Alzheimer Disease Pipeline Update: Inside Look at Promising Agents


With the recent approval of lecanemab (Leqembi; Eisai), NeurologyLive took a closer look at the Alzheimer pipeline, and the potential agents clinicians should keep an eye on in the coming years.

Charles Bernick, MD, neurologist at Cleveland Clinic's Lou Ruvo Center for Brain Health

Charles Bernick, MD

There are an estimated 6.3 million individuals with Alzheimer disease (AD) dementia in the United States, and an estimated 50 million individuals with AD dementia globally. These populations are expected to grow to 12.7 million and 150 million in the US and globally, respectively, by 2050. Fortunately, though, in recent years, drug development has expanded significantly, with several dozens of agents currently progressing through the pipeline.

In total, there were 187 clinical trials across phases 1, 2, and 3, assessing a total of 141 unique drugs. Disease-modifying therapies comprise the most common agents, accounting for 79% of drugs in trials. An additional 28% of candidate therapies are repurposed agents. Transmitter receptors, amyloid, synaptic function, and inflammation, are the most common targets of drugs in the pipeline.

To parallel the ongoing coverage and data presentations at the 2023 Alzheimer's Association International Conference (AAIC), held July 16 to 20, in Amsterdam, Netherlands, NeurologyLive® conducted a pipeline overview of some of the notable agents currently in development. The team focused in on a few main therapuetic groups, with provided commentary from leaders in the field.

Amyloid Therapies

Charles Bernick, MD, a neurologist at Cleveland Clinic's Lou Ruvo Center for Brain Health, offered NeurologyLive this about amyloid therapies: "The defining pathological features of Alzheimer disease is the presence of extracellular amyloid plaques containing amyloid-ß [Aß] peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. Though there is no certainty on how the plaques and tangles may be driving the disease process, the leading idea is based on the 'amyloid hypothesis.' This idea proposes that accumulation of amyloid, up to 10 to 20 years prior to symptom onset, results in toxicity to neurons and synapses and is followed by other injurious changes including progressive spread of tau that resides within neurons in a hyperphosphorylated state.

The rationale for focusing on amyloid as a therapeutic target is supported by animal studies that indicate removal of amyloid plaques leads to improved neuronal activity and reduction of oxidative stress. Utilization of immunotherapies that engage one’s own immune system to remove amyloid plaques has proven consistently successful, though with various risks of adverse effects such as amyloid-related imaging abnormalities [ARIA]. While vaccine-based approaches have been attempted, the most common strategy has been the passive infusion of antibodies directed against amyloid-ß. Most recently, aducanumab [Aduhlem; Biogen] and lecanemab [Leqembi; Eisai], both antiamyloid-ß monoclonal antibodies, are FDA-approved agents that show efficacy in amyloid plaque removal with an associated clinical benefit."

ALZ-801 (Alzheon)

ALZ-801, a prodrug of homotaurine, is currently being analyzed in a large-scale phase 3 study (APOLLOE4; NCT04770220) of 300 individuals with early to mild AD. The double-blind study includes individuals with are homozygous for the ε4 allele of the apolipoprotein (APOE) gene, a well-known gene that influences AD risk. Expected to be complete by June 2024, the study will assess ALZ-801’s impact on several outcomes over a 78-week period, including change in Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), phosphorylated tau levels in cerebrospinal fluid (CSF) and plasma, and change in total hippocampal volume.

Anton Porsteinsson, MD, director of the University of Rochester Alzheimer's Disease Care, Research and Education Program

Anton Porsteinsson, MD

In a phase 2 biomarker study of individuals with APOE ε4/4 or APOE ε3/4 genotype, the agent showed potential as a disease-modifying therapy, as demonstrated by reductions in p-tau 181, slowing of hippocampal atrophy, and stabilization of cognition. At 12 months, hippocampal atrophy was reduced by 25% compared with matched controls from the Alzheimer’s Disease Neuroimaging Initiative. Plasma p-tau 181, a marker of amyloid-induced neuronal injury in AD, was reduced by 41% by week 52 (P = .016), with significant reductions seen as early as 13 weeks. Furthermore, these reductions correlated with significant reduction in plasma Aß42 and Aß40 at the same time point (–5%; P = .002 and P = .005).1

"ALZ-801 is an oral, small molecule, valine conjugate prodrug of tramiprosate with optimized bioavailability and tolerability," Anton Porsteinsson, MD, director of the University of Rochester Alzheimer's Disease Care, Research and Education Program, told NeurologyLive. "ALZ-801 development builds on a post hoc phase 3 subgroup analysis of the originator molecule in APOE ε4 homozygotes. A current phase 2 biomarker study is ongoing and nearing a final readout in Q3 2023. Interim analysis at week 52 showed the asset produced an early and sustained plasma p tau181 reduction as well as preservation of hippocampal volume compared to a matched group from the ADNI study."

