Background

Tricaprilin is the follow-up to Accera's AC-1202/Axona medical food product. It is a proprietary, oral formulation of caprylic triglyceride, which was designed to induce a mild chronic ketosis in order to improve mitochondrial metabolism. Regional reductions in cerebral glucose utilization are an early feature of Alzheimer's disease (Reiman et al., 2004). The rationale behind tricaprilin is to boost cellular metabolism in Alzheimer's by providing a fuel alternative to glucose. Caprylic acid is metabolized into so-called ketone bodies, such as acetoacetic acid and β-hydroxybutyric acid, which can be converted to acetyl-CoA to produce energy via the citric acid cycle.

Findings

Based on clinical experience with Accera's Axona, a medical food similar to tricaprilin, this new formulation entered clinical evaluation in Phase 2/3.

In December 2012, Accera withdrew ALERT, a planned six-month Phase 2/3 trial it had previously registered (NCT01211782), reportedly because it was being redesigned. 

From March 2013 to October 2016, Accera conducted NOURISH AD, a multicenter, six-month efficacy trial with an optional six-month, open-label extension. This trial enrolled 418 patients with mild to moderate AD at 82 locations in the U.S. It compared the effect of once-daily administration of 40 g of AC-1204 containing 20 mg of the active ingredient caprylic triglyceride to placebo on the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS–Cog) in ApoE4 noncarriers. As secondary outcomes, the trial used additional cognitive, clinical, and global measures in ApoE4 noncarriers; other outcomes include overlapping measures in ApoE4 carriers plus still more cognitive and clinical measures in both carriers and non-carriers. 

In 2016, Accera started three Phase 1 studies of AC-1204 in a total of 52 healthy volunteers. One compares serum ketone body levels after administration of AC-1204 versus caprylic triglyceride oil, as well as interactions with a high-fat diet; one compares serum ketone body generation after AC-1204 mixed in water or AC-1202 in water, versus AC-1202 in Ensure; and one compares ketone body generation after a single dose of AC-1204 to similar formulations, including AC-1202. Also in 2016, Accera conducted a pilot safety study of AC-1204 in 10 people with amyotrophic lateral sclerosis.

On February 28, 2017, Accera announced that the NOURISH-AD trial had failed to detect a statistically significant difference between AC-1204 and placebo on the ADAS-cog (see company press release). The data were subsequently published (Henderson et al., 2020). Part of the failure was attributed to poor bioavailability of the new formulation, which produced lower plasma ketone concentrations than did Axona.

Between March 2017 and May 2020, the company performed four Phase 1 trials of new formulations of tricaprilin. As presented at the 2020 CTAD virtual meeting, the AC-SD-03 formulation was chosen for further development based on its pharmacokinetics and tolerability. In an ascending dose study in people over age 50, a 30 mg dose resulted in blood ketone levels above the target of 500 μM. The most common side effects were gastrointestinal, including abdominal distention, discomfort and nausea. The maximum ketone concentrations and total plasma exposure did not differ between Caucasian and Chinese participants.

In October 2018, Accera changed its name to Cerecin, following investments from a Singapore-based agribusiness group and a private equity fund backed by Nestlé (press release).

In December 2019, Cerecin registered a Phase 3 trial of AC-SD-03, now also called CER-0001. It aimed to enroll 300 people with mild to moderate AD who do not carry an ApoE4 allele and whose FDG-PET glucose uptake pattern is typical of AD. They were to drink 20 g of tricaprilin mixed into 240 ml of water twice per day for six months, as an add-on to any ongoing treatments. The primary outcome was change in ADAS-Cog11, with secondary outcomes of safety and tolerability, the Clinical Global Assessment of Change, and measures of disability, dependence, and resource utilization. An optional 30-week open-label extension was planned. This study never began enrolling, and was withdrawn in April 2023.

In July 2022, Cerecin began Phase 1 testing of a new formulation of tricaprilin, designated AC-OLE-01-VA. An initial trial evaluated pharmacokinetics, safety, and tolerability. A second trial began in November 2022, comparing three different titration and dosing schedules against an outcome of discomfort due to nausea, indigestion, abdominal pain, distension, and diarrhea. This trial was to finish in February 2023.

In April 2023, the company registered a Phase 3 trial of AC-OLE-01-VA for Alzheimer’s disease. Meant to start in January 2024, it plans to enroll 535 people with mild to moderate AD who are taking cholinesterase inhibitors or memantine. Participants will titrate to a dose of 20g twice daily for six months, against primary outcomes of the ADAS-Cog and ADCS-Clinical Global Impression of Change. Secondary outcomes are safety, tolerability, and activities of daily living.

In October 2020, the FDA granted Orphan Drug designation to CER-0001 for treatment of infantile spasms, a rare form of epilepsy which occurs in the first year of life, and is improved with a ketogenic diet. An open-label trial began in November 2021 in eight infants in Australia; the company reported positive results (Aug 2023 press release). Cerecin is also developing CER-0001 for migraine prevention.

For all clinical trials on tricaprilin, see clinicaltrials.gov.

Clinical Trial Timeline