ALZN: An Elemental Approach to Alzheimer's Disease

By John Vandermosten, CFA

NASDAQ:ALZN | NASDAQ:BIIB

Alzamend Neuro, Inc. (NASDAQ:ALZN) is an early clinical-stage biopharmaceutical company focused on developing novel products for the treatment of neurodegenerative and psychiatric disorders. The Tampa, Florida-based company is developing multiple candidates primarily targeting Alzheimer’s disease but also bipolar disorder, depression and post-traumatic stress disorder. Its most advanced candidate is AL001, a patented ionic co-crystal technology delivering a therapeutic combination of lithium, proline and salicylate in the treatment of Alzheimer’s disease, or AD, and other neurodegenerative and psychiatric disorders.

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Alzheimer’s disease, which is Alzamend’s primary indication, is a debilitating and eventually fatal disease. It is associated with significant health care costs as it affects 6.2 million Americans; a number expected to increase to near 13 million individuals at an estimated cost of $1.1 trillion by 2050.1  To address the disease, Alzamend has developed a portfolio of product candidates, featuring AL001, a lithium-based compound which is classified as a neuroprotective agent. As lithium has been widely prescribed for bipolar and other mood disorders, it is a well understood and extensively studied drug. Alzamend intends to make the best use of lithium’s existing safety, adverse effect and tolerability data as it advances this neuroactive and neuroprotective agent that has been marketed for decades for multiple indications.

Lithium is considered to have a narrow therapeutic index, therefore, under/ overdoses and the need to monitor blood lithium levels are major disadvantages of currently marketed lithium products. AL001 is a crystal-engineered form of lithium containing salicylate and L-proline that was observed in animal studies to enhance lithium brain concentrations and favorably impact commonly recognized Alzheimer’s biomarkers and behavioral tests. These properties will be studied for translation to human Alzheimer’s sufferers and may improve outcomes for all lithium affective disorder/ neurodegenerative disease patients. Alzamend’s goal is to develop the next generation of lithium therapeutics with products that can enhance lithium brain exposure while reducing exposure elsewhere in the body, thereby requiring lower lithium doses overall to achieve efficacy without the need for routine lithium therapeutic drug level monitoring. As a result, the patient population for AL001 could extend from 6.2 million Americans (over 50 million globally) afflicted with AD to include an additional 33+ million Americans (over 400 million globally) afflicted with bipolar disorder, depression, and post-traumatic stress disorder, or PTSD.

The second candidate in Alzamend’s pipeline is AL002 (CAO22W) which is at a late preclinical stage. This agent relies on a patented method to restore the ability of the patient’s own immune system to battle AD. The technology employs a mutant peptide sensitized cell as a cell-based therapeutic vaccine.

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Alzheimer’s Disease

Alzheimer’s disease is a debilitating and eventually fatal neurodegenerative disorder characterized by progressive cognitive decline and neuropsychiatric findings such as weight loss, anxiety, depression, agitation and aggression. It is one of the most common types of dementia and affects thought, memory and language centers of the brain. Age and family history are often associated with the onset of AD and researchers are also studying the role of education, diet and environment.

A healthy adult brain has roughly 100 billion neurons that have special extensions called axons, which connect them with each other at synaptic junctions. At these intersections, they release various chemicals that function as messengers facilitating the communication between two neurons at the synapses. It is estimated that an adult brain contains 100 trillion synapses. In patients suffering from AD, nerve cells in the parts of brain that are involved in cognitive functions, such as learning and memory, are progressively destroyed.

In patients suffering from AD, protein fragments called beta-amyloid accumulate around the neurons, contributing to damage and death of neurons (neurodegeneration) by interfering with neuron-to-neuron interactions at these synaptic junctions. In addition, a type of abnormal protein, called tau protein (or tau tangles) accumulates within the neurons and blocks the transport of essential neurotransmitters. Tau further damages the cells and leads to a loss of chemical interactions at the synapses.