Donanemab (Eli Lilly)

Donanemab, a humanized IgG1 monoclonal antibody, has been assessed in several notable clinical trials since its development was initiated just over a decade ago. In January, the FDA handed Eli Lilly a complete response letter (CRL) for donanemab, citing a lack of data on the agent that spans more than 12 months.2 The phase 2 TRAILBLAZER-ALZ study, which served as the basis for the biologics license application of donanemab, included more than 100 patients; however, it was designed so that patients would complete the treatment course once they reached a predefined level of amyloid plaque clearance.

In TRAILBLAZER-ALZ, donanemab-treated patients declined 32% slower on the Integrated Alzheimer’s Disease Rating Scale, the primary outcome, and had amyloid plaque reduced by an average of 78%, or an 84-centiloid reduction, over a 76-week period.3 In the CRL, the agency indicated that the data to meet the exposure expectation would likely need to include the unblinded controlled safety data from the ongoing TRAILBLAZER-ALZ-2 trial (NCT04437511) upon completion. TRAILBLAZER-ALZ-2, expected to run through early 2024, was enlarged to become a phase 3 registration study with 1800 participants, with primary efficacy determined in 1000 patients whose tau burden is below the cutoff of 1.46 standardized uptake value ratio.

READ MORE FROM AAIC 2023: Donanemab Demonstrates Slowing of Alzheimer Disease Progression in Phase 3 TRAILBLAZER-ALZ 2 Trial

Remternetug (Eli Lilly)

Considered a follow-on to donanemab, remternetug is an N3pH-Aß monoclonal antibody designed to clear amyloid plaques in AD. Initiated in August 2022, the ongoing phase 3 TRAILRUNNER-ALZ1 study (NCT05463731) assesses the efficacy and safety of the agent in a cohort of 600 individuals with early symptomatic AD for a 52-week period. Following the main study period, participants will continue participation for an additional 52 weeks in an extension period, with both groups crossing over to the opposite treatment. Expected to complete in March 2025, the trial will use percentage of patients who reach amyloid plaque clearance on amyloid PET as the primary outcome measure.4

At the 2023 AD/PD Conference in Gothenburg, Sweden, interim data from a phase 1 multiple ascending dose study (NCT04451408) showed that treatment with remternetug resulted in rapid and robust amyloid plaque reduction. the data revealed that 75% (18 of 24) of participants on remternetug doses between 700 and 2800 mg Q4W had amyloid clearance totaling less than 24.1 centiloids by day 169. In addition to its positive efficacy, the agent was shown to be well-tolerated, with no treatment-emergent antidrug antibodies detected. ARIA, an issue that has plagued the AD community, was the most common treatment-emergent adverse event, observed in 10 participants, with 1 reporting a symptomatic event.5

Gantenerumab (Genentech/Roche)

Gantenerumab is a fully human IgG1 antibody designed to bind with subnanomolar affinity to a conformational epitope on Aß fibrils. It encompasses both N-terminal and central amino acids of Aß. Dating back to 2010, the agent has been assessed in several different clinical trials, including the notable SCarlet RoAD and Marguerite RoAD studies, and most recently, the GRADUATE trials. In late 2022, data announced from GRADUATE 1 and 2 showed that the agent failed to meet its primary end points of slowing functional decline in patients with early AD. All told, gantenerumab-treated patients demonstrated a slowing of clinical decline of –0.31 (= .0954) and ­–0.19 (= .2998) on Clinical Dementia Rating-Sum of Boxes scores in GRADUATE 1 and 2, respectively, which was not statistically significant.6

Gantenerumab was being assessed in the phase 3 SKYLINE trial (NCT05256134) as a preventive treatment for patients with early signs of AD, but the trial was terminated after the results of the GRADUATE program. Genentech’s Alzheimer’s disease pipeline includes investigations for familial Alzheimer's disease and trontinemab (alos known as RG6102) in phase 2 designed to transfer gantenerumab across the blood-brain barrier. From a diagnostics perspective, Genentech is also evaluating the development of biomarker and neuroimaging tests for diagnosing disease and monitoring disease progression.

"We are evaluating novel approaches to help medicines more effectively reach the brain using our investigational Brain Shuttle technology, including trontinemab (formerly referred to as brain-shuttle gantenerumab or RG6102)," a Genentech company spokesperson told NeurologyLive. "Gantenerumab and trontinemab are 2 distinct molecular entities, as there are clear differences in brain entry and central nervous system distribution which may result in significant differences in brain exposure and target engagement, and hence distinct clinical profiles. The trontinemab phase 1b/2a study is ongoing and will provide important evidence around safety, tolerability, pharmacodynamics as well as early clinical effects. We are fully evaluating the phase 3 GRADUATE data from the gantenerumab studies (including the effects on amyloid PET, which were lower than expected) to inform the further development of trontinemab."

ABBV-916 (AbbVie)

Similar to donanemab and remternetug, ABBV-916 is a monoclonal antibody that recognizes N-terminal truncated Aß modified with pyroglutamate at position 3, a form that is aggregated in amyloid plaques. The drug is relatively new to the pipeline, with clinical development beginning in August 2022 with a phase 1/2 study of patients with biomarker-confirmed AD that was subsequently changed to phase 2.

