Overview
Name: Obicetrapib
Synonyms: TA-8995
Therapy Type: Small Molecule (timeline)
Target Type: Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: NewAmsterdam Pharma
Background
This cholesteryl ester transfer protein (CETP) inhibitor is being developed primarily as a cholesterol-targeted therapy to reduce cardiovascular disease. CETP inhibitors block the transfer of cholesteryl esters from high-density lipoprotein (HDL) into other lipoproteins, and thus promote removal of cholesterol by HDL. Drugs of this class were initially developed to increase “good” high-density lipoprotein (HDL) cholesterol, and were shown to also reduce “bad” low-density lipoprotein (LDL) cholesterol in people. Previous CETP inhibitors were discontinued when they showed little or no improvement in cardiovascular outcomes, or even increased deaths, despite raising HDL (see review by Nurmohamed et al., 2022; also Oct 2021 news). Obicetrapib is claimed to be more potent and specific than these failed candidates.
The rationale for testing this CETP inhibitor for Alzheimer’s disease stems from work linking high levels of HDL to longer life and preserved cognition (Barzilai et al., 2006; Lewis et al., 2010). By its ability to elevate HDL, obicetrapib increases cholesterol efflux from cells, a process which may mitigate the risk of AD due to ApoE4, and help clear Aβ from brain (van Capelleveen et al., 2016; Van Valkenburgh et al., 2021). However, low-activity CETP gene variants that mimic inhibition do not decrease the risk of AD (Nordestgaard et al., 2022; Peloso et al., 2018). In one study, genetic variants associated with higher HDL actually raised AD risk (May 2023 news). High HDL is also linked to an elevated risk of age-related macular degeneration (Burgess and Davey Smith, 2017).
No preclinical work is published on obicetrapib in Alzheimer’s models. Mice lack a CETP gene, but a recently produced transgenic animal may be useful for such studies (Oestereich et al., 2022).
Findings
In Phase 1 evaluation in healthy subjects, single and multiple oral doses of obicetrapib from 2.5 to 25 mg daily were well-tolerated and nearly completely inhibited CETP (Ford et al., 2014). The treatment increased high-density lipoprotein-cholesterol (HDL-C) by 96 to 140 percent and decreased low-density lipoprotein-cholesterol (LDL-C) by 40 to 53 percent. No significant effects of age, gender, ethnicity, or food were found. There was no evidence of off-target effects seen with earlier inhibitors, such as changes in blood pressure, serum electrolytes, or aldosterone.
In January 2022, NewAmsterdam Pharma began a Phase 2, open-label proof-of-concept study in 13 patients with a clinical diagnosis of Alzheimer's disease who carried one or two ApoE4 alleles. Treatment consisted of 10 mg obicetrapib daily for 24 weeks. Primary outcomes were concentration of apolipoproteins and high-density lipoprotein particles in plasma and CSF. Other outcomes were pharmacokinetics including CSF levels of drug. The study was completed in June 2023. In September, the company announced top-line data, saying that obicetrapib had been well-tolerated (company press release). No data on lipoprotein levels was reported; instead, the company claimed 10 and 11 percent reductions in CSF 24- and 27-hydroxycholesterol, respectively. This was interpreted as evidence of normalization of cholesterol metabolism in the brain. The treatment nudged up the CSF Aβ42/40 ratio by 8 percent.
Three large, worldwide Phase 3 trials of obicetrapib are ongoing, testing it as an add-on to statins to further lower cholesterol and improve cardiovascular outcomes in people with familial high cholesterol or atherosclerotic cardiovascular disease. In a Phase 2 study, 10 mg obicetrapib added to high-intensity statin treatment decreased LDL and increased HDL (Nicholls et al., 2022). Obicetrapib additively lowered cholesterol when given with statins and ezetimbe, a drug that blocks intestinal cholesterol absorption (Ballantyne et al., 2023). Even though CETP inhibitors raise HDL, their cardiovascular benefits are now attributed to their ability to lower LDL and apolipoprotein B (see Nelson et al., 2022; Mehta et al., 2023).
For details on this study, see clinicaltrials.gov.
Last Updated: 07 Nov 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: Plcg2, App
Modification: Plcg2: Knock-In; App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Plcg2em1Msasn/J x Apptm3.1Tcs/Apptm3.1Tcs
The PLCG2 gene encodes the enzyme phospholipase C gamma 2 (PLCγ2), a mediator of transmembrane signaling in microglia that acts downstream of TREM2.
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+.
Plaques
ThioflavinS-positive amyloid plaques observed in mice studied at 6 months of age. Higher plaque burdens than APPNL-G-F.