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The presence of toxic beta amyloid plaques causes inflammation and immune activation of the cleaning cells of the brain (microglia) which at a certain point cannot cope with the amount of debris to be cleared. Atrophy and shrinkage of the brain eventually ensues. The nerve damage in AD is not limited to memory areas in the brain. As it is a degenerative and progressive disease, AD patients eventually experience damage to other critical higher cortical brain areas eventually leading to the loss of basic bodily functions such as walking and eating, ultimately resulting in death. Alzheimer’s disease is thought to begin almost two decades before clinical symptoms are visible, with small changes in the brain that are initially unnoticeable to the affected person.

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The disease is diagnosed by assessing the medical history of the patient including their psychiatric, cognitive and behavioral changes, asking a family member to provide input regarding the alterations in the patient’s skills and behaviors, running cognitive tests, neurological and physical examinations and ruling out other possible causes by blood tests, cerebrospinal fluid (CSF) analysis by lumbar puncture and imaging studies such as PET-CT.

AD is a multifactorial disease with inherent and modifiable risk factors. Inherent risk factors include age, genetic predisposition and positive family history. A well-identified gene associated with increased risk for AD is the apolipoprotein-e4 (APOE-e4) gene that is associated with a cholesterol transport protein. In 2019, WHO published recommendations for modifiable risk factors such as regular physical activity, quitting smoking, managing hypertension and diabetes to reduce the risk of cognitive decline and dementia.5  In addition, research shows that a healthy diet, life-long learning and cognitive training are associated with lower risk of dementia.

AD Treatment Options

Unfortunately, there are no approved medications that significantly slow or stop the damage and destruction of neurons caused by AD. Until recently, the U.S. Food and Drug Administration (FDA) had approved only five drugs for the treatment of Alzheimer’s disease — rivastigmine, galantamine, donepezil, memantine, and memantine combined with donepezil. With the exception of memantine, these drugs do little but temporarily improve cognitive symptoms by increasing the amount of chemicals, called neurotransmitters, in the brain. Memantine blocks certain receptors in the brain from excess stimulation that can damage nerve cells. The effectiveness of these drugs varies between individuals and is temporary.

On June 7, 2021, the FDA granted approval for Biogen’s (NASDAQ:BIIB) aducanumab (AduhelmTM) as the first new drug in AD treatment for over two decades. In contrast to its predecessors, Aduhelm aims to target the underlying pathology in AD: the amyloid plaques in the brain. Despite the approval, the FDA acknowledges that the data included in the applicant’s submission were complex and residual uncertainties remain regarding Aduhelm’s clinical benefit.6

There are no drugs approved to specifically address the behavioral and psychiatric symptoms that may develop in moderate and severe AD. Antipsychotics are prescribed to tackle the hallucinations, aggression and agitation in severe AD patients; however, research has shown that some antipsychotics are associated with an increased risk of stroke and death in AD patients. The decision to use antipsychotics must be considered with extreme caution. The FDA has ordered manufacturers to label such drugs with a “black box warning” about their risks and a reminder that they are not yet approved to treat dementia symptoms.

Lithium

Lithium was approved by the FDA in 1970 and has been marketed for psychiatric disorders and human toxicology regarding lithium use has been extensively researched and described. Alzamend plans to take advantage of the existing knowledge regarding lithium’s safety profile, potentially reducing the regulatory burden associated with the pathway to approval. Clinical studies have indicated that lithium administered at doses lower than those used for affective disorders can favorably impact Alzheimer’s disease outcomes as discussed in a publication by Forlenza et al.7 Results discussed in this publication indicate that lithium treatment reduced cognitive decline vs. placebo and was safe and well tolerated at therapeutic doses.

AL001 (LiProSal)

AL001 is a patented ionic lithium co-crystal technology delivering a combination of lithium, proline and salicylate which is in development for disease modifying therapy of Alzheimer’s disease. This agent, belonging to the lithium class of neuroprotective drugs, has improved nonclinical pharmacokinetics compared to current FDA-approved lithium products by achieving better brain bioavailability. Lithium salts have historically been used in the treatment of mental disorders and evidence for broader use in neurological diseases and neuroprotection has emerged. Alzamend maintains intellectual property rights for the lithium salicylate proline combination and the molecule is protected by two royalty-bearing worldwide licenses held by the University of South Florida Research Foundation.8 Alzamend has completed the preclinical studies required to begin clinical trials and announced on September 13, 2021 that it began dosing participants in a six-month, Phase I bioavailability study with AL001. The study is expected to determine the frequency and dosing of AL001 to be used in subsequent Phase II safety and efficacy trials for AD patients.

