Research Models

App NL-G-F Knock-in Rat

Synonyms: AppNL-G-F rat, APP Swe-Arc-Ibe knock-in rat

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Species: Rat
Genes: App
Modification: App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Tangles

No Data

  • Changes in LTP/LTD

Plaques

Amyloid plaques apparent as early as 1 month in homozygous knock-ins, 4 months in heterozygotes. Amyloid pathology progresses more rapidly in females than males.

Tangles

No neurofibrillary tangles through 22 months of age, but increases in tau phosphorylation, aggregation, and conformational changes.

Synaptic Loss

Decreased levels of the presynaptic marker synaptophysin and the postsynaptic marker PSD-95 in knock-in rats. Quantitative electron microscopy showed reductions in synaptic density, area, and perimeters in the hippocampus, entorhinal cortex and prefrontal cortex of knock-in brains.

Neuronal Loss

Reduced brain weight, fewer neurons in the hippocampus and cortex, and enlarged lateral ventricles seen at 12 months.

Gliosis

Astrogliosis and microgliosis, particularly pronounced around amyloid plaques, were observed in homozygous knock-in rats at 6 months of age. Gliosis was also seen in year-old heterozygotes.

Changes in LTP/LTD

No data.

Cognitive Impairment

Deficits in the Morris Water Maze task and a paired associate learning task as early as 5 and 7 months of age, respectively.

Last Updated: 08 Feb 2022

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Therapeutics

ALZ-101

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Overview

Name: ALZ-101
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Alzinova AB

Background

This candidate vaccine is designed to provoke an immune response specific to soluble oligomeric Aβ assemblies, but not to monomeric or fibrillar Aβ. A proprietary protein-engineering technology uses disulfide bonds to cross-link Aβ peptides into a conformation that assembles into stable, soluble oligomers or protofibrils (Sandberg et al., 2010; Dubnovitsky et al., 2013). These assemblies are formulated into the ALZ-101 vaccine.

In preclinical work, mice immunized with ALZ-101 were the source of a monoclonal antibody that bound to oligomeric Aβ, but not plaques or non-aggregated peptides (Sandberg et al., 2022). The antibody was able to deplete toxic Aβ from human AD brain extracts.

Findings

In September 2021, Alzinova began a Phase 1b study in Finland to evaluate tolerability, safety and immunological response to the vaccine. The blinded study has enrolled 27 patients with CSF biomarker-confirmed early AD to receive four intramuscular injections of 125 or 250 μg ALZ-101 or placebo over 16 weeks. Primary endpoints are adverse events, especially related to injection, amyloid-related imaging abnormalities, and cognitive or functional worsening in the year after vaccination. Secondary outcomes pertain to Aβ-specific antibody responses. Exploratory endpoints are blood and CSF AD biomarkers. In September 2023, the company added an open-label extension comprising two additional doses over 16 weeks. The trial will run through December 2023.

For trial details, see clinicaltrials.gov.

Last Updated: 06 Oct 2023

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Research Models

SORLA-deficient

Synonyms: Sorl1 knockout, Sorl1-/-, Lr11-/-, Lr11ΔEx4

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Species: Mouse
Genes: Sorl1
Modification: Sorl1: Knock-Out
Disease Relevance: Alzheimer's Disease
Strain Name: N/A

In this model of SORLA deficiency, the 5' region of exon 4 of the murine Sorl1 gene was replaced by a neomycin resistance cassette. Although mice homozygous for the disrupted allele do not make full-length SORLA protein (Andersen et al., 2005), an incomplete form of the receptor has been detected at low levels in the brains of these animals (Dodson et al., 2008).

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Plaques

No Data

  • Tangles
  • Neuronal Loss
  • Gliosis
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

No amyloid plaques observed up to 10 months of age. When SORLA-deficient mice are crossed with APP transgenic models of amyloidosis, amyloid deposition is accelerated, compared with the parental APP transgenic line.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

Neuron loss was not seen in the substantia nigra and ventral tegmental areas, assessed at 5 weeks and 45 weeks. Data on neuron numbers are not available from other brain regions. Nigrostriatal connectivity appears to be disrupted in SORLA-deficient mice.

Gliosis

No data.

Changes in LTP/LTD

No differences in LTP were observed in hippocampal slices from 10- to 12-month-old Sorl1-/- mice and slices from littermates heterozygous for the Sorl1 deletion (Rohe et al., 2008). It is not known whether LTP in these genotypes differs from that of wild-type mice.

Cognitive Impairment

Compared with wild-type mice, SORLA-deficient mice exhibited more arm entries and more time spent in the open arms of the elevated plus maze—behaviors interpreted as evidence of hyperactivity and reduced anxiety. Hyperactivity was also noticed in the open field test.

