Overview
Name: AKST4290
Synonyms: ALK4290, lazucirnon
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2)
Company: Alkahest, Inc.
Background
AKST4290 is an antagonist of the G protein-coupled C-C chemokine receptor type 3 (CCR3). Blocking CCR3 is expected to have broad anti-inflammatory and immune-modulating effects. Alkahest acquired this molecule from Boehringer-Ingelheim; it is taken by mouth.
CCR3 inhibition is of interest for age-related and neurodegenerative diseases because it is the receptor for eotaxin, aka CCL11, a chemokine implicated in cognitive decline. Blood eotaxin levels increase with age, and it was identified as a critical component of old plasma that reduces hippocampal neurogenesis and promotes cognitive decline when given to young mice (Villeda et al., 2011). This chemokine freely enters the brain, and it has been shown to activate microglia (Parajuli et al., 2015). Plasma eotaxin is elevated in people with neurodegenerative diseases, and multiple studies have associated higher plasma concentrations with worse cognitive function in the elderly and in people with AD (e.g., Yang et al., 2021; Elkind et al., 2021; Bettcher et al., 2016).
Elevated plasma and brain eotaxin also have been documented in traumatic brain injury and psychiatric diseases (Hiskins et al., 2021; Cherry et al., 2017; Teixeira et al., 2018).
Genetic studies implicate eotaxin in Alzheimer’s disease. Variants in CCL11 can delay the onset of familial AD by up to a decade, presumably by lowering eotaxin protein levels (Lalli et al., 2015; Guerreiro and Bras, 2015; Andrews et al., 2019).
In aged mice, an anti-CL11 antibody was reported to benefit spatial memory; in a Parkinson's model, a different anti-CL11 antibody, administered peripherally, reduced T cell infiltration into the substantia nigra and suppressed glial cell activation there (Scabia et al., 2021; Chandra et al., 2016).
Some preclinical data on AKST4290 was presented at conferences. The drug reportedly reversed eotaxin-induced memory deficits in healthy mice. In a model of Parkinson’s disease, six weeks of treatment was claimed to improve grip strength and balance, and reduce gliosis in the striatum. AKST4290 was reported to prevent microglial activation and cognitive decline in mice given chronic low-dose lipopolysaccharide to mimic chronic inflammation (Dec 2018 news).
Findings
From January 2020 to April 2021, Alkahest ran a Phase 2 trial in 110 people with Parkinson’s disease. Participants received 400 mg AKST4290 or placebo pills twice daily for 12 weeks. The primary outcome was change in motor function, measured by the MDS-UPRDS Part 3 motor examination while patients were between levodopa doses. Secondary measures included safety plus cognitive, functional, and motor symptom assessments while on levodopa. The trial, at 22 study locations in US and Europe, was supported in part by the Michael J Fox Foundation. No results have been made public.
Other Phase 2 trials are ongoing for age-related macular degeneration, diabetic retinopathy, and the autoimmune skin condition bullous pemphigoid.
For details on AKST4290 trials, see clinicaltrials.gov.
Last Updated: 06 Oct 2021
Further Reading
No Available Further Reading
Overview
Name: TB006
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: TrueBinding, Inc.
Background
This humanized monoclonal antibody targets galactose-specific lectin (galectin) 3, a β-galactosidase-binding protein involved in macrophage activation and antimicrobial immune responses. The rationale for targeting galectin 3 to treat Alzheimer’s disease comes from studies implicating it as a regulator of microglia activation in response to amyloid. Brain galectin 3 expression is increased in people with AD, specifically in microglia associated with amyloid plaques (Boza-Serrano et al., 2019). The same study associated variants in LGALS3, the gene encoding galectin-3, with an increased risk of AD.
In mouse studies, LGLAS3 is among the genes most upregulated in amyloid-plaque-associated microglia, and is part of a disease-associated expression signature in those cells (Kraseman et al., 2017; Keren-Shaul et al., 2017; Butovsky and Weiner, 2018).
Galectin-3 itself activates microglia by binding to TLR-4 receptors (Burguillos et al., 2015). Galectin-3 also induces TREM2 signaling, and knocking it out in a mouse model of AD improved cognition and reduced amyloid plaque burden (Boza-Serrano et al., 2019). In the APP/PS1 mouse amyloidosis model, galectin-3 promoted Aβ aggregation and toxicity (Tao et al., 2019).
Several small human studies have associated elevated galectin-3 in blood or CSF with cognitive impairment or with Alzheimer's disease (Wang et al., 2013; Ashraf and Baeesa, 2018; Venkatraman et al., 2018; Yazar et al., 2020; Boza-Serrano et al., 2022).
For review, see Tan et al., 2021.
Findings
IIn June 2021, TrueBinding began a Phase 1, single-dose escalation study of the safety and pharmacokinetics of TB006 in healthy adults. The trial enrolled 48 participants in five dose cohorts ranging from 70 to 5,000 mg, and one cohort of people of Chinese descent. The drug is given by intravenous infusion. The study ran through November 2022. The company has reported that up to 5,000 mg single doses were safe and well-tolerated. Side effects were generally mild and not dose-dependent, with no adverse safety findings on clinical labs, vital signs or electrocardiograms.
A planned trial in COVID-19 was withdrawn in June 2021 due to recruitment difficulties.
