Overview
Name: MKC-231
Therapy Type: Small Molecule (timeline)
Target Type: Unknown
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Company: Mitsubishi Tanabe Pharma
Approved for: None
Background
MKC-231 is reported to enhance high-affinity choline uptake (HACU), a rate-limiting step in acetylcholine synthesis (Takashina et al., 2008).
Last Updated: 09 Jan 2014
Further Reading
No Available Further Reading
Overview
Name: Milameline
Synonyms: CI 979
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Aventis Pharmaceuticals, Inc. (was Hoechst)
Approved for: None
Background
Milameline is a muscarinic receptor agonist with approximately equal affinities determined at the five subtypes of human muscarinic receptors (hM1–hM5) (Schwarz et al., 1999).
Last Updated: 12 Dec 2013
Further Reading
No Available Further Reading
Overview
Name: Metrifonate
Synonyms: trichlorfon
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Approved for: None
Background
Metrifonate is a long-acting irreversible cholinesterase inhibitor. It was originally used to treat schistosomiasis.
Last Updated: 09 Oct 2023
Further Reading
No Available Further Reading
Overview
Name: Memantine
Synonyms: Ebixa™, Namenda™ , Axura®, Akatinol®, Memary®
Chemical Name: 3, 5-Dimethyl-1-adamantanamine hydrochloride
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Approved)
Company: Forest Laboratories, Inc., Lundbeck, Merz Pharma
Approved for: Alzheimer's Disease
Background
Memantine is marketed for the treatment of moderate to severe Alzheimer's disease in the United States, Canada, Europe, China, and other countries, and for the treatment of dementia in Germany, where it has been on the market since 1989 under the name Akatinol. Memantine received European marketing approval in 2002 and U.S. FDA approval in 2003. It is available as immediate-release tablets, solution, or extended-release capsules. Generic versions are expected to become available in 2015, when Merz Pharmaceuticals's patent to this drug expires. Memantine's side effects include fatigue, increases in blood pressure, dizziness, headache, constipation, confusion, and sleepiness, among others.
Memantine is the only FDA-approved drug for the treatment of Alzheimer's disease that is not an acetyl cholinesterase inhibitor. The drug is a noncompetitive, low- to medium-affinity antagonist of NMDA glutamate receptors in the brain. Memantine's principal mechanism of action is believed to be the blockade of current flow through channels of NMDA receptor-operated ion channels, reducing the effects of excitotoxic glutamate release. Memantine has higher affinity than Mg2+ ions at the NMDA receptor, thereby blocking prolonged Ca2+ influx while preserving transient physiological activation of the ion channels by activity-dependent, synaptically released glutamate. Memantine also is an antagonist of the type 3 serotonergic (5-HT3) receptor, and a low-affinity antagonist of the nicotinic acetylcholine receptor, but does not bind other receptors of neurologic or psychiatric drugs, such as adrenergic, benzodiazepine, dopamine, GABA receptors, or voltage-dependent calcium, sodium, or potassium channels.
Findings
In moderate to severe Alzheimer’s disease, a pooled analysis of six trials found that memantine helped treat and prevent behavioral symptoms of AD. Given at 20 mg/day, memantine treatment improved delusion, hallucinations, agitation, aggression, and irritability as measured by the Neuropsychiatric Inventory (NPI). In patients without these symptoms at baseline, memantine reduced their emergence. A meta-analysis of 1,826 patients in six trials reached the same conclusion (Gauthier et al., 2008; Winblad et al., 2007). Memantine's effect size is small.
In a 28-week, Phase 3 trial of 252 patients with moderate to severe AD, memantine modestly improved attention, global well-being, daily function, and independence. This was measured by the CIBIC, ADCS-ADL, and the Severe Impairment Battery (SIB); examples of functions measured by this scale include following conversations and performing light household chores such as clearing the table. NPI scores for agitation and delusion also improved on memantine, as did behavioral symptoms. The investigators concluded that memantine slows the clinical deterioration at this stage of AD. The open-label extension phase of this study enrolled 175 patients; it showed that a meaningful clinical benefit lasted for a year. Patients who switched to memantine from the blinded study's placebo arm improved on cognitive, functional, and global measures compared with their projected rate of continued decline (see Apr 2003 story on Reisberg et al., 2003; see Jan 2006 story on Reisberg et al., 2006).