Complementary Models

SORL1-deficient human iPSCs

Human induced pluripotent cell lines (iPSCs) are complementary models for the study of SORL1 biology at the cellular level.

An isogenic set of iPSCs homozygous or heterozygous for a SORL1-null allele was generated from a parental cell line expressing wild-type SORL1 (Hung et al., 2021). SORLA-deficient neurons derived from these iPSCs—either heterozygous or homozygous for the SORL1-null allele—showed enlarged early endosomes, compared with the parental cell line. Additionally, homozygous SORL1-null neurons showed enlargement of late endosomes/lysosomes and a time-dependent decrease in levels of full-length APP and increases in levels of CTF-β/APP, Aβ40 and Aβ42. These iPSC lines may be requested from the lead investigator.

Additional SORL1-null iPSC lines have been generated and differentiated into various neural cell types (Knupp et al., 2020; Lee et al., 2023). These lines also may be requested from the lead investigators.

Confirming the finding cited above (Hung et al., 2021), SORL1-null iPSC-derived neurons exhibited enlarged early endosomes (Knupp et al., 2020). APP trafficking was also affected by loss of SORL1: There was increased colocalization of APP with a marker of early endosomes and decreased colocalization with a marker for the trans-Golgi network (Knupp et al., 2020). SORL1-null neurons produced more Aβ40 and Aβ42 than the parental lines, although levels of APP did not differ between genotypes (Knupp et al., 2020; Lee et al., 2023). Expression and release of ApoE and clusterin were reduced and levels of AT8-immunoreactive tau were increased in SORL1-null neurons, compared with the parental cell lines (Lee et al., 2023).  Transcriptomic and Gene Ontology analyses revealed upregulation of genes encoding synaptic proteins and downregulation of genes involved in extracellular matrix organization, SMAD signaling, transmembrane serine/threonine kinase signaling, lysosome localization, endocytosis, lipid biosynthetic processes and lipid-mediated signaling, protein secretion, and calcium-dependent phospholipid binding (Lee et al., 2023). Lipidomic analysis indicated differences between SORL1-null neurons and neurons derived from their parental lines, as well as more and larger lipid droplets in the cells lacking SORL1 (Lee et al., 2023).

Contrary to the findings in iPSC-derived neurons, loss of SORL1 did not affect endosome size in microglia-like cells derived from these iPSCs (Knupp et al., 2020) or levels of ApoE or clusterin (Lee et al., 2023).

Loss of SORL1 led to elevated levels of APOE and CLU mRNA in iPSC-derived astrocytes, while levels of ApoE and clusterin proteins did not depend on SORL1 (Lee et al., 2023).

SORL1 haploinsufficient minipigs

A minipig model of SORL1 haploinsufficiency is commercially available. Animals are heterozygous for the wild-type porcine SORL1 allele and a CRISPR/Cas9-modified allele with a 609-base pair deletion encompassing exon 1. The initial characterization of the model focused on neuropathology and AD-related fluid and imaging biomarkers in a relatively small number of animals ranging in age from 5 to 38 months (Andersen et al., 2022).

Levels of SORL1 mRNA were found to be reduced by approximately half in the cortices and cerebella of 24- to 30-month-old heterozygotes (hereafter referred to as “SORLA-deficient pigs”), compared with wild-type minipigs. While levels of SORLA protein were also reduced in the cortex (by approximately 70 percent), protein levels in the cerebellum did not differ between the SORLA-deficient and wild-type pigs. CSF concentrations of sSORLA, a soluble fragment cleaved from the cell surface, were also reduced in the SORLA-deficient pigs. Levels of APP in the cortex and cerebellum did not differ between genotypes.

No gross or histological abnormalities were observed in the brains of SORLA-deficient pigs at 5 months of age. Immunohistochemical staining of the hippocampi of 30-month-old pigs using polyclonal antibodies directed against Aβ42 or tau phosphorylated at threonine-231 did not show differences between genotypes. Enlarged endosomes were observed in cortical neurons of SORLA-deficient pigs 24 to 30 months of age. Endosomal enlargement was confirmed in fibroblasts cultured from the SORLA-deficient pigs compared with fibroblasts from wild-type pigs.

Levels of Aβ38, Aβ40, and Aβ42 were elevated in the cerebrospinal fluid of SORLA-deficient pigs 5 to 38 months of age, compared with age-matched wild-type pigs, while levels of  neurofilament light chain (NfL) did not differ between genotypes. SORLA deficiency led to elevated levels of CSF tau in 18- to 30-month-old animals.

