Overview
Name: Telmisartan
Synonyms: Micardis
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Boehringer Ingelheim
Approved for: Hypertension
Background
Telmisartan is an angiotensin II receptor antagonist marketed around the world to treat elevated blood pressure and reduce the possibility of cardiovascular risk associated with chronic hypertension. Telmisartan is an alternative medication for people who are unable to take angiotensin-converting enzyme (ACE) inhibitors. In March 2014, a generic version became available in the U.S.
Angiotensin receptor blockers (ARBs) have been linked to reduced risk of AD. They act on the renin-angiotensin system, which regulates blood pressure in the body and the brain. Angiotensin II receptors also mediate inflammation, blood-brain barrier maintenance, and neuron survival. Genetic, epidemiologic, and biological evidence implicates changes in the brain renin-angiotensin system in Alzheimer’s disease (reviewed in Kehoe 2018). ARB use is associated with a reduced incidence of cognitive impairment, dementia, and AD (e.g., Wharton et al., 2015; Barthold et al., 2018; also see Walker et al., 2020). Telmisartan use has been associated with a lower risk of AD specifically in African Americans, and of dementia in East Asians with diabetes and hypertension (Zhang et al., 2022; Liu et al., 2021).
In people with mild cognitive impairment, use of ARBs, but not other antihypertensives, is linked to lower brain amyloid load and CSF tau (Hajjar et al., 2012; Hajjar et al., 2015).
Telmisartan has been proposed to slow AD pathogenesis by controlling cerebral blood flow, protecting the cerebral microvasculature, and reducing plaque formation in the brain (e.g., Baden et al., 2008; Mogi et al., 2008; Kurata et al., 2014). It acts via the peroxisome proliferator-activator receptor γ to reduce inflammation (Fu et al., 2023; Wang et al., 2020). Intranasal administration of telmisartan in the 5XFAD Alzheimer’s mouse model reduced amyloid burden and improved cognition (Torika et al., 2017).
Findings
Two clinical trials are evaluating telmisartan in Alzheimer's disease, both sponsored by academic medical centers, not the drug maker.
In spring 2014, a Phase 2 open-label drug repurposing study sponsored by the Alzheimer's Drug Discovery Foundation started up at three locations in Ontario, Canada. It enrolls 150 people with a clinical diagnosis of mild to moderate AD supported by an MRI scan consistent with that diagnosis. Participants take a one-year course of 40 or 80 mg of telmisartan or, as a comparator, 2, 4, or 8 mg per day of the angiotensin converting enzyme inhibitor (ACEI) antihypertensive drug perindopril. The primary outcome, besides safety, is ventricular enlargement as measured by MRI, to assess whether telmisartan slowed brain atrophy. Secondary outcomes are hippocampal, gray/white matter volume, and cognitive and functional measures. This trial is set to run until September 2023.
A Phase 1 study, sponsored by Emory University, started in April 2015 to enrolled 61 middle-aged African Americans who are at risk of Alzheimer's disease due to having both hypertension and a parent with Alzheimer's (Wharton et al., 2018). The study compared an eight-month course of either 20 mg or 40 mg telmisartan once daily to placebo for change in CSF angiotensin metabolites, Aβ and tau. Secondary outcomes included CSF markers inflammation, and structural and perfusion MRI. This trial finished in April 2022; results are not public.
For details, see clinicaltrials.gov.
Last Updated: 18 Oct 2023
Further Reading
No Available Further Reading
Overview
Name: Nuplazid
Synonyms: Pimavanserin, ACP-103, Pimavanserin tartrate
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia, Dementia, Depression
U.S. FDA Status: Alzheimer's Disease (Rejected), Schizophrenia (Discontinued), Dementia (Rejected), Depression (Discontinued)
Company: Acadia Pharmaceuticals
Approved for: Parkinson's psychosis
Background
Pimavanserin is a serotonergic agent, specifically a selective serotonin (5-HT) 2A receptor inverse agonist. In April 2016, the FDA approved this once-daily atypical antipsychotic to treat the delusions and hallucinations that are a feature of psychosis in Parkinson's disease, and it came on the market in the U.S. in June (Apr 2016 news; prescribing information). Pimavanserin is thought to have fewer adverse effects than older antipsychotic agents used to treat Parkinson's psychosis, but evidence remains limited (e.g., Sarva and Henchcliffe, 2016; Tampi et al., 2019).
The drug carries a black-box warning of increased mortality in elderly people. One large retrospective study reported a higher risk of death in nursing home residents with PD who were prescribed pimavanserin (Hwang et al., 2021), while other analyses found no extra risk (Moreno et al., 2018; FDA analysis). Debate continues regarding these results, and regarding the safety of pimavanserin in real-world use (e.g., see Ganesh and Galetta, 2022; Subbiah et al., 2022; Hwang et al., 2022). A meta-analysis of clinical trials involving 680 patients found significant reduction in hallucinations and delusions, with no change in other symptoms. Adverse events were similar to placebo, except that the pimavanserin group had less orthostatic hypotension (Mansuri et al., 2022). In a small retrospective study of 54 patients, half of patients showed initial improvement in psychosis, but only 15 percent maintained the benefit after a year of treatment (Akbar and Friedman, 2022). An analysis of Medicare beneficiaries with PD who were starting pimavanserin or an atypical antipsychotic indicated lower mortality with pimavanserin, but only during the first 180 days of treatment and only in community-dwelling, not nursing home, patients (Mosholder et al., 2022). Another study found similar reduced mortality for pimavanserin compared to other antipsychotics in the first 180 days, whether patients were at home or in a facility (Layton et al., 2023). A meta-analysis of real-world evidence reported that pimavanserin did not increase the mortality risk in PD psychosis, and performed similarly to other atypical psychotics used in this indication (Isaacson et al., 2024).
