Stuart R. Gallant, MD, PhD
Having discussed the pathological processes of Alzheimer’s disease in the first part of this post, the current status of Alzheimer’s drug development is the subject of the second part.
Licensed Treatments—Non-Course-Altering
Ideally, the time to develop Alzheimer’s disease could be increased. Since it is rare to develop symptoms prior to age 50, a treatment which only doubled or tripled the time for the disease to manifest could allow many patients to live out their lives without significant harm.
The most commonly prescribed medications for Alzheimer’s disease do not alter the course of the illness. Instead, they treat the symptoms of the disease. Acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) prevent degradation of the neurotransmitter acetylcholine, modestly improving brain function in Alzheimer’s sufferers. NMDA receptor antagonists (memantine) reduce the effect of an oversupply of glutamate in brains affected by Alzheimer’s disease.
Just recently, Aducanumab (Aduhelm) was added as a licensed treatment for Alzheimer’s disease—it is among the first medications discussed in the next section of this post.
Molecular
Antibodies against beta amyloid have received several trials. The first approved drug in this class, Aducanumab (Aduhelm), has been a disappointment due to limited efficacy, as well as its side effects. Three antibodies remain in trials; however, data for this class has not been compelling so far.
| Status | Name | Mechanism | Trials |
| Approved | Aducanumab | Anti-amyloid mAB | FDA approved; controversy over low efficacy, as well as side effects |
| Inactive | Bapineuzumab | Anti-amyloid mAB | Phase 3 (discontinued in 2012) |
| Inactive | Crenezumab | Anti-amyloid mAB | Roche’s drug failed in traditional Alzheimer trial and in a family predisposed to disease; halted trials |
| Gantenerumab | Anti-amyloid mAB | Phase 3 (ongoing, will report in 2022); a Roche drug | |
| Lecanemab | Anti-amyloid mAB | Phase 3 (ongoing)–Biogen follow up for Aduhelm. | |
| Solanezumab | Anti-amyloid mAB | Lilly’s drug has failed several Phase 3; currently being trialed in patients with cognitive decline and elevated beta amyloid |
Another approach to preventing amyloid plaque development would be inhibition of aggregation. Presumably, a small change in the propensity to aggregate would be helpful; however, no stars have emerged in this area. Homotaurine and colostrinin failed; while a homotaurine prodrug and GV 971 remain in trials:
| Status | Name | Mechanism | Trials |
| ALZ-801 | Aβ aggregation inhibition | Phase 3 (reports in 2024); focus patients with APOE4 risk; a homotaurine prodrug (homotaurine failed, but had interesting subgroup data) | |
| Inactive | Tramiprosate | Aβ aggregation inhibition | Phase 3 (discontinued in 2007); homotaurine. |
| Inactive | Colostrinin | Aβ aggregation inhibitor | Phase 2 (terminated in 2009); proline rich peptide; sold OTC as a dietary supplement. |
| GV 971 | Aβ aggregation inhibitor | Phase 3 (ongoing); molecule derived from seaweed; has had some financing issues; trial proceeding |
As a class, BASE1 is the major beta-secretase implicated in the amyloidogenic pathway (see figure above). As such, it is an obvious drug target; however, this approach has not been fruitful with clinical trials on five candidates terminated.
| Status | Name | Mechanism | Trials |
| Inactive | Atabecestat | BACE1 reversible inhibition | Phase 2/3 (discontinued for liver toxicity); showed cognitive worsening |
| Inactive | Elenbecestat | BACE1 reversible inhibition | Phase 3 (discontinued in 2019); no significant cognitive improvement |
| Inactive | Lanabecestat | BACE1 reversible inhibition | phase 3 (terminated in 2018); worsening on several cognitive scores |
| Inactive | Umibecestat | BACE1 reversible inhibition | Phase 2/3 (terminated in 2019); cognitive worsening with treatment |
| Inactive | Verubecestat | BACE1 reversible inhibition | Phase 3 (discontinued in 2017); mixed data with some cognitive worsening |
BASE1 inhibitors did not provide the expected improvement in cognitive function. There is good data to indicate that, for example, Lanabecestat was working as intended (dropping both blood and CSF levels of beta-amyloid). Yet, the therapeutic effect was not proportional to the change in measured beta-amyloid, perhaps indicating that the current understanding of Alzheimer’s disease remains incomplete.
Other inhibitors of aggregation have been developed. Of these, TauRx’s LMTM seems to be the most promising with supportive MRI data in Phase 3 Clinical testing; additional data is expected in 2022.
| Status | Name | Mechanism | Trials |
| LMTM | tau aggregation inhibitor | Phase 3 reports in 2018; MRI shows benefit of LMTM. More data expected in 2022. | |
| Thiamet G | tau aggregation inhibitor (O-GlcNAcase enzyme) | Phase 2 expected to report in 2024; a Lilly drug; inhibits tau aggregation | |
| Acitretin | α-Secretase stimulator | One 2014 study report was not followed up. | |
| Epigallocatechin-gallate | α-Secretase stimulator | From green tea; prevents tau aggregation; clinical trials being pushed actively. | |
| Etazolate | α-Secretase stimulator | No recent studies since 2011. | |
| Inactive | Avagacestat | γ-Secretase inhibitor | Phase 2 (discontinued in 2012) |
| Inactive | Semagacestat | γ-secretase inhibitor | Phase 3 (terminated in 2011) |
| Inactive | Tarenflurbil (MPC-7869) | γ-Secretase inhibitor | Phase 3 (terminated in 2009) |
A tau aggregation inhibitor would act to prevent formation of neurofibullary tangles, relieving one of the two main microscopic findings in Alzheimer’s disease.