Synaptic Loss
The P522R variant attenuated the synapse loss observed in APPNL-G-F mice with wild-type PLCγ2.
Gliosis
Microgliosis observed in mice studied at 6 months of age. Attenuated microglia-plaque interactions in the hippocampus, compared with APPNL-G-F.
Complementary Models
Microglial-like cells derived from human induced pluripotent stem cell lines (hIPSCs) have been used to study PLCγ2 biology in human cells in vitro and in vivo after transplantation into mouse brains.
CRISPR/Cas9 gene editing was used to introduce the PLCG2 P522R mutation into hIPSCs derived from skin cells of an apparently healthy, middle-aged Caucasian male. Isogenic clones homozygous for the wild-type P522 allele or mutant R522 allele were differentiated into microglia-like cells (Maguire et al., 2021). Stimulation of PLCγ2 by Fc receptor ligation led to a greater increase in intracellular Ca2+ in cells carrying the mutant allele, consistent with a hypermorphic effect of the mutation. Similar to microglia and macrophages isolated from Plcg2*P522R knock-in mice (Maguire et al., 2021), hIPSC-derived microglia carrying the mutant allele showed decreased phagocytosis (uptake of E. coli particles or zymosan) and increased endocytosis (uptake of Aβ42 oligomers or Dextrans), compared with isogenic hIPSC-derived microglia expressing wild-type PLCγ2.
A second study compared isogenic hIPSC-derived microglia that differed with regard to P522R gene dose—wild-type (PLCγ2WT), heterozygous for the P522R mutation (PLCγ2HET), and homozygous for the mutation (PLCγ2HOM) (Solomon et al., 2022). In this case, the parental hIPSC line was derived from skin fibroblasts donated by a teenaged male (APOE3/4) of black or African-American ancestry with no diagnosed diseases. Here, too, CRISPR gene editing was used to introduce the PLCG2 P522R mutation. IPSC-derived microglia contained similar levels of PLCγ2 protein, regardless of PLCG2 genotype. However, the genotypes differed with regard to functional properties and gene expression—with PLCγ2HET showing more pronounced differences than PLCγ2HOM on several measures (compared with PLCγ2WT). PLCγ2HOM and PLCγ2HET showed increased uptake of fluorescently labeled Aβ42, but only PLCγ2HET cells showed increased uptake of Dextrans. Uptake of synaptosomes was reduced in P522R carriers, regardless of gene dose. LysoTracker staining—a marker for lysosomes—was elevated in P522R carriers, slightly more so in heterozygotes than homozygotes. When co-cultured with IPSC-derived neurons (heterozygous for the PLCG2 P522R mutation), PLCγ2HET microglia engaged in less synaptic pruning—as measured by PSD95 engulfment—than PLCγ2WT microglia, while PLCγ2HOM did not significantly differ from PLCγ2WT. When levels of expression of selected genes related to microglial function were compared between P522R carriers and wild-type cells, several genes were found to be upregulated in PLCγ2HET—in pathways related to lipid metabolism, lysosomal biogenesis, and immune function—while only APOE was upregulated in PLCγ2HOM. Microglial motility and intracellular Ca2+ levels were also greater in PLCγ2HET compared with the other two PLCG2 genotypes. Physiological studies showed a gene-dose-dependent increase in oxidative phosphorylation with PLCγ2HOM > PLCγ2HET > PLCγ2WT.
A third study focused on the effects of the P522R mutation on the transcriptomes of human microglia-like cells in vivo, in the context of amyloidosis (Claes et al., 2022). Once again, CRISPR gene editing was used to introduce the P522R mutation into the PLCG2 gene, this time in an (RFP)-α-tubulin expressing hIPSC line derived from fibroblasts donated by an apparently healthy 30-year-old Japanese man. IPSCs homozygous for the PLCG2 P522R mutation or isogenic hIPSCs with wild-type PLCG2 were differentiated into microglia-like cells in vitro, then grafted into the brains of neonatal immune-deficient 5xFAD or non-transgenic mice. Mice were aged to 7 months, a time when plaque deposition is well underway in 5xFAD brains, and the human cells were harvested for RNA sequencing. PLCG2 P522R microglia from 5xFAD brains showed increased levels of expression of multiple HLA and interferon genes and of genes encoding chemokines that mediate T-cell recruitment to the brain, compared with microglia expressing wild-type PLCG2. Gene Ontology analysis highlighted MHC class II antigen presentation, cytokine/chemokine signaling, interferon signaling, and regulation of T cell proliferation as pathways affected by the P522R mutation. PLCG2 P522R microglia isolated from non-transgenic hosts also showed increased expression of HLA genes, compared with microglia carrying wild-type PLCG2.
