controlled clinical study in human subjects experiencing hypoglycemia, the infusion of ketones was shown to improve cognitive function compared with control subjects, suggesting that increased ketones can substitute for glucose as an energy source for the brain.6,7

In vitro data indicate that the ketone body �-hydroxybutyrate (BHB) can substitute for a large fraction of glucose as an energy substrate, and preserves neuronal integrity and stability.8 Ketone bodies feed directly into the tricarboxylic acid (TCA) cycle in neurons and generate adenosine triphosphate (ATP), as well as increasing pools of acetyl-CoA and succinate. Ketones are neuroprotective against several types of toxic insults,9 and also reduce neuropathological changes, such as �-amyloid levels in animal models of AD.10

Axona is designed to safely elevate serum ketone levels to assist with the clinical dietary management of the metabolic processes and nutritional requirements associated with mild to moderate AD.

Axona should be used with caution in patients with known hypersensitivity to palm or coconut oil.

Axona contains caseinate (milk-derived protein), whey (milk), and lecithin (soy). Do not use in patients allergic to these component ingredients, or sources, that is, to milk or soy.

Axona should be used with caution in patients at risk for ketoacidosis, for example, alcoholics and poorly controlled diabetics.

Axona has demonstrated a favorable safety profile and was well tolerated in multiple clinical trials; however, more Axona subjects have experienced gastrointestinal (GI) adverse events (AEs) than have placebo subjects. The most prominent GI AEs observed during clinical studies have been diarrhea, flatulence, and dyspepsia. Among the 172 subjects receiving Axona, 2 subjects with pre-existing GI conditions developed serious AEs (SAEs), and for this reason, Axona should be used with caution in patients with a history of GI inflammatory conditions, such as irritable bowel syndrome (IBS), diverticular disease, chronic gastritis, and severe gastroesophageal reflux disease.

Mild increases in blood urea nitrogen (BUN), uric acid, or creatinine were occasionally observed among patients receiving Axona in one clinical trial; however, none of these increases exceeded 2.5 x upper limit of normal. Although none of the clinical investigators assessed these laboratory abnormalities as being clinically significant or as being associated with the development of AEs, a possible relationship to Axona cannot be ruled out. Physicians should discuss using Axona with their patients if patients have a history of renal dysfunction.

Elevated triglyceride values were observed in some subjects who presented with probable metabolic syndrome. Triglyceride (TG) levels should be periodically monitored in patients who meet at least 3 of the following 5 criteria indicative of metabolic syndrome: elevated waist circumference (=40 inches in men, =35 inches in women), BP =130/85 mm Hg, TG =150 mg/dL, reduced fasting HDL (<40 mg/dL in men, <50 mg/dL in women), and fasting glucose =100 mg/dL.

The dose-limiting toxicity with MCTs is known to be diarrhea. Animal studies have shown that consuming the equivalent of up to 33 times the recommended human administration of Axona for 3 months had no adverse effects.13 In the unlikely event of overusage of Axona, patients should be managed with systematic and supportive care as soon as possible after the overusage has occurred. Overusage symptoms could vary by patient. Severe episodic diarrhea may occur.