Otherwise known as the HARBOR trial, the trial a multiple-ascending dose phase and a proof-of-concept phase, each containing a 60-day screening period, 24-week double-blind period, and a 16-week safety follow-up period, with the option of a 2-year open-label extension. Patients included are between 50 and 90 years of age, diagnosis of Stage 3 or 4 AD, as defined by the 2018 National Institutes of Aging-AA Research Framework, a Mini-Mental State Examination score between 20 and 28, a positive Precivity AD-Aß blood test, and an amyloid PET scan consistent with amyloid pathology.8


Aaron Ritter, MD, Larkin Family Endowed Chair in Integrative Brain Health and Director, Memory & Cognitive Disorders Program, HOAG Pickup Family Neuroscience Institute

Aaron Ritter, MD

Aaron Ritter, MD, the Larkin Family Endowed Chair in Integrative Brain Health and director of the Memory & Cognitive Disorders Program at the HOAG Pickup Family Neuroscience Institute, on therapies that target inflammation: "The new amyloid therapies are exciting and groundbreaking, however, a clear message that comes out of this data seems to be that simply clearing amyloid is insufficient to stopping or preventing dementia. So what's going on? And while we still don't have a full picture of all the reasons a person develops dementia, a lot of evidence is pointing toward neuroinflammation.

"Neuroinflammation describes the state when the brain's immune system is overactivated. Some activation of the immune system is indeed good and necessary to prevent infection, thwart cancer, and promote a healthy brain. However, when the immune system is overzealous, the immune system itself can damage the brain and either cause or accelerate the damage that causes dementia. At this point, there is overwhelming evidence that in many patients with dementia the inflammatory system is overactivated: we see evidence of inflammatory cells being increased in the spinal fluid, evidence of increased microglial (the primary immune cells) on brain scans, and differences in how immune cells function.

"Amyloid plaques are also a source of inflammation and become engulfed by rings of activated immune cells. In fact, some researchers believe it's inflammation, not the amyloid plaques themselves that are the primary culprit in causing neuron damage. Finally, there is also some evidence that autoimmune conditions may increase the risk of developing dementia. These findings, along with population studies showing that lowering inflammation (through diet, exercise, and vitamins/supplements) is associated with less risk for dementia argue strongly for exploring new treatments that target inflammation as a key opportunity in fighting dementia."

Masitinib (AB Science)

Masitinib, an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system, has been assessed across several neurological conditions, including AD, multiple sclerosis, and amyotrophic lateral sclerosis. It is currently being assessed in the phase 3 Study AB21004 (NCT05564169), an international trial comprised of approximately 600 individuals with mild to moderate AD. Expected to complete in 2025, the randomized, double-blind, placebo-controlled study will aim to confirm the treatment effect of masitinib as an adjunct to cholinesterase inhibitor and/or memantine over a 24-week treatment period.

The potential benefit of the therapy in AD was previously demonstrated in a phase 2 study (AB04024; NCT00976118) and a positive phase 2b/3 study (AB09004; NCT01872598). In the phase 2b/3 trial, treatment with masitinib 4.5 mg/kg per day (n = 182) generated a significant effect on the primary end point of change in ADAS-Cog relative to controls (n = 176; P = .0003). In addition to the effect on cognition and memory, masitinib 4.5 mg/kg/day generated a significant change from baseline in the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) score, an instrument that assesses self-care and activities of daily living (P = .0381).9

Nilotinib (KeifeRx)

Nilotinib, a therapy approved for chronic myeloid leukemia, is an oral Abl tyrosine kinase inhibitor that has been studied in various populations of Parkinson disease, Dementia with Lewy bodies, and AD. In 2021, the drug manufacturers for nilotinib registered a phase 3 clinical trial (NCT05143528) for a new, low-dose formulation of the therapy in AD. In 50 centers across the US, the study is expected to enroll 1275 patients diagnosed with early AD, defined as a Clinical Dementia Rating (CDR) score of 0.5 or 1, Mini-Mental State Examination scores between 20 and 27, and PET or CSF evidence of brain amyloid.

At AAIC 2020, data from a phase 2, double-blind, randomized, placebo-controlled trial (NCT02947893) of individuals with mild to moderate dementia due to AD showed that nilotinib was safe, well-tolerated, and achieved pharmacologically relevant brain concentrations. In the analysis, 37 individuals with a mean age of 70.7 years were randomly assigned 1:1 to nilotinib 150 mg once orally or matching placebo for 26 weeks followed by nilotinib 300 mg compared with matching placebo for another 26 weeks. After 52 weeks, amyloid burden was reduced in the temporal (–0.08; 90% CI, ­­–0.21 to –0.01; P = .04) and frontal lobes (–0.19; 90% CI, 135-1018; P = .02) in the nilotinib group compared with placebo. Furthermore, hippocampal volume loss was attenuated by ­–27% at 12 months and phosphor-tau 181 was reduced at 6 months (–31.6%) and 12 months (–39.6%) in the nilotinib group.10

Semaglutide (Novo Nordisk)

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is approved for type 2 diabetes in both a daily pill formulation and once-per-week injection. In March 2021, the company registered 2 phase 3 trials, each enrolling 1840 individuals with mild cognitive impairment or mild dementia because of AD, confirmed by amyloid PET or CSF Aß42. The study’s’ primary outcome is change in CDR-Sum of Boxes, with secondary outcomes that include other standard cognitive and functional scales, as well as cardiovascular events and stroke.

