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FDA Clears IND for Antiamyloid Antibody for Alzheimer Disease, Set to Initiate Trial

In preclinical studies, the investigational agent has demonstrated a clearance of both pyroglutamate modified and unmodified Aß plaque in brain tissue concentrations.

According to a new announcement, the FDA has cleared an investigational new drug application (IND) for Prothena’s best-in-class antiamyloid-ß (anti-Aß) antibody, PRX012, a treatment in the development for Alzheimer disease (AD) that has shown positive preclinical results.1

The investigational agent will now be evaluated into a phase 1 single ascending dose (SAD) study, beginning by the end of 2022, that will assess safety, tolerability, immunogenicity, and pharmacokinetics in health volunteers and patients with AD. Patients in the randomized, double-blind, placebo-controlled trial will be randomized to receive a single subcutaneous injection of either PRX012 or placebo.

"With Alzheimer’s affecting more than 50 million people worldwide, we are committed to bringing a paradigm-shifting treatment to patients as quickly as possible. Having submitted our IND during this first quarter, we are excited to announce the initiation of this first-in-human study. PRX012’s high binding potency and subcutaneous administration has the potential to serve as a foundational anti-Aβ treatment for Alzheimer’s disease," Gene Kinney, PhD, president and chief executive officer, Prothena, said in a statement.1

Although many antiamyloid agents have been assessed in the AD field, PRX012 is expected to result in less variance of antibody concentrations in the brain relative to others, according to Prothena. In preclinical studies, PRX012 and other Prothena N-terminal anti-Aß antibodies promoted rapid and robust microglia-mediated clearance of Aß species associated with plaques in ex vivo cryostatic sections of human AD tissue.2 Additionally, the agent has been shown to bind to beta amyloid plaques and oligomers with high avidity, enabling effective levels of Aß plaque occupancy at relatively lower dose ranges.1

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In the same analysis, test antibodies or isotype control were applied to plaque-bearing AD tissue samples, which were then incubated with murine microglia for 72 hours. At the end of the analysis, PRX012 significantly reduced both Aß1-42 levels as well as pyroglutamate-modified Aß species, leaving the study investigators to conclude further development of the investigational agent as an immunotherapy for AD.2

Kinney added, "We intend to leverage our multiple decades of experience and expertise in protein dysregulation together with clinical and regulatory learnings from first generation anti-Aβ therapies to maximize the probability of success for our PRX012 program to deliver a best-in-class treatment to patients with Alzheimer’s and their families."1

The conversations of anti-Aß monoclonal antibodies have dominated the AD field for the past 20 years, as researchers continue to search for new disease-modifying therapeutics. In June 2021, aducanumab (Aduhelm; Biogen), another anti-Aß medication, became the first novel FDA-approved drug for patients with AD since 2003.3 Approved under the accelerated approval pathway, which requires additional phase 4 study to confirm benefit of the drug, several other agents that share similar mechanisms may be in line for the same.

Lecanemab (Eisai and Biogen), formerly known as BAN2401, has also shown promise in the pipeline as an anti-Aß medication. In June 2021, it gained breakthrough therapy designation for its phase 2b proof-of-concept trial (NCT017677311) that showed a reduction in brain amyloid in patients with mild cognitive impairment due to AD or Alzheimer dementia.4 A few months later, the companies announced they were in the process of completing a rolling biologics license application submission for lecanemab through the accelerated approval pathway.5

REFERENCES
1. Prothena Announces FDA Clearance of IND for PRX012, a subcutaneous anti-amyloid beta antibody under investigation for the treatment of Alzheimer disease. News release. Prothena. March 28, 2022. Accessed March 29, 2022. https://ir.prothena.com/press-releases/news-release-details/2022/Prothena-Announces-FDA-Clearance-of-IND-for-PRX012-a-Subcutaneous-Anti-Amyloid-Beta-Antibody-Under-Investigation-for-the-Treatment-of-Alzheimers-Disease/default.aspx
2. Tam S, Zhang G, Li L, et al. PRX012 induces microglia-mediated clearance of pyroglutamate-modified Aß in Alzheimer disease brain tissue. Alzheim Dement. 2021;17(S9): e057773. doi:10.1002/alz/057773
3. FDA’s Decision to Approve New Treatment for Alzheimer’s Disease. FDA. June 7, 20121. Accessed March 29, 2022. https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease
4. 18-month, pre-specified analysis showing consistent reduction in clinical outcome measures from a lecanemab (BAN2401) phase 2b clinical trial in early Alzheimer disease published in peer-reviewed journal, Alzheimer’s Research and Therapy. News release. Eisai. Biogen. April 19, 2021. Accessed March 29, 2022. https://www.prnewswire.com/news-releases/18-month-pre-specified-analysis-showing-consistent-reduction-in-clinical-outcome-measures-from-a-lecanemab-ban2401-phase-2b-clinical-trial-in-early-alzheimers-disease-published-in-peer-reviewed-journal-alzheimers-research-an-301271976.html
5. Eisai and Biogen announces US FDA grants breakthrough therapy designation for lecanemab (BAN2401), an anti-amyloid beta protofibril antibody for the treatment of Alzheimer disease. News release. June 23, 2021. Accessed March 29, 2022.https://www.prnewswire.com/news-releases/eisai-and-biogen-inc-announce-us-fda-grants-breakthrough-therapy-designation-for-lecanemab-ban2401-an-anti-amyloid-beta-protofibril-antibody-for-the-treatment-of-alzheimers-disease-301318796.html