Alzheimer's Disease Vaccine and Monoclonal Antibody Clinical Trials 2024

As of May 2024, the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), Japan, and the United Kingdom's NHS have not authorized preventive Alzheimer's disease (AD) vaccines or approved therapeutics for bipolar disorder (BD), major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Recently, monoclonal antibody intravenous infusion therapies (Leqembi® and Aduhelm®) have been approved in the U.S. and Japan to treat, not prevent, early AD, a degenerative brain disease.

Alzheimer's Vaccine Candidates 2024

AADvac1 is a therapeutic vaccine candidate for Alzheimer's disease that targets misfolded tau protein, a common denominator of neurofibrillary pathology.

ACI-35.030 is a first-in-class AD vaccine candidate designed to generate a specific antibody response against pTau proteins in the brain. AC Immune is collaborating with Janssen Pharmaceuticals, Inc. Recent results show that ACI-35.030 treatment rapidly leads to the strong and durable induction of antibodies specific for pathological forms of Tau, such as pTau and its aggregated form, ePHF. In addition, the ACI-35.030-induced antibody response was sustained and could be periodically boosted over 72 weeks. 

Alzamend Neuro, Inc.'s AL001 novel lithium-delivery system can potentially deliver the benefits of marketed lithium salts while mitigating or avoiding currently experienced toxicities associated with lithium. AL001 is designed to distribute lithium in the brain, resulting in lower exposure to other body organs and an improved safety profile compared to currently marketed lithium salts. Alzamend Neuro announced in October 2023 the receipt of a "Study May Proceed" letter from the U.S. FDA for the initiation of study AL001-BD01, a Phase IIA clinical study of AL001 for BD type 1. On March 22, 2023, the Company announced the completion of the clinical portion of its Phase IIA multiple ascending dose study. On November 20, 2023, the Company announced a receipt of a "Study May Proceed" letter from the FDA for the initiation of study AL001-MDD01, a Phase IIA clinical study of AL001 for treating patients with MDD. On December 11, 2023, the Company received a "Study May Proceed" letter from the FDA for the initiation of study AL001-PTSD01, a Phase IIA clinical study of AL001 for treating patients with PTSD. On May 9, 2024, the Company announced a stock offering for $25,000,000.

Alzinova AB's ALZ101 is an active, therapeutic oligomer-specific vaccine candidate that stimulates the production of antibodies against the toxic Aβ oligomers. The first-in-human Phase 1b study in patients with early AD was initiated in 2021. Alzamend is also pursuing AL001 for the treatment of bipolar disorder and PTSD. Topline data for the analysis is anticipated in the second half of 2023. In addition, the Company partnered with the Miller School of Medicine and the Interdisciplinary Stem Cell Institute at the University of Miami in Florida for its Phase I/IIA clinical trial of ALZN002.

Araclon Biotech's ABvac40 is an active vaccine against the Aβ40 peptide for treating patients with early-stage Alzheimer's disease. On October 25, 2023, the Company reported a phase 2 trial met primary endpoints, confirming the vaccine's safety, tolerability, and robust immune response against the Aβ40 peptide in early-stage Alzheimer's patients. ABvac40 treatment slowed disease progression up to 38% compared with placebo as measured by the Mini-Mental State Examination score.

ADvantage Therapeutics is developing AD04™ as a novel immunotherapy for mild Alzheimer's Disease. The compound has been used as an adjuvant in human and animal vaccination programs. The Company believes AD04™ may function as an immunomodulator, stimulating and/or regulating the immune system to reduce AD pathology. On November 27, 2023, the Company announced the first patient enrolled in AD04's European Phase 2b clinical trial.

Alzheimer's Monoclonal Antibody Treatments

Aduhelm™ is an amyloid beta-directed antibody injection of 100 mg/mL for intravenous use indicated to treat AD and was approved by the FDA on July 8, 2021. The FDA issued approval to Biogen and Eisai Co., Ltd. 

Leqembi™ gained U.S. FDA traditional approval for treating AD l on July 6, 2023. The approval of Leqembi (BAN2401, lecanemab-irmb) was granted to Eisai R&D Management Co., Ltd. On September 25, 2023, Japan issued a similar authorization, as did China on January 9, 2024.

Gantenerumab is a fully human IgG1 antibody that binds with subnanomolar affinity to a conformational epitope on Aβ fibrils. It encompasses both N-terminal and central amino acids of Aβ. A November 2023 study found that Gantenerumab led to a lower amyloid plaque burden among persons with early AD than placebo at 116 weeks. Still, it was not associated with slower clinical decline. (GRADUATE I and II; NCT03444870 and NCT03443973. In 2021, Gantenerumab was granted U.S. FDA Breakthrough Therapy Designation in Alzheimer's Disease.

ACI-24.060 is an amyloid-beta (Abeta) antibody produced by AC Immune SA and derived from the Company's SupraAntigen®  platform. The FDA awarded Fast Track destination on June 27, 2023. On May 13, 2024, AC Immune and Takeda announced a partnership.

