Reporting from the Clinical Trials on Alzheimer's Disease 2017 conference:
Samuel Henderson of Accera Inc. in Boulder, Colorado, explained negative results for tricaprilin [ie, caprylic triglyceride], Accera’s latest formulation of caprylic triglycerides to boost ketone body metabolism with a dietary aid. [This is the successor to Axona -MR]. The Nourish-AD was a Phase 3 trial conducted at 61 sites in the U.S., in 413 people who met the NINDS-ADRDA diagnosis of probable AD.
At the end of the trial, the treatment and placebo groups performed equally on the primary outcome measure, cognition as per the ADAS-cog, and the secondary outcome measure, overall function as per the ADCS-CGIC. As with prior formulations of this dietary approach, adverse events included nausea, vomiting, and gastrointestinal discomfort.
At CTAD Henderson ascribed the negative result to low exposure and bioavailability, saying this new formulation generated insufficient amounts of ketone bodies in the brain. As happens frequently in six-month trials in AD, the tricaprilin trial, too, was further hobbled by a relative lack of cognitive decline in the placebo group.
Henderson noted the company still has faith in the rationale behind ketone body therapy for treating neurologic disease, and has developed yet another formulation for its approach.—Pat McCaffrey and Gabrielle Strobel
TRICAPRILIN: RESULTS OF A PHASE 3 STUDY IN MILD-TO-MODERATE ALZHEIMER’S DISEASE PATIENTS.
Samuel Henderson1, Michael Gold2, Judith Walker1, Sabrina Greer1, Janet Vogel1, Aaron Shenkin1
((1) Accera Inc, Boulder, CO, USA; (2) PPD Inc, Wilmington, NC, USA)
Background: Tricaprilin, a ketogenic compound, is in clinical development for the treatment of mild-to-moderate Alzheimer’s disease (AD). In a previous Phase 2b study, Tricaprilin demonstrated significant improvement relative to placebo in a sub-group of subjects (n=29 tricaprilin, 26 placebo) who were non-carriers of the epsilon 4 allele (ε4) of the APOE gene and received 20 grams of tricaprilin QD for 90 days. [MR: I've emphasized this point before: studies of keto diets in AD patients and high-risk groups have generally failed, and to the extent that there have been hints of an effect by genotype they have tended to seem to only work in APOEε4 non-carriers ].
Methods: We conducted a 26 week, double-blind, randomized, placebo-controlled, Phase 3 trial involving patients with mild-to-moderate Alzheimer’s disease. The study population included men and women between the ages of 66 and 90 years old who met the NINCDS-ADRDA criteria for probable AD. Use of cholinesterase inhibitors and/or memantine was permitted (in stable doses). Eligible subjects were stratified by APOEε4 carriage status (+, -) and baseline MMSE score (14-20, 21-26).
Subjects were randomized 1:1 to receive either oral tricaprilin at 20 grams/day or a matching isocaloric placebo. Upon completion of the double-blind treatment phase, participants were eligible to receive tricaprilin in an optional 26 week open-label extension. The primary analysis population was the APOEε4 non-carriers and the primary outcome measures were the ADAS-cog(11) and ADCS-CGIC. Secondary outcomes included the ADCS–ADL, QoL-AD, RUD-Lite, Clock Draw Interpretive Study (CDIS), and the MMSE.
Results: The study enrolled 285 APOEε4 non-carriers and 128 carriers at 61 sites in the USA. Eighty percent of APOEε4 non-carriers completed the study. In the primary analysis population, the mean age (SD) was 76.9 (6.88) and the MMSE score at baseline was 21.2 (3.50). No significant differences between tricaprilin and placebo in change in ADAS-Cog at 26 weeks (least squared means: tricaprilin 1.1; placebo 0.3; p=0.25) or in ADCS-CGIC (p=0.27) were detected.
Conclusion: The study did not meet primary and secondary endpoints. Subsequent analyses revealed two factors that may have influenced study outcome: (1) the formulation used in the study produced lower levels of ketones than formulations used in the earlier studies; (2) there was a marked lack of cognitive decline among the APOEε4 non-carriers. Detailed results of this trial will be presented as well as plans for continued development.