TLSA: IND Cleared by FDA and Alzheimer’s Deep Dive

By John Vandermosten, CFA

NASDAQ:TLSA

Tiziana Life Sciences PLC (NASDAQ:TLSA) announced the clearance of its Investigational New Drug (IND) application for its anti-CD3 foralumab in Alzheimer’s Disease (AD) in an August 15th press release. Foralumab is now the subject of a Phase II clinical trial in AD building on other work being done in an ongoing non-active secondary progressive multiple sclerosis (na-SPMS) study.

Foralumab safety work has already been completed to prepare it for other indications; therefore, following the IND clearance Tiziana may to launch a Phase II exploratory trial. According to the company’s scientific advisor, Dr. Howard Weiner, screening is expected to begin in the fall with first enrollment expected by the beginning of 2024. Results from the trial could be available by the fall of 2024. Brigham and Women’s Hospital will oversee the trial with additional details expected to be shared on clinicaltrials.gov in coming weeks.

Dr. Weiner highlighted the drivers of AD: beta amyloid (βA), tau and inflammation. Two products have recently been approved to address beta amyloid (Aduhelm and Leqembi); however, there are none specifically approved to address tau and inflammation. Tiziana’s anti-CD3 monoclonal antibody has demonstrated the ability to address inflammation¹ and may be not only improve the condition in AD patients but also address some of the side effects of beta amyloid therapies such as cerebral edema.

Alzheimer’s Disease

Alzheimer’s Disease (AD) was the seventh most common cause of death in the United States in 2021² and the fastest growing cause in the top ten over both 10 and 20 year periods. Prevalence of AD is highly associated with age, making it a critical challenge in all regions with a quickly aging population, particularly Europe and China. In contrast to other leading causes of death, a strongly effective disease modifying therapy has eluded medicine; nevertheless, there are symptomatic treatments available for AD and new formulations may improve their safety and efficacy. Two classes of symptomatic treatment include acetylcholinesterase inhibitors (AChEIs), N-methyl-D-aspartate (NMDA) receptor antagonists and beta amyloid therapies.

Alzheimer’s Disease (AD) is a neurodegenerative condition which affects almost seven million Americans³ and over 30 million people worldwide.⁴ Due to faster growth in older population cohorts and the higher prevalence of Alzheimer’s in those over 65, numbers of those diagnosed with AD are expected to almost double and triple by 2030 and 2050 respectively. AD is distinguished among the top ten causes of death as it is the fastest growing since 2000.⁵ Our review of 2020 CDC data found that deaths resulting from heart disease, cancer and cerebrovascular disease increased 17%, 5% and 24% over the last decade compared with Alzheimer’s deaths which rose 61%.

AD is named after Alois Alzheimer who made the first clinical observations of the disease between 1901 and 1906. He observed a 50-year old female patient who experienced memory loss, paranoia and psychological changes. After the patient’s death, an autopsy was performed on her brain which found shrinkage in and around nerve cells and abnormal deposits that were later identified as βA plaques and neurofibrillary tangles.

According to the CDC,⁷ AD is the 7th leading cause of death in the United States in 2020, after chronic lower respiratory diseases and before diabetes. While there are over 6 million individuals in the US diagnosed with AD, many more exhibit earlier stages of the disease called mild cognitive impairment (MCI). MCI is seen as a precursor to AD and is measurable by a change in thinking abilities. A person with MCI can carry on normal everyday tasks, but does show some signs of impairment in sensitive testing.

More women than men suffer from AD. According to data cited by the Alzheimer’s Association report, almost two thirds of Americans with AD are women. Research is not conclusive on why this difference exists and some attribute it to longer life spans while others have suggested biological or genetic variations. Along racial lines, African-Americans and Hispanics are more likely to suffer from dementia. Research has attributed health, lifestyle and socioeconomic elements as well as higher prevalence of associated health conditions such as cardiovascular disease to the difference.

Deaths from AD are underreported due to other conditions being cited on death certificates. Dementia can cause problems with mobility, nutrition and self-care that can lead to pneumonia, which is frequently cited as the main reason for death. AD is unique among the most common forms of death in the older population in its increasing prevalence. While improvements in health care have led to decreases in the rate of cancer, heart disease and stroke mortality, AD has moved in the other direction and increased substantially. This disturbing trend highlights the need to make progress in this difficult therapeutic area.

