Overview
Name: Buntanetap
Synonyms: Posiphen, ANVS-401, Posiphen tartrate
Chemical Name: (3aR)-1, 3a, 8-trimethyl-1, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), alpha-synuclein
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2/3), Parkinson's Disease (Phase 3)
Company: Annovis Bio
Background
Buntanetap, previously known as posiphen or ANVS-401, is the pure (+) enantiomer, i.e. mirror image, of phenserine. Both compounds derive from the intramural research program at NIH and were licensed to Axonyx, Inc., which developed both enantiomers into the clinic. Axonyx merged with Torrey Pines Therapeutics, which licensed posiphen to QR Pharma in 2008.
Both posiphen and phenserine reduce production of amyloid precursor protein by blocking translation of its mRNA (Shaw et al., 2001). Phenserine also inhibits acetylcholinesterase, while posiphen does not. Both are dosed by mouth and enter the brain. Posiphen and phenserine are considered separate therapeutics, as there is no chiral switching between the two, or between their metabolites. Posiphen and phenserine, and their respective metabolites, differ in their pharmacokinetics.
They share a number of common actions and, additionally, have separate actions. Posiphen and phenserine act on iron-response element sequences in the 5' untranslated region of APP mRNA to inhibit APP protein synthesis. They reduced APP and Aβ in neuronal cultures and brains of wild-type and AD transgenic mice (Lahiri et al., 2007; Marutle et al., 2007). Both drugs were reported to be neuroprotective and neurotrophic in AD mouse models (Lilja et al., 2013; Lilja et al., 2013), and posiphen was reported to normalize memory impairment, learning, and synaptic function (Teich et al., 2018). Posiphen was also tested in the APP-overexpressing Ts65DN mouse model of Down's syndrome, where 50 mg/kg for 26 days lowered expression of APP and its C-terminal fragments, corrected deficits in axonal transport, and normalized neurotrophin signaling (Chen et al., 2021).
Posiphen and phenserine reportedly also block translation of α-synuclein mRNA, implying potential application in Parkinson’s disease (Rogers et al., 2011; Mikkilineni et al., 2012; Yu et al., 2013). Posiphen reduced α-synuclein expression in brain and gut, and improved intestinal function in the A53T α-synuclein transgenic mouse model of PD (Kuo et al., 2019).
Posiphen was reported to improve outcomes in rodent stroke models (Yu et al., 2020) and to augment neurogenesis post stroke (Turcato et al., 2018). Pharmacokinetic data are published (Maccecchini and Mould, 2024).
Findings
Results of three Phase 1 studies of posiphen are published (Maccecchini et al., 2012). They include single and multiple dosing in 120 healthy adults and a small proof-of-concept study in five people with MCI. Most common side effects were dizziness, nausea, and vomiting that increased with dose. Adverse effects did not increase significantly at doses of up to 60 mg four times a day for 10 days, at which point posiphen reached brain concentrations presumed sufficient to inhibit APP production. Ten days of treatment in people with MCI led to statistically significant reductions in CSF of APP cleavage fragments sAPPα and β, as well as of both total- and phosphorylated-tau, and the inflammation markers YKL-40, complement C3, and MCP-1. A trend for reduction was evident in CSF levels of Aβ42 (-51.4 percent, p=0.0533).
In March 2017, QR Pharma started a Phase 1/2 trial to study the effect of posiphen on APP synthesis in people with early AD. The study recruited 18 participants with a diagnosis of amnestic MCI or probable mild AD, and CSF levels of Aβ42 consistent with AD. They were randomized to receive 60 mg once, twice, or three times daily, or placebo for 23 to 25 days. Primary endpoints are safety, pharmacokinetics in plasma and CSF, and the rate of turnover of CSF Aβ40 using the stable isotope labeling kinetics (SILK) technique (see Paterson et al., 2019). The Alzheimer Disease Cooperative Study group ran the trial at five academic medical centers in the U.S. As of February 2020, 11 participants had enrolled, and no adverse effects were reported (company press release). The trial was paused from March to October 2020 due to COVID19, then completed in December 2021. Results are posted on clinicaltrials.gov and were published after peer review (Galasko et al., 2024). The drug was safe, with side effects mainly attributed to CSF catheterization for the SILK analysis. Posiphen did not alter the rate of synthesis of Aβ compared to placebo, nor did it change cognitive measures or CSF biomarkers.
In 2019, QR Pharma became Annovis Bio.
In August 2020, Annovis began a Phase 1/2 dose-finding biomarker study in early AD and Parkinson’s disease patients. In Part 1, 14 AD and 14 PD patients were to be randomized roughly 2:1 to 80 mg posiphen or placebo, taken daily for 23 to 27 days. At the last dose, participants undergo blood and CSF sampling. In Part 2 of the study, 40 PD patients will receive 5, 10, 20, 40 or 80 mg posiphen, under the same design as in Part 1. The primary outcome is adverse events. Other endpoints include pharmacokinetic, functional, and cognitive endpoints. A panel of CSF biomarkers to be measured spans amyloid and tau pathology, inflammation, and neuronal death.
Part 1 finished in early 2021, and Annovis presented results at the 2021 AAIC on July 28. There were no serious adverse events. On exploratory efficacy measures, the company claimed a statistically significant within-subject improvement in the ADAS-Cog11 from baseline to 25 days, but the comparison with placebo group fell short of significance. Posiphen-treated PD patients improved on the WAIS coding task, a paper-and-pencil test measuring motor dexterity and cognitive speed compared to placebo. The AD patients had a decrease in all amyloid/tau biomarkers, with a 12 percent reduction in pTau, and improvement in the Aβ42/40 ratio. The neurodegeneration biomarker NfL had 13 percent lower levels in AD and 9 percent in PD, but the change was not statistically significant. The company reported significant reductions by 43 and 28 percent in inflammatory markers sTREM2 and GFAP in treated PD patients; a 55 percent YKL40 reduction did not meet statistical significance. The study finished in January 2022. Full results report improvement on the MDS-UPDRS and WAIS coding in PD patients, with optimal responses occurring at 10-20 mg (Fang et al., 2023).
