Overview
Name: NIO752
Therapy Type: DNA/RNA-based
Target Type: Tau (timeline)
Condition(s): Progressive Supranuclear Palsy, Alzheimer's Disease
U.S. FDA Status: Progressive Supranuclear Palsy (Phase 1), Alzheimer's Disease (Phase 1)
Company: Novartis Pharmaceuticals Corporation
Background
NIO752 is an antisense oligonucleotide to tau, designed to reduce the levels of this protein by interfering with translation of tau mRNA. The antisense strategy assumes that decreasing the abundance of tau will slow the formation of tau aggregates and progression of tau pathology. NIO752 is in development to treat progressive supranuclear palsy, a primary tauopathy caused by accumulation of aggregates containing the 4-repeat tau isoform.
No preclinical work is published on NIO752, but tau antisense oligonucleotides (ASOs) have been shown to reduce toxin-induced seizures, neuronal loss, and neurofibrillary pathology in adult tau-transgenic mouse models. They also have been shown to normalize behavioral phenotypes and lengthen survival in such mice. Infusion of tau ASO into the CSF of cynomolgus monkeys was shown to reduce tau mRNA across different brain regions, and CSF tau levels following ASO exposure have been correlated to hippocampal tau levels (DeVos et al., 2013; DeVos et al., 2017).
Findings
In February 2021, Novartis began a Phase 1 study in 64 people with PSP. Patients in six sequential cohorts were to receive escalating doses of NIO752 or placebo, delivered by intrathecal injection four times over three months, with a nine-month follow-up. Safety assessments include adverse events as well as physical and neurological examinations, ECGs, vital signs, and standard clinical laboratory evaluations. Participants will be monitored for evidence of CSF infection. Run at multiple sites in North America, Germany, and the U.K., the trial finished in October 2024.
In February 2023, the company began a Phase 1b study to evaluate safety, pharmacokinetics and pharmacodynamics in 24 people with early Alzheimer’s. Participants must have positive CSF biomarker for amyloid and tau. After a single intrathecal dose of NIO752 or placebo, participants are being followed up for six months. Two dose cohorts are to be enrolled sequentially. The primary outcome is change in CSF total tau level after three months. Other assessments include pharmacokinetics (PKs), safety, and adverse event monitoring. Participants who finish the follow-up may enroll in an open-label extension and receive two additional NIO752 injections. The trial is fully enrolled with 25 participants, and scheduled to finish in October 2025.
In May 2024, a Phase 1 study was to begin measuring the effect of NIO752 on tau synthesis. Ten participants with sporadic for familial AD are to receive intrathecal NIO752 or placebo, and isotope-labeled leucine. Synthesis rates will be determined by the extent of isotope incorporation in serial CSF samples. As of November 2024, the study at University College London is listed as not yet recruiting; completion is intended in August 2025.
For details on NIO752 trials, see clinicaltrials.gov.
Last Updated: 26 Nov 2024
Further Reading
No Available Further Reading
Overview
Name: DNL788
Synonyms: SAR443820, oditrasertib
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Discontinued)
Company: Denali Therapeutics Inc., Sanofi
Background
This small molecule is a brain-penetrant inhibitor of RIPK1, i.e., receptor-interacting serine/threonine-protein kinase 1. It comes in tablet form, to be taken by mouth.
RIPK1 forms a signaling hub in the TNF receptor pathway, which regulates inflammation and cytokine release, necroptosis and apoptosis (Vandenabeele et al., 2010; Caccamo et al., 2017; Amin et al., 2018). In Alzheimer’s disease, RIPK1 mediates disease-associated microglial activation and pro-inflammatory cytokine release (Ofengeim et al., 2017). The kinase is located in the molecular pathogenic pathway of ALS/FTD caused by mutations in the endogenous RIPK1 suppressors optineurin and TBK1, and has been reported to regulate progranulin expression (Ito et al., 2016; Xu et al., 2018; Mason et al., 2017). RIPK1 has also been implicated in multiple sclerosis, and its inhibition in animal models decreases neuroinflammation and slows disease progression (Ofengeim et al., 2015; Zelic et al., 2021). These and other studies raised the profile of RIPK1 as a glial target to try to reduce neuroinflammation and cell death across several neurodegenerative diseases (Yuan et al., 2019).