Semaglutide is thought to work in a number of ways, including affecting nerve cells, as well as other cell types. This may result in an overall improvement of nerve cells, inflammation, and vascular health that could potentially help to slow the clinical progression of AD. GLP-1 is a hormone produced in the gut that activates receptors in the gut, liver, and pancreas to stimulate insulin release and restore insulin sensitivity. GLP-1 also promotes hippocampal synaptic plasticity, cognition, and cell survival.11

Alzheimer Disease International told NeurologyLive that, "ADI are encouraged that semaglutide is being further investigated in early Alzheimer disease to assess effects that could potentially be beneficial, especially at such a poignant moment in time, where we are seeing research advances in both disease modifying and symptomatic treatments. We continue to encourage vitally needed investment and further research for all dementias."

NE3107 (BioVie Pharma)

Earlier this year, BioVie announced completed patient enrollment for its phase 3 trial (NCT04669028) assessing NE3107, an oral, small molecule, blood-brain permeable compound in development for the treatment of AD. Otherwise known as the NM101 trial, the study uses co-primary end points of cognition, evaluated through the ADAS-Cog12, and function, determined through the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change.12

In a previously conducted phase 2 trial (NCT05227820) of patients with AD, treatment with NE3107 resulted in enhanced cognition using multiple rating scales. Specifically, investigators observed an improvement of 2.2 points on the modified ADAS-Cog12 scale (P = .0173), equating to a 21.1% (P = .0079) changes relative to baseline. Additionally, investigators observed an improvement of 0.11 (P = .0416) on the CDR, otherwise a 19.4% change from baseline, and improvement of 0.07 points (P = .0094) on Alzheimer’s Disease Composite Score. Treated patients experienced a reduction of –1.66 pg/mL (P = .0343) in CSF phosphor-tau levels, and a reduction of –0.0024 (P = .0401) in the ratio of p-tau to Aß42.13

Sargramostim (Sanofi)

Sargramostim is a synthetic form of the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor. It has previously received FDA approval for regenerating neurotrophils, monocytes, and macrophages after bone marrow transplants, radiation therapy, and in conjunction with treatment for several types of leukemia. The rationale for evaluating the immune modulator in AD is that it might increase phagocytosis of pathogenic protein deposits by bone-marrow-derived macrophages or brain-resident microglia, and that it might also stimulate other neuroprotective innate immunity processes.

Huntington Potter, PhD, Kurth N. and Edith von Kaulla Memorial Professor of Neurology, University of Colorado Alzheimer's and Cognition Center

Huntington Potter, PhD

In a randomized, double-blind, placebo-controlled phase 2 trial (NCT01409915) of patients with mild-to-moderate AD, treatment with sargramostim resulted in changed innate immune system markers, with no drug-related serious adverse events or amyloid-related imaging abnormalities. At the end of a 3-week treatment period, Mini-Mental State Examination (MMSE) scores were increased in the sargramostim group relative to placebo. In addition, investigators observed a 10% increase in plasma markers of Aß40 and decreases of 24% (P = .0174) and 42% (P = .0019), respectively, in total tau and plasma ubiquitin C-terminal hydrolase L1, markers of neurodegeneration.14

"The human recombinant protein version of GM-CSF is a promising new therapy for Alzheimer’s disease because it is the only therapy shown in a phase 2 double blind placebo controlled clinical trial to actually lead to improvement in cognition by the mini mental state exam and in all 3 blood biomarkers of Alzheimer neurodegeneration, A-T(N)," Huntington Potter, PhD, the Kurth N. and Edith von Kaulla Memorial Professor of Neurology at the University of Colorado Alzheimer's and Cognition Center, told NeurologyLive. "An Alzheimer’s Association Part the Cloud Grant partly funded that trial, and the NIH is funding the ongoing larger, longer phase 2 trial. We have also found that GM-CSF improves memory in mouse models of normal aging and of Down syndrome and also report at this meeting that GM-CSF reverses pancreatic damage and high blood glucose in a mouse model of type 2 diabetes. The fact that sargramostim is FDA-approved for stimulating the bone marrow and the immune system in other indications means that its path through further testing to approval as an Alzheimer treatment should be rapid."