In the initial characterization (Andersen et al., 2022), no differences were observed between the SORLA-deficient pigs and wild-type animals studied using PiB-PET to visualize amyloid load and FDG-PET to visualize glucose uptake in 21-month-old pigs, and structural and diffusion tensor imaging MRI in 27-month-old pigs. However, a subsequent exploratory study using two other imaging markers—MRI with hyperpolarized [1-13C]pyruvate and sodium (23Na) MRI—found evidence of metabolic dysfunction in SORLA-deficient animals 22 to 27 months of age (Bøgh et al., 2024). The former method measures metabolism through glycolytic pathways, while the latter measures tissue Na+ concentrations (maintenance of the Na+ gradient across cell membranes is energy intensive, and it is postulated that metabolic disturbances lead to Na+ imbalances).

Last Updated: 15 Jan 2025

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Research Models

SORL1 transgenic (Cre-inducible)

Synonyms: Rosa26TgSORL1WT

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Species: Mouse
Genes: SORL1
Modification: SORL1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: Rosa26TgSORL1WT

This mouse model enables Cre-inducible overexpression of human SORL1. A transgene containing SORL1 cDNA downstream of the cytomegalovirus early enhancer/chicken β-actin promoter and a floxed neomycin resistance cassette with a polyA stop element (neo-R) was introduced into the murine Rosa26 locus (mice carrying this transgene are referred to as Rosa26TgSORL1WT). Cre-mediated excision of neo-R induces SORL1 overexpression.

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Changes in LTP/LTD
  • Cognitive Impairment

No Data

  • Plaques
  • Tangles
  • Neuronal Loss
  • Gliosis
  • Synaptic Loss

Plaques

No data.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

No data.

Gliosis

No data.

Changes in LTP/LTD

LTP at Schaffer collateral-CA synapses was similar in hippocampal slices from 3-month-old Rosa26Tg/+ and wild-type mice. The application of Aβ oligomers impaired LTP in slices from wild-type mice but did not affect LTP in SORL1 transgenic mice.

Cognitive Impairment

Three-month-old Rosa26Tg/+ SORL1 transgenic mice performed similarly to wild-type mice in the acquisition and retention phases of the Morris Water Maze test. Hippocampal injection of Aβ oligomers prevented wild-type mice from learning the location of the escape platform but did not affect the performance of the transgenic mice.

Last Updated: 11 Jan 2022

COMMENTS / QUESTIONS

  1. This is an important paper. It appears as one of very few examples of delineated risk factors for AD for which a plausible function linked to Aβ degradation is clearly documented. Of most interest, obviously, is the observation that an AD-linked mutation could directly impair the Aβ-SORLA interaction and lead to enhanced Aβ levels, thereby bringing a biological rational for the original genetic observation. This adds a bit more support to the amyloid cascade hypothesis. In sporadic AD, there are no clues of enhanced Aβ formation. Rather, it is the decrease of degradation rates that leads to increased cerebral loads of peptides.

    This paper further supports the view that Aβ levels are modulated downstream of secretase actions. Both SORLA levels that are diminished in sporadic AD-affected brains and mechanisms of action of SORLA support the view that this receptor contributes to sporadic AD. The fact that the mutation the authors examined, located in the SORLA domain that interacts with Aβ, affects SORLA function is interesting. The question to address is whether other SORLA mutations located outside this VPS10P domain trigger the same effect. It is possible that mutations outside the binding domain could alter the 3-D structure to ultimately affect lysosomal Aβ degradation. Alternatively, it remains possible that additional AD-linked mutations enhance AD risk by affecting other pathways, even unrelated to APP trafficking/processing.

    View all comments by Frédéric Checler

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Therapeutics

Multivitamin-mineral Supplement

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Overview

Name: Multivitamin-mineral Supplement
Synonyms: Centrum Silver
Therapy Type: Supplement, Dietary (timeline)
Target Type: Other (timeline)
Condition(s): Mild Cognitive Impairment
U.S. FDA Status: Mild Cognitive Impairment (Not Regulated)
Company: Pfizer

Background

Multivitamin deficiencies in older adults may increase risk for cognitive decline and dementia (Littlejohns et al., 2014; Mohajeri et al., 2015). In the only large, randomized trial completed to date, a daily multivitamin produced no cognitive benefit in nearly 6,000 male physicians followed for 12 years (Grodstein et al., 2013). A smaller study suggested older people and those at risk of nutritional deficiencies might gain from supplementation (McNeill et al., 2007).

Multivitamin use in the U.S. increased in the 1980s to 2000s, but since then has declined, both in the general population and in older adults (Sandoval, 2023; Cowan et al., 2023). Current studies find approximately 40 percent of older people in the U.S. take multivitamin supplements, with use skewed toward women with higher education levels, frailty, and taking prescription medications (Fravel et al., 2023).

