Overview
Name: ALPHA-1062
Synonyms: GLN-1062 , Memogain
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Alpha Cognition, Galantos Pharma
Background
ALPHA-1062 is an inactive prodrug of galantamine. Originally synthesized as GLN-1062/Memogain, this compound is more lipophilic than galantamine, in order to facilitate its entry into the brain and enzymatically cleave there to release the active drug. The compound was developed at Galantos Pharma in hopes of increasing the brain bioavailability and reducing peripheral side effects of galantamine. Additional goals are to increase the effective dose in the brain and deliver a therapeutic effect rapidly, without the gradual titration up to effective dose that is commonly necessary with oral acetylcholinesterase inhibitors. GLN-1062/Memogain is delivered as a nasal spray formulation; ALPHA-1062 is a delayed release tablet taken by mouth.
In 2013, GLN-1062 was sold to the Canadian company Neurodyn for clinical development. In March 2020, Neurodyn changed its name to Alpha Cognition, and GLN-1062 became ALPHA-1062.
Preclinically, GLN-1062 was reported to improve cognition more strongly than did comparable doses of galantamine in mice, and to reduce vomiting in ferrets. Another study claimed five times higher potency than galantamine in rescuing scopolamine-induced memory impairment in mice, as well as improved memory performance and reduced plaque load in 5xFAD transgenic mice. Pharmacologically, GLN-1062/Memogain was reported to reach 10 times higher concentration in the brain than blood (see Maelicke et al, 2010; Bhattacharya et al., 2015).
Findings
In September 2014, Neurodyn issued a press release claiming that an initial trial in healthy young and old volunteers showed positive results. According to the company, the study primarily compared safety, tolerability, and pharmacokinetics of Memogain to the daily recommended dose of galantamine (16 mg) and donepezil (10 mg). All tested doses of Memogain were reportedly safe and well-tolerated; participants reported nausea at 16 mg of galantamine but not until 44 mg of Memogain. The company further claims that Memogain heightened vigilance and short-term memory in both young and old volunteers compared with untreated controls. The study was conducted in The Netherlands, and results were published after peer review (Baakman et al., 2016).
A second Phase 1 tested seven days of 5.5, 11, or 22 mg twice per day, or placebo, in 48 healthy elderly participants, also in The Netherlands (WHO trials registry). According to published results, Memogain was well-tolerated up to highest dose. A direct comparison of 11 mg Memogain to 16 mg oral galantamine documented fewer instances of diarrhea, nausea, or vomiting with Memogain; however, participants had more nasal discomfort and irritation with increasing dose. Treated participants improved in a test of attention, similar to the single-dose results (Bakker et al., 2020).
In September 2021, Alpha Cognition announced the acceptance of a new drug application for ALPHA-1062, a delayed-release, oral tablet form of the prodrug (press release). The company predicts that this prodrug will be absorbed intact into the small intestine, and activated in the liver, reducing GI side effects. The company is seeking marketing approval on the basis of bioequivalence, where the drug need only demonstrate comparable pharmacokinetics to marketed versions of galantamine. In 2022, Alpha Cognition reported positive results from two bioequivalence studies comparing a single dose of 5 mg ALPHA-1062 to 4 mg galantamine hydrobromide (name brand Razadyne) immediate release, or to 8 mg extended release in healthy adults (June press release; Aug press release). After a planned tolerability study in Alzheimer’s patients starting in late 2022, the company plans to file for FDA approval in 2023 (company presentation).
As of November 2022, no trials were listed in clinicaltrials.gov.
Last Updated: 03 Nov 2022
Further Reading
No Available Further Reading
Overview
Name: TPI 287
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease, Corticobasal Degeneration, Progressive Supranuclear Palsy
U.S. FDA Status: Alzheimer's Disease (Inactive), Corticobasal Degeneration (Inactive), Progressive Supranuclear Palsy (Phase 1)
Company: Cortice Biosciences
Background
TPI 287 is a tubulin-binding and microtubule-stabilizing drug that is being clinically developed by Cortice Biosciences, formerly Archer Biosciences. TPI 287 is an abeo-taxane—a synthetic derivative of the taxane diterpenoid drugs used in cancer therapy, such as paclitaxel. Unlike most taxanes, TPI 287 crosses the blood-brain barrier. It has been reported to accumulate in the brain over plasma, possibly because it is a poor substrate for the P-glycoprotein, aka multi-drug-resistance protein, which is located on epithelial cells of the blood-brain barrier and pumps drugs back out of the brain. For this reason TPI 287 is being evaluated for the treatment of brain cancer and primary tumors that have metastasized to the brain (Fitzgerald et al., 2012).
TPI 287 is also being evaluated for tauopathies. The physiological function of the protein tau includes stabilization of microtubules, and destabilization of these cytoskeletal components related to tau dysfunction is considered an important step in the axonal and dendritic degeneration that leads to neuronal death (for review, see Zempel and Mandelkow, 2014). Prior taxane drugs, e.g. epothilone D, have been tested in Alzheimer's disease, a tauopathy.
Findings
In November 2013, the University of California, San Francisco, began a Phase 1 trial of TPI 287 in 33 patients with mild to moderate Alzheimer's disease whose screening MRI was consistent with this diagnosis. Participants received intravenous infusions of one of three doses of TPI 287 or placebo once every three weeks for nine weeks; those who completed this regimen could opt to continue into an open-label extension comprising three additional infusions and safety monitoring. The primary goal of this study was to determine the maximal tolerated dose of this drug. The secondary goal was to measure drug exposure in plasma and CSF; additional outcome measures included CSF Aβ/tau biomarkers, MRI, and cognitive, behavioral, disability, and safety measures.
