Alzheimer’s Disease Insight Report: Current Therapies, Drug Pipeline and Outlook

Alzheimer's Report September 2019

Alzheimer’s Report September 2019

50 million people worldwide live with symptomatic Alzheimer’s, which has no cure. In honor of September 21st being World Alzheimer’s Day, we evaluated the current therapies, drugs in the pipeline and disease outlook.

Updated as of September 19, 2019

  1. Overview
  2. Diagnosis Strategies
  3. Current Therapies
  4. Drug Pipeline
  5. Outlook

With one in 10 Americans over 65 currently living with symptomatic Alzheimer’s disease, you probably know someone affected by this disease. Worldwide, 50 million people live with symptomatic Alzheimer’s, making it the most common form of dementia. It commonly affects people over 65, but less than 4 percent of the estimated 5.7 million Americans affected have early-onset Alzheimer’s with symptoms beginning before age 65.

By 2050, nearly 14 million Americans are projected to suffer from this disease. Alzheimer’s is 6th leading cause of death in the US, making Alzheimer’s disease a top health concern. Unfortunately, there is no cure, but current medications and management strategies may improve symptoms, prolonging patient independence. In honor of November being Alzheimer’s Awareness month, we evaluated the current therapies, drugs in the pipeline and disease outlook.

Alzheimer’s Disease Overview

Alzheimer’s disease is a degenerative brain disease that typically begins in late middle age or old age. Degeneration of brain cells, called neurons, cause the symptoms of progressive memory loss, impaired thinking, disorientation and mood and personality changes.

Risk factors:

The greatest risk factors are old age, having a family history of Alzheimer’s and carrying a mutation in a certain gene called apolipoprotein E ε4 (APOE4). Environmental and lifestyle factors, such as diet and exercise, also contribute to disease development.

The risk of Alzheimer’s doubles every five years after the age of 65, with nearly 1 in 3 people age 85 or older developing the disease. People with the APOE4 gene variant are thought to have an increased risk for developing late-onset Alzheimer’s, but that’s not a steadfast rule. Inheriting the gene variant does not mean the person will definitely get Alzheimer’s and some Alzheimer’s patients do not have the APOE4 gene variant.


Alzheimer’s develops as a result of a complex interaction between many risk factors, all resulting in neuron damage and death. The buildup of misfolded proteins, such as the tau protein and β-amyloid, create the hallmark protein clumps called tangles and plaques seen in Alzheimer’s brains. While these protein clumps are thought to cause neuron death by blocking nerve cell communication and function, the exact relationship between the protein clump formation and neuron death is still unclear.

The four stages of Alzheimer’s:

Based on the severity of dementia symptoms, Alzheimer’s can be characterized into four stages: preclinical, mild (early-stage), moderate (middle-stage) and severe (late-stage).

The preclinical stage encompasses all the unseen changes in the brain, such as plaque accumulations, happening years before symptoms arise.

Mild Alzheimer’s patients can still function independently, although they begin forgetting familiar words or locations of objects.

As the dementia progresses to become moderate, the patient becomes more forgetful, has greater difficulty doing daily tasks and experiences personality and behavioral changes. At this stage, they may still remember significant life events. The moderate disease stage is the longest, often lasting for many years.

Finally, severe Alzheimer’s patients can no longer respond to their environment, carry a conversation and control their movement or bowels. As the disease progresses, patients require an increasing level of care for daily activities.

Alzheimer’s Life Expectancy:

The earlier the diagnosis, the longer the life expectancy is. People diagnosed in their 60s to early 70s can live as long as 7 to 10 years, whereas those diagnosed in their 90s only average a 3-year life expectancy. Alzheimer’s patients live an average of four to eight years after their diagnosis, but can live as long as 20 years post-diagnosis. However, it’s difficult to link one disease to life expectancy, especially as you age, due to the many variables that influence life expectancy.


The cost burden of Alzheimer’s is as high as its prevalence: Alzheimer’s medications can range from $177 to $400 monthly, adding up to an annual prescription drugs estimated cost of $3,000.

It will cost Americans an estimated $277 billion, including $186 billion in Medicare and Medicaid payments, to care for Alzheimer’s patients by the end of 2018.

By 2050, this cost is projected to be more than $1.1 trillion, accounting for over four-fold increases in government spending through Medicare and Medicaid, as well as out-of-pocket expenses. Up to $7.9 trillion in medical and care costs could be saved by diagnosing earlier and more accurately.

Diagnosis Strategies

Although there is no specific test for Alzheimer’s disease, doctors use a variety of exams, imaging and lab testing to diagnose the disease.

Physical and neurological exams can test reflexes, coordination and memory. Brain imaging is used to rule out other physical abnormalities, such as tumors, stroke or other traumas, that can cause Alzheimer’s-like symptoms.

Imaging can now be used to detect the specific changes that occur in the brains of living Alzheimer’s patients, not just in post-mortem analysis. Structural imaging techniques, such as magnetic resonance imaging (MRI) and computed tomography (CT), are used to rule out other physical injuries as well as assess Alzheimer’s-related brain shrinkage.