Findings

In September 2016, the Cocoa Supplement and Multivitamin Outcomes Study of Cognition (COSMOS-Mind) began enrolling 2,262 people 65 or older without dementia to evaluate the effect of three years of daily supplementation on global cognition. The four-arm study compared a patented, defined cocoa extract plus a Centrum Silver brand multivitamin to the extract plus placebo, the multivitamin plus placebo, or placebo only. The cocoa extract contains 500 mg of flavanols with 80 mg of epicatechin. Participants were recruited by mail across the United States. They took cognitive assessments via telephone at baseline and annually. The primary outcome was a cognitive composite comprising the Telephone Interview for Cognitive Status-modified (TICSm), and telephone versions of delayed recall, oral trail-making test, category and verbal fluency, digit span, and digit ordering. Other outcomes were scores for executive function and memory, and incident MCI and AD-related dementia. The study design is published (Baker et al., 2019). This is an ancillary study of the COSMOS trial, which examined the effect of cocoa extract and a multivitamin on cardiovascular and cancer endpoints in more than 21,000 older adults (Rautiainen et al., 2018; Sesso et al., 2022).

COSMOS-Mind finished in February 2021; results were shown in November at CTAD. Multivitamin supplementation was presented to have improved global cognition, memory, and executive function compared to placebo over three years. In a prespecified subgroup analysis, people with a history of cardiovascular disease started with a lower baseline cognitive composite score but benefitted more from the vitamins. Outcomes modeling suggests the daily multivitamin slowed cognitive aging by 60 percent, or 1.8 years. Cocoa extract had no effect on global cognitive function. Seventy-seven percent of participants completed the trial. Most were white, and had at least some college or higher education. The results were published after peer review (Baker et al., 2023). The study found no difference in the incidence of MCI or dementia with either supplement compared to placebo (Sachs et al., 2023). However, when people taking the multivitamin developed MCI, their scores for global cognition and executive function were higher, and had declined less relative to the previous year, compared to placebo.

In August 2016, another substudy, COSMOS Web, began to measure changes in cognition via an online test battery in 3,947 COSMOS participants randomized to the multivitamin, cocoa extract, both, or placebo, for three years. The primary outcome was change in episodic memory after one year, measured by the ModRey Assessment of Immediate Recall and Learning and Episodic Memory (Hale et al., 2019). The study included additional cognitive tests and MRI measures of brain structure and blood flow as secondary endpoints. It finished in December 2020; results are published (Yeung et al., 2023). People taking the vitamin did better than the placebo group on the ModRey assessment at one and three years. The difference was claimed to represent 3.1 years of age-related memory change. Secondary outcomes did not differ.

For details on these trials, see clinicaltrials.gov.

Last Updated: 03 Jan 2024

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Therapeutics

Cocoa Flavanols

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Overview

Name: Cocoa Flavanols
Therapy Type: Supplement, Dietary (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Mild Cognitive Impairment
U.S. FDA Status: Mild Cognitive Impairment (Not Regulated)

Background

Flavanols are naturally occurring bioactive plant products in tea, wine, and chocolate. The predominant flavanols in cocoa include catechin, epicatechin, and procyanidins, which are thought to give these foods heart and other health benefits. These compounds and their metabolites are credited with improving vascular function, insulin resistance, blood pressure, and with having antioxidant, anti-inflammatory, neurogenic, and neuroprotective effects. Several epidemiological studies and small trials of short duration suggest that cocoa flavanols may preserve cognition in older adults (e.g. Brickman et al., 2014, review by Socci et al., 2017). The CoCoA study, a randomized trial, reported a boost in cognition after eight weeks of 520-993 mg daily cocoflavanol supplement in 90 cognitively healthy adults (Mastroiacovo et al., 2015), or 90 with MCI (Desideri et al., 2012). More recently, in a study of 211 healthy adults, treatment with 12 weeks of cocoa flavanols did not improve performance on the primary outcome of an object-recognition task, but did improve a secondary outcome of hippocampal-dependent list learning (Sloan et al., 2021).

In preclinical work, cocoa extract was reported to reduce Aβ oligomerization in vitro (Wang et al., 2014). Anti-aggregation activity was previously reported for the catechin EGCG extracted from green tea leaves. No results are published on treatment of Alzheimer’s mouse models with cocoa extracts, but epicatechin-containing grape seed extracts were shown to improve plaque and tangle pathology, neuroinflammation, oxidative stress, and cognitive behavior in mouse models of amyloidosis (Wang et al., 2008; Wang et al., 2009; Wang et al., 2010).