Pimavanserin affects heart rhythms and should not be used by people with arrhythmia or those who take drugs that prolong the QT interval. The most common adverse events seen in trials were peripheral edema, nausea, confusion, hallucinations, constipation, and gait disturbance, though Acadia argues that PD with psychoses itself is associated with a higher risk of falls (Forns et al., 2021). In post-marketing reports from the FDA adverse event database, hallucinations and death were most frequently mentioned, while newly identified side effects included sleep disorders and cognitive and behavior changes (Gu et al., 2024). An Acadia-funded analysis of Medicare records claimed that Parkinson’s patients in nursing homes who took pimavanserin had a lower risk of falls and bone fractures, hospitalizations, and emergency room visits, compared to those on other anti-psychotics (Rajagopalan et al., 2024; Rajagopalan et al., 2024). Analysis of a smaller number of Medicare beneficiaries found a lower risk of hospitalization, but similar mortality rates for pimavanserin users compared to quetiapine (Alipour-Haris et al., 2023). Phase 4/real-world trials in Parkinson's psychosis are ongoing (Dashtipour et al., 2021; Cusick and Gupta, 2021).
In efforts to expand the indications for Nuplazid, Acadia initiated trials for psychosis, agitation, and aggression in Alzheimer's disease, for psychosis related to all-cause dementia, and for schizophrenia, insomnia, PTSD, depression, and autism. A different serotonin 2A receptor inverse agonist, nelotanserin, was in Phase 2 development for dementia with Lewy bodies (DLB) but has been discontinued.
Serotonin receptor activation is known to inhibit brain Aβ peptide production by altering the cleavage of amyloid precursor protein (Sheline et al., 2014). In recent preclinical work, pimavanserin or another 5HT2A agonist, M100907, acutely reduced Aβ concentrations in brain interstitial fluid of APP/PS1 transgenic mice. Chronic administration to aged APP/PS1 mice decreased CSF Aβ and brain plaque pathology, and improved cognition (Yuede et al., 2021; Gründer and Cumming, 2021).
Findings
Between November 2013 and November 2016, Acadia conducted a Phase 2 study of pimavanserin in 181 nursing home residents in London, who had psychosis along with their clinical diagnosis of AD. Participants received a 12-week course of 40 mg pimavanserin or placebo, and were evaluated on the nursing home version of the neuropsychiatric inventory (NPI), the short form of the Cohen-Mansfield Agitation Inventory (CMAI-SF), and the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). The primary outcome was change from baseline to six weeks in the NPI-NH, on which lower scores mean fewer symptoms. By two weeks, both the placebo and pimavanserin groups had improved on the test. At six weeks, those taking the drug had a 39.5 percent reduction in NPI-NH scores, compared to 19.3 percent reduction in the placebo group. However, by 12 weeks, scores were down 40 percent from baseline in both groups. These results were presented at CTAD, and later formally published (Dec 2017 conference news; Ballard et al., 2018). A subsequent subgroup analysis claimed a larger treatment benefit in participants with more severe psychosis (Ballard et al., 2019). Another post hoc analysis reported that people who responded to pimavanserin with a 50 percent or greater reduction in psychotic symptoms also improved on measures of agitation and aggression (Ballard et al., 2020).
In November 2016, Acadia started SERENE, a Phase 2 study comparing the effect of 34 mg and 20 mg pimavanserin to placebo in people with agitation and aggression as part of their Alzheimer's disease, on the CMAI-SF as primary outcome. This trial anticipated enrolling 432 patients at 56 sites, but stopped randomizing patients in November 2017 and was marked as complete in March 2018, with 111 patients enrolled and 83 of them having completed treatment. In March 2019, the trial's status was further updated to "terminated." Results, as well as sponsor rules restricting principal investigators from discussing and publishing results, are published in the clinicaltrials.gov History of Changes section of this trial. At 111 actual participants, the trial was underpowered to detect a treatment effect. The SERENE trial had a one-year open-label extension study, which recruited 79 patients and ended in February 2019.
From 2017 to 2019, Acadia conducted a Phase 3 study at 101 study locations in the U.S., Europe, and Chile, to evaluate pimavanserin’s efficacy in preventing psychosis relapse in people who had previously responded to the drug. The HARMONY trial enrolled 392 participants with all-cause dementia who had had symptoms of psychosis for at least two months. In an initial, 12-week open-label phase, all participants took 34 mg pimavanserin with the option to drop to 20 mg. The 217 who responded with a decrease in psychotic symptoms continued into a 26-week double-blind period, in which they were randomized to pimavanserin or placebo. The primary endpoint was delay in psychosis relapse with a p value below 0.0033. Relapse was defined as hospitalization due to dementia-related psychosis, significant deterioration of dementia-related symptoms on clinical scales, withdrawal from the study due to lack of efficacy, or use of an off-label antipsychotic medication. Patients were followed until relapse occurred (Cummings et al., 2018). According to a company press release, an interim analysis indicated that this trial met its primary endpoint early, and the trial was stopped (Sep 2019 news). Trial results published after peer review reported that 13 percent of the pimavanserin group relapsed, compared to 28 percent in the placebo group (Tariot et al., 2021). Of the participants, 66 percent had Alzheimer’s, 15 percent had Parkinson’s, and the remainder had vascular dementia, dementia with Lewy bodies, or frontotemporal dementia. Common treatment-related adverse events were urinary tract infection, headache, and constipation. QT interval prolongation occurred in 1.3 percent of pimavanserin-treated people. The types of side effect commonly associated with antipsychotics were infrequent (see also Tariot et al., 2022).
In May 2018, Acadia started enrolling 300 people who had neuropsychiatric symptoms along with a neurodegenerative disease into a Phase 3 safety study, conducted at 116 sites in Europe, Asia, and North and South America. It enrolled patients living at home or in assisted living. The study compared the effect of an eight-week course of 34 mg pimavanserin to placebo on treatment-emergent adverse events, extrapyramidal symptoms, and the MMSE. In October 2019, enrollment was increased to 750. The study was completed in May 2022 with 784 participants. A one-year open-label extension with 595 participants ran through May 2023. According to published results, the incidence of adverse events was similar between pimavanserin and placebo, and the drug did not affect motor or cognitive function (Alva et al., 2024).