In 2018, Denali partnered with Sanofi to develop RIPK inhibitors for the treatment of AD, ALS, and MS. DNL788 is a second-generation inhibitor, following DNL747, which Denali and Sanofi discontinued after Phase 1 because of concerns about long-term toxicity.
Findings
In 2021, Sanofi ran a Phase 1 trial that, according to the sponsors, showed robust target engagement at doses that met safety goals. Results were published after peer review (Hincelin-Mery et al., 2024). The drug showed good CNS penetration, reaching 0.8 to 1.3 times unbound plasma concentrations in CSF. RIPK1 inhibition in peripheral blood cells reached 90 percent after multiple dosing. The most common adverse events were dizziness and headache, with none leading to discontinuation of treatment.
The sponsors completed three additional Phase 1 trials between August 2021 and July 2022, testing safety and pharmacokinetics in healthy Chinese and Japanese adults, capsule versus tablet formulations, food effects, and drug interactions.
In October 2021, Denali announced that SAR443820/DNL788 had received U.S. FDA Fast-Track designation for ALS (company press release).
In May 2022, Sanofi began Phase 2 testing in people with ALS. In the HIMALAYA trial, 305 patients were randomized 2:1 to twice-daily SAR443820 or placebo for 24 weeks, followed by a long-term open-label extension out to two years. The primary outcome of the placebo-controlled phase is change from baseline in the ALSFRS-R total score. For the long-term extension, the primary outcome will be a combined assessment of function and survival. Secondaries include measures of muscle strength, breathing, and other functions, as well as changes in serum neurofilament light chain, safety, and pharmacokinetics. The trial is taking place at 63 sites in North America, Europe, China, and Japan. The placebo-controlled portion was planned to end in February 2024, with trial completion planned for January 2027. On February 14, 2024, Denali revealed in an SEC filing that HIMALAYA had failed to meet the primary endpoint of change in the ALSFRS-R. The companies terminated the study in March.
In December 2022, a Phase 2 began for relapsing-remitting multiple sclerosis. The study, in Europe, Canada, and China, enrolled 174 patients to twice-daily SAR443820 or placebo for 48 weeks, on a primary outcome of change in serum neurofilament light chain, with a long-term extension for an additional 48 weeks. On October 11, 2024, Denali reported that Sanofi had discontinued the study after it had not met its primary or key secondary endpoints (SEC filing).
For details on SAR443820/DNL788 trials, see clinicaltrials.gov.
Last Updated: 18 Oct 2024
Further Reading
No Available Further Reading
Overview
Name: ALX-001
Synonyms: BMS-984923
Chemical Name: (4R,5R)-5-(2-chlorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Allyx Therapeutics, Inc.
Background
ALX-001 is an allosteric modulator of the metabotropic glutamate receptor type 5 (mGluR5). Originally developed by Bristol Myers Squibb as a potential treatment for schizophrenia, the compound is now in testing for AD.
The rationale for this drug stems from mGluR5’s role as a co-receptor for Aβ oligomers, and a mediator of their synaptotoxcity (e.g., see Um et al., 2013; Hamilton et al., 2016).
In experiments performed in the Strittmatter lab at Yale University, this compound prevented Aβ oligomer-induced mGluR5 activation and synapse loss, without affecting physiological glutamate signaling. A one-month regimen improved synapse density and function, and memory behaviors in APP/PS1 mice with amyloidosis (Haas et al., 2017). The compound may work by inhibiting astrocyte-mediated synapse destruction. Pharmacokinetic studies in rodents and nonhuman primates reported nearly full occupancy of brain mGluR5 receptors after oral dosing, as judged by PET imaging with the mGluR5 ligand 18FFPEB. No toxicity resulted from doses up to 250 times higher than those needed to achieve binding to half of brain receptors. In mice, the brain concentration of drug reached twice that in blood (Spurrier et al., 2022).
In 2021, the Yale-founded biotech company Allyx Therapeutics licensed BMS-984923 from Bristol Myers Squibb, and is developing it for cognitive impairment due to neurodegeneration, under the name ALX-001 (press release).
