Introduction:
The FDA has approved two types of medications for the maangement of Alzheimer’s disease: cholinesterase inhibitors and the NMDA-type glutamate receptor inhibitor memantine. These therapies serve to alleviate cognitive symptoms such as memory loss, confusion and loss of critical thinking abilities in subjects diagnosed with age related dementia. In addiition to these approved therapies, several sutdies have suggested that poole intravenous immunoglbulin is effective in slowing the progression fo symptoms. (Hofbauer, US2014/0271669).
Under certain circumstances, immune cells in the brain, known as microglia, promote the inflammatory and destructive process that can lead to Alzheimer’s disease. It has been reported that once a specific molecule on the surface of microglia, CD40, get activated by its partner, CD40 ligand, the scene is set for microglial injury to the main cells in the brain; the neurons.
Researchers are currently administering anti-CD40 ligand antibody to mice so as to develop symptoms similar to Alzheimer’s disease. The mice can then be immunized with an investigational anti-Alzheimer’s vacine shown to remove beta amyloid plaques that accumulate in the brain, thereby leading to nerve damage and memory loss (Morgan).
Chlinesterase inhibitors: include Aricept (donepezil), Exelon (rivastigmine), Razadyn (galantamine) and Cognek (tacrine)
NMDA-type glutamate receptor inhibitor memantine:
Anti-amyloid Beta Antibodies:
Treatments that focus on amyloid-beta plaque, which is tightly linked to AD include ad
Aducanumab and BAN2401: (Biogen) After poor results in 2019, the company presented positive date from a phase-3 trial. The durg robustly removes amyloid, possible clears tau tangles and at sustained high doses may modestly slow decline.
Bepranemab (UCB0107): Roche’s Genetech had a collaboration in 2020 with UCB to develop an anti-tau antibody and gave over 120 million upfront to UCB with the Belgia company eligible for 2 billion based on certain regulatory approvals. However, Roche terinated the partnership.
Crenezumab: Roche terminated its collaboration with AC Immune over the anti-amyloid beta antibody crenezumab beause it failed Phase II and III clinical trails in 2019 and 2022.
Gantenerumab: failed wo phase III studies in November 2022.
Leqembi (Lecanemab): targets Alzheimer’s disease protein that are thought to be the most toxic to brain cells. It reduces clumps of amyloid-beta proteins, which play a key role in Alzheimer’s disease. However, lecanemab is not helpful for people with full cognitive function or later stages of Alzheimer’s. Lecanemab is manufactured by the Japanese pharmaceutical company Eisai and its U.S. partner Biogen. The drug is not a miracle drug in that it does not stop, reverse or cure the disorder. It can slwo mental decline by 5 months over an 1ucanumab and lecanemab, which were approved in 2021 and 2023, respetively, for mild cognitive impairment adn early AD. These treatments are beleived to reduce plaque in the brain, but they do not bring about cures. There are cases in which the plaque has been completely removed, but the people are still declining, so additional therapeis are needed. 8 month treatment period. But it comes with side effects including the risk of brain swelling and blooding. Despite all these drawbacks, it represents a breakthrough.
Kisunla (donanemab-azbt) (Ili Lilly): is a once monthly injection treatment indicated for adults with early symptomatic Alzheimer’s dieaes (AD) including mild cognitve impariment (MCI) or mild dementia stage of disease with confirm amyloid pathology. Kisunla is the first amyloid plaque targeting therapy with evidence to support stopping therapy when amyloid plaques are removed, which according to Lilly can reduce both the number of infusions needed as well as the treatment cost. The FDA based its approval of Kisunla on positive data form Phase III TRAILBLAZER-ALZ 2 trail (NCT04437511), in which people least advanced in the disease showed the strongest results 18 months after receiving the drug. Treatment with Kisunla significantly slowed clinical decline in two groups: patients with low to medium levels of tau protein and patients mirroring the overall population, which also included participants with high tau levels. Lilly has set a list price of of about 32,000 for a year of treatment which is about 21% above the $26,500 annual list price for Leqembi, an Alzhiemer’s treatment marketed by Isai and Biogen.