In June 2020, based on data from the HARMONY dementia trial, Acadia submitted a supplemental new drug application to the FDA for pimavanserin to treat hallucinations and delusions in people with dementia-related psychosis (press release). On April 5, 2021, the company announced that the agency had declined to approve, citing a lack of substantial evidence of effectiveness. The FDA reportedly noted the absence of statistically significant changes in some of the dementia subgroups, and low numbers of patients with less common dementia subtypes (press release). According to Acadia, the decision was unexpected, given that the FDA had previously approved the study design, which analyzed people with different types of dementia as a single group, and met its primary endpoints. The FDA also rejected results from the SERENE Alzheimer’s trial as supporting evidence, saying the single-center study was not adequate and well-controlled. In February 2022, Acadia resubmitted the application to seek approval for a narrower indication of Alzheimer’s disease psychosis (company release). On June 17, an FDA advisory committee voted 9-3 that the drug appeared to be ineffective for this indication (press release). On August 5, Acadia announced that the FDA had declined to approve pimavanserin (press release). The agency stated that the positive results in the Harmony study appeared to be driven by the robust response among the Parkinson’s dementia subgroup (e.g. see Weintraub et al., 2024). The FDA recommended that Acadia perform another trial for psychosis in Alzheimer’s dementia.
A meta-analysis of safety outcomes in four placebo-controlled trials, presented at CTAD 2020, indicated that the drug caused no cognitive decline. In people treated with pimavanserin for up to nine months, changes in MMSE scores were small and similar to placebo. Of 14 cognition-related adverse events, confusion and memory impairment were reported in all four studies and occurred in fewer than 2 percent of patients. Pimavanserin did not affect motor function.
In October 2020, a 130-person randomized controlled trial started evaluating pimavanserin for a treatment benefit on impulse control disorder in Parkinson's disease. It is projected to run until summer 2023, at 16 sites in France.
In June 2022, a PET study was planned to begin assessing 5HT2A receptor density and occupancy at baseline and after six weeks pimavanserin treatment in people with PD, using the 18FMH.MZ tracer (Kramer et al., 2020). The study began in January 2023 to enroll 75 patients at Vanderbilt University Medical Center, and will run until June 2025.
In March 2024, Acadia stopped all development of pimavanserin in non-Parkinson’s indications after the drug failed a Phase 3 trial for negative symptoms of schizophrenia (press release).
Several investigator-initiated studies are continuing to evaluate pimavanserin for psychosis in people with Lewy body dementia, for sleep and insomnia in people with PD psychosis, and for PTSD, aggression, and autism spectrum disorder symptoms.
For all trials of pimavanserin, see clinicaltrials.gov.
Last Updated: 02 Aug 2024
Further Reading
No Available Further Reading
Overview
Name: Xanamem
Synonyms: UE 2343
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Actinogen Medical
Background
Xanamem is an inhibitor of 11β-hydroxysteroid dehydrogenase type 1, an enzyme in the hypothalamic-pituitary-adrenal (HPA) axis of the body's stress response. 11β-HSD1 converts the stress hormone cortisol to its active form, which binds to glucocorticoid receptors.
A growing body of evidence has begun linking a chronically active stress response, particularly the HPA axis, to amyloid plaque and neurofibrillary pathology deposition in mouse models of Alzheimer’s disease (Dec 2011 conference news). More recently, six-year longitudinal data of the AIBL natural history study was reported to show faster cognitive decline in amyloid-positive participants whose plasma corticol levels were elevated (Pietrzak et al., 2017). 11β-HSD1 acts peripherally and centrally, and has become a drug target (Martocchia et al., 2011).
UE 2343 was originally developed by Corticrine, a venture of the University of Edinburgh; in November 2014 Corticrine was acquired by the Australian biotech company Actinogen Medical.
Another HSD1 inhibitor, Abbvie's ABT-384, was evaluated in Phase 2 in mild to moderate Alzheimer's disease, where it inhibited the enzyme and reduced cortisol levels in the brain, but did not improve cognition.
Findings
In 2013, a Phase 1 study conducted in 48 healthy volunteers in Scotland evaluated the safety, blood exposure, and pharmacokinetic parameters of UE 2343 administered as oral capsules.
In 2015, a second Phase 1 trial in 40 healthy volunteers in Western Australia evaluated 10, 20, or 35 mg doses given twice daily for nine days in a crossover design. Outcome measures were safety and tolerability, plus a detailed set of blood and urine pharmacokinetic measures. The trial listing includes no CSF measures in its outcomes, but mentions a blood-brain barrier measure as part of a protocol amendment. In September 2015, Actinogen Medical announced that lumbar punctures after treatment day five had shown Xanamem crossed the blood-brain barrier "in concentrations that are predicted to very effectively inhibit the 11β-HSD1 enzyme in the brain." Phase 1 results were subsequently published (Webster et al., 2017).
In March 2016, Actinogen listed a Phase 2 trial that was to enroll 200 people with a clinical diagnosis of mild Alzheimer's disease. To ascertain the diagnosis, participants had to have declined over the six months prior to screening and have an MRI scan consistent with AD, but no amyloid-based biomarker was required. The original study protocol compared a 12-week course of 35 mg twice daily with placebo for change in the ADAS-COG14 and AD Composite Score. ADCOMs is a new measure for mild AD that combines elements from the ADAS-Cog v14, Clinical Dementia Rating Scale-Sum of Boxes (CDR-SOB), and Mini-Mental Status Examination (MMSE). Secondary outcomes included the Rey Auditory Verbal Learning Test (RAVLT), CDR-SOB, Mini-Mental Status Examination (MMSE), Neuropsychiatric Inventory (NPI), and Neuropsychological Test Batteries-Executive Domain. The trial also used 14 voluntary outcomes spanning markers of safety, metabolic function, pharmacodynamic changes in blood cortisol, hormones related to cortisol, and drug exposure in the blood. Before enrollment began, the drug dose was lowered to 10 mg once daily. The trial began recruiting in March 2017, at 25 sites in Australia, the U.S., and the U.K.