Findings
From March 2021 to April 2022, a Phase 1, single-dose-escalation study, conducted at Yale, enrolled 36 cognitively normal older adults, who received 10, 40, 70, 100, 150, or 200 mg ALX-001, to assess safety and pharmacokinetics. Some participants also underwent 18FFPEB PET imaging to ascertain brain mGluR5 receptor occupancy. According to results presented at the October 2023 CTAD conference, doses up to 200 mg were safe. Mild adverse events were deemed related to drug, including brief oral sensations and transient dizziness or headache. Plasma levels increased linearly with dose, and were sufficient to achieve 80 percent brain mGluR5 occupancy. Full results are posted on clinicaltrials.gov.
From January to February 2023, an additional Phase 1 study tested food effects on safety and pharmacokinetics in 12 healthy older adults.
In March 2023, a Phase 1b multiple ascending dose study began. The first part plans to enroll healthy older adults for 10 days of twice-daily 50, 100, 150, or 225 mg capsules, or placebo. A second part will enroll Alzheimer’s disease patients for 28 days of 150 or 225 mg twice daily. The primary outcome is safety, with pharmacokinetics as a secondary. In the AD patients, other secondary outcomes include change from baseline in synaptic density on PET, and cognition on the ADAS-COG14. The study plans to enroll 50 participants, and finish in late 2024.
For details on ALX-001/BMS-984923 trials, see clinicaltrials.gov.
Last Updated: 22 Nov 2023
Further Reading
No Available Further Reading
Overview
Name: ABBV-916
Synonyms: N3pG-Abeta mAb
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Background
ABBV-916 is a monoclonal antibody to Aβ. It recognizes N-terminal truncated Aβ modified with pyroglutamate at position 3 (N3), a form that is aggregated in amyloid plaques. Its specificity is similar to Lilly’s donanemab and remternetug. The goal with these antibodies is to remove amyloid plaques quickly and completely.
No preclinical data on this antibody have been made public.
Findings
Clinical development began in August 2022, with a trial that was originally listed as Phase 1/2 with an enrollment target of 288, and was subsequently changed to Phase 2 with an enrollement target of 195. Participants must have early, biomarker-confirmed Alzheimer’s disease and be between 50 and 90 years old.
A first stage will assess multiple ascending doses, and a second will study two fixed doses, given monthly for six months, all with placebo control. The primary outcomes for the MAD portion of the study are safety, pharmacokinetics, and immunogenicity of the antibody. In the fixed-dose phase, primary outcomes will be safety and change in brain amyloid by PET scan. All participants will have the option of participating in a two-year, open-label extension. The study, at 88 centers in North America, Europe, and Japan, is anticipated to end in December 2024.
For details on ABBV-916 trials, see clinicaltrials.gov.
Last Updated: 09 Feb 2023
Further Reading
No Available Further Reading
Overview
Name: OLX-07010
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Oligomerix, Inc.
Background
OLX-07010 is a small-molecule inhibitor of tau self-association that is being tested for Alzheimer’s disease. The rationale for this approach is that blocking this initial step in tau aggregation will prevent the acute toxicity of oligomers (e.g., Fá et al., 2016; Tian et al., 2013), as well as the subsequent formation of fibrils and tangles, and propagation of pathology through the brain.
Much of the publicly available information on this compound comes from meeting presentations. A high-throughput screen for tau self-association, using full-length, non-mutated tau under what were characterized as physiologically relevant pH and protein concentrations, identified several classes of small-molecule leads. Hits were refined for activity in cell-based assays of tau aggregation, and brain penetration (e.g., see AAIC abstracts Moe et al. 2016, Moe et al., 2017).
A published report of preclinical work details the results of feeding OLX-07010 for four months at daily doses of 10, 40 or 100 mg/kg to human tau-expressing htau mice, starting before tau pathology appeared in brain. The middle dose produced the highest brain levels of compound, and reduced soluble tau oligomers, as well as insoluble and phosphorylated tau in brain, compared to untreated mice (Davidowitz et al., 2020). Positive effects on tau and motor behaviors in the JNPL3 tau mutant mice were reported at meetings (e.g. Moe et al., 2021 AAIC). Results of multiple dosing toxicology studies in rats and dogs indicated oral bioavailability greater than 50 percent, and liver effects in both species at higher doses (Moe et al., 2022 AAIC).
Findings
In January 2023, Oligomerix began a first-in-human, Phase 1 study to evaluate safety, tolerability, and pharmacokinetics of OLX-07010 in 88 healthy adults. Volunteers age 18 to 50 will receive single and multiple doses of 25 and 75 mg capsules; an older cohort between 51 and 75 will receive single doses. Funded by the National Institute on Aging, the trial is set for completion in December 2023.
