Overview
Name: CY6463
Synonyms: IW-6463
Chemical Name: 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo [1,2-a]pyrazine
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Cyclerion
Background
CY6463 is a brain-penetrant, positive allosteric modulator of the soluble guanylate cyclase (sGC). It amplifies endogenous nitrous oxide signaling to increase production of the second message cGMP. This signaling pathway regulates regional blood flow and inflammation, among other processes. Impaired NO signaling has been implicated in neurodegenerative disease.
Other sGC modulators are used to treat heart failure due to pulmonary hypertension; CY6463 is the first CNS-accessible sGC stimulator to enter clinical trials.
In preclinical work, CY6463 was reported to raise cGMP levels in cerebrospinal fluid and to elicite changes in CNS function. In rats, it increased fMRI-BOLD signals and EEG gamma band power, and reversed an experimental learning deficit induced an NMDA receptor antagonist. It slowed the loss of dendritic spines in aging mice and in an APP/PS1 transgenic mouse model of AD, and increased synaptic long-term potentiation in hippocampal slices from mice carrying the huntingtin gene expansion known to cause Huntington's disease. The compound reportedly also demonstrated anti-inflammatory activity in obese mice. It lowered blood pressure in rats and mice, as expected for sGC stimulators (Correia et al., 2021).
A related modulator, CYR119, reduced CNS neuroinflammation in cell and animal models (Correia et al., 2021).
Findings
In 2019, Cyclerion ran a first Phase 1 study, evaluating safety, tolerability, and effects on food of single and multiple ascending oral doses in 110 healthy volunteers. According to a January 2020 press release, they drug was well-tolerated, suitable for once-daily dosing with or without food, and achieved CSF levels sufficient for pharmacological activity. No serious adverse events were noted. The drug caused a mild reduction in blood pressure, as expected due to its mechanism of action.
In January 2020, a second Phase 1 began to measure the effects of 15 days of drug or placebo on brain blood flow in 24 healthy elderly volunteers. This trial ended in May 2020 when the study site closed due to COVID-19. In October 2020, the company announced results (press release). All 24 subjects completed at least one arm in the crossover study; 12 completed both. The trial reproduced the pharmacokinetic, brain-penetration, and pharmacodynamic results of the prior Phase 1. No effects were seen on blood flow, but the drug did improve some quantitative EEG parameters, and reduced CSF neuroinflammatory biomarkers
In June 2021, Cyclerion began a Phase 2 study in people with Alzheimer’s disease and vascular pathology (see company website). The planned 40 participants are 60 years or older with confirmed AD pathology and mild to moderate dementia, cardiovascular risk factors (e.g., high blood pressure, diabetes, obesity), and MRI evidence of subcortical vascular disease. They were randomized to a three-month course of once-daily drug or placebo, against a primary outcome of adverse events. Other endpoints include imaging, quantitative EEG, CSF biomarkers of neuroinflammation, and cognitive performance (Glasser et al., 2021). The trial was slated for completion in July 2022.
In June 2022, the company announced positive top-line results for two different indications, an inherited mitochondrial disease called MELAS, and cognitive impairment associated with schizophrenia. The press release claimed improvement in biomarkers of mitochondrial function and inflammation, cerebral blood flow, and neural network connectivity after one month of open-label CY6463 in eight mitochondrial disease patients (press release). In the placebo-controlled schizophrenia trial, two weeks of 15 mg daily were said to improve cognitive performance and inflammatory biomarkers in 48 participants (press release). Higher doses of 30 and 60 mg CY6463 had no effect on cognition. For details of both studies, see company presentation.
In October 2022, Cyclerion announced a decision to focus development of CY6463 on mitochondrial disease, saying it had stopped enrollment in the AD study and expected data in the first half of 2023 (press release).
For details, see clinicaltrials.gov.
Last Updated: 02 Nov 2022
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP
Mutations: APP S679C
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease, MCI due to AD
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+.
Plaques
None observed through 24 months.
Tangles
None observed through 24 months.
Neuronal Loss
None observed through 24 months.
Gliosis
No transgene-related gliosis, but slight age-associated gliosis—also seen in wild-type mice—at 24 months.
Changes in LTP/LTD
LTP decays more rapidly, compared with wild-type mice.
Cognitive Impairment
Learning deficits in the Morris Water Maze.
Last Updated: 31 Jan 2025
Further Reading
No Available Further Reading
Overview
Name: KarXT
Synonyms: xanomeline-trospium, BMS-986510, CobenfyTM
Therapy Type: Combination, Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Bristol-Myers Squibb, Karuna Therapeutics
Approved for: Schizophrenia
Background
KarXT is xanomeline with trospium. Xanomeline is an M1/M4-preferring muscarinic acetylcholine receptor activator that acts throughout the body. Trospium chloride is an FDA-approved muscarinic receptor inhibitor that does not enter the central nervous system. Trospium serves to block xanomeline’s peripheral actions and reduce side effects.
