Breakthrough Clinical Results
Tiziana Life Sciences announced compelling immunologic findings from a moderate Alzheimer's Disease patient treated with intranasal foralumab. Transcriptional analysis revealed profound immune modulatory effects, including changes in CD4, CD8 cells, and monocytes. A reduction in microglial inflammation was observed, linked to improved microglia PET scans. Unexpectedly, increased phagocytosis markers in monocytes suggest foralumab may enhance amyloid plaque clearance. The treatment was well-tolerated. These results, along with reported behavioral improvements, led the patient to continue treatment. The findings highlight the potential of nasal foralumab as a dual-acting therapy targeting both inflammation and amyloid pathology in Alzheimer's Disease.
Key Highlights
- Intranasal foralumab showed profound immune modulatory effects in a moderate Alzheimer's patient.
- Microglia PET scans demonstrated a marked reduction in brain inflammation following treatment.
- Increased phagocytosis markers suggest foralumab may enhance amyloid plaque clearance.
- Treatment was well-tolerated with no reported side effects.
Incidence and Prevalence
Global Estimates of Alzheimer's Disease Prevalence and Burden
Alzheimer's disease is the leading cause of dementia in advanced age with a prevalence of above 40% among persons 80 years or older. As of 2021, there are an estimated 50 million individuals worldwide living with dementia.
The burden of Alzheimer's disease shows significant geographic variation. In low and middle income countries (LMICs), the burden of disease is often greater, and these regions are projected to experience some of the largest increases in dementia prevalence over the coming decades.
According to the Global Burden of Disease Study (GBD) 2021, the global impact of Alzheimer's disease and other dementias has grown substantially. Globally, AD and other dementia-related deaths due to metabolic risks increased from 98,608 to 399,824 between 1990 and 2021, representing a 4.1-fold increase.
The burden of disease shows significant demographic patterns. For dementias related to high fasting plasma glucose and high body mass index, both the age-standardized mortality rates (ASMR) and age-standardized DALY rate (ASDR) increased with age and were higher in females than in males. In 2021, the highest burden was observed in high-income North America.
In the United States specifically, an estimated 6.2 million Americans age 65 and older are living with Alzheimer's dementia as of 2021. This number could grow to 13.8 million by 2060 without medical breakthroughs. In 2019, official death certificates recorded 121,499 deaths from AD in the US, making Alzheimer's the sixth-leading cause of death overall and the fifth-leading cause of death among Americans age 65 and older.
The metabolism-related global burden of AD and other dementias shows a positive correlation with the Socio-Demographic Index (SDI), with higher ASMR and ASDR in high SDI regions. However, more pronounced increases are occurring in low and low-middle SDI regions, with average annual percentage changes of 0.227% and 0.244% respectively.
Cross-country inequality analyses indicate that DALYs of Alzheimer's disease and other dementias are skewed and higher in countries with higher sociodemographic development, with inequality increasing over time.
Research also indicates that biologically defined Alzheimer disease is more prevalent than clinically defined probable Alzheimer disease at any age and is 3 times more prevalent at age 85 years among both women and men.
Between 2000 and 2019, while deaths from stroke, heart disease, and HIV decreased, reported deaths from AD increased more than 145%, highlighting the growing impact of this disease globally.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Alzheimer's Disease
Microglia-Related Mechanisms
Recent research has identified microglial activation as a crucial component in AD pathophysiology. A panel of six proteins (FABP3, MDH1, GDI1, CAPG, CD44, GPNMB) serve as potential indicators for microglial activation, with three (FABP3, GDI1, MDH1) significantly elevated in the CSF of Alzheimer's patients. These markers associate with an early immune response to seeded amyloid. Microglia undergo metabolic reprogramming in AD, with key genes like TREM2, APOE, and HIF-1α orchestrating shifts between oxidative phosphorylation and glycolysis. Lipid dysmetabolism appears to be a common feature across neurodegenerative disorders.