For details on OLX-07010 trials, see clinicaltrials.gov.
Last Updated: 06 Feb 2023
Further Reading
No Available Further Reading
Overview
Name: UB-312
Therapy Type: Immunotherapy (active) (timeline)
Target Type: alpha-synuclein
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2)
Company: United Neuroscience, Vaxxinity
Background
UB-312 is an active vaccine to stimulate an immune response against α-synuclein. A 10-amino-acid fragment from the protein’s C-terminus is fused to a small peptide that activates T-helper cells, and combined with adjuvant for intramuscular injection. Vaxxinity is developing UB-312 for the α-synucleinopathies Parkinson’s disease and multiple system atrophy (MSA).
Antibodies to α-synuclein have been shown to prevent pathogenic α-synuclein spread and promote clearance of aggregates in animal models (Bae et al., 2012; Masliah et al., 2011). In guinea pigs, a 12-amino-acid predecessor of UB-312 elicited antibodies against toxic α-synuclein fibrils and oligomers, but not monomers. These antibodies bound synuclein inclusions in the substantia nigra and basal ganglia in postmortem brain tissue from people with PD, dementia with Lewy bodies, or MSA (Nimmo et al., 2020). In Line 61 transgenic mice that express human α-synuclein, UB-312 vaccination resulted in fewer α-synuclein oligomers in the cortex, hippocampus, and striatum three months later. Vaccinated mice did better at motor tests of walking on a beam and hanging from a wire. The vaccine also cleared α-synuclein from gut tissues (Nimmo et al., 2022).
Findings
In 2019, Phase 1 began with a dose-escalation study in 50 healthy people allocated to receive injections of 40 to 2,000 μg UB-312 or placebo at weeks 1, 5, and 13, in eight different dose groups. The vaccine caused a dose-dependent rise in blood and CSF α-synuclein antibodies, with three 300 μg doses generating a response in all volunteers. Higher dose cohorts were stopped after one participant developed severe flu-like symptoms. Doses up to 300 μg caused only minor side effects, including mild headache, cold-like complaints, fatigue, and pain or redness at the injection site. In CSF, the antibody concentration reached 0.2 percent of blood, on par with that reported for therapeutic monoclonal antibodies (Apr 2022 conference news; Yu et al., 2022).
The trial also enrolled 20 people ages 40 to 85 with early to mid-stage sporadic PD, who received three doses of 300 μg, or a 300/100/100 μg regimen of UB-312 or placebo on a 13-week schedule. Endpoints are safety, tolerability, and immunogenicity. Target engagement was measured by changes in total and free α-synuclein in the blood and CSF. An exploratory biomarker endpoint used protein misfolding cyclic amplification to measure pathogenic synuclein in the CSF before and after vaccination. In November 2022, the company reported that all patients had completed the injection series, and claimed the vaccine was well-tolerated, immunogenic, and generating detectable antibodies in CSF (press release). According to results presented at the March 2024 AD/PD conference, 12 of 13 vaccinated patients developed α-synuclein antibodies. The 300/100/100 μg regimen gave the highest titers in blood, and at that dose four of six patients had detectable antibodies in CSF. The elicited antibodies preferentially bound aggregated α-synuclein over monomeric species. After vaccination, seeded aggregation was reduced in CSF from vaccinated patients who had detectable CSF antibodies. These same patients had improvement in motor symptom scores on the MDS-Unified Parkinson’s Disease Rating Scale part II. Results were published after peer review (Eijsvogel et al., 2024).
In May 2023, investigators at New York University began a Phase 1b trial, whereby four patients with MSA and four with PD are receiving three priming and five booster injections of 300 μg UB-312 over two years. Outcomes are serum and CSF levels of anti-α-synuclein antibodies approximately six months after the last boost. The study is expected to run until April 2025.
For details on UB-312 trials, see clinicaltrials.gov.