The rationale for muscarinic receptor agonists to treat Alzheimer’s disease is broadly supported. The decline of cholinergic function in Alzheimer's disease contributes to cognitive symptoms. Widely used acetylcholinesterase inhibitors modestly improve function by boosting synaptic acetylcholine levels. An alternative strategy is to directly activate receptors with agonists like xanomeline.
In addition to cognitive benefits, M1 receptor activators may also modify disease progression. M1 agonists attenuate Aβ and tau pathology in animal models, and shift APP processing toward a non-amyloidogenic path (e.g., see Fisher et al., 2016; Caccamo et al., 2009). Development of these agents has been hampered by side effects related to activation of receptors outside the nervous system.
Xanomeline was originally developed by Lilly in the 1990s, to treat cognitive decline in people with AD. A full agonist, it attaches to the receptor at the acetylcholine binding site. In a Phase 3 trial, 150 mg/day modestly improved ADAS-Cog scores. Unexpectedly, the drug significantly reduced behavioral symptoms and psychosis, including hallucinations and delusions. However, development was halted because of dose-limiting gastrointestinal side effects of nausea, diarrhea, vomiting, and hypersalivation, all attributed to activation of peripheral muscarinic receptors (Bodick et al., 1997).
Trospium acts on all muscarinic receptor subtypes. It is prescribed for overactive bladder, and works by relaxing bladder muscles. Its side effects include dry mouth and constipation.
A similar strategy of combining a central activator and peripheral inhibitor to attenuate side effects is being pursued with the β-adrenergic receptor agonist clenbuterol, which is being trialed in combination with the peripherally restricted antagonist nadolol. For a review of therapeutic muscarinic receptor activation, see Paul et al., 2024.
Findings
In a Phase 1 study in healthy adults, trospium chloride co-administration reduced xanomeline’s peripheral cholinergic side effects of nausea, vomiting, diarrhea, and excessive sweating and saliva production (Breier et al., 2023).
Karuna developed KarXT as a primary or adjunctive therapy for psychosis and cognitive deficits in people with schizophrenia. In a Phase 2 trial, the drug significantly reduced symptoms, without severe side effects. Few people discontinued treatment due to side effects (Brannon et al., 2021; Correll et al., 2022). In two Phase 3 trials, five weeks of KarXT outperformed placebo at reducing symptom severity on the Positive and Negative Syndrome Scale in hospitalized patients. The scale includes positive symptoms like psychosis or delusions, negative symptoms such as apathy or withdrawal, and cognition. Most patients achieved the maximum dose of 125 mg xanomeline and 30 mg trospium, with a similar incidence of serious adverse events in treated and placebo groups. The most common side effects were mainly mild to moderate, and included constipation, dyspepsia, nausea, vomiting, headache, increases in blood pressure, dizziness, acid reflux, abdominal discomfort, and diarrhea. About one-quarter to one-third of patients discontinued treatment in both groups (Kaul et al., 2024; Kaul et al., 2024; Kaul et al., 2024). In these trials, 60 to 80 percent of participants were black; 20 to 40 percent were white. Post hoc analyses of trial data on individual symptoms suggested that KarXT reduced both positive and negative symptoms, and improved cognition in some patients (Horan et al., 2024; Sauder et al., 2022; Weiden et al., 2022).
Karuna currently has six Phase 3 trials ongoing. In August 2022, the company announced the first Phase 3 results. Five weeks of KarXT was better than placebo at reducing positive schizophrenia symptoms, including psychosis or delusions, negative symptoms like apathy or withdrawal, and cognition, in 252 hospitalized, symptomatic patients (press release). Eighty-one percent of patients achieved the maximum dose of 125 mg xanomeline and 30 mg trospium, with a similar incidence of serious adverse events in treated and placebo groups. The most common side effects were mainly mild to moderate, and included constipation, dyspepsia, nausea, vomiting, headache, increases in blood pressure, dizziness, acid reflux, abdominal discomfort, and diarrhea. About one-quarter of patients discontinued treatment in both groups. In this and in the Phase 2 trial, 75 percent of participants were black; about 20 percent were white.
In preparation for trials in Alzheimer’s disease, the company performed a Phase 1 dose-ranging study in healthy older people. Flexible dosing over two to three weeks showed that a lower dose ratio of trospium to xanomeline was better tolerated in elderly participants, as compared to the dose used in younger patients with schizophrenia. In this trial, most adverse events were mild. The combination did increase heart rate but not blood pressure or fainting. Most people titrated up to 150-200 mg xanomeline daily, spread over three doses (SEC filing).
