Mechanism Of Action/Metabolism
Axona provides a simple and safe method to induce
hyperketonemia, thus providing an alternative energy substrate to glucose in
the brain of patients with AD. After oral administration, Axona is processed by
lipases in the gut, and the resulting medium-chain fatty acids (MCFAs) are
absorbed into the portal vein. The MCFAs rapidly pass directly to the liver,
where they undergo obligate oxidation.15 MCFAs
enter the liver mitochondria as acyl-CoA, where they undergo b-oxidation to
form acetyl-CoA and acetoacetyl-CoA, which, when produced in excess, are
combined to form 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA). HMG-CoA is then
acted on by HMG-CoA lyase to form acetoacetate and BHB, ie, ketone bodies.
Since the liver does not use ketone bodies, they are released into the
circulation to be used by extrahepatic tissues.
The ketone body BHB crosses the blood-brain barrier
and is then taken up by neurons. Ketones are used in a concentration-dependent
manner in the adult human brain, including the elderly brain16,17 until
circulating concentrations reach approximately 12 mM, at which point they
saturate the oxidative machinery.18 In
neurons, ketone bodies enter the mitochondria to produce a cascade effect on
mitochondrial activity that increases mitochondrial efficiency and thereby
reduces the generation of reactive oxygen species. Ketone bodies feed directly
into the TCA cycle in neurons and generate ATP, as well as increase pools of
acetyl-CoA and acetylcholine. Ketone bodies are used by neurons even in the presence
of abundant glucose.
Medium-chain triglycerides are considered saturated
fats, as are many long-chain triglycerides (LCTs). However, MCTs are
metabolized differently from LCTs in that they do not significantly increase
cholesterol levels and are not stored as fat. In a 14-day, open-label bridging
study with Axona, no clinically significant changes in cholesterol, low-density
lipoproteins (LDL), or high-density lipoproteins (HDL) were observed. In a
16-week, randomized, controlled study in 31 patients receiving a
reduced-calorie diet containing either olive oil or MCT oil (18-24 grams
daily), significant and comparable reductions in total cholesterol and LDL were
observed in both study groups.19
Axona has been tested in 3 clinical trials in
populations of patients with a diagnosis of probable mild to moderate AD and
MCI, as well as in normal elderly volunteers.§
Study in Patients With AD or MCI12
The first clinical study was a randomized,
placebo-controlled, crossover-design study to measure the therapeutic effects
of a single administration (40-80 grams) of MCTs on memory in 20 patients
between the ages of 55-85 years and diagnosed with probable AD (n = 15) or MCI (n
= 5). The mean baseline score in the Mini-Mental State Examination (MMSE; a
test used in the diagnosis of AD) was 22.2. Subjects were allowed to continue
on stable concomitant AD treatments. A single 40-gram administration of MCTs
led to elevated BHB serum levels (to approximately 0.5 mM at 90 minutes
following administration) that were positively correlated with improvement in
paragraph recall (a measure of cognition) (P = 0.02). APOE4(–) patients (as
described in Section 1 above) showed greater improvement compared with APOE4(+)
patients in the AD Assessment Scale—Cognitive subscale (ADAS-Cog, which
measures memory and other aspects of cognitive performance) (P = 0.039).
Clinical Study in Patients With
Probable Mild to Moderate AD13
The second clinical study was a DB, randomized,
placebo-controlled, 90-day study with a 2-week washout period performed at
multiple US clinical centers in a population of 152 patients with mild to
moderate AD, randomized 1:1 to receive placebo or Axona. At day 45, ADAS-Cog
scores stabilized in the Axona group, whereas a decline in cognition was
observed in the placebo group. The point difference in ADAS-Cog change from
baseline scores at day 45 between groups was 1.91 (P = 0.024; see Figure 1).
The point difference in ADAS-Cog change from baseline scores at day 90 between
groups was 1.54 (P = 0.0767). Final ADAS-Cog evaluations were performed
following a 2-week washout period (day 104): the Axona group maintained a
slight improvement from baseline, whereas the placebo group still demonstrated
a decline, although the difference between groups was no longer statistically
significant (P = 0.405).
