Alzheimer's Disease Therapies PDF

18 ALZHEIMER’S DISEASE 1  18. ALZHEIMERS’ II — CONTENTS — ❾ Therapeutic Strategies Anti-Ab monoclonal antibodies The acetylcholine pathway Donepezil (Aricept) The glutamate pathway Memantine GLP-1 agonists Nasal Insulin...

18 ALZHEIMER’S DISEASE 1  18. ALZHEIMERS’ II — CONTENTS — ❾ Therapeutic Strategies Anti-Ab monoclonal antibodies The acetylcholine pathway Donepezil (Aricept) The glutamate pathway Memantine GLP-1 agonists Nasal Insulin 2  18.19. INFLAMMATION ALZHEIMER II II ’S DISEASE – LEARNING OBJECTIVES – Assess the different therapeutic strategies based on the factors contributing to Alzheimer’s disease Evaluate the significance of Anti-Ab monoclonal antibodies from their behavioral outcomes Define therapies based on the acetylcholine pathway and their mechanism of action Explain therapies based on the glutamate pathway and their mechanism of action Discuss clinical trials based on the rationale for use of intranasal insulin 3  II. ALZHEIMER’S DISEASE ❾ THERAPEUTIC STRATEGIES Therapeutic strategies in Alzheimer’s disease require recognition of the many factors influencing the development of Alzheimer’s as well as risk factors:  Altered proteolytic processing of the amyloid precursor protein (APP) resulting in the production and aggregation of Ab  The Ab cascade hypothesis and UPR  Insulin in the brain: Alzheimer’s as diabetes type III  Impaired glucose metabolism in Alzheimer's disease  Ab and oxidative stress  Perturbed calcium homeostasis and excitotoxicity  Inflammation in Alzheimer's disease  Risk Factors: ApoE4, Maternal Transmission 4  II. ALZHEIMER’S DISEASE ❾ THERAPEUTIC STRATEGIES The therapeutic (and preventive) strategies either in the clinic or undergoing clinical development require consideration of:  Antecedent events: genes and environment  Ab production, aggregation, and clearance  Oxidative stress and calcium dysregulation  Synapse dysfunction   Impaired plasticity and neurogenesis Synaptic dysfunction  NFT formation and Apoptosis     Antecedent events Ab production Oxidative stress NFT formation Genes / Environment Aggregation/clearance Calcium dysregulation Apoptosis  Impaired plasticity and neurogenesis Risk Reduction Treatment Cognitive stimulation Ab monoclonal antibodies Exercise Cholinergic enhancers Dietary restriction Glutamatergic modulators Anti-inflammatory agents Neurotrophic factors b- and g-secretase inhibitors Antidepressants Cu- and Fe chelation 5  Imaging Ab using [18F]flutematemol positron emission tomography (PET) Since the advent of the first Ab-specific PET ligand, 11C-Pittsburgh compound B, several 18F ligands have been developed that circumvent the limitations of [11C]PIB tied to its short half-life. Such compounds have been approved by the US and European regulatory bodies, including florbetapir, florbetaben, and flutemetamol. HO S 11CH 3 N H N 11C-PIB 18F HO S CH3 N H N 18F-Flutemetamol 6  ❾ Ab MONOCLONAL ANTIBODIES ADUCANUMAB (Aduhelm BIIB037) is a human monoclonal antibody selective for aggregated forms of Ab being investigated as a disease-modifying treatment for Alzheimer’s. This phase 1b study evaluated safety, tolerability, pharmacokinetics, and pharma-codynamics of aducanumab in patients with prodromal or mild Alzheimer’s. Patients selected had a positive florbetapir (18F-AV-45) PET scan. Conclusion: Aducanumab reduced Ab plaques in patients with prodromal (early symptoms) or mild Alzheimer’s. Improvement in cognitive function? 