In October 2021, a Phase 1/2 study began to evaluate the safety and efficacy of TB006 in 140 people with a clinical diagnosis of mild to severe Alzheimer’s disease. Amyloid positivity was not required; about 30 percent of participants had plaques. Part 1 of the study consisted of five once-weekly infusions of 140, 420, or 1,000 mg TB006, or placebo, against primary outcomes of safety, tolerability, pharmacokinetics, and immunogenicity. In Part 2, participants received five weekly infusions of 1,000 mg drug, or placebo, with a primary outcome of change in CDR-Sum of Boxes after three months. Secondary outcomes for Part 2 include cognitive and neuropsychiatric measures, safety, and pharmacokinetics. In May 2022, the trial finished recruiting at 15 sites in the U.S. As presented at the December 2022 CTAD conference, the study narrowly missed statistical significance on its primary outcome. Antibody treatment was reported to have produced 63 percent less worsening on the CDR-SB at three months compared to placebo. MMSE was significantly increased after one month, but not three months. TB006 significantly reduced plasma Aβ42, but did not change the Aβ42/40 ratio, p-Tau181, or NfL. The company claimed a reduction in amyloid plaques after 30 days, detected by PET scan. There were no serious adverse events judged to be treatment related, and no amyloid-related imaging abnormalities reported. More than 100 participants continued to receive 4,000 mg monthly in a two-year open-label extension.
TB006 is also being evaluated for acute ischemic stroke.
For details on TB006 trials, see clinicaltrials.gov.
Last Updated: 16 Dec 2022
Further Reading
No Available Further Reading
Overview
Name: AL101
Synonyms: GSK-4527226
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Alector, GlaxoSmithKline (GSK)
Background
AL101 is a monoclonal antibody to sortilin (SORT1), a trans-Golgi sorting receptor abundantly expressed in the nervous system. This IgG1 antibody is being developed to treat Alzheimer’s disease. Alector is evaluating a different sortilin antibody, AL001, in a Phase 3 trial for frontotemporal dementia (FTD). According to information on Alector’s website, the two antibodies bind different parts of the sortilin protein (see slide 13 in Dec 2023 presentation). AL101 is claimed to have a longer half-life than AL001.
Both AL001 and AL101 have orphan drug designation from the U.S. FDA for the treatment of FTD.
Sortilin is important for neurotrophin signaling, lysosomal degradation, and APP metabolism. It negatively regulates levels of the lysosomal protein progranulin. Genetic mutations that reduce levels of the progranulin protein and induce lysosome dysfunction are a leading cause of frontotemporal dementia and amyotrophic lateral sclerosis. In animal models, loss of progranulin leads to inflammation and neurodegeneration (e.g., Yin et al., 2010). A progranulin polymorphism is associated with risk for AD and PD (Chen et al., 2015).
Both AL001 and AL101 are intended to increase progranulin levels by blocking sortilin, and thus improve lysosome function.
Findings
In December 2019, Alector began a Phase 1 first-in-human safety and tolerability study of AL101 in 88 healthy participants. The placebo-controlled study tested single and multiple ascending doses of intravenously or subcutaneously administered antibody, against a primary outcome of adverse events. Pharmacokinetics and bioavailability were also determined. The trial finished in June 2022.
Results of the single-dose part of the study were presented at the November 2021 CTAD conference (poster). The study enrolled 55 healthy adults averaging 40 years old, for single intravenous doses of 6, 15, 30, or 60 mg/kg or placebo, or a subcutaneous dose of 600 mg. The antibody was well tolerated, with mostly mild to moderate adverse events, the most frequent being headache, anemia, and procedural pain. One severe infusion reaction occurred in the 60 mg/kg IV dose group. Blood and CSF antibody levels were reported to be dose-proportional. Brain concentrations reached 0.1-0.7 percent of serum concentration. Blood levels of progranulin were elevated after all doses, and higher doses also resulted in increased CSF progranulin levels. The subcutaneous dose resulted in an approximately 50 percent increase in CSF progranulin that lasted for about one month. Multiple dose data were presented at the November 2022 CTAD conference, showing that biweekly 300 mg subcutaneous or monthly 30 mg/kg intravenous doses elicited mild to moderate adverse events. IV dosing resulted in sustained, 160 to 200 percent elevation of progranulin in plasma compared to placebo, and an 80 percent increase in CSF (press release). Subcutaneous dosing resulted in insufficient drug levels or progranulin elevation, requiring optimization.
In July 2021, Alector announced an agreement with GlaxoSmithKline to co-develop AL001 and AL101 (press release).
In October 2023, a Phase 2 study began to compare the safety and efficacy of two different doses of AL101 to placebo in 282 people with early Alzheimer’s disease. Participants who are amyloid-positive with mild cognitive impairment or mild dementia are to receive intravenous antibody infusions for 18 months. The primary outcome is change from baseline in the CDR-SB after 12, 15, or 18 months. Secondary outcomes span other standard measures of cognition or function including the iADRS, ADS-COG14, ADCS-ADL-MCI, and ADCOMS. The study is running worldwide through December 2026.
For details on AL101 trials, see clinicaltrials.gov.
Last Updated: 10 Jul 2024
Further Reading
No Available Further Reading
Overview
Name: ASN51
Synonyms: ASN121151
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Asceneuron SA
Background
ASN51 is a small-molecule inhibitor of O-GlycNAcase (OGA), the glycoside hydrolase enzyme that removes O-linked N-acetylglucosamine (N-GlcNAc) from proteins. Asceneuron is developing ASN51 as a potential treatment for Alzheimer’s and Parkinson’s diseases. It is a second-generation version of its lead OGH inhibitor, ASN120290, which is intended to treat the rare tauopathy progressive supranuclear palsy. ASN51 is taken in capsule form.