Functional imaging, such as functional MRI (fMRI) and positron emission tomography (PET), can measure brain cell function by tracking the cells’ sugar and oxygen use.

Specific radioactive molecules, called radiotracers, can be used to detect β-amyloid plaques via PET imaging. Three radiotracers have been approved by the U.S. Food and Drug Administration (FDA) since 2012: Amyvid (18F-florbetapir), Vizamyl (18F-flutametamol) and Neuraceq (18F-florbetaben).

Genetic testing can reveal if someone has a mutation, such as the APOE4 gene variant, that may increase their risk for developing Alzheimer’s. However, it is generally not recommended for Alzheimer’s diagnosis due to the lower accuracy, as many factors contribute to disease development. The exception is early-onset Alzheimer’s: Anyone with a family history of early Alzheimer’s can be screened for certain gene mutations, such as amyloid precursor protein (APP), presenilin-1 (PS-1) and presenilin-2 (PS-2).

Developing better diagnostic testing could facilitate earlier diagnoses, possibly leading to better outcomes. Future testing includes more sensitive mental ability exams and measuring key disease-associated proteins, called biomarkers, in the blood or spinal fluid.

How is Alzheimer’s Treated?

While there is no cure for Alzheimer’s disease, a handful of drugs have been approved by the FDA and shown to somewhat slow symptom progression. They can be broken down into two categories: cholinesterase inhibitors, which increase the amount of the neurotransmitter acetylcholine in the brain, resulting in more cell-to-cell communication; and NMDA receptor antagonists, which also alter how brain cells communicate.

Cholinesterase inhibitors include Eisai’s Aricept (donepezil) and NovartisExelon (rivastigmine), both approved for all stages of Alzheimer’s, as well as Janssen Pharmaceutical’s Razdyne (galantamine), which is approved for mild to moderate Alzheimer’s. Allergan has two NMDA receptor antagonist-based drugs, Namenda (memantine) and the combination drug Namzaric (donepezil and memantine), which are both approved for moderate to severe Alzheimer’s. Antidepressants and anti-anxiety medications are sometimes prescribed as well to help control behavioral symptoms.

Unfortunately, these drugs can cause potentially severe side effects and aren’t overwhelmingly effective compared to placebo, although they have helped stave off mental decline for a while in some patients. However, the need for more effective drugs is clear.

Drug Pipeline

A variety of targeted therapies are currently being explored through clinical trials, including drugs against:

  • the tau protein, which forms distinctive tangles in Alzheimer’s brains;
  • the β-amyloid protein, which forms plaques in the Alzheimer’s brain;
  • β-secretase (BACE), an enzyme that cuts amyloid precursor protein (APP) into β-amyloid
  • and the 5-HT2A serotonin receptor, which is involved in cognition and memory by mediating neurotransmitters, such as acetylcholine and glutamate.

The Alzheimer’s drug development market includes many large players including Eli Lilly with six drugs (two in Phase 1, two in Phase 2 and two in Phase 3); Biogen with five drugs (two in Phase 1, one in Phase 2 and two in Phase 3); Roche, in collaboration with Genentech, AC Immune, and MorphoSys, with three drugs (two in Phase 2 and one in Phase 3); Eisai, in collaboration with Biogen, with one drug in Phase 3; and Eisai alone with one drug in Phase 2 (as of September 13, 2019).

Data for the bar graph was obtained directly from each company’s website. Data for the pie chart was from the following paper: Cummings, J., Lee, G., Ritter, A., Sabbagh, M., & Zhong, K. (2019). Alzheimer’s disease drug development pipeline: 2019. Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 5, 272–293. doi:

As of September 13, 2019, there are over 670 active/recruiting/not yet recruiting clinical trials for Alzheimer’s listed on According to a paper published in July 2019, there were 132 drugs in development for Alzheimer’s: 28 drugs in 42 Phase 3 trials, 74 drugs in 83 Phase 2 trials, and 30 drugs in 31 Phase 1 trials. The figure and legend below, taken from the July 2019 paper, shows all the drugs in clinical trials for Alzheimer’s as of February 2019.

All compounds in AD clinical trials as of February 12, 2019 (the inner ring shows phase 3 agents; the middle ring is comprised of phase 2 agents; the outer ring presents phase 1 compounds; agents in green areas are biologics; agents in purple areas are disease-modifying small molecules; agents in orange areas are symptomatic agents addressing cognitive enhancement or behavioral and neuropsychiatric symptoms; the shape of the icon shows the population of the trial; the icon color shows the class of target for the agent.). Bolded names represent agents new to that phase since 2018. Figure and legend citation: Cummings, J., Lee, G., Ritter, A., Sabbagh, M., & Zhong, K. (2019). Alzheimer’s disease drug development pipeline: 2019. Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 5, 272–293. doi:

UsAgainstAlzheimer’s released their 2019 Alzheimer’s Drug Pipeline report also in July 2019, where they focused on 98 late-stage Alzheimer’s drugs in development that could potentially reach the market in the next 5-10 years. The report included 26 drugs in Phase III trials and 72 drugs in Phase II trials. Their report shows that, despite some large Phase III failures this year, the Alzheimer’s pipeline is still robust.