In August 2022, the company began a Phase 3 study in people with early PD. The study intended to enroll 450 participants for six months of 10 or 20 mg buntanetap daily, or placebo, with a primary outcome of MDS-UPDRS Parts 2 and 3 (activities of daily living and motor exam), and safety. Other outcomes include total MDS-UPDRS total score, clinician and patient impression of change, WAIS, and biomarkers. The study, at approximately 100 locations in the U.S. and Europe, ended in December 2023 with a final enrollment of 523. The primary outcome was modified to the MDS-UPDRS Part 2. On July 2, 2024, the company announced some results (press release). The company did not report on the primary endpoint in the group as a whole. It reported improvement on the MDS-UPRDS for a subgroup of patients with more advanced PD. It also claimed effects on the MMSE, which was not listed as a study outcome. In the study group as a whole, the placebo group declined by a fraction of a point on the MMSE, while the treatment group was reported to have stayed the same.
In April 2023, the company started a Phase 2/3 trial in mild to moderate AD. The dose ranging study randomized 353 participants to 7.5, 15, or 30 mg buntanetap or placebo, once daily for three months. Participants had MMSE scores between 14 and 24, and a clinical diagnosis of AD. No biomarkers were used to confirm diagnosis. Primary outcomes are ADAS-Cog11 and the ADSC-CGIC. Other outcomes include the ADCS-ADL, MMSE, and the Digit Symbol Substitution Test. The trial ran at more than 50 sites in the U.S. until February 2024. On April 29, 2024, the company announced results on a subset of 202 patients with retrospectively confirmed AD pathology based on plasma pTau/tau measurements. In 90 of these participants who had MMSEs between 21-24, the company claimed ADAS-Cog improvement at all three doses, compared to placebo (press release). The highest-dose group did three points better than placebo. In participants with MMSE between 14-20, the buntanetap group reportedly did worse than placebo by 1.79 points. More results are to be presented at the July 2024 AAIC.
For details on posiphen trials, see clinicaltrials.gov.
Last Updated: 23 Jul 2024
Further Reading
No Available Further Reading
Overview
Name: Trontinemab
Synonyms: RO7126209, RG6102 , Brain shuttle gantenerumab
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1/2)
Company: Hoffmann-La Roche
Background
RO7126209 is a new version of the anti-amyloid monoclonal antibody gantenerumab, engineered to more easily cross the blood-brain barrier using Roche’s “brain shuttle” technology. A Fab fragment that binds the human transferrin receptor is attached to the effector (Fc) domain of the gantenerumab monoclonal antibody. RO7126209 circulating in the bloodstream binds the transferrin receptor on the endothelial cells that make up the blood-brain barrier. This leads to its endocytosis and release into the brain parenchyma.
Preclinical work has been published using the mouse version of gantenerumab fused to a single mouse transferrin receptor-binding Fab fragment. In AD mouse models, 50 times more antibody entered the brain and bound to amyloid plaques, compared with unmodified gantenerumab. RO7126209 stimulated plaque clearance by immune cells at doses far lower than did the parent antibody, without initiating immune responses to endothelial cells or other transferrin receptor-bearing bystander cells (Jan 2014 news; Jan 2018 news).
In other preclinical studies, brain shuttle delivery of either BACE1 peptide inhibitors or the protease neprilysin were able to reduce brain amyloid in AD mice (Campos et al., 2020; Ruderisch et al., 2017).
Denali Therapeutics is working on a similar transferrin receptor-mediated brain delivery system (May 2020 news). Roche’s is the first to enter Phase 1 testing in humans.
Findings
In August 2019, Roche began a Phase 1 study of the safety, tolerability, immunogenicity, and pharmacokinetics of RO7126209 in up to 64 healthy men in North Carolina. Volunteers in five sequential cohorts received a single dose of antibody or placebo by intravenous infusion. An adaptive design escalated doses based on results of prior cohorts. Primary outcomes are adverse events, laboratory findings, and vital signs up to two months after dosing. Investigators are also measuring CSF antibody concentrations three or five days after dosing, and anti-RO7126209 antibodies up to two months after. The study was completed in July 2020 with an actual enrollment of 34. Results were presented in March 2021 at AD/PD. Doses of 0.1, 0.4, 1.2, 3.6, and 7.2 mg/kg showed a linear relationship between plasma and CSF concentrations, with a plasma half-life of three to six days. RO7126209's CSF/plasma ratio was 0.8 percent, eightfold higher than gantenerumab's. No anemia or hematology-related safety events were observed, with the exception of a transient effect on immature red blood cells (Mar 2021 conference news, see also Dec 2021 conference news; Grimm et al., 2023).
In March 2021, a Phase 1 trial called Brainshuttle AD began evaluating multiple doses in 120 people who have prodromal or mild to moderate Alzheimer’s disease and a positive amyloid PET scan. Participants are to receive one of four doses from 0.2 to 3.6 mg/kg of RO712620 or placebo, given by infusion once every four weeks for 28 weeks, with 28 weeks of follow-up. The primary outcome is safety; secondary outcomes are change in brain amyloid, drug concentrations in plasma and CSF, and number of people with anti-drug antibodies. In mid-2023 the trial was expanded to 210 participants, boosting the number of patients in some dose cohorts, and adding two new cohorts comparing dose frequency of four or 12 weeks. Change from baseline in brain amyloid was added to the primary outcomes. A two-year open-label trial was also added, in which amyloid-negative people received antibody every 12 weeks, and amyloid-positive every four weeks, until they attain amyloid negativity, i.e., 24 centiloids or less. In April 2024, the trial was expanded again, to 285 participants, adding a fifth, higher dose and extending the follow-up period for previous dosing groups. The trial runs at nearly 50 sites in North and South America, Asia, Australia, and Europe, until 2031.