Chimeric 5xFAD brains were also examined histologically, and no differences were seen between those transplanted with P522R and wild-type PLCG2 hIPSC-derived microglia in the following measures: amyloid plaque burden, number, or size; microglial morphology, number of plaque-associated microglia, or microglial amyloid internalization; “amount” of plaque-associated dystrophic neurites; or numbers of total or plaque-associated astrocytes.
The lack of an effect of the P522R mutation on amyloid-related pathology in chimeric mice contrasted with findings in 5xFAD mice in which the P522R mutation was knocked into the endogenous Plcg2 gene. In the knock-in mice, the P522R mutation reduced amyloidosis, enhanced microglia-plaque interactions, and protected against plaque-associated pathology. The chimeric and knock-in models differ in several aspects that could potentially contribute to these discrepant findings, including intrinsic differences between human and mouse microglia, expression of P522R PLCγ2 in cells other than microglia in the knock-in mice, and lack of immune responses in chimeric hosts.
Last Updated: 27 Oct 2023
Further Reading
No Available Further Reading
Overview
Name: NurOwn™
Synonyms: MSC-NTF Cells, debamestrocel , Neurotrophic factors-secreting Mesenchymal Stromal Cells
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 3)
Company: BrainStorm Cell Therapeutics, Inc.
Background
NurOwn™ comprises mesenchymal stem cells enriched from patients’ own bone marrow, propagated in the lab, and induced to secrete neurotrophic factors. The cells are transplanted back into the patients’ spinal cord and muscle, where the neurotrophic factors are expected to promote neuron survival, and slow down disease progression.
Published preclinical work describes microRNA profiling of MSC-NTF cells (Gothelf et al., 2017), and experiments demonstrating the safety of repeated injections of cryopreserved cells in mice (Gothelf et al., 2014). In mice, MSC-NTF transplant to the brain was reported to improve autism-related behaviors (Perets et al., 2017).
Findings
Two open-label safety studies were conducted between 2011 and 2014, involving 36 ALS patients who received NurOwn™ as one-time intramuscular or intrathecal injections, or both. After a six-month follow-up, the treatment was safe, and provided a possible clinical benefit (Jan 2016 news on Petrou et al., 2016).
A Phase 2, placebo-controlled study from May 2014 to July 2016 treated 48 early stage ALS patients with a one-time intramuscular and intrathecal administration of MSC-NTF cells. All patients underwent bone marrow harvest, followed by active transplants in 36 and placebo injections in 12. The study met its primary outcome of safety six months after transplant, but treatment did not change the clinical outcome of rate of decline on the on ALS-Functional Rating Scale (Berry et al., 2019). In a post hoc analysis, a rapid progressor subgroup of 21 patients showed hints of potential slowing of decline at one and three months after treatment.
In August 2017, a Phase 3 study randomized 196 patients to three intrathecal injections of NurOwn™ or placebo, spaced two months apart. The primary endpoint was the number of patients who met criteria for slowed disease progression on the ALSFRS-R six months after the first injection. Participants who finished the trial could continue treatment under an expanded access program. The trial finished in October 2020, and missed its primary endpoint of efficacy (Cudkowicz et al., 2022). A prespecified subgroup analysis suggested benefits in people with less-severe disease. CSF biomarkers of neuroinflammation, neurotrophic factors, and neurodegeneration improved after treatment. The company claimed an 11 percent reduction in CSF neurofilament light in treated patients (press release; July 2023 Gordon Conference poster).
In September 2022, the company filed a Biologicals License application with the FDA, which refused to review it (press release). This “Refusal to File” applies to applications the agency considers incomplete or to have inadequate scientific information to enable review. The company then used a “File Over Protest” procedure to force a review.
On September 27, 2023, an FDA Advisory Committee voted 17-1 against approving NurOwn™ (press release). In its briefing documents, the FDA said the application did not demonstrate effectiveness on primary or secondary endpoints. According to the agency's analysis, survival was worse in patients who received NurOwn™.
On October 18, the company announced it was withdrawing its licencing application in coordination with the FDA, and would discuss further development steps with the agency (press release).
NurOwn™ has also completed a Phase 2, open-label trial for multiple sclerosis (Cohen et al., 2023).
For details on NurOwn™ trials, see clinicaltrials.gov.