The following analysis of some Alzheimer’s drugs in the pipeline will briefly discuss how each drug works and where it is in clinical trials. This information was up to date as of September 13, 2019. Any text in italics represents failed or terminated trials.

Note: This article is not meant to be completely comprehensive and may unintentionally exclude some drugs in development or clinical trials, especially those trials outside of the United States.

Phase 1

Biogen is exploring multiple antibody drugs against the β-amyloid and tau proteins, including a Phase 1 trial studying the anti-tau antibody BIIB076 in 48 healthy and Alzheimer’s patients; a Phase 2 trial (TANGO) examining the anti-tau antibody BIIB092 (gosuranemab) in 528 early-stage Alzheimer’s patients; a Phase 2 trial in collaboration with Eisai studying the anti-β-amyloid antibody BAN2401 in 800 early-stage Alzheimer’s patients; and a Phase 3 trial (Clarity AD) studying BAN2401 in 1566 early Alzheimer’s patients.

Unfortunately, in March 2019, Biogen and its partner Eisai decided to end all studies involving another one of its anti-β-amyloid antibodies called aducanumab (previously called BIIB037).

The ended trials included their two Phase III trials (ENGAGE and EMERGE), each studying 1605 early-stage Alzheimer’s patients, a Phase II trial (EVOLVE) in 500 Alzheimer’s patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer’s, and a Phase I trial (PRIME) in 197 very mild (prodromal) or mild Alzheimer’s patients.

The studies were stopped because they did not meet their clinical endpoints of slowing cognitive and functional impairment, not due to any safety concerns of the drug.

Eli Lilly is pursuing two chemical entities, a “Tau Morphomer” and an “O-GlcNAcase Inhibitor,” in Phase 1 clinical trials for Alzheimer’s.

Proclara Biosciences combined a part of the human immunoglobulin protein with their unique protein technology, called General Amyloid Interaction Motif (GAIM), to create their fusion protein drug NPT088, which targets both β-amyloid and tau proteins. Their Phase 1a safety trial showed that intravenous NPT088 is safe and well-tolerated in 40 healthy patients. Data from their Phase 1b dosing trial in Alzheimer’s patients is expected in 2019.

Cognition Therapeutics drug candidate CT1812 is a small molecule pill that disrupts β-amyloid binding to a receptor called sigma-2 on brain cells, which is thought to prevent the protein’s toxicity.

CT1812 has been or is being studied in six clinical trials including:

CT1812 was well-tolerated and penetrated the brain very well in 80 healthy patients and 19 mild to moderate Alzheimer’s patients with mild to moderate side effects. Although the treated Alzheimer’s patients had lower levels of Alzheimer’s-related proteins (such as neurogranin and synaptotagmin-1, markers of synaptic damage) in their cerebrospinal fluid, they didn’t show significantly different cognitive functioning compared with the placebo group after 28 days of treatment.

Samus Therapeutics is developing a positron-emitting molecule, called 124I-PU-AD, that inhibits a certain protein complex called epichaperone complex, which reduced tau proteins in the brain, restored long-term memory and increased survival in preclinical animal models. 124

I-PU-AD is also being used as a PET imaging agent to study the epichaperone complex in the brains of Alzheimer’s patients.

They have completed an early Phase I trial in 5 Alzheimer’s and certain cancer patients to evaluate the molecule’s metabolism. Another Phase I study is currently recruiting 24 healthy volunteers to evaluate the safety and tolerance of the drug.

Janssen Research & Development is examining the ability of a radioactive PET imaging agent, called [18F]MNI-1020, to bind to the tau protein in Alzheimer’s patients. An early Phase 1 trial studied the safety and brain uptake efficacy of a single injection of the imaging agent in 15 Alzheimer’s and healthy age-matched patients. That study also compared the location of tau (using [18F]MNI-1020) and β-amyloid (using Amyvid (florbetapir)) in patients with suspected Alzheimer’s.

Longeveron collects stem cells from healthy adult donors to create their own ‘Longeveron mesenchymal stem cells (LMSCs),’ which have been shown to reduce inflammation and promote cell regeneration. Their Phase 1 clinical trial is currently recruiting 30 Alzheimer’s patients to evaluate the safety and efficacy of LMSCs.

Athira Pharma’s small molecule drug NDX-1017 designed to ‘restore lost or build new connections in the brain.’ Their Phase 1 trial is currently recruiting to evaluate the drug’s safety in two parts. Part A involves up to 56 healthy young and elderly participants. Part B involves 44 healthy, mild cognitive impairment or mild to moderate Alzheimer’s patients.

Cortexyme, Inc. is developing COR388, a ‘first-in-class bacterial protease inhibitor’ that targets the bacteria Porphyromonas gingivalis, which is present in Alzheimer’s patient’s brains and cerebrospinal fluid and thought to contribute to the disease. Two completed Phase 1 trials have shown that COR388 is safe and well-tolerated in 58 healthy and nine Alzheimer’s patients. A Phase 2/3 trial is currently enrolling 573 mild to moderate Alzheimer’s patients to assess the drug’s efficacy, safety, and tolerability.