Trials of memantine in mild to moderate AD yielded mixed results. Two six-month, Phase 3 studies in patients with mild to moderate AD showed modest treatment benefits for memantine over placebo. One study, conducted in 403 patients in the United States, showed a benefit for memantine over placebo on both the ADAS-cog scale and the CIBIC-plus global outcome. The other trial, conducted in 470 patients in Europe, showed benefits of memantine only at interim time points, and fell short of statistical significance at study completion. In 2004 Forest Laboratories filed for FDA approval of memantine as a treatment for mild AD, but in 2005 the agency issued a non-approvable letter, requiring a confirmatory study. The drug was never formally approved for the early stages of AD, but is frequently prescribed at this stage. Whether memantine is clinically useful in mild AD is controversial, as meta-analyses have reported conflicting conclusions (Doody et al., 2007; Schneider et al., 2011; see also news story and commentary).
Memantine was studied in combination therapy with the cholinesterase inhibitor donepezil. The first U.S. study assessing both drugs for moderate to severe AD, a six-month, 404-patient trial, showed that memantine treatment augmented the cognitive, functional, and behavioral benefits in patients already receiving donepezil. This is the first combination drug trial for AD to yield positive results (Tariot et al., 2004; Jan 2004 news story).
Pharmacoeconomic studies have been largely positive. The U.K.'s National Health Service reported that memantine is more cost-effective than no drug treatment in patients with moderate to severe AD. Other authors reported that memantine treatment reduced caregiver time and other societal costs, as did combination memantine-cholesterol inhibitor treatment. A systematic literature review found memantine and/or cholinesterase inhibitor treatment to be either cost-effective or cost-saving (Jones et al., 2004; Hunt, 2003; Pfeil et al. 2012, Pouryamout et al., 2012).
Memantine has been prescribed off-label for frontotemporal dementia, and an open-label trial had suggested a possible benefit for the disease's psychiatric aspects. However, in a subsequent randomized controlled trial of 20 mg memantine daily in 81 patients, the drug had no benefit on neuropsychiatric symptoms while worsening cognition in some patients (Boxer et al., 2013).
Memantine is being studied for AIDS-related dementia and cognitive dysfunction in the absence of dementia (NCT01261741), as well as autistic disorder, Asperger syndrome, and pervasive child development disorder not otherwise specified (PDD-NOS) (e.g., NCT01592786, NCT01592747, NCT01592773).
In the past, memantine has been evaluated for a range of conditions other than Alzheimer’s or dementia. Two Phase 3 studies tested this drug in more than 2,000 patients with glaucoma, but the results reportedly fell short of being able to support a marketing application for this disease (see clinicaltrials.gov, Glaucoma Research Foundation release). Memantine was studied unsuccessfully for neuropathic pain and diabetic neuropathy (Rogers et al., 2009, Sang et al., 2002). At least one early clinical trial of memantine in patients with vascular dementia appears to have shown cognitive improvement, but no further studies on this indication have been reported in the past 10 years (Wilcock et al, 2002). Trials of memantine in adults with Down's syndrome were negative (see Jan 2012 news story on Hanney et al., 2012).
For a listing of clinical trials of memantine, see clinicaltrials.gov.
Last Updated: 09 Oct 2023
Further Reading
No Available Further Reading
Overview
Name: MEM 1003
Synonyms: BAY Z 4406
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Mild Cognitive Impairment, Vascular Dementia, Bipolar Disorder
U.S. FDA Status: Alzheimer's Disease (Discontinued), Mild Cognitive Impairment (Discontinued), Vascular Dementia (Discontinued), Bipolar Disorder (Discontinued)
Company: Memory Pharmaceuticals Corporation
Approved for: None
Background
MEM 1003 is a dihydropyridine compound related to nimodipine. It is a Ca2 channel antagonist.
