Overview
Name: Curcumin
Synonyms: diferuloylmethane, Longvida™
Chemical Name: (1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione
Therapy Type: Supplement, Dietary (timeline)
Target Type: Other (timeline), Unknown
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Verdure Sciences
Approved for: None
Background
Curcumin, the natural polyphenol that provides the yellow hue to turmeric, has been used in Indian Ayurvedic as well as traditional Chinese and Southeast Asian medicines for centuries to treat a wide variety of ailments. Animal models have demonstrated diverse beneficial effects of the compound, including anti-inflammatory and antioxidant properties as well as inhibiting Aβ aggregation (Yang et al., 2005). Curcumin is in clinical trials for various cognitive conditions, including AD and MCI.
Last Updated: 09 Jan 2014
Further Reading
No Available Further Reading
Overview
Name: COGNIShunt™
Therapy Type: Procedural Intervention
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Approved for: None
Background
The accumulation of amyloid plaques, neurofibrillary tangles, and neurodegeneration is thought to be due at least in part to the failure to clear circulating soluble Aβ and tau. CSF shunts have been used for decades to treat hydrocephalus, and were proposed as a possible way to clear toxic species from the body, especially because aging is associated with reduced CSF turnover (May et al., 1990). Early reports had also suggested some improvement in patients with comorbid hydrocephalus and AD who were treated with a shunt (Savolainen et al., 1999). The working hypothesis behind this approach is that slow and continuous depletion of CSF may improve dementia symptoms by removing toxic species in the CSF, including Aβ, tau, and oxidized proteins.
Last Updated: 09 Jan 2014
Further Reading
No Available Further Reading
Overview
Name: Clioquinol
Synonyms: iodochlorhydroxyquin, PBT-1
Chemical Name: 5-chloro-7-iodo-quinolin-8-ol
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Metals
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Prana Biotechnology Limited
Background
Clioquinol is an old drug that was used to treat fungal and protozoal infections but was found to be neurotoxic when used chronically at high doses. A one-time epidemic of subacute-myelo-optico-neuropathy in Japan prompted its removal or restrictions on its use in many countries. Topical clioquinol remains in clinical use for certain fungal and other skin disorders. Clioquinol is a hydroxyquinoline ionophore that acts as a zinc and copper chelator (Bareggi and Cornelli, 2012).
Clioquinol has been explored as a treatment for Alzheimer's disease because it is a metal protein-attenuating compound. MPACs have been reported to disrupt the interaction between metals and the Aβ peptide in the brain. According to scientists at Prana, increasing bioactive metal levels in the aging brain accelerate formation of amyloid plaques as well as neurotoxic oxidative processes. The rationale of evaluating clioquinol was that it would prevent Aβ accumulation while restoring copper and zinc ion homoeostasis in cells. For example, clioquinol was reported to cut brain amyloid deposition in half in a mouse model of Alzheimer's amyloidosis (Cherny et al., 2001).
Findings
In December 2003, Prana scientists formally reported a beneficial cognitive and plasma biomarker effect from a pilot Phase 2 trial in 36 patients with moderate to severe Alzheimer's disease (Jan 2004 news story). In October 2004 the company stated that an extension study supported a cognitive benefit and tolerability for clioquinol taken for 18 months (see 2004 press release). An independent meta-analysis according to the Cochrane Handbook for Systematic Reviews of Interventions later reported an absence of evidence that PBT1 was safe or effective in this trial (see Sampson et al., 2014).
While preparing for a Phase 2/3 trial, Prana announced that it was terminating development of clioquinol because the drug's manufacturing process generated a toxic contaminant (Apr 2005 story). The second-generation compound in this line of investigation is PBT-2.
Last Updated: 16 Oct 2014
Further Reading
No Available Further Reading
Overview
Name: Cerebrolysin
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Status in Select Countries: Approved outside the U.S. for cognitive impairment.
Company: Ebewe Pharmaceutical
Approved for:
Last Updated: 22 Nov 2013
Further Reading
No Available Further Reading
Overview
Name: CERE-110
Synonyms: Nerve Growth Factor gene therapy
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Sangamo BioSciences, Inc.
Approved for:
Background
CERE-110 was a gene-therapy approach for neuroprotective treatment of Alzheimer's disease. It employed injection of an AAV2-based vector for expression of the gene encoding the trophic protein nerve growth factor (NGF) into the nucleus basalis of Meynert, a cholinergic brain area that degenerates in the disease. The approach grew out of research showing that local NGF delivery was able to slow age-related neurodegeneration in mouse models and rhesus monkeys, and it has been in small clinical trials since 2000 (Sep 2002 news; Smith et al., 1999; Dec 1999 news). CERE-110 was initially developed by by Ceregene, which was bought by Sangamo BioSciences in 2013.
Findings
A pilot study of a previous form of NGF gene therapy—delivered via genetically engineered autologous fibroblasts—reported safety and hints for a potential long-term benefit for locally produced NGF (Apr 2005 news; Sep 2006 conference news).