Allergan was pursuing a small molecule drug called AGN-242071 that selectively targeted certain receptors in the brain, called muscarinic receptors, which may treat symptomatic cognitive deficits and behavioral symptoms in Alzheimer’s.

Unfortunately, Allergan decided to withdraw their Phase 1 trial evaluating the safety and tolerability of the drug prior to patient recruitment in November 2018.

Corium International has developed a novel delivery method for an approved drug, a once-weekly skin patch (the Corplex Donepezil Transdermal System) that delivers a sustained dose of donepezil. The patch’s safety and drug profile were examined in multiple Phase 1 trials, which showed great skin tolerability and comparable dosages between the weekly patch and the currently prescribed daily donepezil pills. Corium is also developing a once-weekly skin patch to deliver memantine.

Cognoptix has taken a different approach, developing an eye test called Sapphire II to catch and diagnose Alzheimer’s much earlier by detecting β-amyloid deposits in their eyes. A fluorescent drug that binds to the β-amyloid protein (Aftobetin-HCl) is administered to the eye as an ointment and binding is detected with the Sapphire II laser device.

Their Phase 1 study determined the optimal dosing of the fluorescent drug in 15 participants and is currently recruiting 10 normal and 20 mild cognitive impairment (MCI) or mild Alzheimer’s patients for dose testing. If the dosing is optimal, then 30 more MCI and 30 more mild Alzheimer’s patients will be recruited, totaling 105 participants.

Phase 1/2

Ionis Pharmaceuticals is collaborating with Biogen to study their antisense oligonucleotide drug IONIS-MAPTRx (also called BIIB080), which may reduce tau protein production and its accumulation in brain cells. BIIB080 is being evaluated in a Phase I/II trial in 44 mild Alzheimer’s patients.

QR Pharma, Inc.’s small molecule drug Posiphen inhibits APP, tau and α-synuclein (involved with Parkinson’s disease) protein synthesis. They are currently recruiting 24 Alzheimer’s patients for their Phase 1/2 dosage study (DISCOVER).

Following their successful Phase I trial (SEAD) in 15 Alzheimer’s patients, Ausio Pharmaceuticals brought their estrogen receptor activating drug S-equol (also called AUS-131) to a Phase 1/2 trial (SEAD2). The trial is currently recruiting 40 Alzheimer’s patients to test the drugs tolerability and whether or not it affects cognitive abilities. Activating the estrogen receptors on mitochondria is thought to promote mitochondrial functioning, which could restore the reduced mitochondrial activity seen in Alzheimer’s patients. Less mitochondrial activity is thought to contribute to β-amyloid protein build-up in the brain.

Nature Cell Co. is studying a fat cell-derived mesenchymal stem cell (MSC) therapy called AstroStem in an active Phase 1/2 study involving 21 mild to moderate Alzheimer’s patients.

Phase 2

Eli Lilly has two ongoing Phase 2 trials studying antibody drugs: one active trial (TRAILBLAZER-ALZ) evaluating the tolerability and efficacy of a humanized anti-β-amyloid antibody, called donanemab (LY3002813 or N3pG-Aβ MAb), in 266 early symptomatic Alzheimer’s patients; and another currently recruiting trial evaluating the safety and efficacy of a humanized anti-tau antibody, called zagotenemab (LY3303560), in 285 early symptomatic Alzheimer’s patients.

Roche, in partnership with AC Immune, is studying crenezumab (RG7412), an anti-β-amyloid antibody drug that binds to β-amyloid similar to Eli Lilly’s solanezumab.

Crenezumab is being investigated in an active Phase 2 trial involving 252 non-symptomatic adults with a family history of Alzheimer’s who have a particular genetic mutation (autosomal-dominant PSEN1 E280A). Baseline data for 242 of the enrolled patients were presented at the Alzheimer’s Association International Conference in August 2019.

Another not yet recruiting Phase II trial is in the works to study the effect of crenezumab on the longitudinal tau burden via PET imaging of 150 patients enrolled in the active Phase II trial (NCT01998841).

Crenezumab was being investigated in three Phase III trials:

  • CREAD 1 evaluating the drug’s safety and efficacy in 813 mild Alzheimer’s patients;
  • CREAD 2 studying the drug’s safety and efficacy in 750 mild Alzheimer’s patients;
  • and an open-label extension trial (CREAD OLE) examining long-term drug treatment in 149 Alzheimer’s patients.

Unfortunately, in January 2019, Roche discontinued all CREAD trials due to the interim analysis showing crenezumab was unlikely to meet the primary endpoint of improving cognition.

Genentech (a subsidiary of Roche) is partnering with AC Immune to develop the anti-tau antibody drug RO7105705 (also called RG6100 and MTAU9937A), which recognizes tau tangles and is meant to block their spread between cells. An active Phase 2 trial involving 457 prodromal to mild Alzheimer’s patients is studying the drug’s safety and effect on cognitive function.