Last Updated: 23 Nov 2013
Further Reading
No Available Further Reading
Overview
Name: Melatonin
Therapy Type: Supplement, Dietary (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Approved for: None
Last Updated: 23 Nov 2013
Further Reading
No Available Further Reading
Overview
Name: Semagacestat
Synonyms: LY450139 Dihydrate , hydroxylvaleryl monobenzocaprolactam
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Eli Lilly & Co.
Approved for: None
Background
Semagacestat is a γ-secretase inhibitor that reduces Aβ40 and 42 production and secretion by the γ-secretase enzyme complex. The rationale is that reducing the formation of Aβ from its substrate APP targets an upstream event in the amyloid cascade and represents a direct test of the amyloid hypothesis. In preclinical animal studies, semagacestat reduced both soluble Aβ and amyloid plaque burden.
Findings
Semagacestat is the first γ-secretase inhibitor to have been taken into Phase 3 clinical trials. Phase 1 evaluated, in 27 healthy volunteers, three doses of semagacestat for its ability to lower the rate of Aβ synthesis in the CSF. It reported dose-dependent reduction (Bateman et al., 2009). This trial used a new radiolabeling technique to measure production and turnover rates of newly generated proteins in the CSF. Called SILT, it has since become more widely used in CNS drug development (Bateman et al., 2007).
In Phase 2, an initial trial in 70 people with mild to moderate Alzheimer's disease tested 30 mg for one week followed by 40 mg for five weeks (Siemers et al., 2006). A second trial gave 60 mg of semagacestat for two weeks, then 100 mg for another 12 weeks to 51 Alzheimer's patients. On the primary outcome of safety and tolerability, this trial showed a greater number of skin-related side effects in the treatment group, for example rash and lightening hair color. It also showed a significant reduction of plasma Aβ levels, but not in CSF Aβ levels. On secondary efficacy endpoints of cognition and function, this study showed no difference between semagacestat and placebo. A time course showed a biphasic response to semagacestat called "overshoot." Following the inhibitory phase, plasma Aβ exceeded baseline levels and remained elevated at all doses throughout most of a 24-hour post-dose period (Fleisher et al., 2008; Siemers et al., 2007).
Lilly started two pivotal Phase 3 trials, IDENTITY-1 and IDENTITY-2, intending to assess a total of 3,036 patients on up to 21 months of treatment. IDENTITY-1 compared 100 and 140 mg/day of semagacestat to placebo for their ability to improve cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and function as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) in patients with Alzheimer's disease in 24 countries around the world. IDENTITY-2 tested 60 mg/day against the same outcome measures but contained more secondary endpoints and substudy assessments. Both trials were to run until 2012, but were halted in April 2011 because of both an increased risk of skin cancer and infections and lack of efficacy. Notably, both cognition and function not only did not improve but worsened in all three treatment groups (Doody et al., 2013). Lilly terminated development of semagacestat.
Possible explanations for semagacestat's failure center around the compound's broad-based inhibition of all γ-secretase's 40-plus substrates, particularly Notch. This is is thought to have been detrimental to both safety and pharmacology (see conference story). In addition, a toxic function for an intermediate product of APP processing called b-CTF, whose concentration rises with semagacestat treatment, has been proposed (see conference story). At a systems level, disruption of hippocampal network function has been reported (Hajos et al., 2013).
Insight gained from semagacestat development has stimulated the search for APP-versus-Notch selective inhibitors and for γ-secretase modulators. Semagacestat continues to be used in research. For clinical trials of semagacestat, see clinicaltrials.gov.
