Background

Formerly called SDI-118, ABBV-552 is an oral drug that modulates synaptic vesicle glycoprotein 2A (SV2A). It is being investigated for whether it is able to improve cognition in Alzheimer’s and other dementias, as well as in major depression and schizophrenia.

SV2A is the target of the anti-seizure medication levetiracetam, and plays an important if not fully understood role in neuronal excitability and neurotransmission. Discoveries about the contribution of hippocampal hyperexcitability and epileptic brain activity to cognitive decline spurred interest in repurposing epilepsy therapies to treat AD (e.g., Aug 2012 news; Vossel et al., 2016). Levetiracetam and a low-dose formulation, AGB101, are currently in Phase 2/3 trials for AD.

Discovered at UCB Biopharma in Belgium, SDI-118 belongs to a new class of SV2A binders. According to UCB, it lacks anti-convulsant and anti-seizure activity, but maintains efficacy as a cognitive enhancer in preclinical studies (Jun 2019 company report). In 2018, UCB spun out a new company, Syndesi Therapeutics, to further develop SDI-118 and other novel SV2A modulators.

Findings

In November 2019, Syndesi announced completion of a first-in-human study. Single doses of SDI-118 up to 80 mg were reported to be safe and well-tolerated in healthy men. Adverse events were mild, increased with dose, and were mainly dizziness, daytime sleepiness, and longer nighttime sleep. Pharmacokinetics supported once-daily dosing. SV2A target engagement in the brain exceeded 90 percent at higher doses, based on PET imaging (press release; Botermans et al., 2022). In January 2021, the company reported that the drug was well-tolerated after two weeks of dosing in young or elderly participants. A single dose of SDI-118 was claimed to cause changes in brain activity, as measured by quantitative electroencephalography, in healthy young volunteers (press release). 

In September 2021, Syndesi began two additional Phase 1 trials that were listed in clinicaltrials.gov. The first was to enroll 60 elderly men and women with cognitive decline to receive SDI-118 capsules or placebo for 17 days. Endpoints were safety, adverse events, and several cognitive tests including Cogstate Brief Battery, and others. The study, in Germany and the United Kingdom, was also to include functional MRI. A second study with similar endpoints was to enroll 90 people in remission from depression who reported subjective cognitive impairment. 

In March 2022, AbbVie acquired Syndesi and the rights to SDI-118 (press release). At that time, the first trial was terminated after enrolling five patients; the second trial was withdrawn before any participants were enrolled. The cause was listed as a change in development plans.

AbbVie began development of ABBV-552 in January 2023 with a Phase 1 safety study in 18 healthy Japanese and Chinese participants. Dosing is to be one capsule, or one capsule weekly for three weeks, against primary outcomes of adverse events and pharmacokinetics. The trial will finish in April 2023.

For details on SDI-118 and ABBV-552 trials, see clinicaltrials.gov.