Findings

In September 2016, the Cocoa Supplement and Multivitamin Outcomes Study of Cognition (COSMOS-Mind) began enrolling 2,262 people 65 or older without dementia to evaluate the effect of three years of daily supplementation on global cognition. The four-arm study compared a patented cocoa extract plus a multivitamin (Centrum Silver, Pfizer), to the extract plus placebo, multivitamin plus placebo, or placebo only. The cocoa extract contains 500 mg of flavanols with 80 mg of epicatechin. Participants were recruited by mail across the U.S. They took cognitive assessments via telephone at baseline and annually. The primary outcome was a cognitive composite comprising the Telephone Interview for Cognitive Status-modified (TICSm), and telephone versions of delayed recall, oral trail-making test, category and verbal fluency, digit span, and digit ordering. Other outcomes were scores for executive function and memory, and incident MCI and AD-related dementia. The study design is published (Baker et al., 2019). This is an ancillary study of the ongoing COSMOS trial, which examined the effect of cocoa extract and a multivitamin on cardiovascular and cancer endpoints in more than 21,000 older adults (Rautiainen et al., 2018; Sesso et al., 2022).

COSMOS-Mind finished in February 2021; results were shown in November at CTAD. Cocoa extract had no effect on global cognitive function over three years. In contrast, the multivitamin improved cognitive measures, compared to placebo. Seventy-seven percent of participants completed the trial. Most were white, and had at least some college or higher education. Results are published (Baker et al., 2023). On secondary outcomes, the study found no difference in the incidence of MCI or dementia with cocoa supplement compared to placebo (Sachs et al., 2023). A subgroup analysis suggested possible cognitive benefits of cocoa flavanols in people with poorer diet quality (Vyas et al., 2023).

In August 2016, another substudy, COSMOS Web, began to measure changes in cognition via an online test battery in 3,947 COSMOS participants randomized to the cocoa extract, a multivitamin, both, or placebo for three years. The primary outcome was change in episodic memory after one year, measured by the ModRey Assessment of Immediate Recall and Learning and Episodic Memory (Hale et al., 2019). The study included additional cognitive tests and MRI measures of brain structure and blood flow as secondary endpoints. It finished in December 2020. According to published results, cocoa flavanols did not change the primary outcome. However, the supplement did improve ModRey performance in the subgroups of people with poorer-quality diets and with low flavanol intake at baseline (Brickman et al., 2023). Increases in a urine biomarker of flavanol intake correlated with cognitive improvement after one year of supplementation.

From 2015-2019, a placebo-controlled study tested one year of a combination of flavanol-rich dark chocolate and omega-3 fatty acid-rich fish oil in older adults with subjective cognitive impairment or mild cognitive impairment (Vauzour et al., 2023). The trial found no cognitive benefit or change in brain structure from the supplementation, which provided 500 mg flavan-3-ols, 1.1 g DHA, and 0.4 g EPA daily. In a separate study, 200 mg of flavanols plus a berry extract, taken daily for 12 weeks, was reported to improve scores on tests of executive function in healthy adults (García-Cordero et al., 2021).

In January 2019, a study at Columbia University began testing the effects of a cocoa extract on neuroinflammation in normally aging adults. The 146 participants, age 50-69, will take 650 mg Cocoapro flavanols or placebo for three months. The primary outcome is levels of the inflammatory marker HMGB1 in blood, with secondary outcomes of other markers of inflammation. Cognitive endpoints include the ModRey and others. This trial will run until mid-2024.

For details on these trials, see clinicaltrials.gov.

Last Updated: 30 Jan 2024

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Therapeutics

AR1001

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Overview

Name: AR1001
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Aribio Co., Ltd.

Background

Ar1001 is a selective inhibitor of phosphodiesterase 5. This new pyrrolo-pyrimidinone was first developed for treatment of erectile dysfunction in South Korea, and is now being tested for Alzheimer’s disease. Its maker claims AR1001 to be 10-fold more potent at inhibiting PDE5, and better at entering the brain, than approved PDE5 inhibitors, including sildenafil.

The rationale for using PDE5 inhibitors in AD stems from animal studies, where these compounds enhance memory and learning by increasing the intracellular messenger cGMP, and also possibly by improving blood supply to the brain. Several PDE5 inhibitors have been reported to curtail amyloid production, and to lessen neuroinflammation and learning and memory deficits in mouse models of AD (see review by Zuccarello et al., 2020).

Three studies have reported PDE5 effects in people. Men being treated for erectile dysfunction with low doses of the PDE5 inhibitors tadalafil or udenafil daily for eight weeks improved performance on tests of cognition and cerebral blood flow, while a single dose of sildenafil improved brain blood supply in people with AD (Choi et al., 2019; Shim et al., 2014; Sheng et al., 2017). A study of potential AD targets for drug repurposing has identified sildenafil, and a medical records analysis reported that men who used it lowered their risk of AD by 69 percent (Fang et al. 2021). Other analyses found no such evidence (Desai et al., 2022)

The only public preclinical data on AR1001 was presented by Aribio at AAIC 2020, where the company reported reduced Aβ plaque deposition in 5XFAD mice, and improved memory in NSE/APP-C105 mice after treatment (Kang et al., 2020). The company later published similar results using the approved PDE5 inhibitor mirodenafil (Kang et al., 2022).