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The AL001 formulation of lithium addresses several of the shortcomings of previous iterations of lithium carbonate. Previous versions presented a narrow therapeutic window that demanded frequent blood monitoring, required multiple administrations throughout the day to safety reach therapeutic concentrations and were associated with chronic toxicity, poor physicochemical properties and poor brain bioavailability. As illustrated in the following exhibit, AL001 shows improved nonclinical pharmacokinetics and bioavailability compared to approved lithium formulations, relatively flat plasma concentration over 48 hours and improved brain bioavailability.

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Mechanism of Action

AL001 is a novel ionic co-crystal of lithium salicylate proline. In addition to neurodegeneration, accumulation of amyloid proteins and disruption of synaptic connection in the brain, patients with Alzheimer’s disease also experience a range of emotional disturbances including anxiety, apathy, irritability, agitation, aggression and depression. Lithium salts have been used since the 1800s and have been rigorously studied in psychiatric disorders. Even today, lithium salts are considered the gold standard for prevention of manic episodes and suicidal potential in bipolar patients.

Recent data has shown that lithium plays a role in both treatment and prevention of AD. Clinical study results indicate that lithium helps reduce dementia, improve the preservation of cognitive function and reduce biomarkers for AD. The proposed mechanisms of action of lithium in AD are:

➢ Increasing brain-derived neurotrophic factor leading to restoration of learning and memory; and

➢ Attenuation of the production of inflammatory cytokines such as IL-6 and nitric oxide in activated microglia.

Research Findings and Stages

There is substantial evidence suggesting that lithium provides neuroprotective effects. With doses lower than typically used for mood stabilization, these findings translate into improved cognitive function and reduced biomarkers in clinical trials of mild cognitively impaired amnestic and Alzheimer’s disease patients.11  Other studies also suggest that long-term lithium treatment inhibits or slows down the core pathophysiologic features of AD in preclinical studies as well in human studies.12,13  Notably, in a recent review of 28 psychiatric medications, including antipsychotics, anticonvulsants and antidepressants, lithium had the most replicated evidence for neuroprotection in the widest range of neurodegenerative disease models.14

Earlier studies have suggested that this formulation of lithium is more effective in reducing Alzheimer’s disease pathology and has an improved safety profile compared to other formulations of lithium carbonate or lithium salicylate in Alzheimer’s mice models. In 2019, low dose LISPRO, an earlier designation of AL001, was shown to be superior in preventing associative memory decline, reduced irritability in female, transgenic AD mice when compared to other lithium compounds.15

AL001 Alzamend Studies

Alzamend conducted preclinical studies in 2016 and 2017 for AL001 showing safety with respect to major organs including kidney, heart, liver and lungs and was able to achieve 50% higher lithium levels compared with equimolar doses of lithium carbonate. The studies were conducted in both transgenic and non-transgenic mouse models. Cognitive behavior was measured via several standardized approaches (see following exhibit), demonstrating a 50% improvement in cognitive function. Favorable effects on depression were also observed.

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In comparison with lithium carbonate AL001 addresses AD along three axes:

➢ Reduction of amyloid beta;

➢ Reduction of tau phosphorylation; and

➢ Reduction of inflammation.

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Alzamend announced on September 13, 2021, that it began dosing participants in a six-month, Phase I bioavailability study with AL001. The Phase I study will investigate the pharmacokinetics of lithium following a single dose of AL001 compared to a typical single dose of a marketed 300 mg immediate-release lithium carbonate capsule in healthy subjects. The lithium and salicylate components of AL001 will be given within the limits already approved for use in patients. The purpose of the research study is to test the safety, tolerability, and bioavailability of the study drug, compared to the marketed formulation of the comparator, lithium carbonate. Results are expected to determine the optimal dosing and frequency for AL001 administration to be used in subsequent Phase II trials. At least 24 healthy male and female human subjects are targeted to complete the Phase I trial.