In May 2019, Actinogen announced the trial had failed to meet either of the primary endpoints. Xanamem was well-tolerated, with no safety concerns. Actinogen presented no data on cortisol levels, but showed changes in cortisol-related hormones in the expected directions in the treatment group. Results were subsequently posted on clinicaltrials.gov. In October 2022, Actinogen offered a new analysis of the trial data, claiming that a subset of participants with high plasma ptau181 showed less decline in the CDR-SB after 12 weeks treatment compared to placebo (company presentation).
January 2019 saw the start of a new, higher-dose safety study of Xanamem in 84 healthy volunteers age 50 to 75. In this single-center Phase 1 study, 30 people were to take 20 mg and 12 placebo once daily for 12 weeks. Pending results, a dose escalation committee would decide whether to start 42 additional participants on 30 mg once daily or placebo. The study monitors participants for changes in blood and liver markers, ECG, signs of peripheral neuropathy, and suicide risk. Secondary measures include changes in cognitive performance on the CogState battery and serum cortisol.
On September 30, 2019, Actinogen announced completion of the trial’s 20 mg portion. Treatment was associated with a benefit in two of the six tests making up the CogState battery (see press release). Besides statistically significant changes in working memory (p<0.01) and visual attention (p=0.05), Actinogen reported a trend toward improvement in reaction speed (p=0.09), but no effect on three other domains. Treatment resulted in a significant reduction in serum cortisol, without serious adverse events.
A target occupancy study using an 11b-HSD1-specific PET tracer indicated maximum target occupancy was achieved at the 20 mg dose, and the company decided not to proceed with the 30 mg dose (Apr 2020 conference news).
In June 2021, a Phase 1/2 short-term efficacy trial began testing 5 and 10 mg daily against placebo in 107 healthy volunteers. The primary outcome was change on a modified Cogstate battery, and safety, after six weeks of treatment. The trial, at five sites in Australia, finished in February 2022. According to a June 2023 company presentation, the combined 5 and 10 mg groups improved on an attention composite at weeks 4 and 6, but not at week 10 (slides),
In November 2022, the company began a Phase 2 study testing six weeks of 10 mg daily to improve cognition in people with major depressive disorder and cognitive impairment.
In November 2023, Actinogen Medical registered a Phase 2b trial of a 36-week course of 10 mg Xanamem or placebo in 220 people with mild to moderate Alzheimer's dementia. Three primary outcomes include a custom global cognitive test battery and safety measures. Eleven secondary outcomes include seven clinical/cognitive/psychiatric measures such as the CDR-SB and the Amsterdam Instrumental Activities of Daily Living, plus blood biomarkers and participant/care partner global impressions. To be conducted at nine sites across Australia, the trial had not yet begun recruiting as of January 3, 2024.
For all trials of Xanamem, see clinicaltrials.gov.
Last Updated: 03 Jan 2024
Further Reading
No Available Further Reading
Overview
Name: UB-311
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: United Neuroscience, Vaxxinity
Background
UB-311 is a synthetic peptide vaccine developed by United Neuroscience, a spin-off of United Biomedical. UB-311 couples a helper T-cell epitope designed with United Biomedical's UBITh® platform to the Aβ1–14 sequence, packaged in a proprietary vaccine-delivery system. The approach aims to stimulate a T-helper type 2 regulatory immune response over a T-helper type 1 proinflammatory response, and to avoid cross-reactivity with similar endogenous antigens, i.e., autoimmune responses.
A peer-reviewed paper on preclinical studies in small animals, baboons, and macaques reported that the vaccine generated N-terminal anti-Aβ antibodies, which neutralized Aβ toxicity and promoted plaque clearance. The paper also claimed that the vaccine evoked no anti-Aβ cellular responses in a transgenic mouse model for AD, and that both acute and chronic dosing were safe and well-tolerated in cynomolgus macaques (Wang et al., 2007).
Findings
In 2010/2011, a Phase 1 safety, tolerability, and immunogenicity trial evaluated three doses of UB-311 in 19 people with mild to moderate Alzheimer's disease, 14 of whom continued into a long-term follow-up study. At two sites in Taiwan, three shots were administered intramuscularly at baseline, four weeks, and 12 weeks; the follow-up study observed participants out to 48 weeks. Results were reported to have shown that the vaccine was safe and well-tolerated, with the most common adverse events being injection site swelling and agitation. UB-311 produced a specific antibody response in all participants tested (Wang et al., 2017). At CTAD 2017, company scientists claimed the elicited antibodies bound Aβ oligomers, fibrils, and plaques, but not monomers. They reported no amyloid-related imaging abnormalities after vaccination (Dec 2017 conference news).
In October 2015, a Phase 2 trial at four sites in Taiwan started enrolling 43 people with a diagnosis of mild Alzheimer's disease confirmed by amyloid PET, an MMSE between 20 and 26, and a CDR of 0.5 or 1. This study compared two dosing regimens—three priming shots followed by two boosters, and three priming shots followed by four boosters—to placebo, administered over 60 weeks. Besides primary outcomes of safety/tolerability and immunogenicity, this study also assessed cognitive, functional, global, and neuropsychiatric outcomes 18 weeks after the last dose. A safety extension began in August 2018, with 34 participants receiving three or five additional vaccinations over 96 weeks.