Initial data from the multiple dosing were presented at the 2023 CTAD conference (Nov 2023 conference news). Forty-four participants with between 90 and 100 centiloids of plaque at baseline received infusions of 0.2, 0.6, and 1.8 mg/kg, or placebo every four weeks. The company reported a dose-dependent lowering of amyloid. The highest dose completely cleared plaque in three of four participants after six months, an effect estimated to be 40 or 50 times more potent than gantenerumab. Side effects were mainly mild infusion reactions, and anemia. Antidrug antibodies developed in one-quarter of people on the highest dose, and were more frequent at lower doses. There was no ARIA at lower doses, and two cases in the 1.8 mg/kg group were asymptomatic or mild. At the March 2024 AD/PD conference, the company presented interim data on the highest planned dose of 3.6 mg/kg (Mar 2024 conference news). Of eight participants who began with an average of 119 centiloids of plaque, five dropped below the positivity threshold at three months. The group had an average reduction of 91 centiloids, with no ARIA or serious adverse events, or study withdrawals due to adverse events. One person developed anemia, and one developed antidrug antibodies that did not affect drug pharmacokinetics. At the October 2024 CTAD conference, Roche presented 28-week data from the multidose part of the trial. Most of the participants in 1.8 and 3.6 mg groups lost sufficient brain amyloid to achieve the cutoff for negativity. CSF biomarkers of total tau, ptau181, and neurogranin dropped dose-dependently. There were three reported cases of ARIA; they were mild and asymptomatic. The study was expanded with additional safety cohorts that enrolled 100 participants at the two highest doses. One death occurred in the expanded cohort, from a cerebral macrohemorrhage after a second, 1.8 mg dose. The participant had signs of superficial siderosis and probable cerebral amyloid angiopathy at baseline. Roche added these conditions to its exclusion criteria for ongoing and future trials. Another two people in the1.8 mg dose developed ARIA-E, which was mild and asymptomatic. Thirteen percent of participants in Part 1 and 8 percent in Part 2 developed anemia, which was mild and resolved on its own (Nov 2024 conference news).
For details on RO7126209 trials, see clinicaltrials.gov.
Last Updated: 10 Jan 2025
Further Reading
No Available Further Reading
Overview
Name: BPN14770
Chemical Name: 2-(4-{[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl]amino}phenyl)acetamide
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Shionogi Pharma, Tetra Therapeutics
Background
BPN14770 is an allosteric inhibitor of phosphodiesterase 4D (PDE4D), a regulator of the intracellular second messenger cAMP in neurons. Inhibitors of PDE4D raise cAMP levels, which has been reported to support cognition and protect neurons. BPN14770 targets the same pathway as do acetyl cholinesterase inhibitors such as donepezil, but at a different point.
Allosteric PDE4D inhibitors reportedly are less likely to induce vomiting, a dose-limiting side effect of active-site PDE4D inhibitors (Burgin et al., 2010; Jan 2011 news).
In preclinical work, BPN14770 has been tested in a mouse line expressing a humanized PDE4D sequence. This was necessary because BPN14770 binds to a primate-specific, N-terminal region of PDE4D (Gurney et al., 2019). In these mice, BPN14770 enhanced brain cAMP, hippocampal long-term potentiation, and performance in a novel-object-recognition test. BPN14770 antagonized the amnestic effect of the anti-nausea drug scopolamine, whereby two weeks’ dosing boosted hippocampal phospho-CREB and BDNF, markers of memory consolidation. A subsequent study implicated cAMP-PKA-SIRT1-Akt -Bcl-2/Bax signaling in BPN14770's anti-scopolamine effect in these mice (Zhang et al., 2018; Wang et al, 2020). In the same mouse line, bilateral Aβ42 injection into the hippocampi induced memory deficits and synapse damage that was prevented by BPN14770. Two weeks’ dosing resulted in elevation of brain BDNF levels (Cui et al., 2019).
The drug also improved behavioral readouts in a mouse model of Fragile X syndrome (Gurney et al., 2017).
Findings
In 2015 and 2016, Tetra ran two Phase 1 trials evaluating single and multiple oral doses of BPN14770 in 109 healthy adults, including elderly participants. Single doses up to 100 mg were well tolerated and produced linear pharmacokinetics. Higher doses caused transient nausea. In 45 aged volunteers taking 10, 20, or 40 mg twice daily for seven days, headaches were the most common side effect. The 40 mg group showed a decline in cognition. The combined 10 and 20 mg dose groups posted an improvement on the One Card Back working memory test compared to placebo, which appeared after first treatment and continued through the week of dosing (Dec 2016 press release; Dec 2017 conference news).
In January 2017, a Phase 1 trial began testing in 38 healthy volunteers whether a single dose of BPN14770 reverses cognitive impairment induced by scopolamine. The crossover design compared 10 and 50 mg dosing to 10 mg donepezil or placebo; each participant served as his or her own control. The trial ended in June 2017. No results have been presented.
In April 2019, the company started PICASSO, a Phase 2 study in Alzheimer’s disease conducted at 60 sites in the U.S. The trial enrolled 255 participants with clinically diagnosed early AD who were on a stable dose of a cholinesterase inhibitor but not memantine. Proof of amyloid positivity was not required. They were randomized to 10 or 25 mg BPN14770 or placebo twice daily for three months. The primary outcome was change from baseline in the Repeatable Battery for the Assessment of Neurological Status-Delayed Memory Index; secondary outcomes were RBANS total score and other standard measures of memory, cognition, and function, including the ADCS-ADL, MMSE, CDR-SB, and CGI-I. The trial ended in February 2020.
In December 2018, Tetra started a collaboration with Shionogi Pharma to develop BPN14770 for AD, and in January 2020, Shionogi began evaluating single and multiple doses in 112 healthy adults and elderly in a Phase 1 study in Japan. Outcomes are safety and pharmacokinetics, including food effects and drug-drug interactions with midazolam and donepezil.
In May 2020, Shionogi bought Tetra Therapeutics, while also disclosing that PICASSO had missed its primary endpoint. There had been no significant change in the RBANS-D2MI with treatment; however, a subgroup analysis of patients in the 25 mg group with above-median CDR-SB scores at baseline indicated a signal for improvement on the CDR-SB. No safety issues were observed. The results warrant further development of BPN14770, according to Shionogi (see press release).
BPN14770 is also being tested with an orphan drug designation to treat Fragile X. Between July 2018 and July 2020, a Phase 2 trial at Rush University Medical Center compared 25 mg twice daily to placebo for 12 weeks in a crossover design in 30 men with the condition. The primary outcome was safety and tolerability; secondary measures included the computerized cognitive tests, and clinician and caregiver ratings of symptom severity and daily function. The trial met its primary outcome of safety and tolerability. All participants completed the study, with no adverse events attributed to drug. Participants were reported to have improved on secondary measures, including cognitive tests related to language, and caregiver ratings of language and daily function. The benefit was maintained up to 12 weeks after dosing stopped (Berry-Kravis et al., 2021).