Last Updated: 10 Jul 2024
Further Reading
No Available Further Reading
Overview
Name: AV-1959D
Synonyms: AV-1959
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Background
AV-1959D is an NIH-funded DNA vaccine designed to elicit antibodies to Aβ peptides without activating potentially harmful autoreactive T cells. This vaccine fuses coding sequences of three copies of Aβ1-11 to 12 T-cell-activating epitopes. They include a synthetic pan-T cell antigen, antigens derived from Tetanus toxin, and from the hepatitis B and influenza viruses. The foreign antigens function to boost antibody responses by activating memory and helper T cells. This is important in old people in who tend to mount weaker responses to vaccines.
AV-1959D grew out of a years-long optimization process that began with identification of Aβ1-11 as the dominant B-cell epitope in Aβ peptides, followed by preclinical testing of peptide and DNA vaccines combining this epitope with increasing numbers of T-cell epitopes.
Early versions of the vaccine were reported to prevent or reverse plaque accumulation in mouse amyloidosis models, without triggering T cell infiltration in the brain (Movsesyan et al., 2008; Petrushina et al., 2007). In mice, rabbits, and nonhuman primates, electroporation of AV-1959D or similar constructs induced strong Aβ antibody responses (Davtyan et al., 2014; Davtyan et al., 2014; Ghochikyan et al., 2013). AV-1959LR is an mRNA version of the vaccine encapsulated in lipid-based nanoparticles; it generated high-titer Aβ antibodies in mice and nonhuman primates (Hovakimyan et al., 2024).
In preclinical safety studies in mice, the vaccine persisted at the injection site for up to two months, but did not travel to distant tissues. No toxicities or ARIA-like reactions were observed in mice with cerebral amyloid angiopathy Tg-Sw-DI mice. The vaccine induced no T- or B-cell infiltration or glial activation in brain, and did not worsen CAA or cause neurodegeneration (Petrushina et al., 2020).
The same platform, called MultiTEP, was used to produce recombinant protein or DNA vaccines to tau and α-synuclein, and α-synuclein, pyroglutamate-modified Aβ, and a dual Aβ/tau vaccine ( (Hovakimyan et al., 2022; Kim et al., 2022; Zagorski et al., 2023; Davtyan et al., 2019). The tau vaccine AV-1980R/A will begin Phase 1 trials in 2024.
Findings
In December 2022, the Institute for Molecular Medicine in Huntington Beach, California, registered a Phase 1 first-in-human study of AV-1959D, with a start date of February 2023. The single-ascending-dose study is to enroll 48 people with mild cognitive impairment due to Alzheimer’s disease. Three sequential cohorts will receive three needle-free injections into the skin of 500, 1,000, or 2,000 μg vaccine. A fourth cohort will get placebo. The primary outcome is adverse events. Secondary outcomes include other clinical and lab tests for safety, incidence of ARIA-E or -H, and levels of serum Aβ antibodies and autoreactive T helper cells. Funded by the National Institute on Aging, the study is recruiting at six sites in the U.S. through February 2026.
According to data presented at the October 2024 CTAD conference, the first two dose cohorts have been completed with only mild adverse events and no withdrawals. Results are expected in early 2025.
For details on this trial, see clinicaltrials.gov.
Last Updated: 21 Nov 2024
Further Reading
No Available Further Reading
Overview
Name: BMS-986446
Synonyms: PRX005
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Bristol-Myers Squibb, Prothena
Background
PRX005 is Prothena’s anti-tau IgG1 humanized antibody. It recognizes an epitope in the R1, R2, and R3 repeats in the microtubule binding region MTBR. This part of tau's middle section drives tau aggregation, and antibodies to it prevent the spread of misfolded protein in preclinical models (e.g., see Apr 2018 news). The rationale underlying PRX005 is that mid-region antibodies will block the spread of tau pathology more effectively than do N- or C-terminal antibodies, which thus far have been unsuccessful at slowing disease progression in clinical trials. The PRX005 epitope is present in both 3R and 4R tau splice isoforms.
No preclinical work is published on this antibody. According to a conference presentation, PRX005 was chosen from a panel of tau antibodies screened for their ability to block internalization of tau aggregates in cell culture. The antibody binds phosphorylated or unphosphorylated tau, and recognized neurofibrillary tangles and dystrophic neurites in AD brain tissue. It inhibited tau binding to its heparan sulfate proteoglycan target on the cell surface, and protected rat cortical neurons from tau toxicity. In the PS19 mouse tauopathy model, animals treated with PRX005 treatment starting at 6 months old had less phospho-tau accumulation in the brainstem four months later than untreated mice, and improved grip strength. In a mouse model of amyloidosis, weekly antibody injections prevented accumulation of tau aggregates (Mar 2021 conference news and company slides).