In a January 2019 press release, the company announced results of the placebo-controlled portion of the study. UB-311 was safe and generated Aβ antibodies in 96 percent of participants. Changes in secondary endpoints reportedly favored immunization but missed statistical significance. According to results presented at the 2020 CTAD conference, people who received four boosters declined only half as much on the CDR-SB, ADCS-ADL, ADADS-Cog as those who received two boosters or placebo. The same group also showed a modest reduction in brain amyloid at the end of the study. Adverse events data are posted on clinicaltrials.gov. None were judged to be caused by the drug. Results were published after peer review (Yu et al., 2023).
In December 2019, United Neuroscience terminated the extension of this trial based on “a treatment assignment error.” No further information is available.
At CTAD 2020, a Phase 3 development plan was presented, consisting of two identical, double-blind, placebo-controlled, 73-week studies. The parallel trials are to enroll a total of 3,218 participants with MCI or mild AD, who are to receive three priming and four booster immunizations. The CDR-SB is planned as the primary outcome; secondary and exploratory outcomes include a range of cognitive, functional, and biomarker measures. No start date or study locations were announced, and the study was not listed in clinical trial registries. United Neuroscience has been renamed Vaxxinity.
In May 2022, the U.S. FDA granted UB-311 fast-track designation for Alzheimer’s disease, facilitating expedited development and review.
As of January 2023, the company is seeking a partner for Phase 3 development, and has not registered nor begun a large trial of UB-311 (investor presentation slide #10).
For all English-language clinical studies, see clinicaltrials.gov.
Last Updated: 07 Feb 2023
Further Reading
No Available Further Reading
Overview
Name: S47445
Synonyms: CX1632
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Cortex Pharmaceuticals, Inc., Servier
Background
S47445 is an agonist of AMPA receptors for glutamate, the major excitatory neurotransmitter in the brain. S47445 is being developed for the treatment of Alzheimer’s disease and depression. Originally discovered by Cortex, now called RespireRx Pharmaceuticals, and then licensed to Servier, S47445 arose from the same Ampakine® technology that previously generated CX516, now discontinued.
AMPA receptor modulators, aka ampakines, have been studied for some years as potential therapeutics for the cognitive component of various neurological disorders (for review, see Lee et al., 2016). Preclinical characterization of this compound has not been published.
Findings
Phase 1 trials of this compound are not listed in public trials registries.
In February 2015, a Phase 2 study began enrolling 520 people with a clinical diagnosis of both depression and probable Alzheimer's disease of mild to moderate severity. Biomarker ascertainment of the diagnosis was not required. The trial compared a six-month course of either 5, 15, or 50 mg of S47445 or placebo, taken once daily, against change on the ADAS-cog as a primary outcome. Secondary outcomes included a range of clinical measures of cognition, global function, vital signs, and depression; no biomarkers. The study was being conducted at 78 locations in 12 countries in Central and South America, Central and Eastern Europe, Japan, and South Africa.
At the 2017 CTAD conference, Servier announced it will end its work with S47445 in Alzheimer’s, because the trial found no significant differences between drug and placebo groups on the primary outcome or on secondary measures of daily function or depression for either of the three doses used. The drug did get into the CSF, increased glutamate in the brain, and was safe, yet failed to show the desired benefit (see Dec 2017 conference news).
For all trials of this compound, see clinicaltrials.gov.
Last Updated: 25 Nov 2016
Further Reading
No Available Further Reading
Overview
Name: Nelotanserin
Synonyms: APD-125
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Dementia with Lewy Bodies
U.S. FDA Status: Dementia with Lewy Bodies (Discontinued)
Company: Axovant Sciences Ltd.
Background
Nelotanserin is a serotonin, aka 5HT, 2A receptor inverse agonist. Originally called ADP-125, the compound was developed by Arena Pharmaceuticals as a treatment for insomnia, but failed efficacy measures for this indication in Phase 2. In 2015, Axovant Sciences licensed this compound for development, renamed it nelotanserin, and began evaluating it in dementia with Lewy bodies (DLB).
Findings
In December 2015, Axovant started a Phase 2 study in 30 people who had DLB or Parkinson’s disease dementia (PDD) with visual hallucinations. Participants took first 40 mg, then 80 mg, of nelotanserin or placebo once daily for 28 days, and then underwent evaluation for safety, extrapyramidal signs, and whether the frequency and intensity of their hallucinations had changed since baseline. This study was conducted at eight sites in the U.S. In March 2016, a second Phase 2 trial at 23 centers across the U.S. started enrolling what was to be 60 people with a diagnosis of DLB or PDD and frequent episodes of REM sleep behavior disorder; 29 were actually enrolled. Participants took 80 mg of nelotanserin or placebo once daily for 28 days. They were clinically evaluated on change in frequency of RBD since baseline, as well as on severity of their RBD episodes, and safety parameters. This trial ran until May 2018. An open-label extension study for participants in either trial evaluated safety, and efficacy on the hallucination and RBD endpoints of once-daily nelotanserin doses ranging from 20 to 80 mg. It was to run through summer 2019.
In January 2018, Axovant reported results of the first trial. Nelotanserin was well tolerated but produced no changes in any endpoints except for a trend toward improvement in motor function in the UPDRS-III. In a subgroup analysis of 19 DLB patients, a benefit on UPDRS-III was claimed to be statistically significant (Jan 2018 news).
In December 2018, the company announced it was ending development, after nelotanserin failed to reduce RBD events in the second trial (see company press release).
In 2008, nelotanserin was found to be safe but missed primary and secondary endpoints in a Phase 2b trial in 744 people with primary insomnia. In an earlier trial, completed in 2007, in 173 participants with primary insomnia, both 10 and 40 mg oral doses were reported to have improved maintenance and consolidation of sleep, without detrimental cognitive effects the next morning (Rosenberg et al., 2008).
For all clinical trials on this compound, see clinicaltrials.gov/nelotanserin and clinicaltrials.gov/APD125.