Immune
Inhibition of the cascade of immune responses to the presence of beta amyloid may limit the damage that Alzheimer’s disease does to the central nervous system. The most promising treatment reports in this area involve mast cell inhibition. Mast cells, a hemopoietic immune cell type, participate in the immune response along with microglial cells and astrocytes.
| Status | Name | Mechanism | Trials |
| Inactive | Minocycline | Anti-inflammatory, inhibits microglial activation | Phase 2 (discontinued in 2019) |
| ALZT-OP1 | Aβ clearance promotor | Phase 3 (ongoing); a licensed mast cell stabilizer given with ibuprofen; no data reported yet (past expected date?) | |
| Inactive | Saracatinib | Src kinase inhibitor | Phase 2a (terminated in 2018) |
| Masitinib | Tyrosine kinase inhibitor | Mast cell inhibitor; Phase 2 data showed slowing of cognitive decline in combination with standard of care. |
Mast cells interact with the neuroimmune system, constituting a reservoir of reactive oxygen species and cytokines (such as TNF-alpha). As such, they can amplify the response of the neuroimmune system to inflammation [1]:
Mastinib is an already licensed mast cell inhibitor being tested in Alzheimer’s disease. It was able to slow cognitive decline in a Phase 2 trial.
Metabolic
Metabolic disease (diabetes, hypercholesterolemia, hypertension) constitutes a dysregulated medical state which includes numerous pathological pathways, including but not limited to a pro-inflammatory state. It is not surprising that medications for metabolic disease would improve the outcome for some Alzheimer’s disease patients.
| Status | Name | Mechanism | Trials |
| Losartan | Angiotensin II receptor blocker (ARB) | Anti-hypertensive; Phase 2 will report in Oct 2022 | |
| Telmisartan | Angiotensin II receptor blocker (ARB) | Anti-hypertensive; Phase 2 will report in March 2022 | |
| Inactive | Nivaldipine | Calcium channel blocker | Anti-hypertensive; Phase 3 (Inactive since 2018) |
| Liraglutide | Glucagon-like peptide 1 agonist | Diabetes medication; Phase 2b (ongoing); Novo Nordisk; controls blood sugar, anti-inflammatory | |
| Semaglutide | Glucagon-like peptide 1 agonist | Diabetes medication; Phase 3 (started in 2021); Novo Nordisk; controls blood sugar, anti-inflammatory | |
| Inactive | Pioglitazone | Peroxisome proliferator-activated receptor-γ agonist | Diabetes medication; Phase 3 (terminated in 2018) |
| Azeliragon | Receptor for advanced glycation end products (RAGE) inhibitor | Phase 3 (Ongoing); RAGE inhibitor; focus is on diabetic patients. |
One critical element of use of these medications will be in assessing patient risk so that only patients who can benefit from the medication are included in trials and ultimately received the licensed medication. Packaging appropriate diagnostics with the treatment will thus be important.
Neurotransmitter
The outcome of Alzheimer’s disease is widespread damage to neurotransmission. Neuropsychiatric issues such as depression and agitation can be prominent features of the presentation of this disease. For that reason, medications which affect alertness, attention, and mood may have benefit for this group of patients:
| Status | Name | Mechanism | Trials |
| Inactive | Lumateperone (ITI-007) | 5HT2A antagonist, SSRI, glutamate GluN2B receptor phospho-protein modulator | Phase 3 (terminated in 2018, failed to meet the primary end point objectives) |
| Inactive | Idalopirdine | AChE inhibitor and 5HT-6 antagonist | Phase 3 (discontinued in 2017) |
| J-147 | MAO-B inhibitor | Phase 1 completed in 2020; targets mitochondria—anti-aging approach | |
| AVP-786 | NMDA receptor antagonist | Phase 3 (ongoing); dextromethorphan (cough suppressant) for mood | |
| Brexipiperazole | Partial agonist of 5-HT1A and dopamine D2 and D3 receptors | Under study to treat agitation in AD; 1 mg/day ineffective, but 2 mg/day may be; in Phase 3 | |
| Inactive | Encenicline | Partial α7-nAChR Agonist | Phase 3 (on clinical hold for GI issues) |
| Escitalopram | Selective serotonin reuptake inhibitor | Phase 3 (through August 2022); decreases beta amyloid in mice. | |
| Blarcamesine | Sigma-1 receptor activator | Phase 2b/3 enrolling as of 2021; decreases oxidative stress. | |
| Guanfacine | α2A adrenergic receptor agonist | Phase 3 (ongoing); ADHD drug; not altering course of disease. | |
| Inactive | Aripiprazole | Dopamine D2 agonist | Phase 3 (terminated in 2016) |
| Inactive | Atuzaginstat | Irreversible inhibitor of gingipain | Phase 2/3; halted due to liver toxicity; an inhibitor of gingival bacteria |
Use of an SSRI for depression and anxiety makes logical sense for this group of patients, given the tremendous stress that the disease causes—even outside of clinical evidence for the need to replete CNS serotonin stores. However, polypharmacy must be carefully monitored to ensure that any treatment does not have intolerable side-effects.
[1] Beardsley P. M., et al. “Glial modulators as potential treatments of psychostimulant abuse”. Adv. Pharmacol. 69: 1–69. doi:10.1016/B978-0-12-420118-7.00001-9.
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