Infection-Related Mechanisms
Multiple pathogens show association with Alzheimer's disease risk, including numerous herpesviruses (HSV-1, HHV-6, HHV-7), various bacterial species, Chlamydia pneumonia and spirochetes. The host immune response to infection may trigger or accelerate AD processes, including amyloid-β accumulation, pathogenic tau, and neuroinflammation.
Protein Modification Mechanisms
S-palmitoylation, catalyzed by zinc finger DHHC domain containing (zDHHC) S-acyltransferases, affects proteins regulating synaptic plasticity and amyloid-β metabolism. Significant increases in zDHHC7 expression and protein S-palmitoylation were found in hippocampi of both AD mice and post-mortem AD patients. A FoxO1-mediated epigenetic mechanism inducing zDHHC7 expression was identified, triggered by brain insulin resistance.
Novel Therapeutic Targets
Beyond traditional targets, new approaches focus on microglia, triggering receptors expressed on myeloid cells 2 (Trem-2), and notum carboxylesterase. Dual Orexin Receptor Antagonists (DORA) show promise for sleep disturbance in AD. Compounds like Osmundacetone (OAC) directly bind to Aβ, inhibiting fibrillation. Artemisinin (ART) attenuates Aβ-induced astrocyte activation and inflammatory responses. Cycloastragenol (CAG) targets Phosphodiesterase 4B (PDE4B) to regulate microglial activity, enhancing phagocytosis and alleviating memory dysfunction.
Immunomodulatory Approaches
Decoy receptor strategies targeting Interleukin-10 and Interleukin-4 signaling showed disease-modifying effects. Fingolimod, a sphingosine-1-phosphate receptor modulator, inhibits peripheral lymphocyte infiltration into the brain, reducing neuroinflammation. NF-κB signaling inhibition via JSH-23 restores cognitive function and normalizes neuronal excitability.
Metabolic Mechanisms
Thyroid hormones affect critical genes involved in amyloid beta production and clearance. Geniposidic 4-isoamyl ester (GENI) targets AMPK through AMPK/ULK1/LC3B and AMPK/mTOR signaling pathways. Novel-generation antidiabetic drugs, including GLP-1 analogs, SGLT-2 inhibitors, and DPP-4 inhibitors, show promise as therapeutic approaches. Krüppel-like factor 9 (Klf9) stimulates insulin-degrading enzyme (IDE) expression, promoting Aβ degradation.
Epigenetic Mechanisms
Histone deacetylase-11 (HDAC11) is significantly upregulated in Alzheimer's disease brains. HDAC11 inhibition enhances microglial phagocytosis of amyloid beta proteins and modulates inflammatory cytokine levels. PB94, a brain-permeable HDAC11-selective inhibitor, reduces amyloid burden and neuroinflammation, improving cognitive function.
Drug used in other indications
Clinical Trials of Intranasal Foralumab Beyond Alzheimer's Disease
Based on a thorough review of available information, there is insufficient data to provide details about clinical trials of intranasal foralumab for indications other than Alzheimer's Disease. The current information does not contain specific details about:
- Additional indications being investigated for intranasal foralumab
- Intervention models used in these trials
- Dosing regimens for non-Alzheimer's applications
- Study designs of ongoing or planned trials
- Mechanism of action across different neurological or immunological disorders
Intranasal foralumab represents an interesting approach to drug delivery, particularly for neurological conditions, as the intranasal route may facilitate better blood-brain barrier penetration. However, without specific trial information, it is not possible to detail which other conditions beyond Alzheimer's Disease are being targeted with this therapeutic approach.
For patients and clinicians interested in this treatment modality, it would be advisable to consult clinical trial registries such as ClinicalTrials.gov for the most up-to-date information on ongoing studies involving intranasal foralumab across various indications.
The development of novel administration routes for existing medications represents an important area of clinical research, particularly for immunomodulatory therapies like foralumab that may benefit from targeted delivery methods.