Prothena was developing PRX005 in collaboration with Bristol Myers Squibb. In July 2023, Prothena announced that BMS would take over the program, under the drug name BMS-986446 (press release).
Findings
On January 31, 2023, Prothena announced top-line results from a Phase 1, single-ascending-dose study. It tested intravenous infusions at three dose levels against placebo in 19 healthy volunteers. The company reported dose-proportional plasma concentrations and CNS penetration to 0.2 percent of plasma levels. All doses were claimed to be safe and well-tolerated, with no serious adverse events or clinically relevant changes in safety assessments. According to Prothena, a Phase 1 multiple-ascending-dose study is ongoing in healthy volunteers and patients with AD, with results expected by the end of 2023 (press release). This trial was not found in registries.
In October 2023, Bristol Myers Squibb began a Phase 1 trial testing single intravenous doses in 24 healthy volunteers, including some with Japanese ethnicity. The study assessed safety, tolerability, pharmacokinetics, and immunogenicity. It finished in March 2024.
In March 2024, a Phase 2 study began enrolling 475 participants with early Alzheimer’s disease for a 72-week course of treatment with one of two doses of BMS-986446 or placebo. Entry criteria include a Clinical Dementia Rating of 0.5 or 1, episodic memory impairment, and evidence of amyloid pathology. The primary outcome is change from baseline in the CDR-SB. Secondary outcomes include brain tau deposition as per PET, the iADRS, ADASCog14, and ADCS-iADL measures of cognition and function, plus the MMSE. The trial, at 199 sites in North America, Australia, and countries in Asia and Europe, is expected to be complete in 2027.
For details on BMS-986446 trials, see clinicaltrials.gov.
Last Updated: 03 Jun 2024
Further Reading
No Available Further Reading
Overview
Name: DNL919
Synonyms: TAK-920, ATV:TREM2
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Denali Therapeutics Inc., Takeda Pharmaceutical Company
Background
This TREM2 agonist antibody activates microglia to phagocytose amyloid. DNL919 contains a transferrin-receptor binding sequence engineered into its Fc domain. Thus, the antibody binds to the abundant transferrin receptors on endothelial cells of the blood-brain barrier, which facilitate its active transport into the brain.
Although Denali initially provided proof of concept for its antibody transfer vehicle (ATV) technology using BACE-1 antibodies, the company focused development on the TREM2 antibody and other payloads (e.g., Kariolis et al., 2020; Ullman et al., 2020; DNL593). Takeda is partnering on the development of DNL919.
In preclinical work, the mouse version of this antibody was shown to promote TREM2 receptor signaling, increase microglia survival and Aβ phagocytosis, and enhance plaque clearance in a mouse model of amyloidosis (Schlepckow et al., 2020). DNL919 boosted brain microglial activity and glucose metabolism in the 5XFAD mouse model of Alzheimer’s. In mice, the antibody achieved sixfold higher brain entry, and was more efficient at activating TREM2, than a non-ATV version (van Lengerich et al., 2023; Zhao and Bu, 2023).
Findings
In January 2022, the FDA placed a clinical hold on Denali’s investigational new drug application for DNL919 in the U.S., pending clarification of questions regarding the preclinical toxicology, clinical trial protocol, informed consent form, and investigator brochure (press release, SEC disclosure).
In July 2022, Denali began a Phase 1 study in the Netherlands, to assess safety, tolerability, pharmacokinetics, and target engagement after single ascending doses of DNL919 in 80 healthy participants.
On August 8, 2023, Denali announced that the company and Takeda had stopped development of DNL919 (press release). According to the release, DNL919 altered multiple microglial biomarkers, such as CSF1R, SPP1, IL1RA, IP10, MIP1b, MCP-1, indicating target engagement. It caused no serious adverse events, but did trigger moderate, reversible hematological changes at the highest dose tested. A news report cited Denali executives who said the antibody caused anemia.
For details on this trial, see clinicaltrials.gov.
Last Updated: 16 Oct 2023
Further Reading
No Available Further Reading
Overview
Name: Trappsol® Cyclo™
Synonyms: HP-beta-CD, HPbetaCD
Chemical Name: 2-hydroxypropyl-beta-cyclodextrin
Therapy Type: Other
Target Type: Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Cyclo Therapeutics, Inc.