The company is developing PET ligands to PDE4D. Two ligands were tested in primates. Specific binding was highest in prefrontal and temporal cortex and hippocampus, and was displaced by BPN14770. The radiolabeled ligand T1650 was tested in three people with depression but proved unstable (Wakabayashi et al., 2020); the ligand T2310 is being evaluated in a Phase 1 study that began in January 2020 at Weill Cornell College of Medicine, New York.
For details on BPN14770 trials, see clinicaltrials.gov.
Last Updated: 30 Apr 2021
Further Reading
No Available Further Reading
Overview
Name: Bryostatin 1
Chemical Name: (1S,3S,5Z,7R,8E,11S,12S,13E,15S,17R,20R,23R,25S)-25-Acetoxy-1,11,20-trihydroxy-17-[(1R)-1-hydroxyethyl]-5,13-bis(2-methoxy-2-oxoethylidene)-10,10,26,26-tetramethyl-19-oxo-18,27,28,29-tetraoxatetracyclo[21.3.1.13,7.111,15]nonacos-8-en-12-yl (2E,4E)-2,4-oct
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Synaptogenix, Inc.
Background
Bryostatin 1 is a natural product derived from the marine invertebrate Bugula neritina. It has potent and broad antitumor activity. Bryostatin 1 activates protein kinase C family members, with nanomolar potency for PKC1α and ε isotypes.
In the central nervous system, bryostatin 1 activation of PKC boosts synthesis and secretion of the neurotrophic factor BDNF, a synaptic growth factor linked to learning and memory (reviewed in Sun et al., 2015). The compound also activates nonamyloidogenic, α-secretase processing of amyloid precursor protein (Yi et al., 2012).
Preclinical work on bryostatin in nervous system diseases has mainly come from the Alkon lab. In their studies, intraperitoneal administration activated brain PKCε and prevented synaptic loss, Aβ accumulation, and memory decline in Alzheimer’s disease transgenic mice (Etcheberrigaray et al., 2004; Hongpaisan et al., 2011). The drug preserved synapses and improved memory in aged rats, and in rodent models of stroke and Fragile X syndrome (Hongpaisan et al., 2013; Sun et al., 2008; Sun et al., 2016). In a different lab, bryostatin given by mouth improved memory and learning in an AD model (Schrott et al., 2015). In a mouse model of multiple sclerosis, bryostatin promoted anti-inflammatory immune responses and improved neurologic deficits (Kornberg et al., 2018). Bryostatin promoted survival of motor neurons bearing an SOD1 mutation causative for amyotrophic lateral sclerosis (La Cognata et al., 2023).
Findings
Published data from a Phase 1/2 trial beginning in June 2014 describe no safety issues in six Alzheimer’s patients given a single intravenous body-surface-area-based dose of 25 μg/m2 compared with three participants who received placebo (Nelson et al., 2017). Blood levels of bryostatin 1 and PKCε activation in peripheral blood cells reportedly peaked one to two hours after dosing. Patients receiving drug showed a transient increase of 1.8 points in their MMSE scores three hours after dosing, compared with no change in those on placebo.
In an expanded access trial, three severely symptomatic AD patients received multiple bryostatin infusions for five to nine months. The authors describe behavior improvements that occurred rapidly after the first dose and were maintained for weeks. Two participants were nonverbal, so no cognitive testing was possible.
In November 2015, the company began a double-blind, placebo-controlled Phase 2 study enrolling 147 people with moderate to severe AD dementia. Participants had MMSE scores between 4 and 15, and were randomized to 20 or 40 μg bryostatin or placebo given intravenously seven times over 11 weeks. The primary outcomes were safety and an efficacy measure defined by change on the severe impairment battery (SIB) at week 13, two weeks after the last dose. Secondary endpoints included change from baseline SIB at weeks 5, 9, and 15.
Results are published (Farlow et al., 2019). The 20 μg and placebo groups had similar rates of adverse events, with 20 percent dropping out before the end of the trial. The 40 μg group had more side effects, and twice as many dropouts. Common adverse effects included diarrhea, headache, fatigue, and weight loss. Neither dose showed efficacy in the full study group. When the investigators analyzed only those who completed the entire dosing regimen, they found an increase on the SIB for the 20 μg dose. A prespecified exploratory analysis suggested that the improvement occurred only in people not receiving memantine.
In June 2018, a second Phase 2 trial began in 108 AD patients who were not taking memantine. The group was split in two by MMSE scores 4–9 versus 10–15, then randomized to receive the same 20 μg treatment regimen as the previous trial. In a September 2019 press release, the company announced the drug showed no evidence of efficacy, based on the 13-week SIB scores. The study data revealed a baseline imbalance on SIB between placebo and bryostatin groups. A post hoc analysis of change in individual scores over time suggested that SIB improved in the MMSE 10–15 group on both drug and placebo, with a trend toward more improvement on the drug (Jan 2020 press release). Analysis of pooled data from this and the previous Phase 2 trial found increased SIB scores in the MMSE 10-14 group with treatment, compared to no improvement with placebo (Thompson et al., 2022).
In August 2020, the company began a third Phase 2 trial, in patients with moderate dementia due to AD (MMSE 10–18) who are not taking memantine. Funded partially by the NIH, the study enrolled 122 patients for two 11-week treatment cycles, with the primary endpoint again being change on SIB. This placebo-controlled study was completed in November 2022. On December 16, the company reported that it had failed to meet the primary endpoint (press release). Results were published after peer review (Alkon et al., 2023). The company claimed effectiveness in the subgroup of moderately severe patients with MMSE 10-14, who showed no decline on the SIB compared to 12.8 points decline in the placebo group.
Bryostatin completed a clinical trial for eradication of HIV/AIDS. It has been studied extensively for antitumor activity against multiple types of cancer in more than 20 Phase 2 trials, but none progressed to Phase 3. It has FDA Orphan Drug Designation for treatment of Fragile X syndrome.
