Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine in Adults With Down Syndrome: A Phase 1b Randomized Clinical Trial.

Importance: Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-ß (Aß). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aß pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined. Objective: To assess the safety and tolerability of the ACI-24 vaccine among adults with DS as well as its ability to induce immunogenicity measured by anti-Aß immunoglobulin G titers. Design, Setting, and Participants: This multicenter double-blind placebo-controlled dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020. A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate. Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27, 2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts (8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an additional 48 weeks of safety follow-up. Interventions: Participants were randomized to receive 7 subcutaneous injections of ACI-24, 300 µg or 1000 µg, or placebo. Main Outcomes and Measures: Primary outcomes were measures of safety and tolerability as well as antibody titers. Results: Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years; 9 participants were women, and 7 were men. All participants were White, and 1 participant had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events [83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events [85.6%]). No amyloid-related imaging abnormalities with edema or cerebral microhemorrhage and no evidence of central nervous system inflammation were observed on magnetic resonance imaging scans. Increases in anti-Aß immunoglobulin G titers were observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 µg and 2 receiving 1000 µg) compared with 0 participants receiving placebo. In addition, a greater increase was observed in plasma Aß1-40 and Aß1-42 levels among individuals receiving ACI-24. Conclusions and Relevance: In this study, the ACI-24 vaccine was safe and well tolerated in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target engagement were observed, and anti-Aß antibody titers were not associated with any adverse findings. These results support progression to clinical trials using an optimized formulation of the ACI-24 vaccine among individuals with DS. Trial Registration: ClinicalTrials.gov Identifier: NCT02738450.

The Surgical Approach to the Anterior Nucleus of Thalamus in Patients With Refractory Epilepsy: Experience from the International Multicenter Registry (MORE).

BACKGROUND: The Medtronic Registry for Epilepsy (MORE; Medtronic Inc, Dublin, Ireland) is an open label observational study evaluating the long-term effectiveness, safety, and performance of deep brain stimulation (DBS) of the anterior nucleus of thalamus (ANT) for the treatment of refractory epilepsy. OBJECTIVE: To compare the difference in success rate of placing contacts at ANT-target region (ANT-TR) between transventricular (TV) and extraventricular (EV) lead trajectories in 73 ANT-DBS implants in 17 European centers participating in the MORE registry. METHODS: The success rate of placing contacts at ANT-TR was evaluated using a screening method combining both individual patient imaging information and stereotactic atlas information to identify contacts at ANT-TR. RESULTS: EV lead trajectory was used in 53% of the trajectories. Approximately, 90% of the TV lead trajectories had at least 1 contact at ANT-TR, vs only 71% of the EV lead trajectories. The success rate for placing at least 1 contact at ANT-TR bilaterally was 84% for TV implants and 58% for EV implants (P < .05; Fisher's exact). No intracranial bleedings were observed, but 1 cortical infarct was reported following EV lead trajectory. CONCLUSION: The results of this registry support the use of TV lead trajectories for ANT-DBS as they have a higher probability in placing contacts at ANT-TR, without appearing to compromise procedural safety. Follow-up data collection is continuing in the MORE registry. These data will provide outcomes associated with TV and EV trajectories.