AbbVie’s humanized antibody drug ABBV-8E12, which targets the tau protein, is being evaluated for its safety and efficacy in an active Phase 2 trial involving 400 early-stage Alzheimer’s patients. An extension study to study the drug’s long-term safety and tolerability is currently enrolling patients from the Phase 2 study (NCT02880956) by invitation.

Avid Radiopharmaceuticals, a wholly-owned subsidiary of Eli Lilly, is developing the PET imaging agent 18F-AV-1451 (also called Flortaucipir F 18 or F 18 T807). The molecule binds to the tau protein, allowing researchers to study tau in living patients.

There are multiple Phase 2 or Phase 2/3 trials studying the imaging agent’s safety and efficacy.

Five Phase 2 trials currently recruiting or not yet recruiting: one to evaluate the agent’s safety and tau binding via PET imaging in 250 healthy, Alzheimer’s, traumatic brain injury and depression patients; one (ADRC proj 1) to compare tau tangles in the brain with cerebrospinal fluid CSF biomarkers and cognitive status in 80 Alzheimer’s patients; one (DIAN Project, AV ADAD) to study the presence of tau tangles in the brain and cognitive status in 130 adults; one to study the uptake and binding in 80 older HIV-positive adults with and without HIV-associated neurocognitive disorders and HIV-negative age-matched controls; and one (Protocol Z) to study tau and amyloid lesions in the brains of 80 APOE4+ adults with normal cognition or early-stage symptomatic Alzheimer’s.

Neurotrope Bioscience is developing bryostatin-1, a small molecule that activates protein kinase C (PKCε), a protein that is important for learning and memory.

This drug stimulates synapse repair and growth, activates β-amyloid degrading enzymes and prevents tau tangle formation and neuron death. A Phase II trial evaluating the safety and efficacy of bryostatin-1 in 147 moderate to severe Alzheimer’s patients showed positive results: the lower (20 μg) dose improved cognition and the ability to care for oneself.

This prompted a second Phase II trial to study the drug’s safety and efficacy at the lower dose in 108 moderately severe to severe Alzheimer’s patients.

Unfortunately, Neurotrope announced that the second Phase II trial did not show statistically significant improvement in memory, indicating it did not meet its primary endpoint. The primary endpoint was a change in the Severe Impairment Battery (SIB) test total score from baseline to week 13.

EIP Pharma is pursuing a small molecule called neflamapimod (VX-745) that inhibits an enzyme, called p38 MAPKα, found in the neurons that is involved in inflammation and possibly β-amyloid toxicity. Neflamapimod previously showed clinical activity in rheumatoid arthritis patients before being licensed to EIP Pharma. They are currently conducting a Phase 2b efficacy study (REVERSE-SD) in 161 participants with mild Alzheimer’s. A Phase 3 study is scheduled to start in the third quarter of 2020. Another Phase 2 trial is recruiting 40 Alzheimer’s patients to study neflamapimod on brain inflammation.

Actinogen Medical is studying a drug called xanamem, which inhibits a cortisol-producing enzyme in the brain, ultimately blocking local production of cortisol, known as the “stress hormone.”

While blood cortisol levels tend to rise with age, it’s particularly raised in patient with certain diseases, such as Alzheimer’s. Long-term high cortisol levels can be toxic to brain neurons, so preventing cortisol production in the brain may help slow cognitive decline and β-amyloid plaque formation.

After assessing xanamem’s safety and dosing in two Phase I trials, a Phase II trial (XanADu) assessed the drug’s safety and efficacy in 186 early-stage Alzheimer’s patients.

Boehringer Ingelheim’s drug BI 425809 is a glycine transport inhibitor designed to regulate signaling in the brain that contributes to cognitive impairment. An active Phase 2 trial is studying the safety and effect on cognition of multiple dosages of the drug in 611 Alzheimer’s patients.

Neurocentria is developing a dietary supplement called MMFS. MMFS contains a molecule called L-threonic acid magnesium salt (L-TAMS) that increases synapse density in portions of the brain needed for memory and executive functioning, such as the prefrontal cortex and hippocampus. Two previous studies showed improved cognition in mild to moderate Alzheimer’s patients, prompting the active Phase 2 trial that is recruiting 12 mild Alzheimer’s patients to examine the drug’s safety and effect on cognition.

Alkahest is studying intravenously administered plasma-derived product called GRF6019, which is isolated from human plasma (a component of the blood) that has been shown to ‘enhance neurogenesis and improve learning and memory in animals.’ Matching donor and patients’ blood types is not needed because the donor-specific antibodies (called immunoglobulins) are removed. A Phase 2 trial in 40 mild to moderate Alzheimer’s patients studied the safety and feasibility of GRF6019. Another Phase 2 trial is currently recruiting 20 severe Alzheimer’s patients to study the safety, tolerability, and cognitive benefits of the drug.

Suven Life Sciencesdrug SUVN-502 specifically inhibits a certain serotonin receptor (called 5-HT6), which is thought to improve cognition and memory. SUVN-502 in combination with donepezil and memantine was shown to increase the concentration of neurotransmitters, like acetylcholine. An active Phase 2 trial is testing the effect of this triple combination therapy on cognition in 563 moderate Alzheimer’s patients. An expanded access program is also available for eligible patients to receive the drug without being evaluated for safety and efficacy.

