Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial

Samuel T Henderson, Janet L Vogel, Linda J Barr, Fiona Garvin, Julie J Jones, Lauren C Costantini, Samuel T Henderson, Janet L Vogel, Linda J Barr, Fiona Garvin, Julie J Jones, Lauren C Costantini

Abstract

Background: Alzheimer's disease (AD) is characterized by early and region-specific declines in cerebral glucose metabolism. Ketone bodies are produced by the body during glucose deprivation and are metabolized by the brain. An oral ketogenic compound, AC-1202, was tested in subjects with probable AD to examine if ketosis could improve cognitive performance.

Methods: Daily administration of AC-1202 was evaluated in 152 subjects diagnosed with mild to moderate AD in a US-based, 90-day, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were on a normal diet and continued taking approved AD medications. Primary cognitive end points were mean change from Baseline in the AD Assessment Scale-Cognitive subscale (ADAS-Cog), and global scores in the AD Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC). AC-1202 was compared to Placebo in several population groups, including: intention-to-treat (ITT), per protocol, and dosage compliant groups. Results were also stratified by APOE4 carriage status (a predefined analysis based on the epsilon 4 (E4) variant of the apolipoprotein E gene). This trial was registered with ClinicalTrials.gov, registry number NCT00142805, information available at https://ichgcp.net/clinical-trials-registry/NCT00142805

Results: AC-1202 significantly elevated a serum ketone body (beta-hydroxybutyrate) 2 hours after administration when compared to Placebo. In each of the population groups, a significant difference was found 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 ITT; 2.53 point difference, p = 0.0324 in per protocol; 2.6 point difference, p = 0.0215 in dosage compliant. Among participants who did not carry the APOE4 allele (E4(-)), a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45 and Day 90. In the ITT population, E4(-) participants (N = 55) administered AC-1202 had a significant 4.77 point difference in mean change from Baseline in ADAS-Cog scores at Day 45 (p = 0.0005) and a 3.36 point difference at Day 90 (p = 0.0148) compared to Placebo. In the per protocol population, E4(-) participants receiving AC-1202 (N = 37) differed from placebo by 5.73 points at Day 45 (p = 0.0027) and by 4.39 points at Day 90 (p = 0.0143). In the dosage compliant population, E4(-) participants receiving AC-1202 differed from placebo by 6.26 points at Day 45 (p = 0.0011, N = 38) and 5.33 points at Day 90 (p = 0.0063, 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 (p = 0.008). Adverse events occurred more frequently in AC-1202 subjects, were primarily restricted to the gastrointestinal system, and were mainly mild to moderate in severity and transient in nature.

Conclusion: AC-1202 rapidly elevated serum ketone bodies in AD patients and resulted in significant differences in ADAS-Cog scores compared to the Placebo. Effects were most notable in APOE4(-) subjects who were dosage compliant.