The rationale for targeting OGA originated in the observation that addition of N-GlcNAc to tau reduces its propensity to form toxic aggregates (Gong et al., 2005; Liu et al., 2004). OGA inhibitors promote glycosylation, prevent aggregation, and appear to stabilize tau in a soluble, nonpathogenic form. O-GlcNAc modification was reported to reduce the aggregation and toxicity of the α-synuclein protein as well (Marotta et al., 2015; Levine et al., 2019). This modification appears to promote formation of an α-synuclein fibril strain that does not propagate and is not neurotoxic in vivo (Balana et al., 2024).Thus, OGA inhibitors could potentially slow or prevent the progression of neurodegeneration due to these proteins.
No preclinical work is published on ASN51. However, Asceneuron has published data on ASN90, their first-generation OGA inhibitor in development for the primary tauopathy progressive supranuclear palsy. In the P301S mouse model of tauopathy, daily oral dosing enhanced brain tau glycosylation, prevented the development of tau tangles, improved motor behavior and breathing, and increased survival (Permanne et al., 2022). In this study, tau glycosylation in peripheral blood cells mirrored modification in the CNS, and thus was suggested as a potential pharmacodynamic marker of OGA inhibition for clinical trials. Also in this work, ASN90 was shown to enhance α-synuclein glycosylation, and slow the progression of motor impairment in a transgenic model of Parkinson’s disease.
A different OGA inhibitor, thiamet G, has also been reported to increase glycosylated tau, reduce tau neurofibrillary tangle numbers, and decrease neuronal cell loss in three different mouse strains expressing P301L mutant human tau (Yuzwa et al., 2012; Graham et al., 2014; Hastings et al., 2017). One lab found that thiamet G treatment resulted in better motor skills, higher body weight, and longer lifespan (Borghgraef et al., 2013). Thiamet G or OGA knockdown was also shown to reduce the uptake of synuclein fibrils by cells (Tavassoly et al., 2020). Fibril uptake is a proposed mechanism for the spread of α-synuclein pathology in the brain.
Findings
In June 2021, Asceneuron began a Phase 1 first-in-human trial in Melbourne, Australia, investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of ASN51. The placebo-controlled study planned to test single and multiple doses of oral capsules in 64 healthy adults, followed by a 10-day evaluation in 12 people with AD. This study was terminated in August 2022 after completion of the single-dosing portion, and one multiple-dose cohort. The stated reasons were site delays and the impact of COVID.
The company presented results from healthy adults at the December 2022 CTAD conference. Single doses of 20 and 50 mg in young adults and multiple 20 mg doses in eight older adults were safe, with no serious or severe adverse events. The most common side effects were headache and musculoskeletal ache. One person had moderate, transient dizziness. ASN51 produced predictable, dose-proportional plasma PK with a half-life of 40-50 hours, that was unaffected by food or age. CSF concentrations were in the active range, and highly correlated with plasma levels, suggesting the drug freely diffused into the CNS. A pharmacodynamic assay found tau glycosylation to increase in peripheral blood cells after a single 20 or 50 mg dose.
A PET study with an OGA ligand revealed significant target occupancy for up to two days after a single dose of 5 mg or higher. Based on PET results, the investigators estimated that a 10 mg dose would sustain greater than 95 percent brain OGA occupancy for 24 hours.
From February to June of 2023, the company conducted a pharmacokinetic and pharmacodynamic study after repeated dosing in 12 healthy men. According to a presentation at the October 2023 CTAD, 14 days treatment with 10 or 20 mg daily produced no serious adverse events or safety signs, and no study withdrawals. Plasma levels were dose-proportional, reached steady-state by one week, and were maintained for up to a week after dosing stopped. PET revealed greater than 90 percent brain OGA occupancy within hours after the first dose, and three days after the last dose. Two weeks of drug elevated tau glycosylation in peripheral blood cells. Food did not affect this pharmacodynamic marker.
The company is planning a Phase 2 study, to start in 2024.
In February 2025, a study began to assess drug-drug interactions with inhibitors of three cytochrome p450 isotypes. The study will test, in 48 healthy adults, the effect of simultaneous dosing with fluvoxamine, itraconazole, or paroxetine on the pharmacokinetics of ASN51. It will finish in May 2024.
For details on ASN51 trials, see clinicaltrials.gov.
Last Updated: 07 Mar 2024
Further Reading
No Available Further Reading
Overview
Name: Dasatinib + Quercetin
Therapy Type: Combination, Small Molecule (timeline), Supplement, Dietary (timeline)
Target Type: Tau (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1/2)
Background
Dasatinib is a cancer drug, sold under the name Sprycel® to treat certain types of leukemia in adults and children. Its side effects include low blood cell counts, anemia, rash, and diarrhea. It may also cause serious side effects such as bleeding, pulmonary edema, heart failure, and prolonged QT syndrome. The therapeutic dose is 100 mg daily. Quercetin is a naturally occurring flavonoid with antioxidant and anti-inflammatory activity. It is sold as a nutritional supplement, purportedly to treat cancer and other diseases, but with no peer-reviewed evidence to back such claims. Doses up to 1 gram daily appear safe.
This drug combination targets and eliminates senescent cells that are linked to multiple age-related chronic diseases. Senescent cells have undergone irreversible cell-cycle arrest in response to damage or stress, but resist apoptotic cell death; they can persist for years. Some produce pro-inflammatory mediators, and studies implicate them in diabetes, osteoporosis, pulmonary fibrosis, and general age-related frailty, as well as in Alzheimer’s and Parkinson's disease brain, and in other conditions (reviewed in Kirkland and Tchkonia, 2020). Dasatinib induces apoptosis in senescent cells by inhibiting the Src tyrosine kinase, while quercetin does so by inhibiting the anti-apoptotic protein Bcl-xL.