The economic burden from AD is immense. Some individuals suffer for decades with the disease and require substantial amounts of care either from family members or nursing homes. Statistics from a variety of sources peg the annual cost of care at over $340 billion for unpaid caregivers representing over 18 billion hours of service in 2023.⁸ Direct cost of care for AD is estimated at $355 billion, with half of this amount absorbed by Medicare.⁹

The estimate of AD prevalence only includes those diagnosed after the onset of symptoms. However, there are many more individuals in the early stages of the disease and if AD could be detected prior to symptoms developing, the number of individuals that could benefit from treatment would be greater.

It is estimated that approximately 16% to 20% of individuals over 60 years old have MCI with the prevalence increasing as age advances.¹⁰ About a third of those with MCI develop AD within 5 years,¹¹ a proportion that increases over periods greater than 5 years. While many studies have focused on later stages of the disease, it appears that a preventive approach may be more effective.

AD is usually associated with aging. The first signs of the disease are characterized by a loss in short term memory, followed by a progression to forgetfulness about one’s own personal history and relationships. Behavioral changes, confusion about the date and time and becoming lost are other symptoms. In late-stage disease, AD patients cannot speak, total physical care is needed and the body begins to shut down. From the first concrete signs of the disease to death, the progression lasts an average of eight years, however, it can range from two to twenty years, depending on the person and other health conditions.

One of the difficulties with identifying AD is that there are few genetic indicators that allow us to anticipate those predisposed to the disease. The only way to definitively diagnose AD is with a tissue sample; however, brain imaging tests such as magnetic resonance imaging (MRI), computerized tomography (CT) and positron emission tomography (PET) are able to narrow down different types of degenerative brain disease. Biomarkers and risk factors can be evaluated to provide early indications of those who may be susceptible. About 1% of the AD population develops the disease as a result of certain genes that overexpress the amyloid precursor protein (APP), which results in early onset AD. Another group that suffers from AD at a high rate are the 400 thousand Americans with Down Syndrome. This group has an extra copy of chromosome 21, which also codes for the production of APP, leading to Aβ fragments that accumulate into toxic oligomers.

One gene that is closely associated with AD is the apolipoprotein E (APOE) gene on chromosome 19. There are a few forms of APOE, the ε2, ε3 and ε4 alleles. The ε3 allele is the most common and is thought to play a neutral role in the disease, while presence of the ε4 increases the risk of AD and several other diseases including atherosclerosis. Alleles come in pairs, and individuals with both alleles of ε4 are more susceptible to AD than those with one ε4 or no ε4 alleles.¹² It is thought that the ε2 and ε3 forms are more effective at breaking down Aβ than ε4, and the absence of these forms contribute to AD.

The most closely associated risk factor for AD is age. In a minority of cases, early onset Alzheimer’s can occur in those under 65, but analysis of data indicates that about 5% of those with AD are in the 65 to 74 age range while 14% are in the 75 to 84 range. 72% of AD patients are 75 years old or greater.¹³ Family history is also a predictor, but environmental factors and lifestyle also play a role.

Diagnosis

Alzheimer’s Disease is only diagnosed with certainty by brain autopsy, which requires a microscopic examination of brain tissue identifying the characteristic plaques and neurofibrillary tangles. However, there are a number of other methods used that provide evidence of the disease prior to death. PET scans, Aβ concentration in cerebrospinal fluid (CSF), as well as cognitive and functional tests are used to render a diagnosis. A patient’s individual background, along with familial history and behavioral observations are also used to conclude a cause. Memory testing is used to determine if the disease is at an early, middle or late stage. Some examples of neuropsychological tests are the mini-mental state examination (MMSE), clinical dementia rating sum of boxes (CDR-SB), the mini-cog test and tests for depression, as this is usually contemporary with AD.

