ALZN: Coordinated Offensive on Alzheimer’s Disease

By John Vandermosten, CFA

NASDAQ:ALZN

Alzheimer’s Disease (AD) is a feared diagnosis that afflicts many older individuals, particularly women and those with a genetic predisposition for the condition. AD is so frightening in large part because there have been no effective treatments approved for it, despite a dramatic need. With near six million Americans living with AD, growing to an anticipated 13 million by 2050, aggressive action is needed.

Good news emerged last year for AD patients when Biogen’s drug Aduhelm® was approved by the U.S. Food and Drug Administration (FDA). While it was not the cure-all that many wanted to see, the product showed promise in reducing amyloid beta (amyloid β) plaques. Despite its limitations, many see Aduhelm as a stepping stone to more effective approaches in the future for this degenerative disease. One of the companies working hard to develop this next generation of Alzheimer’s drug is Alzamend Neuro (NASDAQ:ALZN). The company is an early clinical-stage biopharmaceutical company focused on developing novel products for the treatment of neurodegenerative and psychiatric disorders. Its two pipeline candidates are both targeting Alzheimer’s, and approaching it from different directions.

In an earlier report titled An Elemental Approach to Alzheimer’s Disease, we reviewed Alzamend’s first candidate, AL001, which recently completed a Phase I clinical trial and is planning to launch a Phase II in the second quarter of 2022. With this leading agent, the company is in the translation phase of research into clinical practice. AL001 is a patented ionic co-crystal of lithium, L-proline, and salicylate. In rodent studies AL001 demonstrated persistent enhanced brain lithium levels and improved neurodegenerative disease efficacy indicators compared to lithium carbonate. These pre-clinical studies demonstrated the potential for effective treatment of AD and other neurodegenerative and psychiatric disorders via a potentially improved systemic safety profile over marketed lithium products. Lithium delivered from AL001 was bioequivalent systemically (measured via blood levels) to lithium carbonate in the Phase I study. Notably, this can help mitigate regulatory burdens when proceeding into later phase studies by serving as a clinical bridge to data from approved and marketed lithium products.

The second candidate in the company’s pipeline is AL002, which is being prepared as the subject of an upcoming investigational new drug (IND) application to the FDA. This preclinical stage drug candidate uses mutant peptide sensitized immune cells as a therapeutic vaccine which seeks to restore the ability of the patient’s immune system to battle AD. AL002 is an autologous (patient-specific) cell therapy produced in the laboratory using peptide-stimulated immune cells derived from CD14+ cells harvested from the patient’s blood. The peptide sensitized dendritic cells (DCs) are manufactured into enriched AL002, which is later injected back into the patient as a therapeutic vaccine.

Alzheimer’s Disease Prevalence and Costs

With a global prevalence of 44 million and US prevalence of approximately 5.5 million cases, AD is a significant health concern associated with a heavy economic burden.1 There are also an estimated 245,000 cases of early onset AD around the globe,2 with 37,000 in the United States, each year.3 Following cancer and cardiovascular disease, AD ranks 3rd in terms of US health expenses, but experts estimate that it will surpass both and emerge as the leading source of health care costs within the next 20 years.4,5 In 2020, annual health care costs for AD were estimated at over $300 billion6 in the United States.

Women live longer than men and AD is mainly associated with age.

By the year 2025, the number of people ≥65 with AD is expected to reach 7.1 million in the United States, representing a near 22% increase from the 5.8 million in 2020. If disease modifying treatments are not found, this number is expected to rise to 13.8 million by 2050.7

Treatment Options for Alzheimer’s Disease

One of the primary therapeutic avenues being explored in the battle against AD is immunotherapy, which involves fine-tuning the immune system by suppressing or enhancing its activity. Introducing immunotherapy (such as vaccination or antibody infusion) against AD-specific peptides has inspired optimism in preventing and treating AD. Immunotherapies may target amyloid β or tau proteins as part of their approach.

An effective immunotherapeutic agent should be able to remove amyloid plaques, restore immunity and slow or reverse cognitive decline. To accomplish this, scientists have been developing methods that employ both active (vaccine) and passive (antibody) immunotherapy to present their own strengths and weaknesses. The most salient example in the AD universe, Aduhelm, employs monoclonal antibodies as passive immunity for treatment.