Findings

In April 2019, Aribio began a Phase 2 study of efficacy in clinically diagnosed people with mild to moderate AD. The trial recruited 210 subjects at 21 sites in the U.S. A 26-week course of 10 or 30 mg daily AR1001 or placebo was followed by an optional 26-week extension, where the 10 and 30 mg groups continued at that dose, and placebo takers were randomized to 10 or 30 mg. Primary endpoints were change from baseline in ADAS-Cog13 and ADCS-CGIC; secondary endpoints included various measures of cognition, behavior and function, and exploratory plasma biomarkers. The study ended in June 2021, and results were presented at the CTAD conference in November. There was 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.

More than half of participants were taking other, unspecified AD medications, and a post hoc subgroup analysis hinted those taking 30 mg AR1001 alone, but not those with concomitant treatment, might have improved on the ADAS-Cog13. The mild, but not the moderate, subgroup also showed improvement on the same endpoint. There was no placebo group for comparison at 52 weeks. The treatment was well-tolerated, with a similar incidence of side effects and discontinuation in all groups. There was one death from COVID, and one person on the high dose had a serious adverse event of fainting, possibly related to drug. According to additional data presented at the October 2023 CTAD conference, both doses led to a decrease in plasma pTau181, compared to an increase in the placebo group. A post hoc analysis suggested that in people with the highest pTau181 levels at the start, and thus most likely to be amyloid positive, the 30 mg dose may have slowed decline on the ADAS-Cog13.

In December 2022, the company began a Phase 3 study in people with MCI or mild dementia due to AD. Called Polaris-AD, it is enrolling, at approximately 65 research sites, 1,150 people with MMSE scores above 20, CDR global ratings of 0.5 or 1, and RBANS of 85 or less, and confirmation of amyloid pathology by CSF test or PET. Participants will take one 30 mg tablet or placebo daily for one year. The primary outcome is change in the CDR-SB after one year; secondary outcomes include ADAS-Cog 13, the Amsterdam Instrumental Activities of Daily Living, Geriatric Depression Scale, MMSE, and RBANS. The study will also track safety, as well as plasma and CSF biomarkers, and offers a two-year open label extension. Completion is anticipated in December 2025.

Aribio has FDA approval for a Phase 2 trial in vascular dementia (Korea Biomedical Review news). On its pipeline, it also lists Phase 2 development for dementia with Lewy bodies and dementia with depression/PTSD, but no trials appear in common registries for these indications.

For details on AR1001 trials, see clinicaltrials.gov.

Last Updated: 19 Dec 2023

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Therapeutics

Sabirnetug

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Overview

Name: Sabirnetug
Synonyms: ACU-193
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2/3)
Company: Acumen Pharmaceuticals, Inc.

Background

This humanized IgG2 monoclonal antibody selectively binds soluble Aβ oligomers, aka Aβ-derived diffusible ligands (ADDLs). Though they constitute a minor fraction of Aβ in the brain, soluble oligomers are believed to be the most neurotoxic, and to be responsible for memory loss and neuronal death (e.g., Gong et al., 2003; Hong et al., 2018). This antibody emerged from a research and development collaboration forged in 2004 between Acumen and Merck. The partnership ended in 2011, at which point Acumen regained development rights.

Preclinical work on ACU193 has been presented at meetings. In 2013, Acumen reported that the antibody binds to soluble Aβ oligomers with low nanomolar affinity and greater than 500-fold selectivity over Aβ monomers or fibrils. ACU193 blocked oligomers from interacting with cultured hippocampal neurons at an IC50 of 17 nM, and was unaffected by addition of excess Aβ monomer. In Tg-AD mice, ACU193 bound soluble oligomers in brain tissue, lessened plaque deposition, and was claimed to reduce abnormal nighttime hyperactivity. Based on ACU193's pharmacokinetics in animals, the company expects to achieve brain levels of ACU193 more than 200 times higher than soluble oligomer concentrations measured in Alzheimer’s patient CSF (Krafft et al., 2013). In 2015, the company described the use of ACU193 in an ultrasensitive immunoassay to detect soluble Aβ oligomers in mice (Cline et al., 2015).

The mouse version of ACU193, ACU-3B3, reportedly blocks Aβ oligomer-induced calcium elevation in hippocampal neurons in culture, and reduces amyloid pathology and behavioral deficits in AD mouse models (Wang et al., 2018; Ma et al., 2019). ACU193 was also used experimentally in studies proposing a physiological signaling role for transient formation of Aβ oligomers in embryonic tissue development (Bartley et al., 2022).

ACU193 coupled to magnetic nanoparticles was used to detect Aβ oligomers in rabbit brain by MRI (Rozema et al., 2020). For a description of the treatment rationale and preclinical data, see Krafft et al., 2022.