In May 2022, Karuna announced a clinical program in Alzheimer's disease. Called ADEPT, the program comprised two Phase 3 registration trials and a long-term safety study. ADEPT-1 began in August 2022 to enroll 380 AD patients with a history of moderate to severe hallucinations or delusions, living at home or in an assisted living facility. In a withdrawal design, all patients would receive treatment for 12 weeks, then be randomized to drug or placebo for an additional 26 weeks. Doses start at 60 mg xanomeline/6 mg trospium daily and can go up to 200/20 mg, given in three divided doses. The primary outcome is time to relapse of psychosis symptoms after randomization; the secondary outcome is time to withdrawal from the trial for any reason. The trial is running in the U.S. and Europe, and is expected to finish in October 2026.
ADEPT-2 began in December 2023 to compare the acute efficacy of 12 weeks of drug to placebo on symptoms of hallucinations and delusions in 400 Alzheimer’s patients. Secondary outcomes include agitation and a clinical global impression of symptom severity. Dosing will be titrated to a maximum of 200 mg xanomeline/20 mg trospium daily. At more than 150 sites worldwide, this trial is planned to end in July 2025. A one-year, open-label safety extension for both ADEPT-1 and -2 began in 2023, to end in 2026.
In March 2024, Bristol Myers Squibb acquired Karuna (press release). On September 27, the FDA approved KarXT for the treatment of schizophrenia. It will be sold under the name CobenfyTM. A Phase 3 dose increase/food effect trial in 100 people with schizophrenia started recruiting the following month.
In September 2024, an additional Phase 3 trial began in Alzheimer’s. ADEPT-4 plans to enroll 406 AD patients with moderate to severe psychosis for a 12-week course of KAR-XT, against a primary outcome of change from baseline in the occurrence of hallucinations and delusions. Multiple secondary outcomes span other measures of neuropsychiatric symptoms, safety, and side effects. Completion is slated for late 2026.
For details on Kar-XT trials, see clinicaltrials.gov.
Last Updated: 25 Nov 2024
Further Reading
No Available Further Reading
Overview
Name: BIIB100
Synonyms: KPT-350
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Discontinued)
Company: Biogen
Background
BIIB100 is an inhibitor of Exportin 1 (XPO1), a protein that mediates export of many proteins and RNA from the cell nucleus. Abnormal movement of proteins and RNA molecules in and out of the nucleus plays a role in neurodegenerative and other diseases.
In preclinical work, this compound showed broad neuroprotective action in animal and cell models of multiple sclerosis, traumatic brain injury, and Huntington’s disease (Haines et al., 2015; Tajiri et al., 2016; Grima et al., 2017; Cantu et al., 2020). A related compound protected against motor neuron death in a C9ORF72-ALS model (Zhang et al., 2015). BIIB100 is orally available and crosses into the brain in animals.
Biogen purchased development rights to this compound from Karyopharm in 2018, and began development for ALS. Karyopharm has another XPO1 inhibitor approved for the treatment of blood cancers.
Findings
In May 2019, Biogen began a Phase 1 study to evaluate the safety and tolerability of single doses of BIIB100 in adults with ALS. The study enrolled 49 participants at 10 sites across the U.S., who received one of six single ascending doses or placebo, against a primary outcome of adverse events. The study, which also evaluated pharmacokinetics, was completed in June 2021.
In a June 2022 SEC filing, Karyopharm disclosed that Biogen had terminated the development agreement.
For details on the BIIB100 trial, see clinicaltrials.gov.
Last Updated: 28 Jul 2022
Further Reading
No Available Further Reading
Overview
Name: APNmAb005
Synonyms: RAA7
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Aprinoia Therapeutics
Background
This is a humanized monoclonal anti-tau IgG antibody that recognizes a conformational epitope in tau oligomers. It was generated by immunizing mice with oligomers encapsulated in artificial lipid vesicles, in an effort to elicit antibodies that would bind to, and clear, tau oligomers from synapses.
According to data in a bioRxiv preprint from Aprinoia scientists, the mouse version of the antibody binds more avidly to tau in synaptosome and insoluble fractions of human brain extracts than to monomeric, cytosolic tau. The antibody reacted with tau aggregates from early stage AD cases, but not with tangles and neuropil threads that form later in the disease (Tai et al., 2022). It recognized aggregates of both the 3R and 4R tau splice forms, including those in Pick’s disease, corticobasal degeneration, and progressive supranuclear palsy.