Last Updated: 11 Feb 2019
Further Reading
No Available Further Reading
Overview
Name: AVP-786
Therapy Type: Combination, Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia
U.S. FDA Status: Alzheimer's Disease (Discontinued), Schizophrenia (Discontinued)
Company: Avanir Pharmaceuticals, Concert Pharmaceuticals, Inc., Otsuka Pharmaceutical Co., Ltd.
Background
This investigational therapeutic is a deuterated, second-generation version of AVP-923/Nuedexta, a fixed-dose combination of two approved drugs.
Both AVP-923 and AVP-786 contain dextromethorphan, the active ingredient in several brands of cough syrup. Dextromethorphan is a weak antagonist of NMDA receptors, and an agonist of sigma 1 receptors, molecular chaperones located in membranes of the endoplasmic reticulum. Both AVP-923 and AVP-786 also contain quinidine. Otherwise prescribed to treat irregular heartbeat, quinidine in this combination increases the bioavailability of dextromethorphan by slowing its oxidative metabolism by the liver enzyme cytochrome P450-2D6 and by inhibiting the blood-brain barrier protein pump P-glycoprotein.
AVP-786 differs from its predecessor in that it contains deuterium, a naturally occurring, heavier isotope of hydrogen. As developed by Sun Pharma, formerly Concert Pharmaceuticals, deuterium chemistry leaves a drug's mechanism of action fundamentally unchanged but can alter its pharmacokinetic properties, for example by slowing its liver metabolism, prolonging exposure in the blood, or reducing its side effect profile.
Avanir engineered AVP-786 together with Concert Pharmaceuticals. In 2014, Otsuka Pharmaceutical Co. acquired Avanir.
Findings
AVP-786's clinical development began in October 2012 with a Phase 1 trial in 48 young, healthy volunteers. It tested safety, tolerability, and pharmacokinetics of deuterated dextromethorphan only. In September 2013, Avanir started a second Phase 1 trial in 56 young, healthy people of deuterated dextromethorphan with a low dose of quinidine sulfate added back in, and compared a one-week course of this combination to AVP-923. Both trials took place in Australia. The company reported that AVP-786 achieved the same steady-state plasma concentrations of dextromethorphan as AVP-923, at a lower quinidine dose (Feb 2013 press release). All subsequent trials use the deuterated combination.
In 2014 and early 2015, Avanir ran three additional Phase 1 trials. One directly compared AVP-786 to AVP-923 in 62 slightly older healthy volunteers in the U.S.; one looked for drug interactions between AVP-786 and two antidepressant medications, paroxetine and duloxetine, in 56 healthy volunteers in Australia; the third trial compared AVP-786 and AVP-923 for their respective interactions with the antifungal itraconazole in 24 healthy adults in Kansas.
In November 2015, the FDA fast-tracked AVP-786 for agitation.
Also that month, Avanir/Otsuka started enrolling for TRIAD-1 and TRIAD-2, two Phase 3 trials to evaluate the combination's efficacy in 325 and 380 patients, respectively, who have moderate Alzheimer's disease with clinically significant agitation. Both trials enrolled the same patient population, both evaluated a 12-week course of twice-a-day AVP-786 administration, and both are conducted in the U.S. and Canada.
Both trials used the same outcome measures. The primary outcome was the Cohen Mansfield Agitation Inventory (CMAI); secondary outcomes included the neuropsychiatric inventory (NPI), the agitation component of the ADCS-CGIC, and other global, quality of life, resource utilization, and cognitive measures. The trials compared two different doses of drug to placebo, but with slightly different designs. TRIAD-1 used a sequential design aimed at minimizing the influence of placebo responders on the outcomes. A sequential design was used in the previous Phase 2 trial of AVP-923, where the drug improved AD-related agitation (Cummings et al., 2015). TRIAD-2 uses a traditional, three-arm parallel comparison.
A third Phase 3 trial began in October 2017. A worldwide version of TRIAD-2, it aimed to enrolling 550 people at 118 study locations in the U.S., Europe, and South Africa, and was planned to run through July 2022.
In March 2019, Avanir announced that the TRIAD-1 sequential design trial met its primary endpoint. According to the company press release, one of the two dose groups improved their scores on the CMAI and on "the key" secondary endpoint, though Avanir did not disclose which secondary endpoint. A trend for a treatment benefit in the other dose group missed statistical significance. Most common adverse effects in the 410-patient study were falls, urinary tract infection, headache, and diarrhea; there were no deaths related to treatment.
In September 2019, the company disclosed negative results for TRIAD-2. In this study of 522 patients in three parallel arms, AVP-786 did not improve agitation compared with placebo (Oct 2019 news). Again, adverse events included falls and urinary tract infection, as well as somnolence, with no deaths related to AVP-786. Soon after, Avanir announced plans to continue clinical development of AVP-786, including the ongoing worldwide Phase 3 (Nov 2019 press release).
A 52-week extension trial of AVP-786 began in 2015 for people who had completed an earlier Phase 2 study of AVP-923, and people who completed any of the Phase 3 trials. It administers one of three doses; all participants know they are on drug, but the trial is blinded to dose. This trial was to enroll 1,000 people, and run until October 2023. It was later enlarged to 1,200 participants, and extended to July 2025.
In 2020, Avanir began two additional Phase 3 trials of AVP-786 in people with AD-associated agitation. In each, 750 participants will be randomized to twice-daily drug or placebo for 12 weeks. CMAI is the primary outcome, and Clinical Global Impression of Severity of illness (CGI-S) is the sole secondary measure. The trials are being conducted at 110 centers worldwide, through December 2024.
On February 12, 2024, the company announced negative topline results of the worldwide TRIAD Phase 3 study (press release). CMAI did not differ between drug and placebo. Falls were more common in the treated group than among patients on placebo.