Neurim Pharmaceuticals is taking a different approach by developing a drug, called piromelatine, that binds to and activates melatonin and serotonin receptors in the brain, promoting sleep and therefore neuroprotective effects. This drug was safe and promoted deeper and more REM sleep in a Phase 2 clinical trial in adults with insomnia. Given the link between sleep and Alzheimer’s, Neurim decided to study piromelatine’s effects on cognition in 500 mild Alzheimer’s patients in an active dose-ranging Phase 2 trial.

Eisai, in collaboration with Purdue Pharma, is studying their orexin receptor antagonist drug lemborexant in a Phase 2 trial involving 62 mild to moderate Alzheimer’s patients. The orexin receptor is involved in the regulation of sleep. Lemborexant binds to the orexin receptor, preventing orexin from binding, which should decrease wakefulness and promote falling and staying asleep naturally. Sleep, especially at appropriate hours, is troublesome for Alzheimer’s patients whose circadian rhythms tend to be dysregulated.

Masitinib showing its capabilities in late stage A

Masitinib showing its capabilities in late stage A

Phase 2/3

Novartis has partnered with Amgen and the Banner Alzheimer’s Institute to pursue Novartis’ drug umibacestat (CNP520), which inhibits BACE1, an enzyme involved in β-amyloid production.

After a successful Phase 2 trial safety study in 124 healthy elderly patients, there were two Phase 2/3 trials. One (Generation S1) of the trials tested the efficacy of CNP520 against an investigational immunotherapy drug (CAD106, a vaccine against a fragment of the β-amyloid protein) in 481 non-symptomatic older patients with two copies of the APOE4 gene.

The other trial (Generation S2) tested the drug’s effect on cognition and underlying Alzheimer’s pathology in 1145 non-symptomatic older patients with at least one APOE4 allele and elevated brain β-amyloid levels.

Unfortunately, both Phase 2/3 trials were discontinued in July 2019 due to worsening cognitive function seen during interim data analysis. As umibacestat was meant to delay the onset of symptoms, participants in the study will discontinue the investigational treatment and discuss further treatment options with their doctors.

TauRx Therapeuticsdrug TRx0237 (also called LMTX®) is their second-generation tau protein aggregation inhibitor, which aims to both dissolve existing tau tangles and prevent new tangles from forming.

Two previous Phase 3 clinical trials studied the safety and efficacy of high doses (150-250 mg/day) and a low dose control (8 mg/day) of the drug in 800 mild and 891 mild to moderate Alzheimer’s patients. Surprisingly, they found that the low dose was as beneficial as the higher doses, prompting a current Phase 2/3 trial (LUCIDITY) recruiting 375 early Alzheimer’s patients studying TRx0237 at low doses (8 and 16 mg/day). An expanded access program is also available to provide the drug to patients who have previously participated in a TauRx clinical trial but do not qualify for an ongoing trial.

Axsome Therapeutics is pursuing a treatment for agitation associated with Alzheimer’s and have been granted fast track status for their drug AXS-05, which combines dextromethorphan and bupropion. Dextromethorphan (called DM and commonly known as an over-the-counter cough suppressant) inhibits serotonin and norepinephrine transporters and the NMDA receptor at high doses. Bupropion increases the bioavailability of dextromethorphan and inhibits norepinephrine and dopamine reuptake.

A Phase 2/3 trial (ADVANCE) is currently recruiting 435 Alzheimer’s patients to study the safety of AXS-05 and its effect on agitation.

Phase 3

Eli Lilly has a Phase III anti-β-amyloid antibody drug called solanezumab (LY2062430), which binds to soluble β-amyloid monomers. The primary endpoints of trials involving this drug is to slow memory and cognitive decline.

The drug is associated with 11 listed trials, including an active Phase III trial (A4) involving 1150 asymptomatic adults with evidence of amyloid plaque build-up in their brains and a currently recruiting Phase 2/3 large collaboration trial (DIAN-TU) comparing solanezumab and gantenerumab in 490 non-symptomatic adults known to have an Alzheimer’s disease-causing mutation.

This collaboration includes Eli Lilly, Roche, Avid Radiopharmaceuticals, Janssen, Alzheimer’s Association, National Institute on Aging (NIA), Accelerating Medicines Partnership (AMP), and Washington University School of Medicine.

Two Phase 3 trials (EXPEDITION and EXPEDITION 2) were completed previously and involved 1040 Alzheimer’s patients each. Although there was no difference in cognition between the treated and placebo groups, patients with mild Alzheimer’s did show slower cognitive decline compared to placebo, prompting further studies.

Unfortunately, the next three Phase III trials (EXPEDITION 3, EXPEDITION EXT and EXPEDITION PRO) were terminated due to lack of meeting primary endpoints. Some of the endpoints including slowing cognitive decline, and “insufficient evidence that solanezumab would likely demonstrate a meaningful benefit to patients with prodromal Alzheimer’s.”