Last Updated: 19 Oct 2023
Further Reading
No Available Further Reading
Overview
Name: RG6289
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1/2)
Company: Hoffmann-La Roche
Background
This second-generation γ-secretase modulator is in development for the treatment of Alzheimer's disease. The rationale is that, unlike γ-secretase inhibitors, which inhibit the enzyme complex outright, modulators shift APP cleavage toward production of shorter Aβ peptides and away from production of longer, aggregation-prone peptides such as Aβ42 and Aβ43, while sparing γ-secretase's physiological cleavages of substrates such as notch (e.g. Wolfe, 2007; Trambauer et al., 2020; Weber et al., 2022).
Multiple studies have tied the ratio of short to long Aβ peptides to AD pathogenesis (e.g., Jan 2022 news; Apr 2022 news).
γ-Secretase modulators are intended to slow amyloidogenesis, not plaque removal (e.g., Brendel et al., 2015).
Previously, a first generation of γ-secretase modulators had failed over toxicology problems (e.g., Aug 2008 news; Dec 2008 news; Apr 2011 news; Nolte et al., 2021).
No information about this new molecule is published. In a presentation at the October 2023 CTAD, the company claimed that RG6289 stabilized APP at the active site, increasing odds of processivity in APP cleavage. Roche reported a potency of below 10 nM for γ-secretase modulation of APP cleavage, and no effect on processing of other substrates. In vitro, RG6289 reduced production of Aβ42 and Aβ40, and proportionally increased Aβ38 and Aβ37. The drug showed dose-dependent γ-secretase modulation in rodents and primates.
Prior studies have reported on the binding characteristics of experimental γ-secretase-modulating compounds (Ebke et al., 2011; Lübbers et al., 2011; Cusulin et al., 2019; Ratni et al., 2020; Rodriguez-Sarmiento et al., 2020; Ratni et al., 2021).
Findings
No trials are registered in clinicaltrials.gov, but Roche indicates in its fall 2023 development pipeline that RG6289 underwent a 127-person, first-in-human trial starting in 2021. The study included single and multiple ascending dosing in healthy young adult volunteers, and 14 days dosing in healthy elderly adults. Aβ peptides were measured in plasma and, in some people, in CSF. According to results that were presented at the October 2023 CTAD conference, RG6289 was safe. Most adverse events were mild and their frequency did not increase with dose. Pharmacokinetics were linear, plasma concentration increased with dose, was barely affected by eating, and was adequate for once-daily oral dosing. The drug achieved CNS levels comparable to free plasma concentrations. RG6289 dose-dependently reduced CSF Aβ42 and Aβ40 and increased Aβ38 and Aβ37. Reductions in plasma Aβ42 correlated with CSF changes (Nov 2023 conference news, abstract).
At the March 2024 AD/PD meeting in Lisbon, Roche presented the protocol for GABriella, a Phase 2a safety and biomarker study that is to begin in the first half of 2024. The multicenter international dose-finding trial will recruit 245 amyloid-positive volunteers who are cognitively normal or have mild cognitive impairment. The trial targets people expected to be rapidly accumulating brain amyloid, with a lower cutoff of 24 centiloids and only 15 percent of the baseline population allowed to have greater than 100 centiloids. Participants will be randomized to one of three doses or placebo for 72 weeks, against primary endpoints of safety, tolerability, and change in amyloid PET. Secondary outcomes include pharmacokinetics, and pharmacodynamic measures of change in Aβ monomers in CSF and blood. For exploratory endpoints, the study will assess multiple CSF and plasma biomarkers of Aβ, tau, neurodegeneration, synaptic integrity, and inflammation, as well as imaging biomarkers, and cognitive measures (AD/PD presentation).
Last Updated: 03 May 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: Plcg2
Modification: Plcg2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Plcg2em1Msasn/J
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+.
Synaptic Loss
Synapse number in hippocampal CA1—assessed as the density of puncta immunoreactive for the presynaptic marker bassoon or the postsynaptic marker PSD95—did not differ between Plcg2*P522R and wild-type mice. However, a slight decrease in the number of thin spines was observed in mutation carriers, while numbers of stubby and mushroom spines did not differ between the genotypes.
Gliosis
Plcg2*P522R knock-in mice had a slightly higher density of Iba1-positive microglia than wild-type mice. Microglia in the knock-in animals were simpler in shape—with less ramified processes—and contained a greater density of puncta immunoreactive for the lysosomal marker CD68, compared with wild-type microglia.
Complementary Models
Microglial-like cells derived from human induced pluripotent stem cell lines (hIPSCs) have been used to study PLCγ2 biology in human cells in vitro and in vivo after transplantation into mouse brains.