Treatment

Acetylcholinesterase Inhibitors (AChEI) and N-methyl-D-aspartate (NMDA) Receptor Antagonists

There are several medicines available that will treat the symptoms of AD. There are five approved medications available to treat the symptoms of AD. Three of them are in the cholinesterase inhibitor class, one is a N-methyl-D-aspartate (NMDA) receptor antagonist and the last is a combination of the two. Cholinesterase inhibitors treat symptoms related to memory, language, judgment and thought processes and they work by increasing levels of acetylcholine, a chemical that facilitates neuronal communication. Galantamine also enables nicotinic receptors to become more sensitive, thereby enhancing the effect. The NMDA receptor antagonist named memantine helps a patient improve memory, attention, reason, language and ability to perform simple tasks. The drug works by regulating glutamate, a chemical involved in information processing, storage and retrieval. In 2014, a combination therapy branded Namzaric was approved, which combines AChEI donepezil and NMDA receptor antagonist memantine.

Aducanumab and Lecanemab

The first new drug to be approved for AD in almost 20 years came to market in 2021. Aducanumab followed a tortuous path full of ups and downs prior to the FDA’s June 2021 approval. The beta-amyloid removing therapy was branded Aduhelm. The process and decision to allow the drug to be marketed was controversial as it was approved on surrogate endpoints that have not been directly tied to clinical benefit. Following approval, uptake of the drug was weak especially after Medicare decided to only cover the drug for individuals enrolled in a clinical trial.

In July 2023, the FDA approved the second beta-amyloid drug for AD, lecanemab or Leqembi as it is branded by Eisai and Biogen. Data for lecanemab was better than that for aducanumab showing a reduction in amyloid plaques and a slowing in cognitive decline. Side effects for lecanemab were also improved over aducanumab as the former showed lower rates of brain swelling and microhemorrhage.

Another in-development amyloid-beta focused product is Eli Lilly’s donanemab which has shown impressive results in slowing cognitive decline. The candidate met primary and secondary endpoints in its pivotal trial and has been submitted to the FDA in a biologics license application (BLA) which should receive a response from the agency before year end 2023.

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1. Moreira, T.G. et al. Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19. Proceedings of the National Academy of Sciences, March 2023.

2. Centers for Disease Control and Prevention, National Center for Health Statistics, Leading Causes of Death. Accessed August 2023.

3. Alzheimer’s Association Facts and Figures. Accessed August 2023.

4. Our adjustments to WHO estimates.

5. Centers for Disease Control and Prevention, National Center for Health Statistics. Underlying Cause of Death 1999-2020 on CDC WONDER Online Database. Accessed at http://wonder.cdc.gov/ucd-icd10.html

6. Center for Disease Control and Prevention, National Center for Health Statistics. Compiled by Zacks’ Analysts

7. Center for Disease Control and Prevention, National Center for Health Statistics. Accessed at http://wonder.cdc.gov/ucd-icd10.html

8. Alzheimer’s Association Factsheet. 2023 Alzheimer’s Disease Facts and Figures.

9. Alzheimer’s Association Factsheet. 2021 Alzheimer’s Disease Facts and Figures.

10. Gillis, Cai, et al. The incidence of mild cognitive impairment: A systematic review and data synthesis. Alzheimer’s Dement (Amst). 2019 Dec; 11: 248–256. Published online 2019 Mar 8. doi: 10.1016/j.dadm.2019.01.004

11. Petersen RC, et al. Practice guideline update summary: Mild cognitive impairment. Neurology 2018;90(3):126-35.

12. “Although 40-65% of AD patients have at least one copy of the ε4 allele, ApoE4 is not a determinant of the disease - at least a third of patients with AD are ApoE4 negative and some ApoE4 homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD. There is also evidence that the ApoE2 allele may serve a protective role in AD. Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is ApoE 4,4. Using genotype ApoE 3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0), individuals with genotype ApoE4,4 have an odds ratio of 14.9 of developing Alzheimer's disease. Individuals with the ApoE 3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (ApoE2,4), have an odds ratio of 2.6. Persons with one copy each of the 2 allele and the 3 allele (ApoE2,3) have an odds ratio of 0.6. Persons with two copies of the 2 allele (ApoE2,2) also have an odds ratio of 0.6.” Wikipedia contributors. (2018, May 1). Apolipoprotein E. In Wikipedia, The Free Encyclopedia. Retrieved 14:06, May 6, 2018, from https://en.wikipedia.org/w/index.php?title=Apolipoprotein_E&oldid=839158512

13. Alzheimer’s Association Factsheet. 2021 Alzheimer’s Disease Facts and Figures.