AVP-786 was also being studied in schizophrenia, but a Phase 2/3 trial was terminated for futility. A trial in intermittent explosive disorder (Rynar and Coccaro, 2018) was stopped due to difficulty recruiting. Trials were completed for behavioral disinhibition (aggression, agitation, and irritability) in patients with traumatic brain injury, and treatment-resistant depression.
On May 22, 2024, Otsuka announced the termination of AVP-786 development for Alzheimer’s agitation (press release).
For all trials on this medication, see clinicaltrials.gov.
Last Updated: 03 Jun 2024
Further Reading
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Overview
Name: Aripiprazole
Synonyms: Abilify, BMS-337039
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia
U.S. FDA Status: Alzheimer's Disease (Phase 3), Schizophrenia (Approved)
Company: Bristol-Myers Squibb, Otsuka Pharmaceutical Co., Ltd.
Background
Aripiprazole is an antipsychotic medication that was FDA-approved in 2002 for the treatment of schizophrenia and is widely used for related affective disorders, as well. Generic versions started becoming available in 2015.
This drug affects multiple receptors, acting as a partial agonist at dopamine and serotonin 1A receptors, and an antagonist at serotonin 2A, α 1 adrenergic, and other receptors.
Aripiprazole has been investigated for its effects on psychosis in patients with moderate to advanced AD, and is currently being investigated for agitation in this population. In the 1990s and early 2000s, several different atypical antipsychotics drugs were being widely prescribed to AD patients to alleviate their symptoms of psychosis and agitation, particularly in nursing homes. Soon after aripiprazole's approval, studies reported increased mortality, stroke, and faster cognitive decline, and meta-analyses reported this to be a class effect of both typical and atypical antipsychotics in this population, triggering an FDA warning (see Oct 2005 news). This led to calls for more research on treatment options for psychosis and agitation in AD (e.g. Ballard and Corbett, 2010). Aripiprazole is among the newer antipsychotic drugs with a lower side effect profile (De Deyn et al., 2013).
Findings
Clinicaltrials.gov lists two Phase 3 studies on aripiprazole in psychosis in AD as having been conducted prior to the 2005 FDA warning. They were not randomized controlled trials (RCT), and dose and patient number is not listed. One Phase 3 RCT on 232 AD patients was conducted over a period of 10 years starting in 2000, evaluating doses ranging from 1 to 15 mg in an acute phase of 10 weeks plus an extension phase of 2.5 years. Results from this trial are posted on clinicaltrials.gov, and show no statistically significant difference on the primary outcome, the NPI.
In 2007, a peer-reviewed paper of a multicenter RCT not listed in clinicaltrials.gov reported 5 and 10 mg of aripiprazole to be safe and somewhat effective at reducing psychosis in Alzheimer's dementia (Mintzer et al., 2007). A subsequent paper reported that the drug did not improve psychotic symptoms but did improve psychological and behavioral symptoms such as agitation, anxiety, and depression in an RCT conducted in 256 nursing home residents with Alzheimer's dementia (Streim et al., 2008).
Between 2003 and 2005, Otsuka conducted a Phase 3 study comparing the tolerability of injecting aripiprazole solution or placebo intramuscularly during acute episodes of agitation in 129 patients with Alzheimer's or vascular or mixed dementia. This study was conducted in nursing homes in the United States, and reported to have shown both more side effects and more efficacy with aripiprazole injections than placebo (Rappaport et al., 2009).
Following the FDA warning, in August 2005 Otsuka started a Phase 4, five-year, open-label study at the University of California, San Diego, comparing side effects of aripiprazole, olanzapine, and risperidone in 406 people with a DSM-IV diagnosis that requires treatment with an antipsychotic medication.
In June 2014, Otsuka started a Phase 3 trial in Japan enrolling 880 people with a clinical diagnosis of AD and an MMSE of between 1 and 22. The study compares a 10-week course of once-daily doses of 2, 3, or 6 mg aripiprazole or placebo for change from baseline on the Cohen Mansfield Agitation Inventory. The trial is set to run until July 2017.
For all trials of aripiprazole in Alzheimer's dementia, see clinicaltrials.gov.
Last Updated: 18 Nov 2016
Further Reading
No Available Further Reading
Overview
Name: Lu AF20513
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Lundbeck, Otsuka Pharmaceutical Co., Ltd.
Background
This active vaccine was designed to overcome the weak immune system of aged populations while avoiding auto-immune T cell responses. The Lu AF20513 epitope intersperses three repeats of the first 12 amino acids of the Aβ peptide with sequences of tetanus toxin. The goal of this kind of mixed-peptide engineering is to rouse an elderly population of non-self memory T cells originally generated by childhood tetanus vaccinations to stimulate T helper cells, which in turn activate a B cell response to produce polyclonal antibodies against Aβ. A preclinical study in mice, guinea pigs, and monkeys characterized the cellular and humoral immune response against this vaccine, reporting high Aβ titers, no autoreactive T cells, and removal of brain amyloid deposits (Davtyan et al., 2013).
Findings
In March 2015, an open-label Phase 1 trial started to enroll 50 people with probable Alzheimer's disease, a CSF Aβ antibody measurement, and a recent MRI consistent with an AD diagnosis. The trial administered multiple shots of either a low, medium, high, or double-high dose to participants, and measured antibody titers as well as safety and tolerability over a period of two years. It took place in Austria, Finland, and Sweden. The trial was terminated in November 2019.
For more detail, see clinicaltrials.gov.