The rationale for so-called “senolytic therapy” for AD arises from studies implicating senescent glia, neurons, and endothelial cells in neurodegeneration due to tau or amyloid pathology (Sep 2018 news; Bryant et al., 2020; Gonzales et al., 2021). In one preclinical study, treating rTg4510 human-mutant-tau-expressing mice with D+Q every two weeks for six months resulted in less tau tangle pathology, preservation of neurons and synapses, and better cerebral blood flow compared to untreated mice (Musi et al., 2018). In the APPPS1 mouse model of AD, senescent oligodendrocytes were found surrounding amyloid plaques. D+Q eliminated the senescent cells, reduced amyloid load and inflammation, and improved memory behaviors (see Apr 2019 news on Zhang et al., 2019). The same study identified senescent oligodendrocytes in human postmortem AD brain tissue. In contrast, D+Q did not reduce senescent cell markers in brain, nor did it improve cognitive behaviors in P301S tau-expressing mice (Riordan et al., 2023). D+Q treatment of healthy young female mice reportedly diminished metabolism and cognition; it had no effect on young males (Fang et al., 2023). Quercetin has been reported to also have anti-amyloid and fibril-disaggregating activity (Jiménez-Aliaga et al., 2011).
D+Q is administered in an intermittent-dosing regimen, based on the idea that the combination quickly eliminates senescent cells, and it takes several weeks for the body's tissues to generate new ones. In people with diabetic kidney disease, three days treatment with D+Q reduced senescent cell numbers and inflammation in adipose tissue biopsies taken 11 days later (Hickson et al., 2019; Hickson et al., 2020).
Findings
In February 2020, a Phase 1/2 study at the at University of Texas Health Center in San Antonio began evaluating if D+Q given orally enters the brain (Gonzales et al., 2022). Five people with a clinical diagnosis of AD and using cholinesterase inhibitors received D+Q for six cycles of two days on/14 days off, for CSF levels of both drugs to be determined. According to results presented at December 2022 CTAD conference, dasatinib, but not quercetin, was detected in CSF 60 to 90 minutes after the last dose. The regimen appeared safe and tolerable. No significant changes in biomarkers of Aβ, tau, or senescence, or in cognition occurred over the 12 weeks of treatment. Study results are posted at clinicaltrials.gov, and were published after peer review (Gonzales et al., 2023).
In December 2021, the Phase 2 SToMP-AD study at Wake Forest University began enrolling 48 participants with MCI or early AD and a positive tau-PET scan or CSF tau (Dec 2021 conference news). Participants receive 100 mg D and 1,000 mg Q, or matching placebo, for two consecutive days out of every 15 days, in six cycles lasting 12 weeks. The primary outcome is serious adverse events over 48 weeks, while secondary outcomes are changes in a panel of blood senescence markers over 12 weeks. The study will also measure CDR-SB, ADAS-Cog 14, and tau PET over 48 weeks. It is expected to run until January 2027.
In May 2022, a second open-label pilot study began in Boston to test cyclic administration of 100 mg D and 1,250 mg Q in 12 older adults with mild cognitive impairment and slow walking speed. The study will assess changes in cerebral blood flow during a cognitive test, change in executive functioning, and gait speed after six cycles of treatment. Other outcomes include measures of physical performance, mobility, grip strength, and biomarkers of cell senescence. The trial is anticipated to finish in June 2024.
In July 2022, the Mayo Clinic started ALSENLITE, a third Phase 1/2 open-label pilot. It will enroll 20 people who have a clinical diagnosis of MCI or AD and a positive tau-PET scan. Their treatment will be the same D+Q regimen as in the Wake Forest study, but with no placebo control. The sole listed outcome is safety and tolerability. Primary completion is slated for December 2023.
D+Q is also being tested in biological aging, for frailty in adult survivors of childhood cancer, premature aging after stem cell transplant or due to psychiatric disease, chronic kidney disease, fatty liver disease, obesity and metabolic disorders, and bone health in elderly women. A pilot trial has been completed for idiopathic pulmonary fibrosis; the drug combination was reportedly well-tolerated (Justice et al., 2019).
For details on D+Q trials, see clinicaltrials.gov.
Last Updated: 21 Sep 2023
Further Reading
No Available Further Reading
Overview
Name: Verdiperstat
Synonyms: AZD3241, BHV-3241
Chemical Name: 1-(2-Isopropoxyethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Motor Neuron Disease, Multiple System Atrophy, Primary Progressive Aphasia
U.S. FDA Status: Motor Neuron Disease (Discontinued), Multiple System Atrophy (Discontinued), Primary Progressive Aphasia (Phase 1)
Company: AstraZeneca, Biohaven Pharmaceuticals
Background
Verdiperstat is an irreversible inhibitor of myeloperoxidase. This enzyme catalyzes the generation of reactive oxygen species by activated microglia and other immune cells. The hypothesized mechanism of action of verdiperstat includes reduction of oxidative stress and neuroinflammation, and countering cell death due to pathological microglia activation. Taken in tablet form, verdiperstat has been shown to enter the brain (Johnström et al., 2015).
Verdiperstat was tested in a mouse model of multiple system atrophy (MSA), a rare and rapidly progressing α-synucleinopathy. In the model, induction of oxidative stress with 3-nitroproprionic acid (3-NP) in animals overexpressing α-synuclein in oligodendrocytes leads to microglia activation, synuclein inclusions, neuron loss, and movement deficits. Treating mice with verdiperstat before and during 3-NP exposure reduced microglial activation, α-synuclein aggregation, and neurodegeneration, and improved motor function (Stefanova et al., 2012). Delaying treatment until mice had developed full-blown pathology still reduced microglial activation and α-synuclein aggregation, but did not improve neuron loss or motor impairments (Kaindlstorfer et al., 2015).