Findings

In June 2021, Acumen began a Phase 1 trial of intravenous ACU193 in 65 people with MCI or mild AD. The study evaluated safety and tolerability, including 12-lead EEG, as well as pharmacokinetic and pharmacodynamic parameters, of up to three different single and multiple doses. Co-sponsored by the National Institute on Aging, this trial ran at 17 sites across the U.S., and finished in July 2023. The rationale and design are published (Siemers et al., 2023). The company presented top-line results at the July 2023 AAIC. The study tested single doses of 2, 10, 25, or 60 mg/kg, and three doses of 10 or 60 mg/kg monthly, or 25 mg/kg every two weeks. Three serious adverse events were deemed unrelated to drug. Four cases of ARIA-H and five of ARIA-E were detected in 48 treated participants, with one symptomatic case in the 60 mg/kg monthly cohort. All improved or resolved by the end of the study. Blood and CSF pharmacokinetics were dose-dependent, with CSF concentrations exceeding reported oligomer levels. Target engagement was assessed by measuring antibody-oligomer complexes in CSF, which were found to increase with dose. Maximum target engagement occurred after 25 mg/kg biweekly or 60 mg/kg monthly. These doses generated a small reduction in plaque load. The antibody had no clear effect on exploratory outcomes of computerized cognitive testing or cerebral blood flow.

At the 2023 CTAD, the company presented pharmacokinetic and target engagement modeling that informed dose selection for a Phase 2/3 study. That study, called ALTITUDE-AD, began in February 2024. It is comparing 18-month courses of 35 mg/kg monthly, 50 mg/kg monthly with titration to mitigate ARIA, and placebo in 2,040 people with early Alzheimer’s disease. The sole primary outcome is change from baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) score. More than 30 secondary outcomes include other measures of cognition, function, quality of life, neuropsychiatric symptoms, resource utilization, caregiver burden, time saved analysis, PET, and pharmacokinetics, as well as oligomer concentrations in CSF and other biomarkers. An open-label extension is planned. The trial was to run in the U.S., Canada, and Europe, through January 2031. In late 2024, it was reclassified to Phase 2, and enrollment was scaled down to 540. This trial is currently running in the U.S. and Canada. It is using plasma pTau217 screening to enrich for likely amyloid-positive candidates prior to PET scanning. Study completion is anticipated in October 2026.

From July to September 2024, the company ran a Phase 1 study to compare the pharmacokinetics of sabirnetug after intravenous infusion, or after subcutaneous administration in combination with recombinant human hyaluronidase (rHuPH20). This FDA-approved enzyme additive breaks down extracellular matrix to facilitate antibody absorption (e.g. Nolan and Printz, 2024).

For details on ACU193 trials, see clinicaltrials.gov.

Last Updated: 15 Nov 2024

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Therapeutics

Lu AF88434

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Overview

Name: Lu AF88434
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Mild Cognitive Impairment
U.S. FDA Status: Mild Cognitive Impairment (Discontinued)
Company: Lundbeck

Background

This small molecule is a potent and selective PDE-1 phosphodiesterase inhibitor that increases neuronal levels of cyclic nucleotide second messengers. Lu AF88434 is intended to enhance neuroplasticity, intracellular signaling, and cognitive functioning.

Findings

In 2019 and 2020, Lundbeck completed two Phase 1 studies in healthy adults. One investigated single ascending doses or placebo in 68 young men against endpoints of safely, pharmacokinetics, and food effects. The second measured brain penetration in eight men by PET scan using a [11C]-Lu AF8843 tracer.

A Phase 2 trial for negative symptoms of schizophrenia was discontinued in August 2020 (press release), and at the end of 2020, Lundbeck dropped Lu AF88434 from their development pipeline.

For details on Lu AF88434 trials, see clinicaltrials.gov.

Last Updated: 12 Oct 2021

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Therapeutics

Fosigotifator

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Overview

Name: Fosigotifator
Synonyms: ABBV-CLS-7262, Fosigotifator sodium tromethamine
Chemical Name: [(2S)-1,4-Bis[[2-(4-chloro-3-fluorophenoxy)acetyl]amino]-2-bicyclo[2.2.2]octanyl]oxymethyl dihydrogen phosphate
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 2/3)
Company: AbbVie, Calico Life Sciences LLC.

Background

ABBV-CLS-7262 is an activator of the eukaryotic initiation factor EIF2b, which participates in starting up protein synthesis from mRNA. In some neurodegenerative diseases, accumulation of misfolded proteins in the endoplasmic reticulum shuts down protein production by inhibiting EIF2b as part of the so-called unfolded protein response, or integrated stress response (for example, see Stutzbach et al., 2013). The resulting deficit in global protein synthesis contributes to synaptic dysfunction and memory impairment.