In May 2014, UCSF and the University of Alabama, Birmingham, began a Phase 1 study of TPI 287 in 66 patients who have a primary four-repeat tauopathy, either corticobasal degeneration (CBD) or progressive supranuclear palsy (PSP). To determine eligibility, this study used consensus criteria for PSP and CBD plus an MRI consistent with the clinical diagnosis. People with cortical amyloid on PET scans were excluded to limit the treatment group to participants with pure tau pathology. Like the AD trial, this study aimed to determine the maximum tolerated dose with a nine-week regimen of four infusions of one of three doses of TPI 287 or placebo, plus an optional six-week, open-label extension. It also used largely the same outcome measures. This study was supported by CBD Solutions and the Tau Consortium. In May 2015, reflecting the difficulty of enrolling patients with these rare tauopathies, the enrollment target was cut back to 44 and the age limit increased to 85.
Results of both trials were presented at CTAD (Dec 2017 conference news) and subsequently published (Tsai et al., 2019). A total of 29 AD, 14 PSP, and 30 CBS patients received doses of 2, 6.3, or 20 mg/meter2 TPI 287, or placebo. Three AD patients on the high dose suffered severe allergic reactions; the maximum tolerated dose for this group was 6.3 mg/meter2. On exploratory cognitive endpoints, MMSE scores declined less in the treated AD group than placebo; however, the placebo group declined faster than expected on MMSE, which may explain the difference. No other endpoints changed significantly.
The CBD/PSP group suffered no allergic reactions; their maximum tolerated dose was 20 mg/meter2. TPI 287, however, caused more falls in CBD and PSP patients, and this cohort had a dose-related worsening on the Clinical Dementia Rating-sum of boxes at three months.
The drug was undetectable in CSF one week after the last infusion. Among the exploratory biomarkers, only YKL-40, a marker of inflammation, was significantly lower in CSF in the drug-treated CBD/PSP group compared with placebo.
TPI 287 has also been tested in Phase 1 and 2 for a range of cancers, but no trials are currently active.
For all clinical trials of TPI 287, see clinicaltrials.gov.
Last Updated: 02 Dec 2019
Further Reading
No Available Further Reading
Overview
Name: Sembragiline
Synonyms: RO4602522, RG1577
Chemical Name: EVT302
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Evotech AG
Background
Sembragiline is an inhibitor of monoamine oxidase B (MAOB), a mitochondrial enzyme that inactivates the neurotransmitter dopamine, and in the process generates reactive free oxygen radicals. MAOB expression is increased in Alzheimer's brain, particularly in reactive astrocytes near amyloid plaques (Saura et al., 1994; Gulyas et al., 2011).
RG1577 was developed by Roche but first licensed to Evotech AG, which began developing it as EVT302 for the treatment of nicotine dependence. That development was discontinued in Phase 2 (see Berlin et al., 2012).
Evotech AG claimed on its website that EVT302 was safer and more tolerable than other MAOB inhibitors marketed for the treatment of Parkinson's disease (see company press release). The compound was reported to be more selective for MAOB over MAOA, a related enzyme that helps metabolize tyramine, a component of certain foods and beverages. For a review on MAO inhibitors, see Finberg, 2014.
Roche and Evotech partner in the development of EVT302/RG1577 for Alzheimer's disease, both to reduce oxidative stress in the brain and to treat dopamine-related symptoms in AD. Roche scientists reported that the compound in enzyme assays is 500-fold selective for human MAOB over MAOA, dose-dependently inhibits MAOB in rat brain at low doses, does not elevate blood pressure in the presence of tyramine, and reduces H2O2 production near amyloid deposits in AD brain sections (Borroni et al., 2013).
Findings
Between 2012 and 2014, Roche conducted four Phase 1 trials of RG1577 in Sweden, the Netherlands, and the United States. One assessed pharmacokinetics and elimination of the compound in six healthy men; one assessed its effect on the liver enzyme complex P450 with a probe compound, the antifungal ketoconazole, in 34 healthy men; and one measured target engagement of a multiple-dose regimen in the brain with a PET tracer in 17 healthy elderly men. The largest Phase 1 trial enrolled 183 healthy men and women in the United States; it is a two-part study to probe the safety of RG1577 at doses higher than the therapeutic dose and assess whether the compound affects cardiac function. In July 2014, the Japanese company Chugai was also testing this compound in Phase 1 (see pipeline).
In 2012, Roche began the MAyflOwer RoAD study. This is a Phase 2 trial to evaluate the safety and efficacy of RG1577 as an adjunct to cholinesterase inhibitor and/or memantine therapy. The trial enrolled 544 patients with moderate to severe Alzheimer's disease at 141 sites in North America, Australia, South Korea, and Europe. Participants received one of two doses of RG1577 or placebo for one year and were assessed on change in the ADAS-Cog-11, ADCS-ADL, and global and behavioral measures. In summer 2015, Roche announced that sembragiline, while safe, fell short of its primary endpoint in this trial (see July 2015 news) and, in October, removed it from its development pipeline. At CTAD in November, data were presented to indicate a possible benefit on behavioral symptoms in a more severely affected subpopulation.
For all clinical trials of this compound, see clinicaltrials.gov.
Last Updated: 20 Nov 2015
Further Reading
No Available Further Reading
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