CRISPR/Cas9 gene editing was used to introduce the PLCG2 P522R mutation into hIPSCs derived from skin cells of an apparently healthy, middle-aged Caucasian male. Isogenic clones homozygous for the wild-type P522 allele or mutant R522 allele were differentiated into microglia-like cells (Maguire et al., 2021). Stimulation of PLCγ2 by Fc receptor ligation led to a greater increase in intracellular Ca2+ in cells carrying the mutant allele, consistent with a hypermorphic effect of the mutation. Similar to microglia and macrophages isolated from Plcg2*P522R knock-in mice (Maguire et al., 2021), hIPSC-derived microglia carrying the mutant allele showed decreased phagocytosis (uptake of E. coli particles or zymosan) and increased endocytosis (uptake of Aβ42 oligomers or Dextrans), compared with isogenic hIPSC-derived microglia expressing wild-type PLCγ2.
A second study compared isogenic hIPSC-derived microglia that differed with regard to P522R gene dose—wild-type (PLCγ2WT), heterozygous for the P522R mutation (PLCγ2HET), and homozygous for the mutation (PLCγ2HOM) (Solomon et al., 2022). In this case, the parental hIPSC line was derived from skin fibroblasts donated by a teenaged male (APOE3/4) of black or African-American ancestry with no diagnosed diseases. Here, too, CRISPR gene editing was used to introduce the PLCG2 P522R mutation. IPSC-derived microglia contained similar levels of PLCγ2 protein, regardless of PLCG2 genotype. However, the genotypes differed with regard to functional properties and gene expression—with PLCγ2HET showing more pronounced differences than PLCγ2HOM on several measures (compared with PLCγ2WT). PLCγ2HOM and PLCγ2HET showed increased uptake of fluorescently labeled Aβ42, but only PLCγ2HET cells showed increased uptake of Dextrans. Uptake of synaptosomes was reduced in P522R carriers, regardless of gene dose. LysoTracker staining—a marker for lysosomes—was elevated in P522R carriers, slightly more so in heterozygotes than homozygotes. When co-cultured with IPSC-derived neurons (heterozygous for the PLCG2 P522R mutation), PLCγ2HET microglia engaged in less synaptic pruning—as measured by PSD95 engulfment—than PLCγ2WT microglia, while PLCγ2HOM did not significantly differ from PLCγ2WT. When levels of expression of selected genes related to microglial function were compared between P522R carriers and wild-type cells, several genes were found to be upregulated in PLCγ2HET—in pathways related to lipid metabolism, lysosomal biogenesis, and immune function—while only APOE was upregulated in PLCγ2HOM. Microglial motility and intracellular Ca2+ levels were also greater in PLCγ2HET compared with the other two PLCG2 genotypes. Physiological studies showed a gene-dose-dependent increase in oxidative phosphorylation with PLCγ2HOM > PLCγ2HET > PLCγ2WT.
A third study focused on the effects of the P522R mutation on the transcriptomes of human microglia-like cells in vivo, in the context of amyloidosis (Claes et al., 2022). Once again, CRISPR gene editing was used to introduce the P522R mutation into the PLCG2 gene, this time in an (RFP)-α-tubulin expressing hIPSC line derived from fibroblasts donated by an apparently healthy 30-year-old Japanese man. IPSCs homozygous for the PLCG2 P522R mutation or isogenic hIPSCs with wild-type PLCG2 were differentiated into microglia-like cells in vitro, then grafted into the brains of neonatal immune-deficient 5xFAD or non-transgenic mice. Mice were aged to 7 months, a time when plaque deposition is well underway in 5xFAD brains, and the human cells were harvested for RNA sequencing. PLCG2 P522R microglia from 5xFAD brains showed increased levels of expression of multiple HLA and interferon genes and of genes encoding chemokines that mediate T-cell recruitment to the brain, compared with microglia expressing wild-type PLCG2. Gene Ontology analysis highlighted MHC class II antigen presentation, cytokine/chemokine signaling, interferon signaling, and regulation of T cell proliferation as pathways affected by the P522R mutation. PLCG2 P522R microglia isolated from non-transgenic hosts also showed increased expression of HLA genes, compared with microglia carrying wild-type PLCG2.
Chimeric 5xFAD brains were also examined histologically, and no differences were seen between those transplanted with P522R and wild-type PLCG2 hIPSC-derived microglia in the following measures: amyloid plaque burden, number, or size; microglial morphology, number of plaque-associated microglia, or microglial amyloid internalization; “amount” of plaque-associated dystrophic neurites; or numbers of total or plaque-associated astrocytes.
The lack of an effect of the P522R mutation on amyloid-related pathology in chimeric mice contrasted with findings in 5xFAD mice in which the P522R mutation was knocked into the endogenous Plcg2 gene. In the knock-in mice, the P522R mutation reduced amyloidosis, enhanced microglia-plaque interactions, and protected against plaque-associated pathology. The chimeric and knock-in models differ in several aspects that could potentially contribute to these discrepant findings, including intrinsic differences between human and mouse microglia, expression of P522R PLCγ2 in cells other than microglia in the knock-in mice, and lack of immune responses in chimeric hosts.