Neurotransmitter Therapies

In general, neurotransmitters serve as natural chemical messengers for the body, facilitating the process of neurotransmission. The role of the neurotransmitters involves transferring signals between neurons as well as at neuromuscular junctions, effectively bridging the gaps across synapses.15 Neurotransmitter therapies in AD help with the transmission of signaling the body to reduce symptoms of the disease in patients.

AXS-05 (Axsome Therapeutics)

AXS-05 is a combination of 2 approved drugs for the treatment of agitation in people with AD. One of the treatments is dextromethorphan,an agonist of sigma 1 receptors, andthe other is bupropion, which slows the metabolism of dextromethorphan and increases its plasma concentration.16 In April 2020, topline results from ADVANCE (NCT03226522), a phase 2/3 multisite study, claimed a statistically significant 15.4-point reduction in Cohen-Mansfield Agitation Inventory (CMAI) with treatment, compared to a decrease of 11.5 points with placebo or 10.0 points with bupropion alone.17 Following these findings, the FDA granted AXS-05 breakthrough therapy designation for agitation in AD on June 26, 2020.

Then in November 2022, top-line results from the phase 3 trial ACCORD (NCT04797715)showed that treatment delayed time to relapse, resulting in a 3.6-fold lower risk of relapse. Secondary outcomes also improved with treatment such as reducing relapse rate from 25.9 percent in the placebo group to 7.5 percent with the treated participants.18 In September 2022, ADVANCE-2 (NCT03622905), a phase 3 trial for AD agitation began to enroll 350 people for up to 5 weeks treatment with twice-daily AXS-05, with an optional 6-month open-label extension. The primary outcome will be change in the CMAI and completion for the trial is slated for the first half of 2024.19

AR1001 (Aribio)

Ar1001 is a selective inhibitor of phosphodiesterase 5.At the 2021 CTAD conference, results of the phase 2 study (NCT03625622) of efficacy in people with mild to moderate AD showed no significant change from baseline in either the ADAS-Cog13 or ADCS-CGIC at 26 or 52 weeks, and no difference from placebo at 26 weeks.20 More than half of participants were taking other, unspecified AD medications, and a post hoc subgroup analysis showed those taking 30 mg AR1001 alone, but not with concomitant treatment, improved on the ADAS-Cog13. The mild, but not the moderate, subgroup also showed improvement on the same endpoint. The treatment was well tolerated, with a similar incidence of side effects and discontinuation in all group

In December 2022, the company began a phase 3 study (NCT05531526) in people with MCI or mild dementia because of AD. The participants will take a single 30-mg tablet or placebo daily for 1 year. The primary outcome is change in the CDR-SB after 1 year. The secondary outcomes will include ADAS-Cog 13, the Amsterdam Instrumental Activities of Daily Living, Geriatric Depression Scale, MMSE, and RBANS. Also, the study plans to track safety, as well as plasma and CSF biomarkers, and offering a 2-year open label extension with completion anticipated in December 2025.21

CST-2032 (CuraSen)

CST-2032 is a proprietary, brain-penetrant β2-adrenergic receptor agonist, that activates the norepinephrine receptors in the brain to compensate for the loss of this neurotransmitter from neurodegenerative diseases. In September 2020, CuraSen began a first-in-human study in New Zealand and Belgium to assess the safety and pharmacokinetics of CST-2032 in 118 healthy patients and patients with PD or MCI. The trial was stopped early in January 2021 for business reasons with data on 79 participants.22 Despite the trial stopping, the company got the data they needed from the study, going straight to the FDA and receiving IND clearance.

Anthony Ford, PhD, chief executive officer, CuraSen Therapeutics.

Anthony Ford, PhD

In March 2022, a phase 2 trial (NCT05104463)of the treatment began recruiting 60 participants with either mild dementia or MCI because of AD or PD with completion expected later in 2023. The crossover trial tests plan to do 2 weeks of 3 or 6 mg CST-2032 plus 3 mg CST-107/nadolol, and 2 weeks of placebo, assessing the primary outcomes of adverse events, vital signs and ECG. The secondary outcomes will include CANTAB tests of attention, memory, and learning, and a test of facial emotional expression recognition.23

“Unlike other Alzheimer’s approaches, most of which have failed over the years, we are targeting the restoration of stimulus from a specific brainstem area called the locus coeruleus (LC), described by some as the “hypocenter” of neurodegeneration, where the earliest pathologic findings and neuronal loss are observed in neurodegenerative diseases like AD and PD,” Anthony Ford, PhD, chief executive officer of CuraSen Therapeutics, said. " With CST-2032, we have developed a targeted medicine to stimulate key adrenergic receptors expressed abundantly on several cell types normally regulated by healthy adrenergic function in cortical and limbic areas of the brain that maintain and protect cognitive functions and healthy neurotrophic actions. Activation of these cells by CST-2032 compensates for critical brain functions lost early in the disease process due to adrenergic decline (emanating from the LC). Our drugs are designed to elevate cognition, memory, attentiveness, daily activity and mood, and substantively improve the lives of patients, their families and caregivers."