Findings
Between 2008 and 2013, AstraZeneca completed multiple Phase 1 studies of AZD3241/verdiperstat, and a Phase 2 safety and tolerability study in people with Parkinson’s disease (PD). In these trials, verdiperstat was reported to dose-proportionally reduce MPO activity in plasma (Tong et al., 2018).
In 2012, the company used PET imaging to assess the effects of verdiperstat on microglia activation in the brains of 24 people with Parkinson’s disease. The study used 11-CPBR28 tracer, a tracer that binds to the transporter protein (TSPO) in activated glia. Results are published, showing that eight weeks of treatment with 600 mg twice daily verdiperstat led to a reduction in the PET TSPO signal (Jucaite et al., 2015). No serious adverse events were reported in this small trial; the most common side effects in the treated group were headache, nausea, and insomnia.
In 2015-2016, a Phase 2 trial tested a 12-week course of verdiperstat or placebo against a primary outcome of change in microglial activation in the striata in people with MSA. The 59 participants took 300 or 600 mg twice daily or placebo, and underwent the 11CPBR28 PET. Secondary outcomes included myeloperoxidase inhibition in plasma, and exploratory efficacy outcomes including change in the Unified MSA Rating Scale (UMSARS). Results are posted at clinicaltrials.gov. No significant changes from baseline, or between groups, were detected.
In 2018, Biohaven licensed verdiperstat from AstraZeneca. At that time, the company disclosed some results on the exploratory efficacy outcomes of the Phase 2 MSA trial (press release). Among 52 people who completed the trial, Biohaven reported a dose-related trend for slowing disease worsening with verdiperstat, which was not statistically significant. The placebo group registered a 4.6-point decrease on the 104-point scale. The 300 mg group declined by 3.7 points; the 600 mg group lost 2.6 points. The drug significantly decreased MPO activity in plasma, the company claimed.
In July 2019, Biohaven began enrolling 336 people with MSA for a 48-week, Phase 3 trial. The study compared 600 mg twice daily to placebo on primary endpoints of a subset of measures from UMSARS, and safety and tolerability. Secondary endpoints included Clinical Global Impression of Improvement, quality of life, and total UMSARS. The trial was to run through September 2022, but on September 27, 2021, Biohaven announced that the trial had been completed at full enrollment, and that it had failed on its primary outcome and on key secondary efficacy measures (press release). Biohaven stopped an expanded access program, and discontinued development for MSA.
In July 2020, a Phase 2/3 trial began testing verdiperstat in ALS. This study is part of the Healey ALS platform trial, a multicenter clinical collaboration testing four different interventions in parallel against a common placebo group. As with all interventions in the Healey trial, verdiperstat was selected by an independent review board, based on evidence for the role of oxidative damage and microglia activation in ALS, including an observed elevation of TSPO-PET signals in ALS patients (Zürcher et al., 2015; Ratai et al., 2018). One hundred and sixty ALS patients were to receive 600 mg verdiperstat twice daily for 24 weeks. The primary outcome was disease progression on the ALS Functional Rating scale, with secondary outcomes spanning breathing function, muscle strength, and survival. The trial ended in April 2022, with a final enrollment of 167. On September 29, 2022, the company announced that verdiperstat had failed to show any difference from placebo on the primary or key secondary measures of disease progression (press release). Verdiperstat has been removed from the company pipeline.
In December 2020, Biohaven began a small study assessing the newer TSPO PET ligand 18FPBR06, before and after verdiperstat treatment (Fujimura et al., 2010). This study enrolled 19 people with MSA who will have a scan at baseline and after six months of verdiperstat. Eight of the patients had previous scans during a six- to nine-month observational phase to establish the trajectory of changes in 18FPBR06 signal, followed by six months of verdiperstat and a final scan. The study was completed in January 2022.
In March 2022, a Phase 1 began recruiting 64 people with semantic variant primary progressive aphasia (svPPA) due to frontal temporal lobal degeneration with TDP-43 pathology. Called Veri-T, this trial will randomize patients 3:1 to 600 mg verdiperstat daily or placebo for 24 weeks. The primary outcome is adverse events. Secondary outcomes include CSF and plasma pharmacokinetics, and exploratory biomarkers of CSF neurofilament light chain, and imaging, as well measures of dementia, cognitive function, and neuropsychiatric symptoms. Participants cannot have evidence of amyloid or tau pathology, or a clinical diagnosis of Alzheimer’s disease or an FTLD-associated clinical syndrome other than svPPA. The single-site study, at the University of California, San Francisco, will finish in June 2026.
Verdiperstat has fast-track and orphan-drug designations by the U.S. FDA and the European Medicine Agency for MSA.
For details on verdiperstat trials, see clinicaltrials.gov.
Last Updated: 03 Nov 2022
Further Reading
No Available Further Reading
Overview
Name: Levodopa
Synonyms: L-Dopa, Sinemet, Duodopa, Duopa, Inbrija, Parcopa, Prolopa, Rytary, Stalevo, Foslevodopa
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Approved)
Company: AbbVie, Acorda Therapeutics, Inc., Amneal Pharmaceuticals, Inc.
Background
This dopamine replacement therapy is the mainstay of treatment for motor symptoms of Parkinson’s disease. Levodopa eases tremors, stiffness, and slowness of movement caused by loss of dopaminergic neurons. A prodrug, levodopa crosses the blood-brain barrier, where dopamine decarboxylase converts it to dopamine. Levodopa is formulated with carbidopa, a decarboxylase inhibitor that prevents the conversion to dopamine in peripheral tissues. This helps prevent the nausea and vomiting produced by levodopa alone, and enables delivery of higher doses to the brain.