Last Updated: 27 Oct 2023
Further Reading
No Available Further Reading
Overview
Name: MK-8189
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Merck
Background
MK-8189 is a selective inhibitor of phosphodiesterase 10A (PDE10A). This enzyme catalyzes the breakdown of second messengers cGMP and cAMP. PDE10A is abundantly expressed in the striatum in the human brain, and not in other tissues. Abnormal output from the striatum is implicated in positive schizophrenia symptoms of psychosis, hallucinations and delusions. These symptoms also occur in people with Alzheimer’s disease, and are frequently treated with antipsychotic medications.
Preclinical work suggests that PDE10A inhibitors have the potential to alleviate both dopaminergic and glutamatergic dysfunction, which suggests compounds like MK-8189 could have broad-spectrum activity against cognitive impairment in addition to psychosis symptoms (Grauer et al., 2009).
Discovered at Merck, MK-8189 was shown to cross the blood-brain barrier in rats, and to achieve complete brain receptor occupancy by PET displacement studies. It was active in a rat model of psychosis, and in the novel object recognition test of memory (Layton et al., 2023).
Findings
This drug has completed five Phase 1 trials in healthy people and schizophrenia patients, and some data is posted on clinicaltrials.gov (see NCT02181803, NCT03565068). According to a meeting abstract, in a Phase 2a study with 224 participants, 12 mg daily for four weeks did not significantly affect the primary outcome of total symptoms, but did improve positive symptoms (Mukai et al., 2022). Side effects were mild, and few participants discontinued the drug. It caused significant weight loss, compared to the antipsychotic risperidone, which caused weight gain. A larger Phase 2 study began in December 2020, testing higher doses of 16 and 24 mg, for 12 weeks.
From July 2022 to January 2023, Merck ran a Phase 1 trial testing multiple ascending doses of MK-8189 in 29 people with Alzheimer’s disease, with or without symptoms of agitation-aggression and/or psychosis. The placebo-controlled trial compared three titration schedules, from 4 or 8 mg per day to 16 or 24 mg final dose over 28 days. Primary outcomes are adverse events and discontinuations. No results have been made public.
For details on registered trials, see clinicaltrials.gov.
Last Updated: 21 Sep 2023
Further Reading
No Available Further Reading
Overview
Name: Deep Brain Stimulation-nucleus basalis of Meynert
Synonyms: DBS-nbM
Therapy Type: Procedural Intervention
Target Type: Cholinergic System (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Background
Deep Brain Stimulation (DBS) is an invasive treatment. Pairs of electrodes are surgically implanted in the brain and connected to a pulse generator placed under the skin on the chest. DBS-nbM delivers low-frequency stimulation to the nucleus basalis of Meynert in the basal forebrain. The nbM is a major source of acetylcholine in the brain, with projections to the hippocampus and cortex. Its degeneration in Alzheimer’s, Parkinson’s, and Lewy body diseases results in loss of cholinergic transmission and subsequent cognitive decline. In Parkinson’s patients, acetylcholine deficits are also linked to delusions and visual hallucinations. Using DBS to activate these neurons and stimulate acetylcholine release thus targets the same pathway as cholinesterase inhibitors.
In addition to enhanced acetylcholine release, potential mechanisms of DBS-nbM include increased cerebral blood flow, neurotrophic factor release, neuroplasticity, and hippocampal enlargement. DBS-nbM improved cognitive measures in rats with basal forebrain cholinergic neuron lesions, and promoted neurogenesis, synaptic plasticity, and cognitive performance in rats with scopolamine-induced dementia (Lee et al., 2016; Liu et al., 2022). Healthy adult rats, but not aged rats, increased secretion of nerve growth factor in the cortex in response to DBS-nbM (Hotta et al., 2009). In the APP/PS1 model of AD, high-frequency, bilateral nbM stimulation improved animals’ performance in the Morris water maze (Huang et al., 2019). In a transgenic rat model of AD, bilateral intermittent DBS-nbM led to supernormal performance on a spatial memory task (Koulousakis et al., 2020). Monkeys exposed to intermittent stimulation improved performance in a working memory task, and DBS was as effective as an acetylcholinesterase inhibitor (Liu et al., 2017). In this study, continuous stimulation impaired performance (for review of primate studies, see Bava et al., 2023).
