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Clinical Trial
. 2022 Jun 1;79(6):565-574.
doi: 10.1001/jamaneurol.2022.0983.

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

Michael S Rafii  1 , Olivier Sol  2 , William C Mobley  3 , Saskia Delpretti  2 , Brian G Skotko  4 , Anna D Burke  5 , Marwan N Sabbagh  5 , Shauna H Yuan  6 , Robert A Rissman  3 , Margaret Pulsifer  4 , Casey Evans  4 , A Carol Evans  3 , Gregory Beth  2 , Nicolas Fournier  2 , Julian A Gray  2 , Antonio Melo Dos Santos  2 , Valerie Hliva  2 , Marija Vukicevic  2 , Marie Kosco-Vilbois  2 , Johannes Streffer  2 , Andrea Pfeifer  2 , Howard H Feldman  3   7
Affiliations
Clinical Trial

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

Michael S Rafii et al. JAMA Neurol. .

Abstract

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-β (Aβ). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aβ 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-Aβ 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-Aβ 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 Aβ1-40 and Aβ1-42 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-Aβ 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rafii reported receiving grants from the National Institutes of Health (NIH) and personal fees from AC Immune during the conduct of the study and personal fees from Alzheon and Keystone Bio outside the submitted work. Dr Sol reported receiving personal fees from AC Immune outside the submitted work. Dr Mobley reported receiving grants from AC Immune, the LuMind IDSC Foundation, and the NIH and personal fees from AC Immune during the conduct of the study; grants from AC Immune, Annovis Bio, and Samumed (now Biosplice Therapeutics); personal fees from AC Immune, Alzheon, Annovis Bio, Cortexyme, Pfizer, and Samumed (now Biosplice Therapeutics); serving as a board member of ProMIS Neurosciences; owning stock options in CuraSen Therapeutics; and owning a patent for a gamma secretase modulator (licensed to the University of California, San Diego [UCSD]) outside the submitted work. Dr Delpretti reported receiving grants from the LuMind IDSC Foundation and the NIH and personal fees from AC Immune during the conduct of the study and receiving personal fees from AC Immune outside the submitted work. Dr Skotko reported receiving grants from UCSD during the conduct of the study; grants from F. Hoffmann-La Roche and the LuMind IDSC Foundation; personal fees from the Gerson Lehrman Group; and royalties from Woodbine House and serving on the honorary board of directors of the Massachusetts Down Syndrome Congress and the professional advisory committee of the National Center for Prenatal and Postnatal Down Syndrome Resources outside the submitted work. Dr Sabbagh reported receiving personal fees from Biogen, Cortexyme, Eisai Co, Eli Lilly and Company, Qynapse, Renew Research, Roche, and T3D Therapeutics and owning stock in Alzheon, Athira Pharma, Cognoptix, and uMethodHealth outside the submitted work. Dr Evans reported receiving grants from the LuMind IDCS Foundation during the conduct of the study. Dr Beth reported receiving grants from the LuMind IDCS Foundation and the NIH and personal fees from AC Immune during the conduct of the study and receiving personal fees from AC Immune outside the submitted work. Dr Fournier reported receiving grants from the LuMind IDSC Foundation and the NIH and personal fees from AC Immune during the conduct of the study and receiving personal fees from AC Immune outside the submitted work. Dr Gray reported receiving grants from AC Immune, the LuMind IDSC Foundation and the NIH and personal fees from AC Immune during the conduct of the study and receiving personal fees from AC Immune outside the submitted work. Dr Melo dos Santos reported receiving grants from the LuMind IDSC Foundation and the NIH and personal fees from AC Immune during the conduct of the study and receiving personal fees from AC Immune outside the submitted work. Dr Hliva reported receiving grants from the LuMind IDSC Foundation and the NIH and personal fees from AC Immune during the conduct of the study and receiving personal fees from AC Immune outside the submitted work. Dr Vukicevic reported receiving grants from the LuMind IDSC Foundation and the NIH and personal fees from AC Immune during the conduct of the study and receiving personal fees from AC Immune outside the submitted work. Dr Kosco-Vilbois reported receiving grants from the LuMind IDSC Foundation and the NIH and personal fees from AC Immune during the conduct of the study. Dr Streffer reported receiving grants from the LuMind IDSC Foundation and the NIH and personal fees from AC Immune during the conduct of the study and receiving personal fees from AC Immune outside the submitted work. Dr Pfeifer reported receiving personal fees from AC Immune during the conduct of the study and outside the submitted work. Dr Feldman reported receiving grants from AC Immune and the NIH during the conduct of the study and receiving grants from Annovis Bio, Biohaven Pharmaceutical Holding Company, the LuMind IDSC Foundation, and Vivoryon Therapeutics and personal fees from the World Events Forum and serving as a consultant for Arkuda Therapeutics, Axon Neuroscience, Biosplice Therapeutics, Janssen Pharmaceuticals, Novo Nordisk, Roche/Genentech, Samus Therapeutics, and the Tau Consortium outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flowchart
aOne participant was rescreened. bTwo participants discontinued participation because they were unwilling to attend the final study visit (week 96) due to the risk of COVID-19.
Figure 2.
Figure 2.. Anti–Amyloid-β (Anti-Aβ) 1-42 Immunoglobulin G Titer Values in Serum of Modified Intention-to-Treat Population by Study Visit
Values were obtained using the Meso Scale Discovery Free Assay. Whiskers represent 95% CIs. Arrows indicate time points of study drug administration. IgG indicates immunoglobulin G; LLOQ, lower limit of quantification.
Figure 3.
Figure 3.. Amyloid-β (Aβ) 1-40 and Aβ 1-42 Levels in Plasma of Modified Intention-to-Treat Population by Study Visit
Whiskers represent 95% CIs. Arrows indicate time points of study drug administration.
See this image and copyright information in PMC

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