"While the recently approved Leqembi reduced amyloid beta plaques on the brain and showed clinical benefit (CDR-sob or ADAS-cog scores), the actual cognitive benefit appears to be modest, along with a hefty price tag and clear risk associated with this class of drugs," Ford said. "We believe CST-2032 (given as a combination drug product with CST-107) used alone or potentially in combination with Leqembi or similar emerging therapies, will provide a meaningful and rapid onset option to reduce symptoms, and potentially further slow disease progression."

Synaptic Plasticity/Neuroprotection Therapies

Synaptic plasticity is the capacity of neurons to alter the intensity of their connections and neuroprotection involves the administration of therapeutic agents to safeguard against or reverse neuronal damage, preserving normal physiological function.24

Fosgonimenton (Athira Pharma)

Fosgonimeton is a prodrug formulation of a small molecule originally identified in a screen for positive modulators of HGF/MET signaling. The first-in-human, phase 1 (NCT03298672) safety study of single- and multiple-ascending doses in 88 healthy people and patients with AD, showed that NDX-1017 was reported to cause a dose-related increase in gamma power in healthy people; in the AD group, multiple dosing led to improvements in gamma power and p300 latency.25 In June 2022, the phase 2 study ACT-AD assesses the relationship between ERP changes and cognition in 77 people with mild to moderate AD, had failed to meet its primary endpoint.26

Hans Moebius, MD, PhD, chief medical officer, Athira

Hans Moebius, MD, PhD

In September 2020, the phase 2 trial LIFT-AD (NCT04488419) began to recruit participants with clinically diagnosed mild to moderate AD, and compare 2 doses of drug to placebo, given once daily using prefilled syringes, for 6 months. The primary outcome will be the Global Statistical Test, a combination of scores from the ADAS-Cog11 and the ADCS-Clinical Global Impression of Change. Secondary endpoints will include ADAS-Cog11, ADCS CGIC, and ADCS-ADL. In early 2022, the company increased enrollment to 420, and reclassified the trial to phase 3. In 2023, enrollment was further increased to 475, with completion expected in January 2024.27

Hans Moebius, MD, PhD, chief medical officer at Athira, said “The pathology of Alzheimer’s disease is complex and multifactorial, including protein pathology, neuroinflammation, and metabolic and synaptic dysfunction. These factors ultimately lead to neurodegeneration and a decline in brain function. Fosgonimeton is a novel small molecule that positively modulates the neurotrophic HGF system with the potential to uniquely address many of these known pathological processes in Alzheimer’s disease with the aim to preserve and protect the independence of people living with this progressive disease.”

AGB101 (AgeneBio)

AGB101 is a proprietary, once-daily, extended-release, low-dose formulation of the FDA-approved atypical anti-convulsant medication levetiracetam which may prevent the spread of tau pathology and disease progression. Completed in March 2021, the phase 2 research study on AGB101 compared the effects of 2 weeks of 220 mg/day AGB101 or placebo on functional brain networks. It enrolled 50 healthy older people, half APOE ε4 carriers and half noncarriers. The primary endpoint was change in functional connectivity in the hippocampus and default mode networks, assessed by functional MRI with the secondary measures including tests of episodic memory.28

The HOPE4MCI trial (NCT03486938) was intended to evaluate AGB101 safety, and its efficacy at slowing cognitive and functional impairment, in 830 people who fulfill criteria for MCI and have a positive PET scan for brain amyloid. Participants receive 220 mg AGB101 or placebo once daily for 78 weeks. The primary outcome is change in CDR-SB score at 78 weeks; secondary measures include change on the MMSE and Functional Activities Questionnaire. In August 2020, the trial registration was changed from phase 3 to phase 2/3. In April 2021, AgeneBio announced completion of enrollment in HOPE4MCI, with only 164 participants and 609 screen failures. The company now refers to the trial as a phase 2b, rather than phase 3, study. It finished in November 2022; results are expected in early 2023.29

Tau Therapies

Targeting the dysfunctional tau protein may prove as a more effective therapy in enhancing cognitive function in cases of AD compared with amyloid, given the stronger association between dysfunctional tau protein and dementia.30

Semorinemab (AC Immune SA)

At the 2017 AD/PD and AAIC conferences, the phase 1 (NCT02820896) study comprising of both healthy controls and people with mild to moderate AD that single doses in healthy volunteers went as high as 16,800 mg, with a 15-day window observed between a given dose and the next-higher dose, and that 70 percent of the subcutaneous doses were bioavailable. In September 2020, topline results from the TAURIEL phase 2 (NCT03289143) study in 457 people with prodromal or probable AD ascertained by a positive amyloid PET or CSF Aβ42 finding, and mild symptoms. Semorinemab missed the primary efficacy endpoint of reducing decline on the CDR sum of boxes, and missed on both secondary end points, the ADAS-Cog13 and ADCS-ADL.31

Percy Griffin, PhD, MS, director of scientific engagement at the Alzheimer’s Association

Percy Griffin, PhD, MS

In February 2019, Roche started LAURIET, another phase 2 study (NCT03828747) in 272 people with a diagnosis of probable AD confirmed by amyloid positivity via PET or CSF testing, and with moderate dementia. On August 31, 2021, topline results indicated a 43.6% slowing of decline on the ADAS-Cog11 co-primary, though no benefit of the other cognitive or functional outcomes.32 A phase 3 decision is pending additional data from LAURIET's ongoing long-term extension study and biomarker measurements. In November at CTAD, the company showed this trial's data, and reported the treatment did not change tangle accumulation measured by GTP1 PET.