Gantenerumab: (Chugai Pharmaceutical Co., Ltd., Hoffmann-LaRoche): is a fully human IgG1 antibody designed to bind with subnanomlar affinity to a conformational epitope on amyloid-beta fibrils. It encompasses both N-terminal and central amino acids of amyloid-beta. The therapetuic rationale is that it acts to disassemble and degrade amyloid plaques by recuiting microglia and activating phagocytosis. Gantenerumab preferentially interacts with aggregated brain amyloidbeta, both parenchymal and vascular.
Patents:
Du (US 2002/0009445) discloses infusion of human IgG anti-amyloid beta antibodies for treatment of AD patients. The Anti-amyloid beta antibodies were recovered form a body fluid such as plasma using amyloid beta affinity chromatography.
Hyman (Ann Neurol, 2001, 49, pp. 808-810) discloses analysis of the plasma of 365 individuals for the presence of antibodies to amyloid-beta. There were detectable but very low levels of anti-amyloid-beta antibodies in just over 50% of all samples and modest levels in under 5% of all samples. However, neither the presence nor the level of anti-amyloid-beta antibodies correlated with the likelihood of developing demential or with plasma levels of amyloid-beta peptide.
Math (Neuromolecualr Med. 2003; 3(1): 29-39) disclose that AD patietns exhibit an enhanced immune response to Abeta adn that, contrary to expectation, Abeta antibodies enhance the neurotoxic activity of the peptide. Serum titers to Abeta were significantly elevated in AD patients and Abeta antibodies were found in association with amyloid plques in their brains, but there was no evidence of cell mediated immune responses to Abeta in the patents.
IVIG administration:
It has been shown that antibodies against beta-amyloid (Abeta) are present in human immunoglobuilin preprations (IVIgG). Commerically available IVIG preparations contain IgGs that specifically recognize epitopes of varous conformers of amyloid beta (e.g., amyloid beta monomers, amyloid beta fibrils and cross-linked amyloid beta protein species CAPS). Form example, GAMMAGARD LIQUID (10% immune globulin infusion (humna) contain 0.1% anti-amyloid beta fibril IgG, 0.04% anti-CAPS IgG and 0.02% anti-amyloid beta monomer IgG.
Dodel (J Nuerol Nuerosurg Psychiatry, 2004, 75(10) 1472-4) reports that in a study of 5 patients with AD who received monthly IVIgG over 6 month period, total Abeta levels in the CSF decreased by 30.1% and imporvement was deetected using an ADAS-cog.
Eggenburg (US 15/385721, published as US 2017/0218051) discloses a high titer anti-amyloid beta pooled immunogloublin G composiiton that contains at least 0.1 antiamyloid beta IgG. In one embodiment, the composition contains at least 1% anti-amyloid beta fibril IgG, at least 0.4% anti-amyloid beta oligomer immunogloublin G, at least 0.2% anti-amyloid beta monomer IgG and a pharmaceutically acceptable stablizing agent. In some embodiments, the composition further includes anti-RAGE IgGor anti-alpha-synuclein IgG. Methods for administering a therapeutically effective amoun of the IgG compostions for the treatment of a disorder such as Alzheimer’s disease are also disclosed.
Puli (J Neuroinflammation, 2012, 9:105) disclose that treatment of transgenic and WT mice with hIVIG provided no reduction in amyloid beta pathology but rather increased soluble levels of AB40 adn AB42.
Relkin (Nuerobiology of Aging 30 (2009) 1728-1736) discloses that antibodies against beta-amyloid which are contained in IVIg which was infused into AD patients decreased cerebrospinal fluid AB and also led to improvement indicators such as mini-mental state scores.
Anti-Tau antibodies:
Semorinemab: Roche ended its partnership with AC Immune regarding its anti-tau antibody semorinemab becaseu semorinemab failed to hit its priary endpoint, as well as two secondary endpoints.