Interest in DBS-nbM for Parkinson’s disease was spurred by a case report that stimulation of the nbM in a PD patient with dementia led to a marked improvement in several cognitive tests, which reversed to baseline when the electrodes were shut off (see Jun 2009 news on Freund et al., 2009). Another case report supported the feasibility of dual stimulation, e.g., using a single lead with multiple electrodes to simultaneously stimulate the nbM and the subthalamic nuclei (STN, Nombela et al., 2019). The latter is a standard clinical target for DBS to control motor symptoms of Parkinson’s disease.
Other clinical studies evaluating DBS for AD are targeting the fornix and the ventral capsule/ventral striatum, a modulator of frontal lobe networks (Scharre et al., 2018).
Findings
The first clinical trial of DBS-nbM for Alzheimer’s disease began in January 2010 in Germany, where six mild to moderate AD patients were implanted with bilateral electrodes, and received continuous, low-frequency stimulation for two weeks. This was followed by a two-week off period, and then stimulation for 11 months. The primary endpoint was the ADAS-Cog. According to published results, the intervention was safe. After one year, four patients were stable or improved on the ADAS-Cog, and three had increased glucose uptake on FDG-PET (May 2014 news on Kuhn et al., 2014). Additional analyses reported improvements in nutritional status during treatment, and associated treatment effects with preserved cortical thickness (Noreik et al., 2015; Baldermann et al., 2017; Hardenacke et al., 2016). A separate study by the same group described cognitive improvements in two younger patients treated at an earlier stage of AD (Kuhn et al., 2015).
In 2017, a study began in Spain to test stimulation of the nbM or fornix in six people with AD. The study ended after treating just one patient, who received a fornix implant (Barcia et al., 2022).
In April 2020, the Beijing Pins Medical Company registered a study using its implantable neurostimulator for DBS-nbM. The status of the study, involving 30 AD patients at one hospital in Beijing, is unknown. In another trial of the same device, eight patients with advanced AD received DBS-nbM for 12 months. The study reported transient cognitive improvement on the MMSE at one month (Jiang et al., 2022; Zhang et al., 2021).
A study in Parkinson’s disease dementia ran at the University College London from 2012-2015. The crossover, sham-controlled trial in six patients found six weeks of low-frequency DBS-nbM was safe but elicited no improvement on a cognitive battery, the primary outcome (Gratwicke et al., 2018). Some improvement on psychiatric scores was reported. A three-year follow-up found varying rates of cognitive decline among the patients, but reached no conclusions about effects of stimulation (Cappon et al., 2022).
A 2014-2016 trial of DBS-nbM for Lewy body disease at University College London treated six patients with mild to moderate dementia. After implantation, participants received six weeks of electrodes on and six weeks off in the crossover design, with primary outcomes assessing cognitive, psychiatric, and motor symptoms. The treatment was safe. It did not improve cognition, but reduced neuropsychiatric symptoms in three of five patients. Functional MRI revealed stimulation-associated functional connectivity changes in brain networks involved in cognition (Gratwicke et al., 2020; also see comment by Liu and Yu). A different trial in six French patients compared active stimulation to sham for three months each in a crossover design. The primary outcome of selective recall did not differ between groups, but the authors noted significant decreases in some cognitive test scores after implantation, and after starting stimulation (Maltête et al., 2021).
Several PD trials have tested, or are testing, combined stimulation paradigms that target both the STN and the nbM. One, a 2017 sham-controlled study in Canada found no cognitive improvement from one year of combined stimulation in six patients (Sasikumar et al., 2022). A similar study was conducted in 10 patients in Germany starting in 2016 (Daniels et al., 2020); its results have not been posted to date. A dual stimulation study is ongoing at the University of São Paulo General Hospital in Brazil. Enrolling 10 patients with PD and mild cognitive impairment, its primary outcome is safety. The trial will also assess a long list of secondary cognitive and motor outcomes after 16 weeks of dual stimulation. The study is slated to complete in January 2024.
Another study is planned to begin in October 2023 testing the safety of implanting nbM leads as an add-on to STN leads in 10 PD patients. Thus, investigators will place a total of four leads during surgery. The trial will compare two surgical approaches for targeting the nbM, and assess novel stimulation patterns. Secondary outcomes are motor and cognitive tests over two years. Funded by the NINDS, the trial will run at Stanford University in California until August 2027.
Also in October 2023, a new AD study is set to begin testing intermittent nbM stimulation in people with mild cognitive impairment or early dementia. The study, at Vanderbilt University, will enroll eight people, who will receive one hour of low-frequency stimulation per day, or sham stimulation, for one year. The primary outcome is Clinical Dementia Rating score. The expected finish date is October 2028.