Last Updated: 12 Oct 2021
Further Reading
No Available Further Reading
Overview
Name: Semorinemab
Synonyms: RO7105705 , MTAU9937A, RG6100
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Company: AC Immune SA, Genentech, Hoffmann-La Roche
Background
This is an anti-tau IgG4 antibody that grew out of a research collaboration between AC Immune and Genentech, part of the Roche Group. The collaboration focused on approaches that target extracellular, not intracellular, tau. The aim was to explore antibodies with reduced effector function in an effort to limit microglial activation leading to inflammatory responses (Lee et al., 2016). At the 2017 AD/PD conference, Genentech reported that RO7105705 binds the N-terminus of all six isoforms of human tau, both monomeric and oligomeric, regardless of phosphorylation status, and that 13 weeks of treatment with either 3, 10, or 30 mg/kg of the antibody dose-dependently reduced brain pathology while raising plasma tau levels in P301L mice. Chronic dosing was safe in mice or cynomolgus monkeys, Genentech also reported (Apr 2017 conference news).
Findings
From June 2016 to June 2017, Genentech ran a Phase 1 study of 74 volunteers comprising both healthy controls and people with mild to moderate Alzheimer's disease. Conducted in Tennessee, this trial compared the antibody to placebo on safety, tolerability, pharmacokinetics, and preliminary activity outcomes. It combined single doses, dose escalation, and multiple dosing, given both intravenously and subcutaneously. At the 2017 AD/PD and AAIC conferences, Genentech reported that single doses in healthy volunteers went as high as 16,800 mg, with a 15-day window observed between a given dose and the next-higher dose, and that 70 percent of the subcutaneous doses were bioavailable. Results remained blinded at this point in time, but the trial had not generated serious adverse events; minor AEs related to the drug included bruising and pain at the injection site. RO7105705 plasma half-life was 32 days, and plasma and CSF concentration increased with dose (Apr 2017 conference news; Aug 2017 conference news). Phase 1 data was subsequently published (Ayalon et al., 2021).
In October 2017, Genentech started TAURIEL, a Phase 2 study in 457 people with prodromal or probable AD ascertained by a positive amyloid PET or CSF Aβ42 finding, and mild symptoms. Participants were randomized to an 18-month course of monthly infusions of placebo or 1,500, 4,500, or 8,100 mg of RO7105705, with a 96-week open-label extension option for those who completed the blinded portion of the trial. This trial used Genentech's tau PET tracer GTP1 at baseline and to measure treatment response at week 73. Primary outcomes were change on the CDR sum of boxes and safety; secondary measures include the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), the new Amsterdam Instrumental Activity of Daily Living questionnaire, the ADAS-Cog13 and ADCS-ADL Inventory, as well as serum drug concentration and anti-drug antibodies. This trial ran at 97 locations in North America, Australia, and various European countries.
The placebo-controlled phase completed in July 2020 and in September, Genentech reported top-line results. Semorinemab missed the primary efficacy endpoint of reducing decline on the CDR sum of boxes, and missed on both of two secondary endpoints, the ADAS-Cog13 and ADCS-ADL (press release). According to results presented at the 2020 CTAD, there was no change in any other secondary clinical endpoint, either, nor did the antibody slow tangle accumulation in brain relative to placebo. Tau-PET showed a significant increase from baseline in all groups by 12 months, and continued accumulation out to 18 months. Antibody pharmacokinetics were dose-proportional, and the two highest doses elicited maximal increases in plasma tau. The drug was safe. The company terminated the trial during the open-label period, and it ended in January 2021. Additional biomarker data were presented at AD/PD 2021 (Mar 2021 conference news). CSF total tau and phosphorylated tau decreased in all treated groups, but downstream markers of neurodegeneration and inflammation did not change. Trial results were published after peer review (Teng et al., 2022).
In February 2019, Roche started LAURIET, another Phase 2 study in 272 people with a diagnosis of probable AD confirmed by amyloid positivity via PET or CSF testing, and with moderate dementia. The study comprised a screening, double-blind treatment, optional open-label extension period, and a safety follow-up period. The study was to have up to three cohorts, receiving 4,500 mg monthly for 48, 60, or 72 weeks, though the last cohort was never enrolled. Co-primary endpoints were change from baseline on both ADAS-Cog11 and ADCS-ADL; secondary endpoints included CDR-SB, MMSE, adverse events, serum concentration of RO7105705, and anti-drug antibodies to RO7105705. This trial used GTP1 to monitor tauopathy. It ran at 49 sites across the United States, France, Poland and Spain. The placebo-controlled part of the study ran until July 2021, and the study was completed in August 2023.
On August 31, 2021, the sponsors announced topline results indicating a 43.6% slowing of decline on the ADAS-Cog11 co-primary, though no benefit of the other cognitive or functional outcomes (see Sep 2021 news). A Phase 3 decision is pending additional data from LAURIET's ongoing long-term extension study and biomarker measurements. In November at CTAD, Genentech showed this trial's data, and reported the treatment did not change tangle accumulation measured by GTP1 PET (Nov 2021 conference news). According to published results, most of the benefit on the ADAS-Cog was driven by the memory domain, specifically word recognition (Monteiro et al., 2023). This could explain the lack of effect on other outcome measures, or may be a false positive result (see accompanying 2023 editorial by Edland and Llibre-Guerra). As in TAURIEL, the LAURIET CSF substudy found significant reductions in total tau and ptau181, suggesting target engagement. Modeling of semorinemab pharmacokinetics and plasma tau measures across the trials suggested greater than 90 percent peripheral target engagement (Ramakrishnan et al., 2024). A separate computational modeling study claimed that target engagement in the synaptic cleft, the location of tau propagation, could be as low as 1 percent (Geerts et al., 2023).
On January 22, 2024, Genentech and Roche ended its collaboration with AC Immune to develop semorinemab (press release).
An evaluation of putative biomarkers for neuroinflammation identified multiple complement proteins to be elevated in AD patient CSF compared to cognitively unimpaired elderly. However, CSF samples from TAURIEL and LAURIET showed no difference in these proteins in treated versus placebo groups (Sandoval et al., 2024).
For all trials with this antibody, see clinicaltrials.gov.
Last Updated: 09 Nov 2024
Further Reading
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