Besides nausea, other common side effects are low blood pressure, confusion, and involuntary movements known as dyskinesias. Levodopa can also cause sudden onset of sleep, hallucinations, and increased risk-taking behavior.
Over time, many patients on levodopa experience the intermittent return of symptoms. These periods are known as motor fluctuations or OFF periods, when the medication stops working between doses. This may be due to the progressive loss of dopamine neurons, or impaired absorption of drug as the disease advances. As patients require increasing doses, dyskinesias also increase, associated with peak drug concentrations.
Levodopa does not improve non-motor symptoms of PD, or slow disease progression.
Findings
In 1975, the U.S. FDA approved the levodopa/carbidopa LD/CD pill, sold under the name Sinemet. Formulations include disintegrating tablets, and immediate or extended-release tablets, and are available as generics. Dosing is three or four times daily.
In 2015, the FDA approved two new LD/CD formulations, both aimed at smoothing out fluctuations in plasma concentration to lengthen the time of drug action and shorten OFF time (Jan 2015 news). Rytary (Amneal Pharmaceuticals) is an extended-release capsule, containing both immediate and slow-release levodopa. In a Phase 3 trial, it halved OFF time compared to oral LD/CD, with fewer doses needed per day (Hauser et al., 2013). An LD/CD intestinal gel (Duopa, Abbvie), delivered by continuous infusion into the small intestine via a feeding tube and portable pump, likewise reduced daily OFF time by almost two hours compared with immediate-release oral tablets (Olanow et al., 2014). Duopa requires surgical implantation of a feeding tube, and is used for advanced PD patients with severe motor fluctuations. Rytary was approved in Europe in 2015; Duopa has been available there since 2004.
In 2018, the FDA approved an inhaled powder formulation of levodopa as a rescue treatment for OFF episodes occurring between oral levodopa doses. Inbrija (previously known as CVT-301, Acorda Therapeutics), delivers LD/CD to the blood stream in minutes, compared to up to an hour for the pill form (Safirstein et al., 2020). In a Phase 3 trial, an 84 mg inhaled dose outperformed placebo at improving motor symptoms 30 minutes after dosing during an OFF period in patients using oral LD/CD. The most common side effect was cough (LeWitt et al., 2019).
AbbVie is developing a new LD/CD formulation for continuous subcutaneous infusion. ABBV-951 contains foslevodopa and foscarbidopa, which are modified with phosphate groups to render them more water-soluble. A portable infusion pump delivers this combination under the skin of the abdomen. The goal is to smooth out the peaks and valleys of oral dosing, thus minimizing OFF time. In Phase 1 trials in healthy volunteers, the infusion produced consistent and stable plasma levels of levodopa (Rosebraugh et al., 2021; Rosebraugh et al., 2023). Delivery of drug was comparable to that of Duopa intestinal gel (Rosebraugh et al., 2022).
Between May 2017 and June 2019, AbbVie conducted two Phase 1 studies in people with PD. The first study assessed safety of single 24- or 72-hour infusions in 29 people in the lab. The second evaluated four weeks of continuous infusion at home in 20 people. In the single infusion trial, blood levodopa concentrations quickly reached steady state and remained stable over 72 hours (Rosebraugh et al., 2021). Results of the second study were presented at the October 2020 Movement Disorders Society conference. According to news reports, the continuous infusion improved symptoms during waking hours, most noticeably early in the morning. Infused patients had significantly less OFF time compared to a pre-infusion observation period (Aug 2021 Medscape news).
Phase 3 began in April 2019. An open-label study in 240 PD patients assessed safety and tolerability of continuous infusion for one year via a portable external pump. The primary outcomes are 48 clinical measures of safety; secondary outcomes include daily ON and OFF times, PD symptoms, and quality of life. The study was completed in August 2022; no results have been made public. A 96-week safety extension is planned to run until 2025.
In October 2020, AbbVie began a 12-week Phase 3 study comparing ABBV-951 continuous infusion to oral LD/CD in 130 advanced PD patients. Half the participants received ABBV-951 plus placebo pills; the other half had a placebo infusion and active pills. The primary outcome is change in ON time without troublesome dyskinesias, based on patient diary reports. Secondary outcomes measure other symptoms and quality of life. In October 2021, AbbVie announced positive topline results (press release), and complete trial data were later published (Soileau et al., 2022). Patients taking ABBV-951 had significant increases in ON time without troublesome dyskinesia, and reductions in OFF time, compared to oral levodopa. The main side effects were non-serious infusion site complications. This trial has a 96-week open label extension, running until August 2023.
From January 2022 to March 2023, AbbVie ran an additional Phase 1 pharmacokinetic analysis in 16 patients to assess bioavailability from different infusion sites on the arm, thigh, flank, or abdomen.
In May 2022, AbbVie submitted a new drug application to the FDA (press release). The agency rejected it in March 2023, requesting more information about the pump device used to administer ABBV-951 (press release). The agency did not request additional trials.
For details on ABBV-951 trials, see clinicaltrials.gov.
Last Updated: 10 May 2023
Further Reading
No Available Further Reading
Overview
Name: Safinamide
Synonyms: Xadago, Onstryv
Chemical Name: N2-{4-[(3-fluorobenzyl)oxy]benzyl}-L-alaninamide
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Multiple System Atrophy, Parkinson's Disease
U.S. FDA Status: Multiple System Atrophy (Phase 2), Parkinson's Disease (Approved)
Company: Newron, Zambon Company S.p.A.
Background
Safinamide is a reversible monoamine oxidase B inhibitor, taken as a pill by mouth. MAO-B degrades the neurotransmitter dopamine, and safinamide raises dopamine levels in synapses. It serves as an add-on treatment to shorten periods of lost motor control in people with mid- to late-stage Parkinson's disease who are taking levodopa. Safinamide was approved in Europe in 2015, and in the U.S. in 2017.