Roche is currently investigating gantenerumab, an anti-β-amyloid antibody drug that binds and neutralizes β-amyloid plaques. Gantenerumab, brought back after failing in previous clinical trials, is involved in four Phase III trials:

  • two active trials studying the drug’s effect on cognitive function in 799 prodromal and 389 mild Alzheimer’s patients;
  • two currently recruiting trials studying the drug’s effect on cognition in 760 early Alzheimer’s patients each.

Eisai, in collaboration with Biogen, is studying their small molecule BACE1 inhibitor elenbecestat (also called E2609) in two Phase 3 trials (MISSION AD1 and MISSION AD2) currently recruiting 950 early-stage Alzheimer’s patients each. Inhibiting BACE1 is thought to interfere with β-amyloid production.

Unfortunately, the companies announced that they were discontinuing their MISSION AD1 and AD2 Phase 3 trials on September 13, 2019. The decision was made based on results from a safety review that showed an “unfavorable risk-benefit ratio” of elenbecestat.

Avid Radiopharmaceuticals and Eli Lilly reported positive results earlier this year from their Phase 3 trial on the tau-binding PET imaging agent flortaucipir F 18 (18F-AV-1451 or Tau imaging agent) in Alzheimer’s patients. The trial met its two primary endpoints, successfully predicting both the disease-related role of tau in the brain and an Alzheimer’s diagnosis. PET imaging was performed on 156 end-of-life patients with cognition ranging from normal to dementia, with 67 of these patients being evaluated post-mortem. Flortaucipir could significantly detect Alzheimer’s-related changes in the brain, including both tau and β-amyloid plaque densities. Being able to accurately image and diagnose Alzheimer’s patients is a critical component in understanding the disease and being able to manage it. There are currently 33 studies listed on for flortaucipir and Alzheimer’s.

AZTherapies, Inc. is studying the combination drug ALZT-OP1, which consists of the inhaled drug cromolyn and oral drug ibuprofen, both of which are anti-inflammatory. Inflammation in the brain is thought to trigger neuronal death, which causes progressive brain damage. Cromolyn was also shown to prevent β-amyloid aggregation in one study. A Phase 3 trial (COGNITE) is currently studying the effect of this combination drug on cognitive decline in 620 early-stage Alzheimer’s patients.

ACADIA Pharmaceuticals drug pimavanserin (previously called ACP 103) is a ‘selective serotonin inverse agonist’ (SSIA), meaning it both binds to serotonin receptor subtype 5-HT2A and blocks serotonin signaling.

Following a few Phase II trials specifically in Alzheimer’s patients, there are currently three recruiting Phase III trials for a broader range of dementia patients.

One trial is an efficacy study examining pimavanserin’s ability to prevent relapse of dementia-related psychosis symptoms in 356 dementia patients.

The second trial is a safety study in 300 patients with neurodegenerative disease. The third trial is and an open-label extension study examining the drug’s long-term safety in 300 patients with neurodegenerative disease who previously participated in another pimavanserin clinical trial by ACADIA.

Intra-Cellular Therapies is developing lumateperone (ITI-007), a molecule that simultaneously affects serotonin, dopamine and glutamate signaling, which play important roles in multiple mental illnesses. Following a Phase 1b/2 study, they recruited 177 dementia patients, including Alzheimer’s patients, for a Phase 3 trial studying the safety and efficacy of the drug for reducing agitation.

However, the Phase 3 trial was terminated early due to interim data analysis indicating lumateperone’s lack of efficacy.

AVANIR Pharmaceuticalsdrug AVP-786 combines two approved drugs: deuterated dextromethorphan (d6-DM), which has better bioavailability and less side effects than regular DM, and an “ultra-low dose” of quinidine, which slows the metabolism of d6-DM by inhibiting an enzyme (CYP 2D6) that breaks down d6-DM. AVP-786 is a second-generation version of Nuedexta (formerly AVP-923). It is currently approved to treat pseudobulbar affect (PBA).

Currently, there are four recruiting or active Phase III trials studying the safety and efficacy of AVP-786 in treating agitation in Alzheimer’s patients: one recruiting 412 Alzheimer’s patients with moderate to severe agitation worldwide, one active study involving 522 Alzheimer’s patients in the U.S., one completed study involving 410 Alzheimer’s patients in the U.S. and a long-term extension study recruiting 700 patients who have completed previous clinical trials of AVP-786 by Avanir.

Otsuka Pharmaceutical Co. and Lundbeck are collaborating to develop brexpiprazole (brand name Rexulti) for treating agitation and behavioral symptoms in Alzheimer’s patients.

Rexulti, which binds to and activates a particular dopamine receptor (D2), is currently FDA approved to treat schizophrenia and as an add-on treatment for major depression disorder.

Two Phase 3 trials examining brexpiprazole at either fixed or flexible doses in a total of 703 Alzheimer’s patients showed reduced agitation compared to the placebo.