7  ❾ Ab MONOCLONAL ANTIBODIES DONANEMAB (Lily’s) is an anti-Ab monoclonal antibody. Although not approved by FDA yet, DONANEMAB significantly delivered 35% slowing of cognitive and functional decline in a Phase 3 study* on early Alzheimer’s disease: 47% of participants on DONANEMAB showed no decline on Clinical Dementia Rating-Sum of Boxes (CDR-SB) 52% of participants completed their course of treatment by 1 year and 72% by 18 months achieving plaque clearance. Participants on DONANEMAB had 40% less decline in ability to perform activities of daily living at 18 months (iADRS: integrated Alzheimer’s Disease Rating Scale) Participants on DONANEMAB experience a 39% lower risk of progressing to the next stage of disease. *TRAILBLAZER-ALZ 2 (NCT04437511) is a Phase 3, double-blind, placebo-controlled study to evaluate the safety and efficacy of donanemab in participants ages 60-85 years with early symptomatic Alzheimer's disease (MCI or mild dementia due to Alzheimer's disease) with the presence of confirmed Alzheimer's disease neuropathology. The trial enrolled 1736 participants selected based on cognitive assessments in conjunction with amyloid plaque imaging and tau staging by PET imaging.  ❾ Ab MONOCLONAL ANTIBODIES LECANEMAB (Esai’s and Biogen’s) is an anti-Ab monoclonal antibody recently approved by FDA; LECANEMAB significantly delivered 27% slowing of cognitive and functional decline. LECANEMAB is recommended for patients with Mild Cognitive Impairment (MCI) and mild Alzheimer’s disease (not recommended yet for moderate or severe Alzheimer’s disease) or patients who are ApoE4 positive. “Now that we have an approve therapy aimed at toxic amyloid plaques in the brain, it is more important than ever to double down on developing a diverse generation of drugs to use alongside it. We will need to combine amyloid- targeting drugs like Lecanemab with other therapies aimed at the many novel pathways which contribute to Alzheimer’s. We the help of complementary biomarkers, this will allow us to tailor precision treatments to individual patients, giving us the best change to defeat this disease.” Alzheimer’s Drug Discovery Foundation  ❾ Ab MONOCLONAL ANTIBODIES SLOWING COGNITIVE DECLINE ________________________ ADUCANUMAB (ADUHELM) (Biogen) 22% ? DONANEMAB (Lily) 35% LECANEMAB (LEQEMBI) (Esai and Biogen) 27% “Although the lecanemab clinical trial showed some slowing of disease, there is concern that it did not adequately assess long-term benefits and harms and that the trial participants were not representative of the Medicare population because patients with some comorbidities were excluded and Black participants and women were underrepresented” Elisabeth Mahase BMJ 2022, 379:02912 11 In an exciting step forward for Alzheimer’s diagnosis and treatment, the Centers for Medicare & Medicaid Services (CMS) have expanded coverage of amyloid PET scans, helping to ensure that as amyloid-targeting drugs continue to come to market, they will reach the patients who will most benefit from them. The decision effectively removes the current limitation of one scan per lifetime, opening the door for this important tool to be used more widely. As an early investor in the Amyvid PET scan, the ADDF understands the critical impact diagnostics can have. Wider access will limit potentially harmful side effects from anti-amyloid drugs by ensuring the patients taking them really do have amyloid in their brains and by opening the possibility that patients can stop taking the drug once amyloid is removed. As the next generation of drugs aimed at targets beyond amyloid continues to progress through the pipeline, the ADDF is working through our Diagnostics Accelerator to bring even more tools to market, which will help to track not only amyloid levels, but biomarkers associated with all of the many causes of Alzheimer’s disease. This will allow us to ensure that the right drugs reach the right patients at the right time and open the path to revolutionizing Alzheimer’s treatment through a precision approach. ALZHEIMER’S DRUG DISCOVERY FOUNDATION 12 II. ALZHEIMER’S DISEASE 13 14 15  Alzheimer’s Association Disappointed by Medicare Coverage Policy for FDA-Approved Alzheimer’s Disease Treatments April 7, 2022 CHICAGO, April 7, 2022 — On behalf of those impacted by Alzheimer’s disease, the Alzheimer's Association is deeply disappointed that the Centers for Medicare & Medicaid Services (CMS) has essentially ignored the needs of people living with Alzheimer's disease. Today's decision by CMS to tightly restrict coverage of Food and Drug Administration (FDA) approved Alzheimer's treatments in this class under the Accelerated Approval Pathway is wrong. "CMS has created unnecessary barriers for individuals with Alzheimer's disease. Patients with Alzheimer's, a fatal disease, should have FDA- approved treatments covered by Medicare just as those facing other diseases do," said Harry Johns, Alzheimer's Association chief executive officer. 