In preclinical work reported in the same manuscript, the antibody reacted with tau aggregates in rTg4510 mice expressing P301L tau. The antibody recognized tau in distal neurites in young mice, and later, in cell bodies. APNmAb005 blocked the transmission of pathogenic tau in cells treated with rTg4510 mouse brain extracts. Twelve weeks of antibody injection partially rescued synaptic and neuronal loss in the hippocampus without changing overall tau levels.
Findings
In May 2022, Aprinoia began a Phase 1, first-in-human study. It will enroll 40 healthy people in five dosing groups to receive single intravenous infusions of 5, 10, 25, 50 or 70 mg/kg, or placebo. Adverse events, vital signs, electrocardiograms, clinical lab measures, and study discontinuations will be tracked for 70 days after each dose, before proceeding to the next-highest dose. Other outcomes include pharmacokinetics and antidrug antibodies, as well as plasma and CSF Tau and phosphoTau-181, -217, and -231. Completion is expected in January 2023.
Aprinoia is also developing a PET tracer, now in Phase 2 trials in the U.S., and Phase 3 in China (company pipeline; Mar 2020 news; Feb 2020 news).
In January 2023, this private company merged with a special-purpose acquisition company to create a publicly traded corporation focused on neurodegenerative diseases (press release).
For details on this trial, see clinicaltrials.gov.
Last Updated: 07 Feb 2023
Further Reading
No Available Further Reading
Overview
Name: Lomecel-B
Synonyms: mesenchymal stem cells
Therapy Type: Other
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Longeveron
Background
Lomecel-B is a preparation of multipotent stem and progenitor cells isolated from donated bone marrow of young healthy adults, and expanded in culture. The cells are administered by intravenous infusion and are claimed to travel to sites of tissue damage to quell inflammation and stimulate repair. These allogeneic cells do not need to be immunologically matched to recipients, and have been shown safe in several conditions (e.g., see Thompson et al., 2020).
In preclinical work in Alzheimer's disease mouse models, systemically infused mesenchymal stem cells were reported with varying efficacy to cross the blood-brain barrier, inhibit Aβ deposition and tau phosphorylation, promote Aβ clearance, neurogenesis, and improve memory performance (e.g., Neves et al., 2021). In one study, the cells decreased inflammation and released chemoattractants that recruited microglia to clear Aβ (Lee et al., 2012).
Findings
In October 2016, Longeveron began a Phase 1 study funded by the Alzheimer’s Association. At three sites in Florida, 32 people with clinically diagnosed Alzheimer’s disease and PET evidence of brain amyloid were randomized 2:2:1 to receive a single infusion of 20 million or 100 million cells or placebo, and then followed up for one year. The primary outcome was safety; secondary endpoints included a battery of neurological, cognitive, and quality-of-life assessments, plus blood and CSF inflammatory and AD biomarkers. The study was completed in September 2021; results were published after peer review (Brody et al., 2022). No adverse effects were seen related to treatment. ARIA was not observed. One patient who withdrew from the study died 20 weeks after the infusion. The study was not powered to show efficacy; even so, the company reported improvements compared to placebo in biomarkers of inflammation and vascular function, a transient increase in hippocampal volume, and, in the low-dose group, some slowing of decline on cognitive and functional measures.
In December 2021, the company began a 48-person Phase 2a study. Participants have mild Alzheimer’s disease, with MMSE scores between 19 and 23, and positive amyloid PET scans. Four groups of 12 patients each received one or four infusions of 25 million cells, four infusions of 100 million cells, or placebo, over a span of 12 weeks. The primary outcome was safety, with monitoring for six months for adverse events, including MRI for ARIA and microhemorrhages. As a secondary outcome, the trial registry listed changes in the ADAS-Cog13 and MMSE. This trial occurred at two sites in Miami, and was completed in September 2023.
On October 5, 2023, the company announced top-line results (press release). The treatment met the safety endpoint; no ARIA or microhemorrhages were detected. According to the release, serious adverse events in three patients were judged to be unrelated to the drug. On secondary outcomes, the company claimed a statistically significant improvement among the lowest-dose group on the Composite Alzheimer Disease Score. The CADS is made up of the ADAS-cog-13, ADCS-ADL, CDR-SB, and left hippocampal volume. Data were not shown for other doses. According to a company presentation at the 2024 AAIC, the lowest (single-) dose group improved slightly on the CADS, while the placebo-treated patients declined. The difference, less than 0.5 points, was significant at the p<0.1 prespecified threshold. In the multidose groups, CADs was unchanged from baseline, and not different from placebo. The rate of hippocampal volume loss on MRI and inflammation per diffusion tension imaging were both reduced in treated groups, though not all changes were statistically significant.