“Semorinemab is an antibody targeting 1 end of all 6 forms of human tau. This was tested in a phase 2 clinical trial; the researchers found no slowing of tau accumulation or clinical decline. Despite this, the drug is still being tested in an open label extension to inform a potential phase 3 trial,” Percy Griffin, PhD, MS, director of scientific engagement at the Alzheimer’s Association, told NeurologyLive.

Bepranemab (Hoffmann-La Roche)

This humanized, monoclonal IgG4 antibody binds to the central region of tau, recognizing amino acids 235–250 near tau's microtubule-binding domain. In December 2018, the first, single-ascending-dose study to evaluate safety and tolerability of UCB0107 intravenous infusion showed all participants in the 7 dose groups completed the study. No drug-related adverse events or changes in safety results were reported. Serum and CSF concentrations increased with dose, and the CSF/serum ratio held constant across doses. There was no evidence of anti-drug antibodies.33

The AD (NCT04867616) study began in June 2021. The phase 2 trial plans to randomize 450 people with mild cognitive impairment or mild AD dementia to 1 of 2 doses of bepranemab or placebo for 80 weeks. Enrollment requires clinical diagnosis and evidence of amyloid accumulation by PET or CSF markers. The primary end point is change from baseline in the CDR-SB. Secondary outcomes include adverse events, ADAS-Cog14, Amsterdam Instrumental Activities of Daily Living, MMSE, tau-PET, and serum drug concentrations. A 48-week open-label extension is planned. The study will run until November 2025.

“Bepranemab is an antibody directed against a region of the tau protein near the microtubule binding region being tested in phase 2 trials. This antibody binds preferentially to aggregated forms of tau, which are associated with spread from 1 cell to another. Aggregated tau is associated with Alzheimer’s disease and reducing it may reduce brain cell death,” Griffin told NeurologyLive.

ACI-35 (AC Immune SA)

ACI-35 is a liposome-based vaccine. In December 2013, the phase 1b (NCT04445831) study compared a 6-month course of undisclosed low, medium, and high doses of ACI-35 to placebo in 24 people with mild to moderate AD. ACI-35 raised no safety concerns, but elicited a weak immune response and booster shots had little effect.34 A redesigned version, ACI-35.030, includes a second adjuvant and an epitope to activate helper T cells. According to the findings, the second-generation vaccine produced a stronger immune response in rhesus monkeys than the original, and booster shots increased antibody titers. The antibodies were specific for phosphorylated tau, and recognized paired helical filaments extracted from AD brain.

In July 2019, AC Immune and Janssen initiated a small phase 1b/2a trial to test safety and immunogenicity of ACI-35.030 in people with early AD. The trial enrolls 24 people for sequential testing of up to 3 dose levels of the vaccine versus placebo, administered multiple times over 48 weeks. Primary outcomes are adverse events and other safety measures, plus anti-phosphoTau IgG titers in blood up to 74 weeks after baseline. This trial will also evaluate the presence of anti-tau antibodies, and monitor cognition and behavior changes using the CDR-SB, RBANS, and NPI. At the 2022 CTAD conference, AC Immune showed data on all 3 dose groups of ACI-35.030. All participants were reported to have mounted an antibody response to phosphorylated tau 2 weeks after injection.35 Most also had antibodies to paired helical filaments and nonphosphorylated tau, although titers against phosphorylated tau were highest. Antibodies to phosphorylated tau and paired helical filaments were sustained for more than a year, while those recognizing unphosphorylated tau waned.

"This vaccine is a specific antibody that targets phosphorylated tau. It is currently being tested in phase 2 clinical trials in people aged 50-75 with early Alzheimer’s. This therapeutic approach is intriguing because it leverages the body’s immune system to produce antibodies, instead of introducing them externally,” Griffin said.

E2814 (Eisai)

This humanized, monoclonal IgG1 antibody recognizes an HVPGG epitope in the microtubule-binding domain near the mid-domain of tau. In December 2019, Eisai began a phase 1 trial (NCT04971733) testing the safety and tolerability of a single intravenous infusion in healthy adults. Treatment resulted in no significant drug-related clinical changes or dose-limiting events. Serum and CSF pharmacokinetics were dose-proportional, and comparable to other antibodies. The results showed a dose-related increase in antibody-tau association, which persisted for at least a month. At the 30 mg/kg dose, 60 percent of tau mid-domain fragments were complexed with antibody.