Background
Trappsol® Cyclo™ is a proprietary, intravenous formulation of 2-hydroxypropyl-β-cyclodextrin in development to treat diseases associated with impaired cholesterol metabolism, including Alzheimer's disease. This cyclic oligosaccharide sequesters cholesterol, solubilizing it and extracting it from cells.
Produced from starch by enzymatic conversion, cyclodextrins are widely used in food, cosmetics, and for drug delivery, where they confer solubility and stability, and improve bioavailability. When taken by mouth, HP-β-CD is generally considered safe, but animal studies revealed a potential for damage to hearing and kidney function, especially when the drug is given by infusion or injection (e.g. Cronin et al., 2015; Scantlebery et al., 2019).
Trappsol® Cyclo™ is being evaluated in a Phase 3 trial to treat Niemann-Pick disease type C, a rare genetic disorder that leads to cholesterol accumulation in lysosomes, neurodegeneration, and death in childhood or adolescence. NPC shares features with Alzheimer's disease, including tau tangles, amyloid deposition, and cognitive decline (Malnar et al., 2014). In animal models of NPC, HP-β-CD removed sequestered cholesterol from lysosomes of multiple organs including the brain, delayed symptom onset, and prolonged life (e.g. Davidson et al., 2009; Liu et al., 2010).
In preclinical work related to AD, HP-β-CD injections improved spatial learning and memory deficits, and lessened amyloid plaque deposition and tau-containing dystrophic neurites in the Tg19959 mouse amyloidosis model. The drug reduced APP cleavage and upregulated genes associated with cholesterol transport and Aβ clearance (Yao et al., 2012). In other models with impaired autophagy-mediated clearance of Aβ, HP-β-CD normalized lysosomal function (Yang et al., 2017; Barbero-Camps et al., 2018). HP-β-CD itself sequestered Aβ in vitro, inhibiting peptide aggregation and toxicity (Ren et al., 2016).
In other preclinical work, HP-β-CD removed cholesterol from blood vessel plaques and promoted their regression in a mouse model of atherosclerosis (Zimmer et al., 2016).
Findings
Development of Trappsol® Cyclo™ in Niemann-Pick disease began with a compassionate use program in 12 children that supported its safety and potential benefit of intravenous treatment (Hastings et al., 2019). Cyclo Therapeutics subsequently conducted open-label Phase 1 and Phase 2 studies of up to 48 weeks treatment in children and adults. In these trials, the drug had mainly mild to moderate side effects, most notably hearing impairment and infusion reactions. In a 14-week Phase 1 study in 13 adults, two withdrew because of changes in hearing. The drug was detected in CSF, and changes in CSF tau and serum 14S-hydroxycholesterol were consistent with target engagement in the central nervous system (Hastings et al., 2022). A 48-week Phase 1/2 in 12 children yielded similar results, as well as stabilization or improvement in symptoms in the eight who completed the study (Jun 2021 company presentation).
In July 2021, the company began a Phase 3 trial enrolling 93 children and adults age 3 and older to receive 2,000 mg/kg or placebo, every two weeks for two years, against an endpoint of change from baseline in symptom severity at one and two years. This trial is being conducted at 13 sites in the U.S., Australia, Germany, Poland, Spain, Israel, and Turkey, through December 2023. It includes a two-year open-label extension to run through the end of 2025. The study also provides open-label treatment of 12 infants or toddlers younger than 3 years old in a preventive paradigm.
Investigations for Alzheimer's disease began with an 18-month compassionate use trial in one patient with late-onset AD, who started on a 500 mg/kg monthly infusion. According to a company report, the drug was safe, and the patient’s disease did not progress. Improvements in agitation and word finding were reported (Jun 2020 press release).
In September 2022, a Phase 2 study began to test the drug in early Alzheimer’s disease. The study is enrolling 90 people, at five sites in the U.S., to receive six monthly infusions of 500 mg/kg, 1,000 mg/kg or placebo. The primary outcome is safety; secondaries include changes in standard cognitive and functional measures. The study will run through March 2024.
For details on Trappsol® Cyclo™ trials, see clinicaltrials.gov.
Last Updated: 19 Jan 2023
Further Reading
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