For details on DBS-nbM trials, see clinicaltrials.gov.
Last Updated: 21 Sep 2023
Further Reading
No Available Further Reading
Overview
Name: CS6253
Synonyms: Cogpep™, CS-6253
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Artery Therapeutics, Inc.
Background
This agonist peptide increases the activity of the adenosine triphosphate-binding cassette transporter A1 (ABCA1), which regulates cholesterol efflux from cells. ABCA1 transfers lipids to ApoE, and thus facilitates clearance of amyloid peptides from the brain. Loss-of-function variants in the ABCA1 gene are associated with low plasma levels of ApoE, and a higher risk of Alzheimer’s disease (Holstege et al., 2022; Nordestgaard et al., 2015).
Designed to mimic sequences at the carboxy terminus of ApoE, CS96253 was shown to enhance ABCA1-mediated lipid efflux from cells and formation of HDL particles in vitro (Hafiane et al., 2015; Hafiane et al., 2019). This peptide was initially pursued for its potential to improve or prevent cardiovascular disease.
However, in mice expressing the human AD risk gene ApoE4, CS6253 was reported to reverse hypo-lipidation of E4, slow Aβ accumulation and tau hyperphosphorylation in neurons, and improve synaptic and cognitive function (Boehm-Cagan et al., 2016). In the same mice, it restored blood lipoproteins to normal levels, and countered the ApoE4-induced lysosomal degradation of ABCA1 (Boehm-Cagan et al., 2016; Rawat et al., 2019). Intravenous injection of CS6253 in monkeys transiently increased plasma ApoE and Aβ42/40 (Noveir et al., 2022).
In other models, CS62523 was neuroprotective in fruit flies expressing a human ApoE4 gene (Moulton et al., 2021). It induced insulin secretion and improved glucose tolerance in mice with diet-induced obesity (Azhar et al., 2019), and reduced disability in a mouse model of multiple sclerosis (Itoh et al., 2018).
Findings
A Phase 1 safety trial is slated to begin in September 2023. It will enroll up to 64 healthy adults in five single-ascending-dose cohorts from 1 to 10 mg/kg, and two or more multiple dose groups. In the multiple dose part of the study, each cohort of eight will have at least four ApoE4 carriers. The drug is administered by intravenous injection. Primary endpoints are safety, and plasma and CSF pharmacokinetics. The trial, funded by the National Institutes of Health and the Alzheimer’s Association, is expected to last one year.
For details on this trial, see clinicaltrials.gov.
Last Updated: 21 Sep 2023
Further Reading
No Available Further Reading
Overview
Name: SNP318
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: SciNeuro Pharmaceuticals
Background
SNP318 inhibits the enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2). Also known as plasma platelet-activating factor acetyl hydrolase, this enzyme produces inflammatory mediators that damage blood vessels and increase the permeability of the blood-brain barrier. Lp-PLA2 circulates in the blood in association with LDL cholesterol, and is linked to the formation of atherosclerotic plaques. Inhibitors were originally developed to treat atherosclerosis; the rationale for use in Alzheimer’s disease stems from their anti-inflammatory, anti-oxidative, and pro-vascular effects.
SNP318 is a second-generation Lp-PLA2 inhibitor related to rilapladib, a compound discovered at GlaxoSmithKline, and tested for AD. In a Phase 2 trial in people with both mild Alzheimer’s dementia and neurovascular disease, rilapladib improved a composite of executive function/working memory, but did not change CSF Aβ42 or other endpoints (Maher-Edwards et al., 2015).
In June 2022, SciNeuro bought the rights to rilapladib and other Lp-PLA2 inhibitors from GSK (press release). SciNeuro claims that SNP318 penetrates the CNS better than rilapladib (press release).
Findings
In March 2023, SNP318 began a Phase 1 safety, tolerability and pharmacokinetics study in 86 healthy adults. The placebo-controlled trial includes single ascending doses starting at 1 mg, and multiple doses starting at 30 mg, all in capsule form. It includes cerebrospinal fluid sampling. The study is running in Australia through October 2023.
For details on SNP318 trials, see clinicaltrials.gov
Last Updated: 21 Sep 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: Sorl1
Modification: Sorl1: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Sorl1em1Adiuj/J
A528T is a common variant of SORL1 that has been shown to associate with a slightly increased risk of AD (~15 percent) in people of European ancestry and to segregate with disease in some families. CRISPR/Cas9 gene editing was used to introduce the A528T missense mutation into the mouse Sorl1 gene.
Heterozygous and homozygous mice are viable and fertile.
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+.
Last Updated: 18 Sep 2023
Further Reading
No Available Further Reading
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