Peptides/small molecuels:
Companies: NervGen
Protein tyrosine Phosphatase signma (PTPsigma): (NervGen): Their lead product NVG-291 provides a potential therapy for Alzehimer’s. The peptide binds preferentially to the PTPsignma receptor and effectively present inhibition from happening. Scar romation is a would healing process that takes place thorugh the body, including the nervous system. After an injury, more chonditin sulfate proteolycans (CSPs) is produced in its location. These sticky proteins act as a potent barrier to protect a wound and creat a wall to constrain inflammation and isolate it form healthy tissue. Unfortuantley, CSPs are the main reason why a nervous system does not repair itself by regrowing nerves. It was disocvered that a specific receptor on nerve cells (PTPsignma) recognizes CSPGs wihtin scar tissue and binds to them. Their interaction forms a very strong bond that effectively traps nerves permanetly within the scar. NervGen’s peptide binds preferentially to the PTPsigma receptor and effectvely present inhibition from occuring. The end result is release of trapped axons and presention of new ones form getting trapped in the scar. That enalbles the nervous system to regrow and repair itself in those previously inhibited area.
NVG-291 (NerGene): Their core technology targets PT
Fosgonimeton (Athira): is a small molecule that can cross the blood-brain varreir and apepars to protect neuronal cells and extend their lives, thus improving patients’ congition and funciton. The molecule is, basically, a grwoth factor enhancer for nerve cells. It promtoes nuron grwoth and creates new connections. This molecuel was also evaluated in a Phase II trail for Parkinson’s disease dementia and dementia with Lewy bodeis. Taht 28 person Phase II study measrued conitive improvement from baseline, using the Alzhimer’s Diease Assessment Scale for cognitive impairment (ADAS-Cog13). Resutls form 5 patients treated with 40 mg fosgonimeton in a modified intent to treat population showed a 7.2 point improvement by week 26, whcih suggets that fosgonimeton may be valuable therapeutic for patients with neurodegeenrative diseases.
Orexin-2 Receptor Blockers:
Seltorexant: is a human orexin-2 receptor blocker intended for treatment of agitation or aggression i Alzheimers which is being studied in a Phase II trail. However, J&J will no longer develop the drug for this indication but will continue to evaluate seltorexant for a treatment for major depressive disorder with insomina symptoms.
Tetrahydrocannabinol (THC):
THC+Melatonin
Melatoin (N-acetyl-t-methoxytryptamind) is a tryptophan metabolite syntehzied mainly in the pineal grland and plays an important role in regulation of amny physiological functions. Sutides have shown decreased levels of melatoin in serum and cerebrospinal fluid of AD patients. Mukunda (WO2019/190608)
Cao (US 11,065,225; see also Cao “The potential therapeutic effects of THC on Alzheimer’s Disease” J. Alzheier’s Disease 42 (2014) 973-984) discloses treatment of Alzheimer’s disease using THC, alone or in combination with melatonin, at an ultra-low dose amount sufficient to reduce amyloidbeta expression and aggregation, mianin APP expression, enhance mitochondrial function, decrease phosphorylation of GSK3beta protein, decrease the expression of GSK3beta protein, decrease phosphorylation of Tau protein and/or maintain Tau protein expression without side effects associated with higher doses of THC. In one embodiment, THC is administered in an amount of at least 0.2 ug/kg of body weight of a patient but less than the amount that causes psychological impairments and side effects associated with higher doses of THC. In a futher embodiment, THC and melatonin is administered without severe impairments and side effects associated with higher doses of THC where the ratio of THC: melatonin is from about 1:400.
US 2018/0133272 (Farm to Farma, Inc) discloses a composition that includes cannabis extract and melatonin. In some embodiments, the cannabis extract includes tetrahydrocannabinol (THC) and/or other cannabinoids such as cannabidiol. The composition is used for treating a wide range of disorders including Alzheimer’s dementia.