Active and Passive Immunotherapy

Immunotherapy-targeting AD can be divided into two camps: active immunotherapy, which involves injection of amyloid β-42-containing antigens (vaccination) and passive immunotherapy, where preformed antibodies against the amyloid β-42 peptide (such as monoclonal antibodies) are administered. Thus, an immunotherapeutic approach involves active injection of amyloid β-based immunogens or passive infusion of amyloid β-specific antibodies.8

Active immunotherapy includes immunization of subjects employing amyloid β in a vaccine. In the active approach, the subject must undergo an incubation period after vaccination to produce sufficient antibodies. This will take a period of time as the body builds an immune response. In a middle-aged individual this could take a few weeks, but in the elderly, it can take longer or yield no reaction at all. In cases where the immune system is weaker and the disease is present, passive immunotherapy may be more appropriate. This effort directly delivers an antigen-specific antibody to individuals who show early signs of disease symptoms.

Most AD vaccines directly or indirectly target amyloid β-42 peptides to elicit an appropriate immune response (anti- amyloid β antibodies) that will not only clear the amyloid β deposits, but also improve cognitive and functional abilities.9 Using this technique, patients are injected with a purified form of an antigen, usually coupled to a different protein carrier or adjuvant that helps to prime the immune reaction. Active AD vaccines aim to elicit an adequate immune response to clear accumulated proteins. This method may generate long-term protective polyclonal antibodies through short-term administration of vaccines at a limited cost. However, it may also stimulate an adverse immunologic reaction and long-lasting adverse effects, especially in older people with low immune competence.10,11 Most active vaccine trials involve the administration of amyloid β-42 antigenic peptides. However, more recent studies make use of small amyloid β peptides, their DNA sequences, or prime-boost approaches to elicit the anti-amyloid β antibody production. This is usually achieved through B cell activation while avoiding T cell activation, which may still trigger autoimmunity.12,13 As the presence of amyloid β plaques is common across different forms of AD, the amyloid β peptide is a practical target.

AL002

Even though there are FDA-approved drugs for treatment of symptoms of AD, there has been limited success in slowing down AD, and no success in stopping the disease. However, science has learned a great deal from its investigations and has refined both the approach and the target. One of the candidates in pre-clinical development that has generated enthusiasm is AL002. It is more specific than many predecessors as it centers on toxic plaques. The drug is a patented molecule using mutant peptide sensitized immune cells as a therapeutic vaccine that may target the toxic molecules and restore the immune system’s ability to combat the neurodegenerative disorder. The candidate is licensed through a royalty-bearing worldwide license from the University of South Florida Research Foundation.14

The drug offers autologous treatment for AD. Its manufacturing process extracts CD14+ monocytes from a patient via leukapheresis and subsequently modifies the monocytes into DCs outside the body. The DCs are then stimulated with E22W, a man-made version of amyloid β that may trigger a more specific immune reaction in the patient. DCs are the primary antigen presenting cells in the immune system with critical roles. In the circulatory system, they are specialized for antigen uptake, processing and presentation to T-cells. Antigen-stimulated DCs migrate to secondary lymphoid organs to stimulate T-cells and initiate an immune response. DCs act as a natural adjuvant and provide balance to the immune system in contrast to other approaches which may stimulate an autoimmune response.

E22W is a peptide with a mutated T cell epitope of the patient’s own amyloid β. This E22W DC process may result in a more powerful and safer vaccine, since the mutation generates more new T cell epitopes on the peptide and can sensitize DCs without causing unwanted side effects. The process is conducted in the laboratory to bypass the anergy of an aged immune system. The E22W-stimulated DCs are primed to recognize features on toxic amyloid β plaques, but bypass harmless endogenous amyloid β. The modified cells are then enriched and returned to the patient in a series of injections. It is worth highlighting that E22W mutates the T cell epitope in order to avoid a natural T cell epitope induced autoimmune response and also generates more novel T cell epitopes. Thus, this subtle change broadens peptide exposures for DC sensitization to generate a more powerful personalized medicine for the AD patient.

Mechanism of Action

Except for the controversial Aduhelm, approved AD treatment options do not address the abundance of plaques in the brain of an AD subject. The presence of this extracellular protein led to the use of misfolded molecules contained in the plaques as the antigenic component of AL002. The brain’s lymphatic system then serves as a conduit for the circulation of the DC-based vaccine.15 AL002 is being developed as an anti-AD vaccine, which employs pulsed-DC activation of Tcells that stimulate the immune system, generating amyloid β-specific antibodies, which go on to clear amyloid plaques in the brain.16

For AD, in addition to obtaining desired effects, scientists must also fine tune the immune response in the target population. As with most of our body’s systems, the activity of our immune system diminishes as we age. In order to stimulate sufficient immunogenicity, Alzamend has proposed methods with high immune-effective cell conversion that were tested in senile mice by sensitizing DC cells.17

AL002 is thought to work by stimulating the immune system to prevent the formation and facilitate the breakdown of amyloid β, which builds up in the brain to form plaques and subsequently blocks neurological brain signals, ultimately leading to the symptoms and onset of AD. AL002 is an immunotherapeutic agent designed to appropriately modify the immune response in a manner consistent with the underlying disease. It may strengthen the immune system of AD patients who are predominantly elderly individuals with less active immune systems. The immune-based approach attempts to inhibit the natural process of immunological aging by restoring the balance of the immune system through immunomodulation.