As defined in the Study Statistical Plan, the
ADAS-Cog change from baseline score was also analyzed in subgroups of patients
based on APOE4 genotype. The APOE4(–) patients receiving Axona showed improved
cognitive function when compared with APOE4(–) patients receiving placebo (n =
29, Axona; n = 26, placebo). The point difference in change from baseline
ADAS-Cog scores for APOE4(–) Axona and placebo patients at day 45 was 4.77 (P <
0.0005), and was 3.36 at day 90 (P = 0.015; see Figure 2). In APOE4(+) patients
(n = 38, Axona; n = 31, placebo), the mean change in ADAS-Cog total scores for
the 2 groups was essentially identical at all time points, with more patients
showing decline rather than improvement at day 45 and day 90.
Additional analyses were performed among patients
who were dosage compliant (defined as patients who reported consuming at least
80% of the total intended dose). In this subset, the difference from baseline
in ADAS-Cog scores between Axona and placebo groups was more pronounced than
that observed in the overall study population. Among dosage-compliant patients,
the difference in change from baseline ADAS-Cog scores between Axona and
placebo groups at day 45 was 2.60 points (P = 0.0215) and at day 90 was 2.26
points (P = 0.064) (Figure 1). Among E4(–) dosage-compliant subjects, a
significant difference in change from baseline in ADAS-Cog scores between Axona
and placebo groups was notable on day 45 (6.26-point difference; P = 0.001) and
day 90 (5.33-point difference; P = 0.006) (Figure 2). Among E4(+)
dosage-compliant subjects, there was no significant difference in change from
baseline in ADAS-Cog scores between those administered Axona and placebo.
Figure 1: Improvements in ADAS-Cog for all patients
with Alzheimer's disease
Figure 2: Significant improvements in ADAS-Cog for
A total of 49 patients who completed the 90-day DB
phase of the study enrolled in the 6-month OL extension. Since the OL phase did
not include an active control group, the significance of efficacy results was
Bridging Study in Normal Elderly Volunteers
The third clinical study was an open-label,
randomized bridging study in 66 normal elderly volunteers to establish the
tolerability, safety, and pharmacokinetic (PK) profile of 3 different
formulations of Axona administered for 14 days either with a 7-day titration (7
days at 10 grams MCTs followed by 7 days at 20 grams MCTs) or without titration
(14 days at 20 grams MCTs). The original formulation of Axona used in the AD
controlled clinical trial required reconstitution with a “meal replacement
drink,” such as Ensure®, in order to
enhance product tolerability. The 2 new formulations tested each contained an
identical amount of MCTs as the original formulation, but different amounts of
proteins and carbohydrates, and allowed for reconstitution in 4-8 ounces of
water. The highest mean BHB levels (Cmax)
and area-under-the-curve (AUC) values were observed in the cohort of subjects
receiving the high-protein formulation at the 20-gram MCT level. This cohort of
subjects receiving the high-protein formulation at the 20-gram MCT level also
experienced the latest onset of most GI AEs. This is the formulation of Axona
selected for marketing.
§ Further information on these clinical trials may be found at www.about-axona.com
12. Reger MA, Henderson ST, Hale C, et al. Effects of
b-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging.
13. Henderson ST, Vogel JL, Barr LJ, et al. Study of the
ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized,
double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond). 2009;6:31.
15. Bach AC, Babayan VK. Medium-chain triglycerides:
an update. Am J Clin Nutr. 1982;36(5):950-962.
16. Laffel L. Ketone bodies: a review of physiology,
pathophysiology and application of monitoring to diabetes. Diabetes Metab Res
17. Morris AA. Cerebral ketone body metabolism. J
Inherit Metab Dis. 2005;28(2):109-121.
18. Mayes PA. Oxidation of fatty acids: ketogenesis.
In: Murray RK, Granner DK, Mayes PA, Rodwell VW, eds. Harper's Biochemistry.
New York, NY: McGraw-Hill; 2000.
19. St-Onge MP, Bosarge A, Goree LL, Darnell B.
Medium chain triglyceride oil consumption as part of a weight loss diet does
not lead to an adverse metabolic profile when compared to olive oil. J Am Coll