For details on bryostatin 1 trials, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
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Last Updated: 18 Oct 2023
Further Reading
No Available Further Reading
Overview
Name: Kynmobi
Synonyms: APL-130277, apomorphine hydrochloride sublingual thin film
Chemical Name: (9R)-10-methyl-10-azatetracyclo[7.7.1.0²,⁷.0¹³,¹⁷]heptadeca-1(16),2(7),3,5,13(17),14-hexaene-3,4-diol
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Approved)
Company: Sunovion Pharmaceuticals Inc.
Background
APL-130277 is a sublingual thin film formulation of apomorphine, a dopamine receptor agonist with anti-parkinsonian actions similar to levodopa. In May 2020, the FDA approved Kynmobi for on-demand treatment of Parkinson’s OFF episodes (company press release). This NDA was a resubmission of an earlier application in January 2019 that the agency had rejected.
Kynmobi’s active compound is apomorphine, which results from the chemical decomposition of morphine. It does not contain morphine or bind to opioid receptors. Apomorphine is used for the acute treatment of Parkinson’s symptom flare-ups called motor fluctuations. These OFF episodes plague people with advanced Parkinson’s disease who are otherwise stable on dopamine treatment.
Apomorphine is usually injected subcutaneously or infused. This mode of administration requires passage through the liver and its metabolism before apomorphine reaches the brain (Borkar et al., 2018). APL-130277 represents a new formulation that delivers apomorphine noninvasively, and more quickly, through the lining of the mouth, from a disintegrating strip placed under the tongue.
Apomorphine's side effects include nausea and vomiting, and it is normally given along with an anti-nausea drug. Other side effects are low blood pressure leading to drowsiness and fainting. In the 2000s, low-dose, sublingual tablet formulations of apomorphine were briefly marketed for erectile dysfunction, but were discontinued when safer and more effective PDE5 inhibitors took over for that indication.
In vitro, apomorphine was found to inhibit Aβ fibril formation (Lashuel et al., 2002). In the 3xTg-AD mouse model, it was reported to improve memory and reduced levels of Aβ and hyperphosphorylated tau (Himeno et al., 2010; Himeno et al., 2011).
Findings
Starting in August 2014, a Phase 2, open-label study evaluated 10 to 30 mg doses of APL-130277 in 19 Parkinson’s patients after their previous dose of levodopa had worn off and they were in an OFF state. Within 30 minutes, 15 showed significant improvement in motor function as measured by the Movement Disorder Society Unified Parkinson’s disease rating scale (MDS-UPDRS) part III (Hauser et al., 2016). The most common side effects were dizziness, sleepiness, and nausea.
In June 2015, a Phase 3, placebo-controlled study began enrolling PD patients who suffered predictable morning OFF episodes plus two or more hours of OFF time daily, while on a stable dose of L-DOPA. After an open-label titration from 10 to 35 mg in 141 patients, 109 responders were randomized to drug or placebo for a 12-week double-blind phase. Apomorphine is intended to be used up to five times a day; most participants used it two or three times. Treatment resulted in an improvement in the primary outcome, i.e., change in MDS-UPDRS from pre-dose to 30 minutes after dosing measured in the clinic at the 12-week visit. The secondary outcome was also positive, with a higher percentage of patients showing a fuller response to drug than placebo, both in the clinic and at home. One-third of patients discontinued apomorphine treatment compared with 16 percent dropout on placebo, mainly because of mild to moderate mouth and throat irritation. Other side effects included transient nausea, sleepiness, and dizziness. Orthostatic hypotension, syncope, dyskinesia, hallucinations, prolonged QT interval, and impulse control disorders were rare, but one patient on apomorphine who had known cardiac risk factors died from cardiac arrest (Olanow et al., 2020).
Sunovion is recruiting up to 226 participants for a 24-week, open-label extension to the Phase 2 and 3 studies that will continue through March 2023.
The company has completed two additional Phase 2 studies. One evaluated drug effects on heart rhythms in people with Parkinson’s; the other compared Kynmobi to two brands of injectable apomorphine on pharmacokinetic outcomes. No results have been disclosed.
In December 2018, the company began a Phase 3 trial comparing Kynmobi’s effectiveness to that of subcutaneously injected apomorphine in 106 people with Parkinson’s. The study will run through October 2020.
For details on APL-130277 trials, see clinicaltrials.gov
Last Updated: 28 May 2020
Further Reading
No Available Further Reading
Overview
Name: DNL201
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Inactive)
Company: Biogen, Denali Therapeutics Inc.
Background
DNL201 is an orally available, brain-penetrant inhibitor of the leucine-rich repeat kinase 2 (LRRK2). It was being developed to treat Parkinson’s disease.
Also known as Dardarin, LRRK2 is a large, multidomain protein containing serine and threonine kinase activity. Kinase-activating mutations in the LRRK2 gene are the most frequent cause of inherited PD (reviewed in Schneider and Alcalay, 2020). Other variants in the gene are associated with higher risk of sporadic PD, and there is some evidence for LRRK2 kinase activation in idiopathic PD (Di Maio et al., 2018). Increased LRRK2 kinase activity impairs vesicle trafficking and lysosome function, and promotes neuroinflammation, processes that contribute to PD pathology (see review by Taylor and Alessi, 2020; Shutinoski et al., 2019; Sept 2018 news). Several companies are pursing LRRK2 inhibitors for treating PD; Denali was the first to begin clinical testing.
In animal studies, reducing LRRK2 activity using inhibitors or by genetic knockdown in rodent models of PD reduces α-synuclein aggregation, neuroinflammation, and dopaminergic neuron loss (Daher et al., 2014; Daher et al., 2015).
Besides brain, LRRK2 is highly expressed in the lungs, kidneys, and spleen. Knockout or systemic inhibition of LRRK2 was found to change lung morphology in rats or macaque monkeys, possibly by affecting lysosomal function (Fuji et al., 2015). This prompted safety concerns about systemic LRRK2 inhibition. Recent data confirmed that three different inhibitors caused an accumulation of large vacuoles in lung cells of treated monkeys; this response did not compromise lung function after two weeks of treatment, and the changes reversed after the drugs were stopped (Baptista et al., 2020). For a review of patents on LRRK2 inhibitors see Ding and Ren, 2020.