As an MAO-B inhibitor, safinamide acts in the same way as selegiline and rasagiline. However, it also modulates sodium and calcium channels and reduces glutamate release. Glutamate is thought to contribute to the involuntary, uncontrolled movements called dyskinesia that develop over time in patients on levodopa; safinamide is also being investigated for its potential to reduce dyskinesias.
The therapeutic dose for Parkinson's is 50 or 100 mg daily. In clinical trials, safinamide’s most common side effects were reported to be dyskinesia, falls, nausea, and insomnia.
Findings
Between 2007 and 2012, two pivotal Phase 3 trials evaluated the efficacy of safinamide to reduce periods of fluctuating motor control in PD patients on a stable levodopa regimen. In the six-month SETTLE study of 549 patients, safinamide increased daily ON time of motor control without dyskinesias (Schapira et al., 2017). In a two-year study of more than 544 people, safinamide extended ON time by 0.5 to 0.9 hours per day. It improved scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), and on quality-of-life measures, depressive symptoms, and activities of daily living. Safinamide did not change scores on the Dyskinesia Rating Scale in the group as a whole after two years, but improvement was seen in patients who were at least moderately dyskinetic at the start of the study (Borgohain et al., 2014). In both trials, patients tolerated safinamide well and few dropped out.
Other trials during the same time period examined safinamide effects on levodopa-induced dyskinesia or on cognitive impairment in people with PD. A large trial of 679 people with early PD tested safinamide as an add-on to a dopamine agonist. No results have been published.
From 2017 to 2020, a Phase 4 observational study evaluated motor and non-motor symptoms in 164 people with PD who were newly prescribed safinamide. Raw results are available on ClinicalTrials.gov.
An open-label study, from May 2019 to February 2020, suggested that safinamide improved non-motor symptoms including pain, mood, and sleep (Garcia et al., 2021; see also Huang et al., 2021). A placebo-controlled trial tested safinamide for pain relief in 71 people with PD; the trial ended in 2021 and results have not been disclosed. Another study is looking at the effect of open-label safinamide on sleep quality in 23 people with PD.
In August 2019, Zambon began a study in China, testing safinamide as an add-on to levodopa in 307 PD patients. The primary outcome is total OFF time when patients lose motor control. Study completion is slated for August 2021.
Beginning in September 2019, Zambon tested safinamide in multiple-system atrophy, a rare neurodegenerative disease that shares with Parkinson’s the pathological hallmark of α-synuclein deposition. Forty-nine people with MSA received 200 mg safinamide or placebo daily for 12 weeks. The primary endpoint was safety, and secondary outcomes spanned clinical, quality of life, cognition, and movement measures. The trial finished in January 2021.
Zambon registered a study to start in October 2019 to assess a 26-week course of 100 or 150 mg of safinamide on a primary outcome of levodopa-induced dyskinesia in 300 patients. The trial was withdrawn before starting, for the given reason that the drug development plan had been updated. In March 2021, Newron announced to investors that the companies would jointly run a study in patients with PD and levodopa-induced dyskinesia, expected to start in 2021 (see company report).
In December 2019, Newron began an observational study comparing safinamide to rasagiline or other standard-of-care medications in 1,235 PD patients. The primary outcome is function and well-being, as measured by the PDQ-39 self-report questionnaire. Other endpoints assess motor function, pain, other medication use, healthcare resource use, days lost from work, and safety. The study will run through April 2024.
For details on safinamide trials, see clinicaltrials.gov.
Last Updated: 02 Aug 2021
Further Reading
No Available Further Reading
Overview
Name: Bemdaneprocel
Synonyms: BRT-DA01, MSK-DA01
Therapy Type: Other
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1)
Company: Bayer, BlueRock Therapeutics
Background
This cell-based therapy consists of a neuron graft for the treatment of Parkinson’s disease. The grafting cells are derived from human embryonic pluripotent stem cells, and converted in the lab to dopamine-producing neuron progenitors. They are surgically implanted into the putamen.
The protocol for differentiating stem cells to MSK-DA01 originated at Memorial Sloan Kettering Cancer Center (Kim et al., 2021). The same group generated large quantities of clinical-grade, frozen cells for preclinical and toxicology testing. In immunodeficient rats lesioned with 6-hydroxydopamine to mimic Parkinson’s disease, the cells rescued motor deficits. Postmortem examination of treated rats found large, well-differentiated human dopamine neurons in the striatum. Toxicology studies in immunocompetent mice noted no obvious adverse effects. None of the injected cells were detected outside the brain, and no overgrowth or tumor formation was observed (Piao et al., 2021).
Similar efforts to develop stem cell-derived dopaminergic grafts are ongoing in Kyoto, Japan (see Takahashi, 2020) and Lund University in Sweden. A Phase 1 trial began in Japan in 2018, and expanded to the University of California, San Diego, in June 2024, in collaboration with Sumitomo Pharma (press release; clinicaltrials.gov). Lund researchers are collaborating with Novo Nordisk to conduct a safety trial in Sweden and the United Kingdom that begin in November 2022 (clinicaltrials.gov).
