Therapeutics

AV-1959D

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Overview

Name: AV-1959D
Synonyms: AV-1959
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)

Background

AV-1959D is an NIH-funded DNA vaccine designed to elicit antibodies to Aβ peptides without activating potentially harmful autoreactive T cells. This vaccine fuses coding sequences of three copies of Aβ1-11 to 12 T-cell-activating epitopes. They include a synthetic pan-T cell antigen, antigens derived from Tetanus toxin, and from the hepatitis B and influenza viruses. The foreign antigens function to boost antibody responses by activating memory and helper T cells. This is important in old people in who tend to mount weaker responses to vaccines.

AV-1959D grew out of a years-long optimization process that began with identification of Aβ1-11 as the dominant B-cell epitope in Aβ peptides, followed by preclinical testing of peptide and DNA vaccines combining this epitope with increasing numbers of T-cell epitopes.

Early versions of the vaccine were reported to prevent or reverse plaque accumulation in mouse amyloidosis models, without triggering T cell infiltration in the brain (Movsesyan et al., 2008; Petrushina et al., 2007). In mice, rabbits, and nonhuman primates, electroporation of AV-1959D or similar constructs induced strong Aβ antibody responses (Davtyan et al., 2014; Davtyan et al., 2014; Ghochikyan et al., 2013). AV-1959LR is an mRNA version of the vaccine encapsulated in lipid-based nanoparticles; it generated high-titer Aβ antibodies in mice and nonhuman primates (Hovakimyan et al., 2024).

In preclinical safety studies in mice, the vaccine persisted at the injection site for up to two months, but did not travel to distant tissues. No toxicities or ARIA-like reactions were observed in mice with cerebral amyloid angiopathy Tg-Sw-DI mice. The vaccine induced no T- or B-cell infiltration or glial activation in brain, and did not worsen CAA or cause neurodegeneration (Petrushina et al., 2020).

The same platform, called MultiTEP, was used to produce recombinant protein or DNA vaccines to tau and α-synuclein, and α-synuclein, pyroglutamate-modified Aβ, and a dual Aβ/tau vaccine ( (Hovakimyan et al., 2022; Kim et al., 2022; Zagorski et al., 2023; Davtyan et al., 2019). The tau vaccine AV-1980R/A will begin Phase 1 trials in 2024.

Findings

In December 2022, the Institute for Molecular Medicine in Huntington Beach, California, registered a Phase 1 first-in-human study of AV-1959D, with a start date of February 2023. The single-ascending-dose study is to enroll 48 people with mild cognitive impairment due to Alzheimer’s disease. Three sequential cohorts will receive three needle-free injections into the skin of 500, 1,000, or 2,000 μg vaccine. A fourth cohort will get placebo. The primary outcome is adverse events. Secondary outcomes include other clinical and lab tests for safety, incidence of ARIA-E or -H, and levels of serum Aβ antibodies and autoreactive T helper cells. Funded by the National Institute on Aging, the study is recruiting at six sites in the U.S. through February 2026.

According to data presented at the October 2024 CTAD conference, the first two dose cohorts have been completed with only mild adverse events and no withdrawals. Results are expected in early 2025.

For details on this trial, see clinicaltrials.gov.