Michael Irizarry, MD, deputy chief clinical officer and senior vice president of Clinical Research, Alzheimer's Disease and Brain Health at Eisai

Michael Irizarry, MD

Beginning in November 2021, the DIAN-TU study (NCT01760005)will enroll 168 participants with normal cognition, mild cognitive impairment or mild dementia.36 People with mild cognitive impairment or dementia will receive open-label intravenous lecanemab for 24 weeks, and then be randomized to intravenous E2814 or placebo plus lecanemab for the remainder of the 4-year trial. Participants with normal cognition will start on E2814 or placebo for 1 year, and then add open-labellecanemab. The trial’s primary endpoint is tau spread during E2814 treatment, measured by tau PET in the symptomatic cohort. Secondary outcomes in this group include change in a cognitive composite, amyloid PET, and CSF neurofilament light chain. In the asymptomatic population, change in CSF ptau217/total tau ratio is the outcome. The study will run through 2027 with 39 locations around the world.

“E2814 is an investigational anti-microtubule binding region (MTBR) tau antibody that is being developed as a potential disease-modifying agent for AD. It is believed that E2814 captures and removes extracellular MTBR-tau to prevent the spread of tau pathology, which may result in a reduction in cognitive function decline. In addition to the promise the individual therapy may hold, there is strong scientific rationale that targeting both tau and amyloid in a combination therapy, such as Eisai’s newly approvedlecanemab, may possibly provide a greater benefit to people living with the early stages of AD,” Michael Irizarry, MD, deputy chief clinical officer and senior vice president of Clinical Research, Alzheimer's Disease and Brain Health at Eisai, told NeurologyLive. “In March 2021, the Dominantly Inherited Alzheimer’s disease Trial Unit (DIAN-TU) at Washington University St. Louis selected E2814 as the first investigational medicine among anti-tau drugs for the Tau NexGen study. With increasing evidence from clinical studies showing that targeting amyloid can reduce biomarkers of AD, the Tau NexGen clinical trial leaders selected Eisai’s anti-Aβ protofibril antibody LEQEMBI as the background anti-amyloid therapy to combine with the tau therapies.”

“This drug is an antibody being tested in phase 2/3 clinical trials in people who have Dominantly Inherited Alzheimer’s Disease, which develops in people in their 30s, 40s, and 50s. It targets a region of the tau protein called the Microtubule Binding Region (MTBR) and was recently shown to be a specific biomarker for tau tangles. E2814 is promising because MTBR tau is more specific for the tangles compared to other forms of tau,” Griffin told NeurologyLive.

LX1001 (Lexeo Therapeutics)

This gene-therapy approach uses a viral vector to drive expression of human APOE ε2 protein (APOE ε2) in the central nervous system. In March 2022, top-line results were reported from the lowest-dose group.37 The APOE ε2 protein was detectable in CSF after 3 months in all 4 participants in the cohort, and after 1 year in the 2 who reached that time point. In these 2, total tau and phosphorylated tau reportedly declined from baseline at 1 year with no serious adverse events reported.

R. Nolan Townsend, chief executive officer of LEXEO Therapeutics

R. Nolan Townsend

In November 2019, a phase 1 trial evaluating LX1001 in 15 volunteers who carry 2 APOE ε4 alleles and have PET- or CSF-confirmed brain amyloid deposition and a clinical diagnosis of mild cognitive impairment to moderate dementia. This open-label, dose-ranging study involves a single intrathecal injection of 1 of 3 doses of LX1001, and a 1-year follow-up. Its goals are to establish the maximum tolerable dose and determine if APOE ε2 protein appears in the cerebrospinal fluid. The primary endpoint is safety and the number of adverse events or serious adverse events 1 year after injection. Secondary endpoints include change in CSF APOE isoforms and biomarkers, amyloid PET, volumetric MRI, and cognitive and functional measures. The trial is set to end in April 2024 with a 5-year follow-up to assess safety and biomarkers to run until 2028.

APOE ε4 is known to be the most common genetic risk factor for Alzheimer’s disease, as individuals with 2 copies of the APOE ε4 allele have a ~15 times greater likelihood of developing Alzheimer’s disease than the general population. At LEXEO, we are developing LX1001 to address this subgroup of Alzheimer’s disease patients by delivering a gene therapy to express the neuroprotective APOE ε2 allele. By focusing on the underlying genetics of Alzheimer’s disease via gene therapy we have the potential to address multiple pathogenic mechanisms involved in the progression of Alzheimer’s disease simultaneously, in particular both the amyloid pathway and tau pathways,” R. Nolan Townsend, chief executive officer of LEXEO Therapeutics, told NeurologyLive.

"This is a gene therapy that is looking to increase the level of protective APOE ε2 in people who are APOE ε4 homozygous. The drug is currently being tested in phase 1 clinical trials in people aged 50 and older. This drug is promising because it increases the expression of a protein—APOE ε2—found to be protective against developing cognitive impairment,” Griffin said.

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