Findings
In 2017 and 2018, Denali conducted a Phase 1 safety study of DNL201 in 122 healthy volunteers. The trial was not registered. According to one company press release, the highest evaluated dose of DNL201 inhibited LRRK2 by 90 percent and 50 percent at peak and trough blood concentrations, respectively. Kinase activity was measured by phosphorylation of LRRK2 itself and a substrate, Rab10, in blood. The drug was detected in cerebrospinal fluid, indicating it entered the brain. In a second press release, Denali reported no serious adverse events in the participants, including healthy elderly, in this single- and multiple-dose study.
In December 2018, Denali began a Phase 1b study in 29 people with Parkinson’s disease. Participants with or without an LRRK2 mutation were randomized to one of two doses of drug or placebo, taken twice daily for 28 days. The primary outcomes consisted of adverse events and abnormalities in laboratory tests, vital signs, electrocardiogram, or neurological exam. Secondary outcomes included plasma pharmacokinetics, drug concentration in CSF, and LRRK2 and Rab10 phosphorylation. The trial also measured levels of the lipid BMP in urine, a biomarker of lysosome function. It was completed in December 2019.
In a January 2020 press release, the company announced that both doses achieved more than 50 percent inhibition of LRRK2 and Rab10 phosphorylation in blood, and improved BMP in urine. At the low dose, most participants had no or mild adverse events. At the high dose, most experienced mild or moderate adverse events. One person had a dose reduction due to severe headache, and one withdrew due to headache and nausea. There was one case of Legionella pneumonia; there was no dose-dependent effect on pulmonary function. Preclinical and Phase 1 data were published after peer review (see news and commentary on Jennings et al., 2022).
Denali has a second LRRK2 inhibitor, DNL151. In August 2020, the company announced it would advance DNL151, in collaboration with Biogen (press release). DNL201 will serve as a backup.
For details on DNL201 trials, see clinicaltrials.gov.
Last Updated: 13 Jan 2023
Further Reading
No Available Further Reading
Overview
Name: DNL151
Synonyms: BIIB122
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2)
Company: Biogen, Denali Therapeutics Inc.
Background
DNL151 is an orally available, brain-penetrant inhibitor of the leucine-rich repeat kinase 2 (LRRK2). It started out as a backup to Denali’s lead LRRK2 inhibitor, DNL201; but it is now its lead candidate after development of DNL201 was stopped in 2020.
LRRK2, also known as Dardarin, is a large, multidomain protein containing serine and threonine kinase activity. Kinase-activating mutations in the LRRK2 gene are the most frequent cause of inherited PD (reviewed in Schneider and Alcalay, 2020). Other variants in the gene are associated with higher risk of sporadic PD, and there is some evidence for LRRK2 kinase activation in idiopathic PD (Di Maio et al., 2018). Increased LRRK2 kinase activity impairs vesicle trafficking and lysosome function, and promotes neuroinflammation, processes that contribute to PD pathology (see review by Taylor and Alessi, 2020; Shutinoski et al., 2019; Sep 2018 news).
Several companies are pursing LRRK2 inhibitors for treating PD; Denali was the first to begin clinical testing. Recently, cryoEM structures of wild-type and PD-linked mutants of LRRK2, with and without investigational inhibitors or it endogenous activator Rab29, were solved, supporting structure-based design of compounds targeting its kinase domain (Murillo et al., 2023, Zhu et al., 2023).
No preclinical data have been published on DNL151. However, reducing LRRK2 activity using other inhibitors or by genetic knockdown in rodent models of PD has been reported to reduce α-synuclein aggregation, neuroinflammation, and dopaminergic neuron loss (Daher et al., 2014; Daher et al., 2015, Ho et al., 2022; Ho et al., 2022). Inhibitors also promoted physiological tetramerization and synaptic localization of α-synuclein (Fonseca-Ornales et al., 2022; Brzozowski et al., 2021). In animal and cell models of Aβ42 toxicity, inhibiting LRRK2 attenuated neuroinflammation (Mutti et al., 2023; Filippini et al., 2023).
Besides brain, LRRK2 is highly expressed in the lungs, kidneys, and spleen. Knockout or systemic inhibition of LRRK2 was found to change lung morphology in rats or macaque monkeys, possibly by affecting lysosomal function (Fuji et al., 2015). This raised safety concerns of systemic LRRK2 inhibition. Recent data confirmed that three different inhibitors caused an accumulation of large vacuoles in lung cells of treated monkeys; this response did not compromise lung function after two weeks of treatment, and the changes reversed after the drugs were stopped (Baptista et al., 2020). Other investigational LRRK2 inhibitors have been reported to cause lasting changes in lung tissue (Miller et al., 2023). LRRK2 knockout in rats caused changes in kidney function and morphology, which could be mitigated by diet (Ness et al., 2013; Gu et al., 2023). In people, mutations in one copy of the LRRK2 gene that lead to partial reductions in kinase activity do not impair lung, liver, or kidney, function, or appear to cause specific health problems (Whiffin et al., 2020).
For a review of patents on LRRK2 inhibitors, see Ding and Ren, 2020.
Findings
In December 2017, Denali began Phase 1 dosing of DNL151 (press release) with a 186-participant trial in the Netherlands. A January 2020 press release announced that DNL151 met biomarker and safety goals after evaluation in 153 healthy volunteers. The majority of participants had no or mild AEs at all doses tested. DNL151 dose-dependently reduced LRRK2 kinase activity by up to 80 percent, based on measuring phosphorylation of LRRK2 and its substrate pRab10 in blood. Urine levels of the lipid BMP, a marker of lysosome dysfunction, were reduced, as well. Based on these safety, target, and pathway engagement data, the trial was expanded to higher doses. It finished in February 2021. According to published results, DNL151 readily penetrated the brain, and showed evidence of LRRK2 inhibition in CSF (Jennings et al., 2023).