Lomecel-B is also in clinical trials for congenital heart malformation, and aging-related frailty (pipeline; see also Yousefi et al., 2022). Outside of these trials, patients with frailty, mild cognitive impairment, Alzheimer’s, and related dementias, or osteoarthritis can receive Lomecel-B infusions at their own expense, as part of a treatment registry study in the Bahamas. Lomecel-B is not an approved treatment in the U.S.
For all trials of Lomecel-B, see clinicaltrials.gov.
Last Updated: 19 Aug 2024
Further Reading
No Available Further Reading
Overview
Name: TPN-101
Synonyms: OBP-601, BMS-986001, censavudine, festinavir, 4'-ethynyl stavudine, 4'-ethynyl-d4T
Chemical Name: 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine
Therapy Type: Small Molecule (timeline), DNA/RNA-based
Target Type: Inflammation (timeline)
Condition(s): ALS-FTD, Progressive Supranuclear Palsy
U.S. FDA Status: ALS-FTD (Phase 2), Progressive Supranuclear Palsy (Phase 2)
Company: Transposon Therapeutics
Background
This nucleoside analog reverse transcriptase inhibitor was originally developed for the treatment of human immunodeficiency virus infection. It is being repurposed based on recent work implicating the activation of retrotransposons in the pathology of amyotrophic lateral sclerosis, Alzheimer’s, and other neurodegenerative diseases. It is taken as a once-daily, oral capsule formulation. The company says TPN-101 enters the brain.
Retrotransposable elements are virus-derived pieces of DNA that make up a large part of the human genome. They are normally silenced by chromatin packing and other mechanisms. However, their tight regulation loosens with age, and there is evidence from fly and mouse models that reactivation of these elements by toxic tau species can drive neurodegeneration (Sun et al., 2018; Guo et al., 2018; Ramirez et al., 2022; Jan 2023 news).
In ALS and frontotemporal dementia, the loss of functional nuclear TDP-43 protein is thought to cause reactivation of long interspersed nuclear elements 1 (LINE1) and other retrotransposons, with expression of reverse transcriptase (e.g. Li et al., 2012; Liu et al., 2019). The subsequent processing and accumulation of RNA products triggers an antiviral immune response in cells, and neuroinflammation subsequently leads to cell death (e.g. Rodriguez et al., 2021; LaRocca et al., 2019). By inhibiting LINE1 reverse transcriptase, TPN-101 is expected to prevent this immune response and protect cells.
TPN-101 is a derivative of stavudine/3TC, an HIV treatment marketed from 1994 to 2020. The companies Oncolys BioPharma and Bristol Myers Squibb began to develop TPN-101 for HIV, but stopped in 2014 for business reasons (pipeline). In 2020, Transposon licensed the drug for neurodegeneration and other diseases.
No preclinical work is published on TPN-101, but stavudine was reported to suppress neurodegeneration, measured in part via lifespan and dendritic collapse, in fruit fly models of TDP-43 toxicity or frontotemporal dementia (Krug et al, 2017; Fort-Aznar et al., 2020).
Stavudine was reported to inhibit the NLRP3 inflammasome in blood cells from Alzheimer’s patients, and to stimulate Aβ autophagy by macrophages in vitro (La Rosa et al., 2022; La Rosa et al., 2019). An ongoing Phase 1/2 pilot study is testing stavudine’s CNS penetration and target engagement in 12 people with Alzheimer’s disease.
Findings
In HIV trials, single doses of 10-900 mg of TPN-101 were said to be well-tolerated in healthy adults (Urata et al., 2014). In a trial of 200 people with HIV, repeated dosing at 100, 200, 300, or 600 mg daily for 10 days produced mild adverse events that were nonspecific and deemed unrelated to the drug. No deaths or discontinuations were reported, and TPN-101 substantially reduced blood levels of HIV (Cotte et al., 2013).
In October 2021, a Phase 2a trial began recruiting 40 patients with C9ORF72 ALS or FTD. Participants are taking 100, 200 or 400 mg TPN-101 daily or placebo for six months, followed by six months of 400 mg open-label. The primary endpoints are safety and tolerability, with secondary measures comprising pharmacokinetics in plasma and CSF, changes in CSF and blood neurofilament light chain, and change in the ALS Functional Rating Scale-revised. The trial will also look for evidence of LINE1 transcription and biomarkers of inflammation. Running at 20 locations in the United States and Europe, the trial is fully enrolled with 42 patients, and was to run until September 2023. A detailed webinar about this trial, recorded on May 6, 2022, is publicly available on the website of NEALS, the Northeast Amyotrophic Lateral Sclerosis Consortium. Interim results from this study were announced on February 13, 2024 (press release). The company claimed effects on multiple biomarkers and on the clinical endpoint of vital capacity, after six months treatment. No data were shown.