Figures

Figure 1
Figure 1
Study randomization and group allocation for the ITT population.
Figure 2
Figure 2
Mean change in ADAS-Cog scores from Baseline in the ITT population w/LOCF and stratified by APOE4 carriage status. Y axis is change from Baseline. X axis is time in days. Red circles and lines represent subjects taking AC-1202. Blue squares and lines represent subjects taking Placebo. Error bars represent standard error of the mean. Asterisks (*) indicate a significant (p-value < 0.05) difference in mean change from Baseline between AC-1202 and Placebo. A) Intention to treat subjects (N = 77AC, N = 63PL) administered AC-1202 demonstrate a significant difference from Placebo at Day 45. B) Genotyped subjects lacking the APOE4 allele (APOE4(-)) (N = 29AC, N = 26PL) and administered AC-1202 demonstrate a significant difference from Placebo at Days 45 and 90. C) Genotyped subjects carrying the APOE4 allele (APOE4(+)) (N = 38AC, N = 31PL) do not differ from Placebo at any time point. For confidence intervals and p-values see Table 5.
Figure 3
Figure 3
Mean pre and post-dose serum BHB levels at each study visit. Post-dose samples were taken 2 hours after administration of investigational product. Blue bars represent Placebo, red bars represent AC-1202. Error bars represent standard error of the mean. Significant increases in BHB levels were found post-dose in AC-1202 subjects compared to Placebo subjects. Subjects were given 1/2 dose at Baseline (10 grams), full dose on Days 45 and 90 (20 grams), and no dose was administered on Day 104. Asterisks (*) represent significant differences between AC-1202 and Placebo groups (p < 0.0001).
Figure 4
Figure 4
Mean change in ADAS-Cog scores from Baseline in per protocol and dosage compliant populations without LOCF and stratified by APOE4 carriage status. Y axis is change from Baseline. X axis is time in days. Solid red circles and lines represent per protocol subjects taking AC-1202. Solid blue squares and lines represent per protocol subjects taking Placebo. Open red circles and dashed lines represent dosage compliant subjects taking AC-1202. Open blue squares and dashed lines represent dosage compliant subjects taking Placebo. Error bars represent standard error of the mean. Asterisks (*) indicate a significant (p-value < 0.05) difference in mean change from Baseline between AC-1202 and Placebo. A) Per protocol and dosage compliant subjects administered AC-1202 regardless of genotype, both cohorts demonstrate a significant difference from Placebo at Day 45. B) Per protocol and dosage compliant subjects lacking the APOE4 allele (APOE4(-)) and administered AC-1202 demonstrate a significant difference from Placebo at both Days 45 and 90. C) Per protocol and dosage compliant subjects carrying the APOE4 allele (APOE4(+)) do not differ at any time point. For number of subjects, confidence intervals, and p-values, see Tables 6 and 7.
Figure 5
Figure 5
Linear fit of change from Baseline at Day 90 in ADAS-Cog score and log transformed total dosage stratified by APOE4 carriage status. Only reported ADAS-Cog scores were used; no data was imputed. Solid circles represent APOE4(+) subjects, open circles represent APOE4(-) subjects. Crosses represent non-dosage compliant subjects. Red line indicates linear fit for all genotypes, green line for APOE4(-) subjects, and blue line for APOE4(+) subjects. A) Among subjects taking AC-1202, a significant correlation was found in APOE4(-) subjects in change from Baseline at Day 90 in ADAS-Cog score and log transformed total dosage. B) Among subjects taking Placebo, no significant correlations were found in change from Baseline at Day 90 in ADAS-Cog score and log transformed total dosage.
Figure 6
Figure 6
Plot of change in ADAS-Cog and total dose administered for each of the per protocol participants. Y axis is change in ADAS-Cog score from Baseline. X axis is total dose in grams. Each subject is represented by three symbols. A red x represents the change from Baseline score at Day 45. A green square represents the change from Baseline at Day 90. A blue diamond represents the change from Baseline at Day 104. APOE4(-) subjects who received more than 4000 grams generally improved in ADAS-Cog score.
Figure 7
Figure 7
Linear fit of change from Baseline at Day 90 in ADAS-Cog score and log transformed post-dose serum BHB levels in the per protocol population stratified by APOE4 carriage status. Red symbols represent subjects taking AC-1202. Blue symbols represent subjects taking Placebo. Circles and squares indicate dosage compliant subjects, crosses represent non-compliant subjects. The solid lines represent the linear fit in the per protocol population. The dashed lines represent the linear fit in the dosage compliant sub-population of the per protocol population. A) A significant correlation was found in the per protocol population between serum BHB levels and change in ADAS-Cog on Day 90. B) A significant correlation was found in E4(-) per protocol subjects between serum BHB levels and change in ADAS-Cog on Day 90. C) No significant correlation was found in E4(+) per protocol subjects between serum BHB levels and change in ADAS-Cog on Day 90. In each case the linear fit of the dosage compliant subgroup is very similar to the overall per protocol population.
Figure 8
Figure 8
Summary graph of mean change from Baseline at Day 90 for ITT w/LOCF, per protocol and dosage compliant groups stratified by APOE4 carriage status. Red columns represent subjects receiving AC-1202. Blue columns represent subjects receiving Placebo. Error bars represent standard error of the mean. Table displays mean change from Baseline for each group. Mean changes from Baseline was largest in APOE4(-) subjects who were dosage compliant.

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