They are currently recruiting for three Phase 3 trials: one evaluating the safety, efficacy, and tolerability in 225 Alzheimer’s patients with dementia-associated agitation in the US; one studying long-term treatment in 157 Alzheimer’s patients with dementia-associated agitation in Japan; and a 12-week extension study for 250 Alzheimer’s patients with dementia-associated agitation who were previously enrolled in other Otsuka trials studying brexpiprazole.

They are also recruiting for a Phase 2/3 study in 407 Alzheimer’s patients with dementia-associated agitation in Japan.

Merck Sharp & Dohme Corp., a subsidiary of Merck, is studying their FDA approved drug suvorexant (previously called MK-4305, brand name Belsomra) to treat insomnia in Alzheimer’s patients. Currently approved for insomnia patients, the small molecule drug works by inhibiting the orexin receptor in the signaling system involved in wakefulness. Their Phase 3 trial studying suvorexant’s safety and efficacy at improving sleep in 285 Alzheimer’s patients and patients with insomnia concluded in October 2018, but results have not been posted yet.

Preclinical Candidates

A few companies are investigating drugs in the preclinical laboratory setting, hoping to gather promising data to bring their drugs to clinical trials.

Servier and TREVENTIS Corporation partnered in January 2018 to begin a large drug discovery program to identify drugs against the tau and β-amyloid proteins. One molecule, called TRV 101, significantly reduced the toxic accumulations of both the tau and β-amyloid proteins in multiple mouse models of Alzheimer’s.

ProMis Neurosciences is also developing a molecule that specifically binds to β-amyloid plaques. Their antibody drug, called PMN310, showed significantly more binding to plaques in human Alzheimer’s brain samples compared with Biogen’s aducanumab, another human antibody targeting β-amyloid plaques. As of September 2019, PMN310 is in IND-enabling development.

Regenacy Pharmaceuticals’ drug, called RCY-1305, is a molecule that inhibits a group of enzymes, called histone deacetylases (HDACs), which regulate gene expression in the brain. Abnormal gene expression caused by increased histone acetylation, the ‘off’ switch for genes, is involved in Alzheimer’s. Reducing acetylation by blocking HDACs may help reverse cognitive impairment. In fact, RCY-1305 showed improved cognitive function in two mouse models of familial (early-onset) Alzheimer’s.


While the road of drug discovery and approval isn’t easy, paving the way to effective Alzheimer’s drugs is proving to be particularly difficult.

“One of the biggest issues in coming up with effective therapies for Alzheimer’s disease is that we really don’t know critical elements [underlying] the mechanism [of the disease] in most people with the illness,” said David Geldmacher, a neurologist at the University of Alabama at Birmingham. Geldmacher is working on a Phase 3 trial of aducanumab with Biogen.

Having a better understanding of what goes wrong during the disease and how that correlates to symptoms and disease progression will be the key to developing an effective treatment.

Fortunately, pharmaceutical companies are likely not going to give up the pursuit of effective Alzheimer’s treatments. The worldwide market for such therapies is huge because of the large unmet medical need in Alzheimer’s.

A report titled “Researching Alzheimer’s Medicines: Setbacks and Stepping Stones” by the Pharmaceutical Research and Manufacturers of America (PhRMA) in November 2018 painted Alzheimer’s drug discovery in an optimistic light. Although there have been 146 drug development failures for Alzheimer’s between 1998 and 2017 and only four drug approvals – only a 2.7 percent success rate – the drug pipeline seems promising. Of the 92 drugs in Phase 2 and 3 trials at the time, UsAgainstAlzheimer’s says approximately 75 percent have the potential to become ‘disease-modifying treatments.’

In July 2019, UsAgainstAlzheimer’s published their 2019 Alzheimer’s Drug Pipeline report, which also showed the Alzheimer’s drug pipeline to still be robust despite the huge Phase 2/3 and Phase 3 trial discontinuations in 2019.

Learning from drug failures and recent technological advances – notably being able to see β-amyloid plaques in living patients via PET scan – have allowed researchers to shift the focus of trials from treating patients after symptoms arise to before or as soon as symptoms appear.

“The process of Alzheimer’s disease begins in the brain years, probably decades, before the first symptoms emerge,” Geldmacher adds. “In many cases, we’ve been trying to treat the illness too late in its course.”

By targeting what goes wrong in Alzheimer’s early on, the hope is to slow or prevent disease progression before it is too late. Combining drugs will likely also provide better benefits, so developing different drugs with various targets is beneficial.

Changing how we view Alzheimer’s can also impact how we treat it and evaluate drug candidate success. Researchers recently proposed dividing Alzheimer’s patients into six subgroups based on their cognitive functioning and found genetic differences between the subgroups.

“Alzheimer’s, like breast cancer, is not one disease,” said Shubhabrata Mukherjee, research assistant professor of medicine at the University of Washington School of Medicine and lead author of the study. “I think a good drug might fail in a clinical trial because not all the subjects have the same kind of Alzheimer’s.”

This interesting perspective on Alzheimer’s could lead to more personalized treatment and possibly better clinical trial outcomes by having more defined enrollment criteria within the blanket of Alzheimer’s disease.