Also in October 2021, a separate trial began in 40 people with the tauopathy progressive supranuclear palsy. This study tested 100, 200, or 400 mg/day against placebo for six months, and also offered a six-month open-label extension. Endpoints were as for the ALS/FTD trial, except that the clinical endpoint was score on the PSP rating scale. The study, at 14 sites in the U.S., concluded in December 2023. In November 2023, the company announced interim results (press release). TPN-101 at 400 mg caused an 18.4 percent reduction in CSF NfL, and a 51.6 percent reduction the inflammatory biomarker IL-6, compared to placebo. Final results were announced in a February 13, 2024, press release, and later presented in a poster at the March 2024 AD/PD conference. In the open-label extension, participants who switched from placebo to six months of 400 mg TPN-101 showed reductions in CSF NfL similar to the first treated group. After one year, NfL levels had returned to baseline, whereas IL-6 continued to decline. Worsening on the PSP rating scale slowed during the open-label period in patients who had received 400 mg continuously, but the result was not statistically significant in this small study. Of 42 patients who began the trial, 39 completed the first phase, 37 completed the open-label extension. Rates of adverse events were similar between treated and placebo groups. One serious adverse event of loss of consciousness occurred in the 100 mg TPN-101 group.
In March 2023, the company began a Phase 2 trial for children and adults with Aicardi-Goutières Syndrome, a rare inflammatory disorder that affects the brain and skin. AGS is caused by mutations in DNA repair genes. The accumulation of unrepaired DNA damage is thought to activate innate immune responses that cause inflammation and neurodegeneration. The study plans to enroll 16 patients to assess safety and changes in innate immune signaling.
For details on TPN-101 trials, see clinicaltrials.gov.
Last Updated: 08 Mar 2024
Further Reading
No Available Further Reading
Overview
Name: DNL593
Synonyms: PTV:PGRN, TAK-594
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Frontotemporal Dementia
U.S. FDA Status: Frontotemporal Dementia (Phase 1/2)
Company: Denali Therapeutics Inc., Takeda Pharmaceutical Company
Background
DNL593 is a replacement therapy for frontotemporal dementia caused by granulin gene mutations. In this type of FTD, a deficit of brain progranulin protein interferes with proper lysosomal function, leading to build-up of toxic proteins, neuroinflammation, and neurodegeneration (e.g., Sept 2017 news). To restore brain progranulin levels, DNL593 uses a "brain shuttle" technology, aka protein transfer vehicle (PTV), to move intravenously administered protein across the blood-brain barrier into the central nervous system. Protein transfer vehicles were developed to deliver BACE-1 antibodies into the brain, but can be used to transport other payloads, as well (e.g., Kariolis et al., 2020).
DNL593 consists of progranulin protein fused to an antibody fragment that binds to the transferrin receptor. Association with transferrin receptors on BBB endothelial cells facilitates the receptor-mediated transcytosis of progranulin protein into the brain.
In preclinical studies, DNL593 enhanced brain uptake of peripherally administered progranulin by three- to 10-fold over a progranulin fusion protein that did not bind transferrin receptor. The progranulin entered neurons and glia in the brain, and improved lysosomal function. DNL593 prevented neurodegeneration and microglial dysfunction in PGRN-deficient mice (Logan et al., 2021).
Findings
In February 2022, Denali and Takeda began a Phase 1/2 study of the safety, tolerability, and pharmacokinetics of single and multiple doses of DNL593. The placebo-controlled study plans to enroll 106 participants in two parts. The first phase will evaluate single doses in healthy adults. The second phase plans to test multiple ascending doses over six months in people with FTD. An optional 18-month, open-label extension will follow the second part. Primary outcomes are adverse events and safety signals related to laboratory values, vital signs, electrocardiogram, clinical findings, and suicidality. Secondary outcomes are pharmacokinetics in serum and CSF concentrations of DNL593. The trial is running at 14 sites in Europe, Turkey, and Brazil, until November 2025.
The company presented results of the single-dose study at the July 2023 AAIC in Amsterdam. DNL593 was well tolerated over a 30-fold dose range, with no serious adverse events. Mild to moderate side effects were similar to placebo. The drug showed predictable pharmacokinetics with low person-to-person variability. CSF PRGN concentrations increased with dose.
For details, see clinicaltrials.gov.
Last Updated: 23 Oct 2023
Further Reading
No Available Further Reading
Overview
Name: ABBV-552
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: AbbVie
Background
Formerly called SDI-118, ABBV-552 is an oral drug that modulates synaptic vesicle glycoprotein 2A (SV2A). It is being investigated for whether it is able to improve cognition in Alzheimer’s and other dementias, as well as in major depression and schizophrenia.