17  ❾ CHOLINERGIC ENHANCERS AND GLUTAMATERGIC INHIBITORS Current therapies: Where do we go from here? The current therapies for Alzheimer’s disease target: 1. The acetylcholine pathway, that considers that Alzheimer’s disease is associated with neuronal death resulting in reduced production of acetylcholine. Donepezil hydrochloride (Aricept, Cognex, Razadyne) 2. The glutamate pathway, that considers that sustained activation of the NMDA receptor leads to excessive Ca2+ influx (excitotoxicity), neuronal dysfunction, and cell death. Memantine hydrochloride (Namenda, Namzaric) 18 19  ❾ CHOLINERGIC ENHANCERS Current therapies: Where do we go from here? The current therapies for Alzheimer’s disease target: 1. The acetylcholine pathway, that considers that Alzheimer’s disease is associated with neuronal death resulting in reduced production of acetylcholine. Donepezil hydrochloride (Aricept, Cognex, Razadyne) 2. The glutamate pathway, that considers that sustained activation of the NMDA receptor leads to excessive Ca2+ influx (excitotoxicity), neuronal dysfunction, and cell death. Memantine hydrochloride (Namenda, Namzaric) 20  CELL-SURFACE RECEPTORS Extracellular signal molecules bind to specific receptor proteins on the surface (plasma membrane) of target cells. These cell-surface receptors act as signal transducers by converting an extracellular ligand-binding event to intracellular signals that alter the behavior of the cell. There are three types of cell-surface receptor proteins: 1 Ion-channel-coupled receptors 2 G-protein-coupled receptors 3 Enzyme-coupled receptors 21  CELL-SURFACE RECEPTORS 1 Ion channel-coupled receptors are also ligand Na+, Cl–, Ca++ known as transmitter-gated ion channels or ionotropic receptors; they are involved in rapid synaptic signaling between neurons. Neurotransmitters transiently open or close an ion channel to which they bind, thus changing the ion permeability of the K+ membrane and excitability of the post- ligand-gated ion channel ligand-gated ion channel synaptic target cell. There are two main CLOSED OPEN types of transmitter-gated ion channels: Inhibitory Neurotransmitters (Open Cl– or K+) GABAA, glycine (the GABAA Excitatory Neurotransmitters (Influx of receptors are ionotropic receptors; Na+) acetylcholine, glutamate, serotonin GABAB receptors are GPCR). Na+ Cl–, K+ Na+ Cl–, K+ 22  ❾ CHOLINERGIC ENHANCERS Transmitter-gated ion channels convert extracellular chemical signals into electrical signals at chemical synapses. Transient opening (brief permeability change) of the transmitter-gated ion channel in the plasma membrane of the postsynaptic target cell occurs upon binding to the neurotransmitter. nerve terminal of presynaptic cell neurotransmitter in synaptic vesicles neurotransmitter synaptic cleft transmitter-gated ion channel target cell plasma membrane 23  ❾ CHOLINERGIC ENHANCERS 1. The acetylcholine pathway Acetylcholine (Ach) is synthesized from glucose (glucose – pyruvate – acetyl-CoA) and choline (imported from the synaptic cleft) by Choline Acetyl Trans- ferase (CAT). Ach is transported into vesicles upon exchange of H+ or degraded glucose to acetate and choline by acetyl-choline-ester- pyruvate ase (AChE), thus replenishing the storage acetyl-CoA vesicles choline pool. Ach released into the H+ synaptic cleft binds to the transmitter- acetyl-CoA gated ion channel. choline-acetyl VAChT transferase acetyl-choline (CAT) acetylcholine- (ACh ) sterase (AChE) choline choline + acetate choline 24  ❾ CHOLINERGIC ENHANCERS 8 Therapeutic Strategies 1. The acetylcholine pathway Donepezil (Aricept) inhibits the acetylcholinesterase (AChE), thereby preventing ACh degradation and enabling ACh binding to the transmitter-gated ion channel. ACh Donepezil Donepezil Donepezil AChE AChE AChE Transmitter-gated ion channel 25  ❾ GLUTAMATERGIC INHIBITORS Current therapies: Where do we go from here? The current therapies for Alzheimer’s disease target 1. The acetylcholine pathway, that considers that Alzheimer’s disease is associated with neuronal death resulting in reduced production of acetylcholine. Donepezil hydrochloride (Aricept, Cognex, Razadyne) 2. The glutamate pathway, that considers that sustained activation of the NMDA receptor leads to excessive Ca2+ influx (excitotoxicity), neuronal dysfunction, and cell death. Memantine hydrochloride (Namenda, Namzaric) 26  ❾ GLUTAMATERGIC INHIBITORS PERTURBED CA++ HOMEOSTASIS AND EXCITOTOXICITY Excitotoxicity NMDA receptors are made of different subunits: NR1 and NR2A-D. NR1 and NR2 are the binding sites for glycine (required co-agonist) and glutamate (the endogenous agonist), respectively. When glutamate and glycine bind and the cell is depolarized to remove the Mg2+ block, the NMDA receptor opens with influx of Ca2+ and Na+. The two regulatory sites of the NMDA receptor are the Mg2+ site in the NR1 NR2 Na+ Ca2+ SNO the ion channel and an S-nitrosylation Gly Glu site located in the extracellular region Zn +++ out of the receptor. S-nitrosylation of NR1 NR2 ––– in cysteine protein in the receptor decre- Mg++ ases channel activity associated with Na+ Ca2+ stimulation of the NMDA receptor. ! 27  ❾ GLUTAMATERGIC INHIBITORS PERTURBED CA++ HOMEOSTASIS AND EXCITOTOXICITY Excessive release of glutamate or overstimulation of the NMDA receptor causes excitotoxic cell death also known as apoptotic-like excitotoxicity. Ca2+ influx following activation of the NMDA receptor triggers a variety of processes than can lead to apoptosis: Ca2+ NMDA-R  activation of the p38 MAPK pathway that contributes to cell death..  activation of nNOS with formation of NO and nNOS subsequent toxic effects. ❷  activation of the mitochondrial permeability ❸ Ca2+ ❶ transition with formation of reactive oxygen MTP p38 species and release of proapoptotic factors, such as cytochrome c and subsequent activa- cyt c ROS MEF2 NO ↓ ↓ ↓ ↓ tion of the caspase cascade CELL DEATH 28  Ca normal synaptic function neuronal survival ❾ GLUTAMATERGIC INHIBITORS Glu Memantine – To be clinically acceptable, Glu an anti-excitotoxic Gly HGly 2N Gly Ca GluCa Gly Ca GluCa Glu therapy must block excessive activation of theGluNMDA receptor Ca Gly Ca Gly Ca Ca while leaving normal function relatively intact to avoid side effects. Gly Gly Drugs that simply compete with glutamate Glu or glycine Gly Glu at the agonist Glu Gly Glu binding sites block normal function and therefore do not meet this H3C CH3 requirement and have thus failed in clinical trials to date because of side effects (drowsiness, hallucinations, and even coma). Memantine is used in the clinic and Ca Ca Ca inhibits excitotoxicity by targeting the NMDA Ca receptor. Memantine has receivedCaFDA approval Ca for use in Alzheimer's disease. The drug normalslows synaptic the development of the disease function neuronal survival and is of modest protein misfolding mitochondrial dysfunction benefit to patients in the moderately severe to severe range of the disease. apoptosis Glu Gly Glu Gly Glu Gly Ca GluCa Glu Gly Ca GluCa Glu Gly Ca GluCa Glu Ca Gly Gly Gly Gly Ca Ca Ca Ca Ca Regulation inhibition byby Gly Gly memantine Gly Glu Glu Glu memantine Glu Glu Glu Gly Gly Gly Ca Ca Ca Ca Ca Ca Ca preservation of normal normal synaptic function synaptic function neuronal survival protein misfolding mitochondrial dysfunction neuronal survival apoptosis 29 Glu Gly ❾ CHOLINERGIC ENHANCERS