In July 2019, a Phase 1b safety study began in 34 people with Parkinson’s disease. Participants with or without an LRRK2 mutation were randomized to a low, middle, or high dose of DNL151 or placebo, taken daily for 28 days. The primary outcome comprises adverse events and laboratory tests, vital signs, electrocardiogram, or neurological exam. Secondary outcomes include plasma pharmacokinetics, drug concentration in the CSF, and LRRK2 and Rab10 phosphorylation in blood. The trial finished in December 2020, after enrolling 36 participants in eight centers in the U.S. and Europe. In a January 2021 press release, Denali stated that the trial met target and pathway engagement goals.
In August 2020, Denali announced it would advance clinical development of DNL151 in collaboration with Biogen (press release).
In 2021, the companies completed additional Phase 1 studies of the absorption, metabolism, excretion, and bioavailability of radiolabeled DNL151 after single or multiple doses in healthy subjects. In 2022, another Phase 1 compared the pharmacokinetics, safety, and tolerability of single or multiple doses in 84 healthy Japanese, Chinese, and Caucasian people.
In May 2022, the companies began the Phase 2b LUMA trial in people with early stage Parkinson’s disease without a LRRK2 mutation. The 640 participants are receiving 225 mg BIIB122 once daily or matching placebo tablets, for 48 to 144 weeks. The primary outcome of time to worsening in the Movement Disorder Society-Unified Parkinson’s Disease Rating scale parts II and III assesses mainly motor symptoms and function. Secondary outcomes are adverse events, and change from baseline MDS-UPDRS, and time to worsening in daily activities. The trial is enrolling at 98 centers in North America, Asia, Europe, and Israel, and is expected to end in August 2025.
In September 2022, the LIGHTHOUSE Phase 3 study began recruiting a target number of 400 people with early stage Parkinson’s and specific LRRK2 mutations, for a similar course of treatment for up to 180 weeks, against the same primary and secondary outcome measures. This trial, at multiple sites in the U.S. and Europe, was slated for completion in January 2031. On June 5, 2023, Biogen announced a change in their development plan (press release). The company discontinued LIGHTHOUSE, reportedly due to its complexity and long time line. They amended the LUMA protocol to include patients with LRRK2 mutations, to get a quicker efficacy readout in patients without and without LRRK2 mutations. The seven patients who had enrolled in LIGHTHOUSE can join LUMA, whose end date remains August 2025.
For details on DNL151 trials, see clinicaltrials.gov.
Last Updated: 30 Jan 2024
Further Reading
No Available Further Reading
Overview
Name: BIIB094
Synonyms: ION859, IONIS-BIIB7Rx
Therapy Type: DNA/RNA-based
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1)
Company: Biogen, IONIS Pharmaceuticals
Background
This drug is an antisense oligonucleotide (ASO). It binds the mRNA for leucine-rich repeat kinase 2 and mediates its degradation. This results in lower LRRK2 protein levels. BIIB094 is being developed to treat Parkinson’s disease.
Also known as Dardarin, LRRK2 is a large, multidomain protein containing serine and threonine kinase activity. Kinase-activating mutations in the LRRK2 gene are the most frequent genetic cause of inherited PD (reviewed in Schneider and Alcalay, 2020). Other LRRK2 variants are associated with higher risk of sporadic PD, and there is some evidence for LRRK2 kinase activation in idiopathic PD (Di Maio et al., 2018). Increased LRRK2 kinase activity impairs vesicle trafficking and lysosome function, and promotes neuroinflammation, processes that contribute to PD pathogenesis (reviewed by Taylor and Alessi, 2020; Shutinoski et al., 2019; Sept 2018 news). Multiple companies are pursing small-molecule LRRK2 inhibitors to treat PD. BIIB094 is the first antisense approach in clinical trials.
In preclinical models, intracerebral injection of LRRK2 ASOs reduced LRRK2 protein levels in brain. In a mouse model of α-synuclein fibril infection into the brain, treatment with LRRK2 ASOs lessened fibril formation by endogenous α-synuclein and dopaminergic neuron loss while improving grip strength (Zhao et al., 2017). Intracerebral injection did not reduce LRRK2 mRNA in kidney or lungs, a concern with systemic inhibitors (Fuji et al., 2015; April 2020 news).
Findings
In August 2019, a Phase 1 safety trial began evaluating BIIB094 in people with Parkinson’s disease. It was to enroll 62 participants, with or without a PD-related LRRK2 mutation, for an intrathecal injection of a single dose, or multiple doses, of drug or placebo. The study will tally the number of participants with adverse events or serious adverse events for up to one year after injection. Secondary outcomes include pharmacokinetics of the ASO in blood. After the trial started, two more single dose cohorts were added, increasing total enrollment to 82. The trial will run through December 2023 at 18 centers in North America, Spain, Norway, the U.K., and Israel.
For details on BIIB094 trials, see clinicaltrials.gov.
Last Updated: 12 May 2023
Further Reading
No Available Further Reading
Overview
Name: CVN424
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2)
Company: Cerevance
Background
Cerevance performs single-nuclei RNA sequencing of defined cell types isolated from postmortem brain tissue to identify therapeutic targets for neurologic diseases (Xu et al., 2018).
CVN424 is an orally available, brain-penetrant small molecule. It suppresses activity of the orphan G-protein-coupled receptor GPR6, present in striatal neurons that express dopamine receptor D2 (Sun et al., 2021). These neurons are part of a brain circuit that shows abnormal overactivity in Parkinson’s disease patients. The company claims that CVN424 does not affect D1-dependent pathways, hence affects dopaminergic signaling indirectly. This selective targeting will help avoid dyskinesia, a side effect of long-term therapy with current Parkinson’s therapies associated with D1 activation. CVN424 is being developed as an add-on to levodopa therapy for Parkinson’s disease.
In preclinical work, CVN424 induced locomotor activity in mice, and reversed haloperidol-induced catalepsy, both indications that it suppresses activity in D2-dependent pathways. It also improved movement in a rat 6-hydroxydopamine lesion model of Parkinson’s disease (Brice et al., 2021).
Findings
In May 2019, Cerevance completed a Phase 1 single- and multiple-dose safety study in healthy adults. Sixty-four volunteers received single CVN424 doses from one to 225 mg, or seven daily doses of 25, 75, and 150 mg or matching placebo. According to an April 2019 company press release, the drug caused no serious adverse events or changes in common safety measures including vital signs, cardiac function, and laboratory analyses. Results were later published (Margolin et al., 2022).