SV2A is the target of the anti-seizure medication levetiracetam, and plays an important if not fully understood role in neuronal excitability and neurotransmission. Discoveries about the contribution of hippocampal hyperexcitability and epileptic brain activity to cognitive decline spurred interest in repurposing epilepsy therapies to treat AD (e.g., Aug 2012 news; Vossel et al., 2016). Levetiracetam and a low-dose formulation, AGB101, are currently in Phase 2/3 trials for AD.
Discovered at UCB Biopharma in Belgium, SDI-118 belongs to a new class of SV2A binders. According to UCB, it lacks anti-convulsant and anti-seizure activity, but maintains efficacy as a cognitive enhancer in preclinical studies (Jun 2019 company report). In 2018, UCB spun out a new company, Syndesi Therapeutics, to further develop SDI-118 and other novel SV2A modulators.
Findings
In November 2019, Syndesi announced completion of a first-in-human study. Single doses of SDI-118 up to 80 mg were reported to be safe and well-tolerated in healthy men. Adverse events were mild, increased with dose, and were mainly dizziness, daytime sleepiness, and longer nighttime sleep. Pharmacokinetics supported once-daily dosing. SV2A target engagement in the brain exceeded 90 percent at higher doses, based on PET imaging (press release; Botermans et al., 2022). In January 2021, the company reported that the drug was well-tolerated after two weeks of dosing in young or elderly participants. A single dose of SDI-118 was claimed to cause changes in brain activity, as measured by quantitative electroencephalography, in healthy young volunteers (press release).
In September 2021, Syndesi began two additional Phase 1 trials that were listed in clinicaltrials.gov. The first was to enroll 60 elderly men and women with cognitive decline to receive SDI-118 capsules or placebo for 17 days. Endpoints were safety, adverse events, and several cognitive tests including Cogstate Brief Battery, and others. The study, in Germany and the United Kingdom, was also to include functional MRI. A second study with similar endpoints was to enroll 90 people in remission from depression who reported subjective cognitive impairment.
In March 2022, AbbVie acquired Syndesi and the rights to SDI-118 (press release). At that time, the first trial was terminated after enrolling five patients; the second trial was withdrawn before any participants were enrolled. The cause was listed as a change in development plans.
AbbVie began development of ABBV-552 in January 2023 with a Phase 1 safety study in 18 healthy Japanese and Chinese participants. Dosing is to be one capsule, or one capsule weekly for three weeks, against primary outcomes of adverse events and pharmacokinetics. The trial will finish in April 2023.
For details on SDI-118 and ABBV-552 trials, see clinicaltrials.gov.
Last Updated: 28 Feb 2023
Further Reading
No Available Further Reading
Overview
Name: SAGE-718
Synonyms: Dalzanemdor
Chemical Name: (3S,8R,9S,10R,13R,14S,17R)-3,13-Dimethyl-17-[(2R,5S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-2-yl]-2,4,7,8,9,10,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease, Huntington's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2), Parkinson's Disease (Discontinued), Huntington's Disease (Phase 2)
Company: Sage Therapeutics, Inc.
Background
SAGE-718 is a derivative of the endogenous steroid 24(S)-hydroxycholesterol. It is a positive allosteric modulator of the NMDA receptor, whose activity induces long-term potentiation of synapses, and thus is essential for learning and memory. SAGE-718 is being developed to treat cognitive dysfunction in people with neurodegenerative diseases.
The role of 24(S)-hydroxycholesterol in brain function, and in neurodegenerative diseases, is complex and controversial. It is the most abundant cholesterol metabolite in the brain. Some studies, but not all, suggest its levels decrease with aging and in AD. It has been reported to have both beneficial and detrimental effects on neuronal function, survival, and amyloid or tau pathology (reviewed by Gamba et al., 2021). Work from SAGE and other labs reported decreases in plasma 24(S)-hydroxycholesterol in patients with Huntington’s disease, which correlated with more severe cognitive symptoms (2019 ACNP poster M-147; see also Leoni et al., 2008). This metabolite is also reported to be decreased in people with PD (e.g. Di Natale et al., 2018; Huang et al., 2019), though that finding is not universal (e.g. Bjorkhem et al., 2018).
Company scientists published on NMDA receptor modulatory activity of 24(S)-hydroxycholesterol and several synthetic drug-like derivatives. The derivatives enhanced NMDA receptor-mediated LTP in hippocampal slices, and reversed behavioral and cognitive deficits in mice and rats treated with NMDA receptor channel blockers (Paul et al., 2013). The structure and synthesis of SAGE-718 was subsequently disclosed (Hill et al., 2022). It was shown to potentiate NMDA receptor activity, and rescue NMDA receptor hypofunction in preclinical models. SAGE-718 did not produce seizures or neurotoxicity in animals (Beckley et al., 2024).