AL002 Development

With an influx of funding from its June 2021 initial public offering (IPO), Alzamend began toxicology work on AL002 in an effort to advance it further toward the clinic. Results from the testing were reported in July 2021. Toxicology studies were conducted using a transgenic mouse model of AD and a cell-based therapeutic vaccine in an effort to boost immunity and mitigate AD. In this study, AL002-sensitized cells in transgenic mice were administered five doses of AL002 in an attempt to sensitize them and to determine tolerability. Following the administration of five injections over a three-month period, the mice were evaluated for potential toxicity and reversibility of any findings at 75 and 90 days after dosing. Histopathology results showed that there was no indication of T-cell infiltration or meningoencephalitis suggesting that AL002 therapy is safe and tolerable as there were no concerning adverse effects. With respect to other safety concerns, in the animal models there were no treatment-related mortalities, adverse effects on clinical observations, body weight parameters, organ weight parameters, clinical pathology parameters, gross pathology observations, or histopathologic observations in the main study or the recovery phase.

In late July, Alzamend submitted a pre-IND meeting request for AL002 to the FDA. Two months later, the company received a written response. Based on the therapeutic candidate’s favorable toxicology results, Alzamend expects to conduct a combined Phase I/II study following an IND application submission in the second quarter of 2022. If the FDA clears Alzamend’s IND, the clinical trial is expected to start in the third quarter of 2022. The Phase I aspect of the study is designed as a placebo-controlled, double-blinded, clinical trial in patients with early stage, mild to moderate AD. It will evaluate feasibility based on the efficacy, safety, and tolerability of AL002 treatment. Participants will be enrolled and dosed for six months and then followed for another six months to evaluate safety and efficacy durability, for a total enrollment time of one year. An interim statistical analysis is planned six months after the multiple-dosing phase of the study.

The primary endpoint is safety. For efficacy, blood and CSF amyloid β and phosphorylated tau 217, T cells, interferon γ and cytokines will be monitored. PET scans will be conducted to identify amyloid β in the brain and amyloid β-specific antibodies will be measured in blood and CSF.

Summary

Following its June 2021 IPO, Alzamend initiated efforts to advance both of its AD candidates into the clinic. The lead candidate, AL001, recently conducted a Phase I clinical trial in Alzheimer’s patients and will soon begin a Phase II. AL002 is close on its heels and should start in a human clinical trial shortly after IND clearance. AL002 is a therapeutic vaccine that uses the body’s immune system to identify and clear amyloid β plaques. Approaching AD from a variety of directions is key to finding a solution for this pervasive, expensive, and devastating disease and Alzamend’s immunotherapy-based therapeutic vaccine has demonstrated early potential. Preclinical work with the candidate supports its safety and tolerability and its ability to elicit a high and long-lasting antibody response. Following IND clearance, AL002 is expected to start enrolling Alzheimer’s patients later this year in a combined Phase I/II study, offering a novel approach to addressing this burdensome disease.

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1. Alzheimer’s Disease Statistics. Prevalence. Accessed January 2021.

2. In Alzheimer’s Association, Global Dementia Cases Forecasted to Triple by 2050 there were 350,000 estimated cases of early onset dementia per year. 60-80% of dementia cases are considered Alzheimer’s disease (2020 Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2020 Mar 10. doi: 10.1002/alz.12068). We applied the median proportion (70%) to the number of dementia cases to generate the estimate as to the number of early onset AD.

3. Blue Cross Blue Shield. Early-Onset Dementia and Alzheimer’s Rates Grow for Younger American Adults. February 27, 2020.

4. Alzheimer’s Association. 2012 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association (2012; 8(2):131–168.

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14. https://www.reuters.com/companies/ALZN.OQ

15. Cheng J, Lin X, Morgan D, Gordon M, Chen X, Wang ZH, Li HN, He LJ, Zhou SF, Cao C. Dendritic and Langerhans cells respond to Aβ peptides differently: implication for AD immunotherapy. Oncotarget. 2015 Nov 3;6(34):35443-57.

16. https://alzamend.com/about/

17. Cheng J, Lin X, Morgan D, Gordon M, Chen X, Wang ZH, Li HN, He LJ, Zhou SF, Cao C. Dendritic and Langerhans cells respond to Aβ peptides differently: implication for AD immunotherapy. Oncotarget. 2015 Nov 3;6(34):35443-57.

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