In December 2019, a Phase 2, randomized, placebo-controlled study began enrolling 141 people with Parkinson's who experience motor fluctuations on a stable dose of levodopa. To be eligible, patients must average more than two hours per day of “off time,” i.e., periods when symptoms reappear between levodopa doses. Participants were randomized to high- or low-dose drug or placebo, taken as an oral suspension once daily for one month. The primary outcome was adverse events, and secondary outcomes included additional safety measures, as well as an efficacy endpoint of daily off time, as reported by patients. This trial took place at 21 sites across the U.S., and ended in December 2021. In March 2022, the company announced positive top-line results. At the high dose, CVN424 improved off time by 1.3 hours a day compared to placebo, which was statistically significant. The company said the drug also increased on time without dyskinesia, and reduced daytime sleepiness (press release). The most common side effects, were nausea, vomiting, or headache, reported by 4 percent of patients.
For details on CVN424 trials, see clinicaltrials.gov.
Last Updated: 16 Aug 2022
Further Reading
No Available Further Reading
Overview
Name: Ezeprogind
Synonyms: AZP2006 , AZP-2006
Chemical Name: N-[3-[4-[3-[bis(2-methylpropyl)amino]propyl]piperazin-1-yl]propyl]-1H-benzimidazol-2-amine
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline), Inflammation (timeline), Other (timeline)
Condition(s): Progressive Supranuclear Palsy
U.S. FDA Status: Progressive Supranuclear Palsy (Phase 2)
Company: AlzProtect
Background
This small molecule is said to increase levels of the neurotrophic factor progranulin. According to information from its maker, AZP2006 binds to prosaposin, a cofactor for progranulin processing. Prosaposin and progranulin are lysosomal proteins that are genetically implicated in Parkinson’s risk (e.g., Valdez et al., 2020; Oji et al., 2020). Prosaposin regulates progranulin, and increased levels of both have been associated with AD neuropathology (Nicholson et al., 2016; Mendsaikhan et al., 2019).
AZP2006 stabilizes the prosaposin-progranulin complex. The drug-development rationale is that this stabilization prevents progranulin cleavage and increases progranulin secretion. Previously, an effect blocking tau phosphorylation had been claimed (Medina, 2018; Jadhav et al., 2019).
The drug is being developed for treatment of Alzheimer’s disease and progressive supranuclear palsy, a rapidly progressing tauopathy that strikes in mid-life.
At the 2020 AAT-AD/PD Focus meeting, the company presented results from cell and animal models. In primary rat neuron/microglia co-cultures exposed to Aβ42, the compound reportedly promoted neuron survival and prevented neurite loss. It increased progranulin secretion, inhibited microglial activation and proinflammatory cytokine production, and decreased tau phosphorylation. In a naturally occurring mouse model of accelerated aging, called SamP8, AZP2006 reportedly prevented or reversed cognitive deficits, while decreasing phosphorylated tau, Aβ, oxidative stress, and neuroinflammation. In tau-overexpressing mice, AZP2006 was reported to decrease tau phosphorylation. A subsequent peer-reviewed publication included these results, and also reported reductions in phosphotau181 and markers of inflammation, along with improved learning and memory behaviors, in mice injected with Aβ (Callizot et al., 2021).
At the 2023 AD/PD conference, the company presented preclinical data in a Parkinson’s disease cell model. AZP2006 was claimed to normalize lysosome function and protect against α-synuclein toxicity in neurons bearing a Parkinson’s-associated mutation in the glucocerebrosidase gene GBA.
Findings
At AAT-AD/PD, the company presented on three Phase 1 studies conducted between 2015 and 2017 in France. The trials tested eight single doses from 3 to 500 mg, or multiple doses of 30, 60, or 120 mg daily for 10 days, in 88 healthy men. The trials revealed no safety issues.
In July 2019, the company registered a Phase 2 trial in patients with progressive supranuclear palsy (PSP). This biomarker-driven study will enroll 36 men and women age 40 to 80 with probable or possible PSP according to clinical criteria, at two hospitals in Paris and Lille. Participants will be randomized to three equal groups and receive 60 mg AZP2006 for 12 weeks; 80 mg for 10 days followed by 50 mg for 12 weeks; or placebo, taken as an oral solution once daily. The primary outcomes are safety and tolerability. Secondary and exploratory outcomes include CSF tau, phosphorylated tau, Aβ, progranulin, as well as biomarkers of oxidative stress, inflammation, and neurodegeneration. Recruitment is scheduled to begin in June 2020, and the trial will run through October 2021.
In June 2020, the company began a Phase 2 trial in patients with progressive supranuclear palsy. This biomarker-driven study enrolled 36 men and women age 40 to 80 with probable or possible PSP according to clinical criteria, at three hospitals in Paris and Lille. Participants were randomized to three equal groups and received 60 mg AZP2006 daily for 12 weeks; 80 mg for 10 days followed by 50 mg for 12 weeks; or placebo, taken as an oral solution once daily. Primary outcomes were safety and tolerability. Secondary and exploratory outcomes included CSF tau, phosphorylated tau, Aβ, progranulin, as well as markers of oxidative stress, inflammation, and neurodegeneration. The company presented results at the 2023 AD/PD conference. AZP2006 was well tolerated at the 60 mg dose, with no serious drug-related adverse events. Blood levels reached steady state four to six weeks after the start of dosing. Half-life was 30 days, and CSF concentrations reached about 3 percent of plasma levels. The treatment group had elevated plasma progranulin relative to baseline, and less decline in CSF progranulin than the placebo group. AZP2006 reduced total tau and phosphotau181 compared to baseline; no changes in other markers of neurodegeneration or inflammation were seen. The company reported numerical improvements in exploratory clinical endpoints of the PSP-Rating Scale score and gait score. The trial is continuing through July 2024 with an open-label extension treating 20 patients with 60 mg daily. The company is planning a 12-month, Phase 2/3 study in Europe and the U.S., to begin in 2024.
AZP2006 received orphan drug designation for PSP in Europe in 2015 and in the United States in 2017.
For details on AZP2006 trials, see clinicaltrials.gov.
Last Updated: 22 Nov 2023
Further Reading
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