ADvantage Therapeutics, Inc. announced that the UK's MHRA had granted AD04™ an Innovation Passport for treating AD under the Innovative Licensing and Access Pathway on April 5, 2023. Authorities in Poland, Bulgaria, and Slovakia approved its Clinical Trial Application on June 20, 2023, to conduct a clinical trial with AD04.

ProMIS therapeutic product candidate PMN310 is a monoclonal therapeutic antibody designed to treat AD, consisting of an AβO conformational peptide epitope conjugated to KLH as a carrier protein to provide T cell help, elicited robust and sustained antibody responses with either alum or QS-21 as the adjuvants.

UB-311 is a synthetic, peptide-based active immunotherapy candidate targeting toxic forms of aggregated beta-amyloid in the brain to treat and prevent Alzheimer's disease. Phase 1, Phase 2a, and Phase 2a long-term extension trials have shown UB-311 to be well tolerated in mild-to-moderate AD patients over three years of repeat dosing, with a safety profile comparable to placebo and no cases of amyloid-related imaging abnormalities-edema in the Phase 2a trial. It was granted U.S. FDA Fast Track status.

Alzheimer's Treatments

Eli Lilly and Company announced on January 19, 2023, that the U.S. FDA had issued a complete response letter for the accelerated approval submission of donanemab for the treatment of early symptomatic Alzheimer's disease due to the limited number of patients with at least 12 months of drug exposure data provided in the submission. No other deficiencies in the application were noted. The confirmatory Phase 3 TRAILBLAZER-ALZ 2 clinical trial is ongoing, with topline data read-out expected in 2023.

Eli Lilly and Company presented an interim analysis from a phase 1 study of LY3372993 on March 31, 2023. Remternetug (LY3372993) is an IgG1 monoclonal antibody directed at the pyroglutamate modification of the third amino acid of the amyloid-beta peptide that is present only in brain amyloid plaques. This antibody demonstrated rapid and robust amyloid plaque reduction in participants with AD. The safety, tolerability, and pharmacokinetic/pharmacodynamic data support the ongoing Phase 3 trial (NCT05463731)

Alzamend Neuro, Inc.'s AL001 is a patented ionic cocrystal technology that delivers a therapeutic combination of lithium, proline, and salicylate to treat Alzheimer's and other neurodegenerative diseases and psychiatric disorders. ALZN002 immunotherapy is intended to treat patients diagnosed with Alzheimer's by inducing their antibodies. These are targeted to remove the Aβ1‑42 protein, reducing the deposition of amyloid plaque in the brain and thereby reducing the progression of disease-associated clinical signs and symptoms. The Company partnered with Biorasi as its contract research organization.

Prothena Corporation's PRX012 is a next-generation, high-binding potency antibody designed to enable subcutaneous dosing on a patient-friendly, convenient administration schedule, potentially providing greater accessibility for AD patients and caregivers. Accordingly, the U.S. FDA granted Fast Track Designation on April 26, 2022.

Synaptogenix, Inc.'s Bryostatin-1 is targeting Alzheimer's disease. The paper "Advanced Alzheimer's Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial" concluded that the Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial. In contrast, the placebo patients declined by -12.8 SIB points.

BCG Vaccination and Dementia

An Original Investigation led by investigators at Massachusetts General Hospital and Brigham and Women's Hospital was published by The JAMA Network on May 19, 2023, concluding that BCG vaccination was associated with a lower rate and risk of Alzheimer's disease and related Dementia. In a risks analysis, the BCG vaccine was associated with a lower risk of Alzheimer's disease and related dementias (ADRD) (5-year risk difference, −0.011; 95% CI, −0.019 to −0.003) and a decreased risk of death in patients without an earlier diagnosis of ADRD (5-year risk difference, −0.056; 95% CI, −0.075 to −0.037).

Alzheimer's Testing

Researchers at Karolinska Institutet announced on April 12, 2023, that a type of sugar molecule in the blood is associated with the level of Tau. This protein plays a critical role in the development of severe Dementia. Therefore, bisecting N-acetylglucosamine and Tau are valuable blood biomarkers for predicting AD. The U.S. FDA permitted marketing on May 4, 2022, for Fujirebio Diagnostics, Inc. Lumipulse G β-Amyloid Ratio (1-42/1-40) in vitro diagnostic test intended to be used in adult patients aged 55 years and older, presenting with cognitive impairment who are being evaluated for AD and other causes of cognitive decline.

On December 27, 2022, a new study, Brain-derived Tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration, presented a novel blood test that assessed brain-derived Tau-detected Alzheimer' s-related neurodegeneration and differentiated Alzheimer's from other neurodegenerative diseases. Furthermore, this innovative test outperformed total Tau and, unlike neurofilament light, showed specificity to Alzheimer's disease-type neurodegeneration. Thus, brain-derived Tau demonstrates the potential to complete the AT(N) scheme in blood and will be used in evaluating.

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