WO 2019/036243 (Molecular Infusions, LLC) discloses a composition which includes at least one active ingredients selected from one or more cannaboinoids and melatonin, caffeine or resveratrol. The cannabinoid can be selected from a group that incldues tetrahydrocannabino, delta9-tetrahydrcannabinol (THC), delta8-tetrahydrocannabinol, a cannabis extract and tetrahydrocannabinolic acid (THCA). In a preferred embodiment, the cannabinoid is in the form of a Cannabis sativa extract. In a specific embodiment, the composition includes THC, CBD, and melatonin. In one aspect, the composition is used for treating a disease such as Alzheimer Disease. In a further embodiment, the method includes reducing the level of a cytokine such as TNF or IFN-gamma in a mammal.
Mukunda (WO2019/190608) discloses compositions and methods for treating disorders of the CNS such as AD using THC alone or with melatonin. In some embodimetn curcumin which is a polyphenolic natural compound derived form root Curcuma longa or turmeric can also be used. The THC does is preferably an ultra-low dose from abut 14 ug to about 2.0 g for a 70kg patient.
–THC+ Melatonin + insulin:
Cao (US20220280613 & WO 2021/011421) discloses compositions which include THC, melatonin and insulin for treating Alzheimer’s disease. In some embodiments, the THC is organic THC, synthetic THC, Dronabinol, delta9-THC or THC-A. The inventors disclose that the composition is useful in reducing amyloid beta (amyloid beta 40 and/or amyloid beta-42). In some embodiment the composition includes about 5 ug to 20 mg THC, 1 -150 mg melatonin and about 1-50 IU insulin. In some embodimetns, the composition is formulated for intranasal administration.
WO2007/058902 (Colorado State University Rsearch Foundation) discloses a method for treating a disease of the CNS associated with tissue shrinkage or atrophy such as Azheimer’s disease by administering insulin. In one emobdiment the insulin is administered in an amount from about 0.001 Unites to 0.001 IU per kg body weight per day to about 10 IU per kg body weight per day. Insulin preparations are defined in IU because different insulin preparations can vary in the number of milligrams needed per unit. Adults rats were randomly assigned to groups and one group was treated with streptozotocin to induce diabetes. Streptozotocin binds to and destroys the beta cells of the pancreas resulting in the inability to produce insulin. The diabetic rat is a model of a brain disorder associated with brain atrophy and impaired learning/memory. There as a significant loss of brain wet weight, dry weight, DNA and protein in the rat model of brain atrophy associated with demential. However, adminstiered insulin completely normalzied brain weight in diabetic rats.
THC + Insulin:
Craft “Intranasal insulin therapy for Alzheimer Disease and amnestic ild cognitive impairment” Arch Neurol. 2012, 69(1); 29-38) discloses the effects of intranaslal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impariment of AD. Participants received placebo or 20 or 40 IU insulin. The results shown that adinistration of intranasal insulin stablized or improved cognition and function in regions affected by AD. (NCT00438568)
Increasing Insulin:
Boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Insulin action is critically important in the developing nervous system, directing differentiation, proliferation, and neurite growth. (Fisher, ” Insulin action in the brain regulates both central and peripheral functions” Am J. Phsy Endocri. Path., 2021 Jul 1; 321(1): E156–E163)
–Insulin + dimethyl sulfoxide:
Maher (US 2012/0322727) discloses a pharmaceutical composition for intranasal administration that includes insulin, dimethyl sulfoxide and a pharmaceutically acceptable excipient. In AD patietns, high levels of zinc, copper and iron in their redox active state were detected in their serum and CSF and were found to accumulate in the plaque of the AD brain, particularly in the olfactory, hippocampus and amygdalia regions. The pathogenesis of AD is closely related to the oxidative stress of amyloidbeta deposition in the neocortex. The oxidative or oxidation stress involves the generation of free radical oxygen (O2) and H2(2 in the presence of biometals such as zinic, copper and iron.; they facilitate the aggregation and toxicity of amyloidbeta. The use of chelators as a strategy for treating and reversing AD can thus be beneficial.
Anti-Sortilin Antibodies:
GSK4527226 (GSK): is an anti-sortilin antibody for the treatment of Alzheimer’s disease.