Findings
In May 2021, BlueRock Therapeutics, a subsidiary of Bayer, began a Phase 1 safety study. Twelve people who have had Parkinson’s disease for five to 15 years, and still respond to levodopa, had a one-time surgical implantation of cells in their putamen bilaterally. Five people received 0.9 million cells per putamen, and seven got 2.7 million. All took immunosuppressants for one year. Primary outcomes were serious adverse events and signs of abnormal overgrowth of transplanted cells during the first year. Secondary outcomes include evidence of cell survival by 18F-dopamine PET scan, PD symptoms, and safety after two years. The trial, at two sites in the U.S. and one in Canada, finished the one-year follow-up in May 2023. The treatment met safety goals, according to data presented in August 2023 at the International Congress of Parkinson’s Disease and Movement Disorders in Copenhagen, Denmark (press release). No serious adverse events related to the implant were reported after one year. A seizure in one patient was attributed to the surgical procedure, and resolved fully. PET imaging demonstrated evidence of cell survival and engraftment in both low- and high-dose cohorts. Patients improved on secondary endpoints measuring motor symptoms using the MDS-Unified Parkinson’s Disease Rating Scale Part III and the Hauser Diary, with greater benefits observed in the higher dose cohort. At 18 months, the therapy continued to be safe, according to presentations at the March 2024 AD/PD conference. At this time, immunosuppression had been stopped for six months. There were no deaths or discontinuations, or graft-induced dyskinesias. Clinical scores remained stable or trended toward improvement. On PET imaging, 18F-dopamine uptake in the transplanted region was increased compared to baseline, and increased or stable compared to one year. Uptake in the caudate, a non-transplanted region, was lower than baseline. MRI revealed no evidence of intracerebral hemorrhage, cellular overgrowth, or tumor formation. After twenty-four months of treatment, there was continued safety, cell survival, and potential clinical benefits, especially in the higher dose patients, the company reported in September 2024 (press release). This trial will continue to evaluate patients for up to five years.
In July 2021, the U.S. FDA granted fast-track status to DA01 for treatment of advanced Parkinson's.
In July 2022, BlueRock began a large, non-interventional study evaluating the variability, reliability, and compliance of self-reporting using the PD Diary to assess motor symptoms. The study completed enrollment with 194 patients in the U.S., Canada, and Europe, and will run until 2025.
In October 2023, Bayer announced the opening of a new cell therapy production plant in California to produce material for additional clinical trials of BRT-DA01 (press release).
A Phase 2 trial wass expected to start in late 2024 (Bayer press release).
In May 2024, the U.S. FDA granted bemdaneprocel a regenerative medicine advanced therapy designation, opening up the potential for an expedited review (press release).
In January 2025, the company announced it would skip Phase 2 and initiate a Phase 3 registration trial (press release). The exPDite-2 trial, planned to begin in the first half of 2025, aims to enroll 102 people with moderate Parkinson’s disease to undergo cell transplantation or a sham surgery control. Participants will receive the high dose from Phase 1 of 3 million cells bilaterally. The primary endpoint is change in ON-time without troublesome dyskinesia after 18 months. Secondary endpoints will include measures of movement, safety and tolerability, activities of daily living, and quality of life. This trial does not appear yet in the trial registry.
For details on these trials, see clinicaltrials.gov.
Last Updated: 24 Jan 2025
Further Reading
No Available Further Reading
Overview
Name: WVE-004
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): Frontotemporal Dementia, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Frontotemporal Dementia (Discontinued), Amyotrophic Lateral Sclerosis (Discontinued)
Company: Wave Life Sciences USA, Inc.
Background
WVE-004 is an antisense oligonucleotide (ASO) targeting the C9ORF72 mutation that causes amyotrophic lateral sclerosis and frontotemporal dementia. The ASO mediates degradation of hexanucleotide expansion-containing C9ORF72 mRNAs. Both the mRNA and the dipeptide proteins produced from the hexanucleotide repeats are believed to be toxic to neurons, hence the rationale that reducing them will be beneficial.
Wave has reported the production of stereoisomerically pure ASOs that preferentially knock down repeat-containing C9ORF72 mRNAs and preserve normal protein expression (Liu et al., 2021). They previously demonstrated that stereopure ASOs more potently initiate mRNA degradation than standard oligomers with random stereochemistry (Iwamoto et al, 2017).
WVE-004 was tested in motor neurons derived from patient cells and in a transgenic mouse carrying the human C9ORF72 gene with a repeat expansion; results were presented at conferences in 2021 (abstract, ALS News Today coverage). In cultured cells, the ASO reportedly decreased repeat-containing mRNA; in mice, injection into the CSF resulted in reductions of repeat-containing mRNA by 60 to 80 percent in spinal cord and 40 to 50 percent in cortex up to six months later. WVE-004 also diminished dipeptide repeat proteins by approximately 90 percent in the spinal cord and cortex, but did not affect normal protein levels. The data was later published after peer review (Liu et al., 2022).
Findings
In June 2021, Wave began a Phase 1/2 safety study in 42 people with C9ORF72-associated ALS or FTD. Each participant received a single intrathecal injection of 10, 20, 30, or 60 mg WVE-004 or placebo. A multidosing phase administered 10 mg or placebo every four or 12 weeks; followed by an option for open-label extension. The primary outcome was the proportion of patients with adverse events 24 weeks after injection. The trial also measured WVE-004 and C9ORF72-derived glycine-proline dipeptides in CSF at the beginning and end of study. The study ended up enrolling 35 participants. It was performed at 17 sites in Australia, New Zealand, Canada, and Europe. On May 23, 2023, the company reported topline results (press release). Several of the trialed doses were associated with a 50 percent reduction in CSF poly(GP), but no improvement on exploratory clinical outcomes after 24 weeks. In individual participants, poly(GP) levels did not correlate with clinical changes. The company announced it would stop development and terminate an ongoing open-label extension.
For details on this trial, see clinicaltrials.gov.
Last Updated: 25 May 2023
Further Reading
No Available Further Reading
Comments
No Available Comments
Make a Comment
To make a comment you must login or register.