AND GLUTAMATERGIC INHIBITORS Current symptomatic therapies for Alzheimer’s include: ACETYLCHOLINESTERASE INHIBITORS (donepezil (Aricept); Eisai/Pfizer), galantamine (Razadyne; Johnson & Johnson), and rivastigmine (Exelon; Novartis). These inhibitors mediate their effects by remediating, in part, the cholinergic deficit in AD. Overall, the effects of these drugs are limited as they modestly improve some of the symptoms but do not treat the underlying causes of the disease. LOW-AFFINITY NMDA RECEPTOR ANTAGONIST (memantine) for moderate to severe AD 30  ❾ CHOLINERGIC ENHANCERS AND GLUTAMATERGIC INHIBITORS JAMA 291, 317 (2004) Memantine Treatment in Patients With Moderate to Severe Alzheimer Disease Already Receiving Donepezil A Randomized Controlled Trial ________________________________________________________________________________________________________________ Pierre N. Tariot, MD Conclusions In patients with moderate to severe _____________________________________________ Martin R. Farlow, MD AD receiving stable doses of donepezil, memantine _____________________________________________ George T. Grossberg, MD resulted in significantly better outcomes than _____________________________________________ Stephen M. Graham, PhD placebo on measures of cognition, activities of _____________________________________________ daily living, global outcome, and behavior and was Scott McDonald, PhD _____________________________________________ well tolerated. These results, together with previous Ivan Gergel, MD _____________________________________________ studies, suggest that memantine represents a new (for the Memantine Study Group) approach for the treatment of patients with moderate to severe AD. 31  INCRETIN MIMETICS AND ALZHEIMER’S DISEASE Type II Diabetes (T2DM) has been identified as a risk factor for Alzheimer’s disease. Furthermore, insulin signaling is impaired in Alzheimer’s disease patients, thus contributing to its pathological features. Hence, normalizing insulin signaling in the brain is a viable strategy for Alzheimer’s disease treatment. In a range of mouse models of Alzheimer’s disease, GLP-1 receptor agonists (liraglutide) were found to be neuroprotective. GUT incretin hormones LIRAGLUTIDE GDIP glucose GLP-1 GLP1 receptor insulin secretion (postprandial) Femminella et al. Evaluating the effects of novel GLP-1 liraglutide in Alzheimer’s disease: study protocol for a randomized controlled trial (ELAD study) Trials 2019; 20: 191. 32 MECHANISM OF ACTION OF CENTRALLY ACTING ANTI-OBESITY DRUGS LORCASERIN 5-HT2CR POMC GLP1R NALTREXONE MOPR MC4R LIRAGLUTIDE SEMAGLUTIDE BUPROPION 33 2. Neural Control OBESITY ¯ FOOD INTAKE ­ FOOD INTAKE POMC AgR/NYP LR GR IR IR leptin Insulin ghrelin Insulin binds to IRs on POMC neurons to increase the expression of anorexigenic peptides (POMC and CaRT). Conversely, insulin acts on AgRP neurons to inhibit the expression of orexigenic peptides (AgRP and NPY). 34  ¯Food Intake ­Learning and Memory ­ Neuroprotection ¯ Inflammation ¯ Reward behavior ¯ Apoptosis (+) LIRAGLUTIDE Hölscher C. (2022) Front Synaptic Neurosci 14:955258 35 JAMA Published online January 8, 2020, E1-E3 36 37 38 39 40 J Prev Alz Dis 2022; Editorial Published online April 5, 2022, http://dx.doi.org/10.14283/jpad.2022.35 © Serdi and Springer Nature Switzerland AG 2022 Where Do We Go from Here? R.C. Petersen Mayo Clinic, Rochester, Minnesota, USA Corresponding Author: Ronald C. Petersen, PhD, MD, Mayo Clinic, Rochester, Minnesota, USA, [email protected]  Altered proteolytic processing of APP resulting in the production and aggregation of Ab  The Ab cascade hypothesis and UPR  Insulin in the brain: Alzheimer’s as diabetes type III  Impaired glucose metabolism in Alzheimer's disease  Ab and oxidative stress  Perturbed calcium homeostasis and excitotoxicity  Inflammation in Alzheimer's disease  Risk Factors: ApoE4 mAbs ❾ Therapeutic strategies cholinergic enhancers + glutamatergic regulators 42