Last Updated: 25 Oct 2023
Further Reading
No Available Further Reading
Overview
Name: LU25-109
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Approved for: None
Background
LU25-109 is a selective partial M1 agonist and an M2/M3 antagonist.
Last Updated: 12 Dec 2013
Further Reading
No Available Further Reading
Overview
Name: Linopirdine
Synonyms: DuP996
Chemical Name: 1-phenyl-3,3-bis(pyridin-4-ylmethyl)-1,3-dihydro-2H-indol-2-one
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Approved for: None
Findings
Linopirdine increases acetylcholine release in rat brain (Schnee & Brown, 1998). The mechanism is thought to involve linopirdine's inhibition of voltage-gated, calcium-activated, and leak K-positive currents, especially the M-type K-oositive current (IM) (Schnee & Brown, 1998).
Last Updated: 12 Dec 2013
Further Reading
No Available Further Reading
Overview
Name: Leuprolide
Synonyms: Leuprolide acetate , Lupron Depot, Eligard
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Tolmar Pharmaceuticals, Inc.
Approved for: Advanced prostate cancer
Background
Leuprolide acetate is a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH). It acts as an agonist at pituitary GnRH receptors; however, by interrupting the normal pulsatile stimulation of the receptors, it indirectly downregulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Leuprolide is one of several androgen deprivation drugs used to treat prostate cancer. It is also used in fertility regimens, for severe endometriosis and uterine fibroids, and to prevent precocious puberty in children.
The rationale behind repurposing leuprolide for the treatment of Alzheimer’s disease is based on the hypothesis that LH, which becomes elevated later in life and in some people with Alzheimer's (Short et al., 2001), induces post-mitotic neurons to re-enter the cell cycle, leading to cell death and cognitive decline (Atwood and Bowen, 2015). Medicare hospitalization claims data were reported to support a protective effect on cognition (Smith et al., 2018). Other studies have linked androgen deprivation therapy used in men with prostate cancer to a higher risk of subsequent dementia (Jayadevappa et al., 2019).
In preclinical work, decreasing LH was reported to improve cognitive performance and decrease amyloid deposition and tau phosphorylation in animal models of aging and AD (for example, see Bryan et al., 2010; Casadesus et al., 2006). Other mouse studies did not replicate these findings (Rosario et al., 2012).
Findings
From 2003-2004, a Phase 2 study enrolled 109 women with mild to moderate AD to test the effect of leuprolide on cognition. Participants were randomized to 11.25 mg or 22.5 mg leuprolide acetate (Lupron Depot, AbbVie) or placebo, given by injection every 12 weeks for one year. This trial found no overall efficacy on the primary outcomes of ADAS-Cog or ADCS-Clinical Global Impression of Change. In a preplanned subgroup analysis, women treated with the higher dose who were already taking an acetylcholinesterase inhibitor declined significantly less on both endpoints. The mean decline in the ADASCog was 0.18 points in the high-dose group compared to 3.30 points in the placebo group and 4.21 points in the low-dose group (Bowen et al., 2015).
In November 2020, a new Phase 2 trial began. Called LUCINDA, the study plans to enroll 150 women with measurable cognitive decline and cortical amyloid on a PET scan. Participants must be taking donepezil. An additional 30 people who meet all inclusion criteria except amyloid positivity will be randomized into a separate sub-study. The drug regimen of 22.5 mg leuprolide (Eligard, Tolmar Pharmaceuticals), or placebo, is to be injected subcutaneously once every 12 weeks for 48 weeks. ADAS-Cog11 is the lone primary outcome; secondaries include ADCS-ADL, ADCS-CGIC+, and other measures of cognition, behavior, and pain. Fluid biomarkers of inflammation, hormonal changes, and AD will be measured, along with volumetric MRI and hippocampal perfusion by ASL. Sponsored by Weill Cornell Medical College, the study is taking place at three centers in the U.S., with completion slated for February 2026 (Butler et al., 2021).
For details on these trials, see clinicaltrials.gov.
Last Updated: 12 Oct 2021
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