Summary

Alzheimer’s is a debilitating disease that robs an individual’s ability to remember, organize logical thought, control emotions and even regulate basic functions such as eating and walking. It affects not only the individual with the disease but also creates a heavy burden for the health care system and the patient’s caregivers. It is the only major disease where the death rate has increased over recent decades and where, disregarding the controversial Aduhelm, no disease modifying therapy has been successful. Alzamend’s repurposing of lithium and reformulation using co-crystal technology has demonstrated early promise in addressing AD along the axes of reduction in amyloid beta, phosphorylated tau and neuroinflammation. With supportive preclinical work, Alzamend’s initiation of human trials provides hope for the future in treatment and prevention of this terrible disease.

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________________________

1. 2021 Alzheimer’s Disease Facts and Figures; Race, Ethnicity and Alzheimer’s in America. Alzheimer’s Association, 2021.

2. Source: Alzamend 10-K (Annual report filed pursuant to Section 13 and 15(d)) filed with the Securities and Exchange Commission on July 29, 2021.

3. Source: Jeff Brender, January 2012. Structure of amyloid beta 1-40 created from pdb file 2lfm (public database) showing long range NOE constraints in red

4. 2020 Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2020 Mar 10. doi: 10.1002/alz.12068.

5. World Health Organization. Risk reduction of cognitive decline and dementia: WHO guidelines. https://www.who.int/mental_health/neurology/dementia/guidelines_risk_reduction/en/.

6. https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease

7. Forlenza, O.V, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. The British Journal of Psychiatry (2011) 198, 351–356. doi: 10.1192/bjp.bp.110.080044

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

9. Source: Alzamend June 2021 Corporate Presentation

10. Source: Alzamend June 2021 Corporate Presentation

11. Forlenza OV, Aprahamian I, de Paula VJ, & Hajek T (2016). Lithium, a Therapy for AD: Current Evidence from Clinical Trials of Neurodegenerative Disorders. Curr Alzheimer Res, 13(8), 879–886.

12. Fajardo VA, Fajardo VA, LeBlanc PJ, & MacPherson REK (2018). Examining the Relationship between Trace Lithium in Drinking Water and the Rising Rates of Age- Adjusted Alzheimer’s Disease Mortality in Texas. Journal of Alzheimer’s Disease, 61(1), 425–434.

13. Zhang X, Heng X, Li T, Li L, Yang D, Zhang X, … Le W (2011). Long-term treatment with lithium alleviates memory deficits and reduces amyloid-beta production in an aged Alzheimer’s disease transgenic mouse model. Journal of Alzheimer’s Disease, 24(4), 739–749.

14. Lauterbach EC, & Mendez MF (2011). Psychopharmacological Neuroprotection in Neurodegenerative Diseases, Part III: Criteria-Based Assessment: A Report of the ANPA Committee on Research. Journal of Neuropsychiatry and Clinical Neurosciences, 23(3), 242–260.

15. Habib A, Shytle RD, Sawmiller D, Koilraj S, Munna SA, Rongo D, Hou H, Borlongan CV, Currier G, Tan J. Comparing the effect of the novel ionic cocrystal of lithium salicylate proline (LISPRO) with lithium carbonate and lithium salicylate on memory and behavior in female APPswe/PS1dE9 Alzheimer’s mice. J Neurosci Res. 2019 Sep;97(9):1066-1080.

16. Habib A, Shytle RD, Sawmiller D, Koilraj S, Munna SA, Rongo D, Hou H, Borlongan CV, Currier G, Tan J. Comparing the effect of the novel ionic cocrystal of lithium salicylate proline (LISPRO) with lithium carbonate and lithium salicylate on memory and behavior in female APPswe/PS1dE9 Alzheimer’s mice. J Neurosci Res. 2019 Sep;97(9):1066-1080.

17. Source: Alzamend June 2021 Corporate Presentation

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