Findings
In 2018 and 2019, Sage conducted Phase 1 studies in healthy volunteers to assess safety and pharmacodynamics. The latter was measured by SAGE-718's ability to reverse the synaptic effects of a low dose of the NMDA blocker ketamine using electrophysiology and MRI spectroscopy. According to results presented at the 2020 AD/PD conference, single doses of the drug normalized ketamine-induced changes in synaptic activity and neurotransmitter levels. In a multi-dosing study, endpoints included cognitive testing. In that study, 11 days of SAGE-718 improved performance on more difficult CogState tests of working memory and executive function, compared to placebo. On simpler tasks, treatment and placebo groups performed equally well. In another Phase 1 study of six people with Huntington’s disease, two weeks of SAGE-718 improved working memory (Apr 2020 news).
In September 2020, SAGE began Phase 2 in Parkinson’s patients with mild cognitive impairment. In an open-label study, 18 participants took 3 mg tablets once daily for two or four weeks. Primary outcomes were adverse events; other safety outcomes included vital signs, lab assessments, ECG, and suicidal ideation. The study finished in March 2022, and some results were presented at the AD/PD meeting that year. According to news sources, the patients treated for two weeks showed significant improvements in measures of executive function. The benefits were maintained for one month, with no serious side effects reported (news). This study used no placebo control.
In February 2021, another Phase 2 open-label study, called LUMINARY, began evaluating safety and efficacy of 3 mg daily of SAGE-718 in 26 people with MCI and mild dementia due to Alzheimer’s disease. The two-week trial also included a cognitive battery and functional assessments, and was completed in September 2021. According to data presented at the March 2022 American Academy of Neurology meeting, patients improved their executive performance and learning and memory after two weeks of treatment, compared to baseline. The company reported a 2.3-point improvement on the MoCA, and gains in daily function on the Clinical Global Impression of Change and Amsterdam Instrumental Activities of Daily Living Questionnaire. There was no placebo group for comparison. Eight mild or moderate treatment-emergent adverse events in seven patients were reported, but not identified. There were no serious adverse events or deaths (press release).
In September 2021, the FDA granted SAGE-718 fast track designation for Huntington’s disease (news).
In February 2022, the company began DIMENSION, a placebo-controlled Phase 2 trial in Huntington’s patients with mild to moderate cognitive impairment. The study is recruiting 178 participants to test a regimen of 1.2 mg daily for one month, followed by two months at 0.9 mg, against primary outcome of change from baseline in the Huntington's Disease Cognitive Assessment Battery (HD-CAB). The trial, at sites in the U.S., Canada, Australia, and the U.K., is expected to finish in December 2024. An open-label extension is planned.
In June 2022, the company began another Phase 2 study in early stage Huntington's patients, of whom 40 will take 1.2 mg SAGE-718 or placebo daily for four weeks, with a primary outcome of the HD-CAB composite. This trial also includes a comparison group of 40 healthy adults who will receive no treatment but will complete the cognitive assessments (May 2022 investor presentation).
Also in May 2022, a Phase 2 placebo-controlled study began for MCI due to Parkinson’s disease. It planned to enroll 76 people, to take 1.2 mg SAGE-718 per day in softgel capsules for six weeks. The primary outcome is change from baseline on the Wechsler Adult Intelligence Scale-IV Coding Test (WAIS-IV), which measures processing speed. The secondary outcomes relate to adverse events. The study finished in February 2024.
In December 2022, the company began a placebo-controlled Phase 2 trial for Alzheimer’s. It will enroll 150 people with mild cognitive impairment to mild dementia due to AD, for a course of six weeks of 1.2 mg SAGE-718 daily, then six weeks of 0.9 mg. The primary outcome is change from baseline in the WAIS-IV; secondary outcomes are adverse events and study withdrawals. The trial is running at 35 sites in the U.S and one in Puerto Rico until December 2024.
Also in December 2022, an open-label safety and tolerability trial began for patients with Huntington’s. It will include up to 300 patients, either rollovers from previous studies or new volunteers. Treatment will last for one year, and outcomes are adverse events, withdrawals, changes in vital and other safety signs, and suicidality. This trial will end in December 2025.
On April 17, 2024, Sage announced that the Phase 2 Parkinson’s trial had missed its primary endpoint, and that the company was stopping development of SAGE-718 for PD (press release). Results from the ongoing Phase 2 trials in AD and HD are expected in mid- to late 2024.
For details on SAGE-718 trials, see clinicaltrials.gov
Last Updated: 15 May 2024
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