Last Updated: 21 Nov 2024

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References

Paper Citations

  1. Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud PB, Head E, Biragyn A, Cribbs DH, Agadjanyan MG. Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy. PLoS One. 2008;3(5):e2124. PubMed.
  2. Petrushina I, Ghochikyan A, Mktrichyan M, Mamikonyan G, Movsesyan N, Davtyan H, Patel A, Head E, Cribbs DH, Agadjanyan MG. Alzheimer's disease peptide epitope vaccine reduces insoluble but not soluble/oligomeric Abeta species in amyloid precursor protein transgenic mice. J Neurosci. 2007 Nov 14;27(46):12721-31. PubMed.
  3. Davtyan H, Ghochikyan A, Petrushina I, Hovakimyan A, Davtyan A, Cribbs DH, Agadjanyan MG. The MultiTEP platform-based Alzheimer's disease epitope vaccine activates a broad repertoire of T helper cells in nonhuman primates. Alzheimers Dement. 2014 May;10(3):271-83. Epub 2014 Feb 20 PubMed.
  4. Davtyan H, Hovakimyan A, Zagorski K, Davtyan A, Petrushina I, Agdashian D, Murthy V, Cribbs DH, Agadjanyan MG, Ghochikyan A. BTX AgilePulse(TM) system is an effective electroporation device for intramuscular and intradermal delivery of DNA vaccine. Curr Gene Ther. 2014;14(3):190-9. PubMed.
  5. Ghochikyan A, Davtyan H, Petrushina I, Hovakimyan A, Movsesyan N, Davtyan A, Kiyatkin A, Cribbs DH, Agadjanyan MG. Refinement of a DNA based Alzheimer's disease epitope vaccine in rabbits. Hum Vaccin Immunother. 2013 Feb 11;9(5) PubMed.
  6. Hovakimyan A, Chilingaryan G, King O, Capocchi JK, Chadarevian JP, Davtyan H, Kniazev R, Agadjanyan MG, Ghochikyan A. mRNA Vaccine for Alzheimer's Disease: Pilot Study. Vaccines (Basel). 2024 Jun 14;12(6) PubMed.
  7. Petrushina I, Hovakimyan A, Harahap-Carrillo IS, Davtyan H, Antonyan T, Chailyan G, Kazarian K, Antonenko M, Jullienne A, Hamer MM, Obenaus A, King O, Zagorski K, Blurton-Jones M, Cribbs DH, Lander H, Ghochikyan A, Agadjanyan MG. Characterization and preclinical evaluation of the cGMP grade DNA based vaccine, AV-1959D to enter the first-in-human clinical trials. Neurobiol Dis. 2020 Jun;139:104823. Epub 2020 Feb 28 PubMed.
  8. Hovakimyan A, Zagorski K, Chailyan G, Antonyan T, Melikyan L, Petrushina I, Batt DG, King O, Ghazaryan M, Donthi A, Foose C, Petrovsky N, Cribbs DH, Agadjanyan MG, Ghochikyan A. Immunogenicity of MultiTEP platform technology-based Tau vaccine in non-human primates. NPJ Vaccines. 2022 Oct 12;7(1):117. PubMed.
  9. Kim C, Hovakimyan A, Zagorski K, Antonyan T, Petrushina I, Davtyan H, Chailyan G, Hasselmann J, Iba M, Adame A, Rockenstein E, Szabo M, Blurton-Jones M, Cribbs DH, Ghochikyan A, Masliah E, Agadjanyan MG. Efficacy and immunogenicity of MultiTEP-based DNA vaccines targeting human α-synuclein: prelude for IND enabling studies. NPJ Vaccines. 2022 Jan 10;7(1):1. PubMed. Correction.
  10. Zagorski K, King O, Hovakimyan A, Petrushina I, Antonyan T, Chailyan G, Ghazaryan M, Hyrc KL, Chadarevian JP, Davtyan H, Blurton-Jones M, Cribbs DH, Agadjanyan MG, Ghochikyan A. Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer's Disease. Int J Mol Sci. 2023 Jun 6;24(12) PubMed.
  11. Davtyan H, Hovakimyan A, Kiani Shabestari S, Antonyan T, Coburn MA, Zagorski K, Chailyan G, Petrushina I, Svystun O, Danhash E, Petrovsky N, Cribbs DH, Agadjanyan MG, Blurton-Jones M, Ghochikyan A. Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice. Alzheimers Res Ther. 2019 Dec 17;11(1):107. PubMed.

External Citations

  1. clinicaltrials.gov
  2. NIH-funded

Further Reading