Restoring EIF2b activity has been shown to protect against neurodegeneration in preclinical models of prion disease, frontotemporal dementia, and ALS (reviewed in Smith and Mallucci, 2016).

Calico licensed ABBV-CLS-7262 from Peter Walter's laboratory at the University of California at San Francisco. This group has published multiple papers on the integrated stress response inhibitor ISRIB, an activator of EIF2b that improves learning and memory in mice (Sidrauski et al., 2013; Sidrauski et al., 2015; Sidrauski et al., 2015). In preclinical work, ISRIB was neuroprotective in models of head trauma, Down's syndrome, and vanishing white-matter disease (Chou et al., 2017; Zhu et al., 2019; Abbink et al., 2019). It also protected neurons from SOD-1 toxicity in a cellular model of ALS (Bugallo et al., 2020).

In Alzheimer’s models, ISRIB generated mixed results. It prevented Aβ-induced cell death (Hosoi et al., 2016) but did not improve cognition in either the APPswe or hAPP-J20 models of AD, and daily dosing led to significant mortality in the former (Briggs et al., 2017; Johnson and Kang, 2016). Other researchers reported that ISRIB prevented synaptic loss and memory deficits in an Aβ toxicity model, and restored synaptic function and memory in older APP/PS1 mice (Oliveira et al., 2021). ISRIB was reported to normalize protein synthesis in the hippocampus and abrogate learning and memory deficits due to Aβ42 oligomer toxicity in rats (Hu et al., 2022). It also prevented Tau phosphorylation at residues 181 and 217 that occurred in response to synaptic long-term depression (Zhang et al., 2022).

The ISRIB binding site on EIF2b has been resolved by X-ray crystallography (Zyryanova et al., 2018; Tsai et al., 2018; and review by Marintchev and Ito, 2020).

Denali Therapeutics also has an EIF2b activator in clinical trials for ALS (see DNL343).

Findings

In September 2021, Calico and AbbVie began a Phase 1 study of the safety and pharmacokinetics of ABBV-CLS-7262 in 31 people with ALS, conducted at multiple sites in Canada and the U.S. The design calls for a four-week comparison of three oral doses with placebo, followed by up to three years of open-label treatment. The placebo-controlled portion finished in January 2023. Trial completion is set for November 2025.

In March 2023, the company began an open-label exploratory Phase 1b/2 study in adults and children with vanishing white matter disease. This genetic degenerative condition is caused by reduced EIF2b activity due to mutations affecting its subunit proteins. Fifty participants in three age-defined cohorts will receive treatment for four years, against primary outcomes of adverse events and plasma drug concentration. Completion is slated for November 2027. Starting in September 2024, the company began an expanded access program offering fosigotifator for vanishing white matter disease and its severe form of Cree leukoencephalopathy.

Also in March 2023, a Phase 2/3 trial began testing ABBV-CLS-7262 in ALS. This study is part of the Healey ALS platform trial, a multicenter clinical collaboration testing different interventions in parallel against a common placebo group. The 24-week study will compare two different doses in 300 patients, enrolled 3:1 to active treatment or placebo. The primary outcome is disease progression on the ALS-Functional Rating Scale-Revised, and mortality. Secondary outcomes include muscle strength, respiratory function, and serum neurofilament light chain levels. Enrollment was completed in April 2024 (press release). The trial was to finish in September 2024.

On January 6, 2025, MGH and Calico announced that the trial had failed to meet the primary endpoint of delaying ALS progression (press release; press release). Fosigotifator at either dose did not change key secondary endpoints of respiratory function and health-related quality of life. On a prespecified analysis of muscle strength, the high dose slowed deterioration in the upper extremities by 32 percent, and in the lower by 62 percent, compared to placebo. Treatment-emergent adverse events were similar in treated and placebo groups. The trial treated 155 participants with the primary dose, and 79 with the high dose, and compared them to 126 in the common placebo group.

In 2023 and 2024, the company completed three additional Phase 1 studies in healthy adults. One explored the effects of ABBV-CLS-7262 on the pharmacokinetics of rosuvastatin and digoxin in 12 participants. Another assessed food effects. From March to June 2024, the company tested the effects of ABBV-CLS-7262 on heart electrical activity. This study evaluated possible effects on the electrocardiogram QTc interval in 72 healthy adults. A Phase 1 study assessed safety, pharmacokinetics, elimination, and major drug metabolites after a single dose of radioactive [14C] ABBV-CLS-7262 in healthy men.

In October 2024, AbbVie began a Phase 1b placebo-controlled safety study in 106 adults with major depressive disorder.

For details on ABBV-CLS-7262/fosigotifator trials, see clinicaltrials.gov.

Last Updated: 23 Jan 2025

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