Between 2004 and 2010, a two-year, open-label Phase 1 trial conducted in San Diego and Chicago investigated the safety, tolerability, and biological activity of increasing doses of CERE-110 delivered directly by bilateral stereotactic surgery into 10 patients with mild to moderate Alzheimer's disease. In this trial, CERE-110 was reported to have been safe and well-tolerated for up to two years of observation. Stable expression and biological activity were reported based on postmortem pathology (Nov 2013 conference news; Rafii et al., 2014).
From 2009 to 2015, a multicenter, sham-surgery controlled Phase 2 trial run by the ADCS evaluated CERE-110 in 49 people with mild to moderate AD for its ability to slow decline on the ADAS-cog, NPI, and ADCS-ADL batteries and to measure efficacy on cognition, neuropsychiatric well-being, and activities of daily living. In this study, CERE-110 was again safe and well-tolerated, but ineffective. In April 2015, Sangamo announced it was terminating the program (see company press release).
For all trials of CERE-110, see clinicaltrials.gov.
Last Updated: 09 Oct 2015
Further Reading
No Available Further Reading
Overview
Name: Amilomotide
Synonyms: CAD106
Therapy Type: Immunotherapy (active) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Company: Novartis Pharmaceuticals Corporation
Approved for: None
Background
This is an active vaccination strategy that aims to elicit a strong antibody response while avoiding inflammatory T cell activation (reviewed in Lemere and Masliah, 2010). CAD106 combines multiple copies of Aβ1-6 peptide derived from the N-terminal B cell epitope of Aβ, coupled to a Qβ virus-like particle. In animals, CAD106 induced Aβ-antibody titers without activating Aβ-reactive T cells. Administration of CAD106 to APP-transgenic mice showed a reduction of amyloid accumulation in the brain (Wiessner et al., 2011).
In March 2015, GlaxoSmithKline bought Novartis' vaccine business, but CAD106 was not part of this transaction.
Findings
In 2008, a one-year Phase 1 trial of two doses of CAD106 in 58 people with mild to moderate Alzheimer's disease in Sweden concluded that the vaccine dose-dependently induced Aβ IgG titers that met prespecified "responder" criteria for an immune response while being generally safe and well-tolerated. No meningoencephalitis was reported (Winblad et al., 2012).
CAD106 has since been tested with subcutaneous and intramuscular injections in five multicenter Phase 2 trials in the U.S. and Europe. Two 66-week extension trials ending in 2010 and 2011 explored antibody response and tolerability of additional doses, i.e., different longer-injection/booster-shot regimens. They found prolonged antibody titers in responders (Farlow et al., 2015). A 90-week trial of 120 people with mild to moderate Alzheimer's tested two doses of vaccine and two doses of adjuvant at 36 study sites. This trial contained pharmacogenomic and amyloid PET substudies. It ended in December 2012. Partial results were reported in 2014 at AAIC as indicating antibody maturation and continued safety after seven injections and follow-up of 2½ years. Full results of this study were published after peer review (Vandenberghe et al., 2017). The higher-dose vaccine (450 μg) produced a strong antibody response in 80 percent of recipients. Serious adverse events occurred in 24.5 percent of the vaccine group versus 6.7 percent of placebo. ARIA occurred in six cases, all strong responders; none were symptomatic. Strong responders had amyloid reductions that correlated with antibody titer, and a decrease in brain volume.
In July 2014, Novartis partnered with the Banner Alzheimer Research Institute to conduct a secondary prevention trial within the Alzheimer Prevention Initiative (API, see July 2014 conference news). This Phase 2/3 trial began in November 2015 and was set to run until 2023, with a five-year treatment period. It planned to enroll 1,340 homozygous ApoE4 carriers between the ages of 60 and 75 who were cognitively normal. About half of participants were to be randomized to compare CAD106 to matching placebo injected intramuscularly at weeks 1, 7, 13, 24 and then quarterly. The other half were to be randomized to compare once-daily umibecestat to matching placebo. As primary outcome, the trial planned to measure ability to delay diagnosis to MCI or AD dementia and change on the APICC cognitive composite (Langbaum et al., 2015). An extensive list of secondary outcomes included change on the Clinical Dementia Rating Scale sum of boxes (CDR-SB) along with other cognitive/functional scales, fluid biomarkers including CSF Aβ and tau, brain imaging including volumetric MRI plus amyloid PET and tau PET measurement of brain amyloid and tangle deposition, respectively, as well as safety measures and Aβ titers (see Jul 2014 conference news, Lopez et al., 2019). As part of this trial, an outreach and screening registry was built (Walsh et al., 2023).
The umibecestat part of the trial was terminated in July 2019, due to worsening cognition in that cohort. The CAD106 portion of the trial was terminated in September 2019, reportedly due to negative results from other anti-amyloid therapies. Results are posted on ClinicalTrials.gov, and were published after peer review (Riviere et al., 2023). Of 65 people randomized, 42 received vaccine, 23 placebo. All but one of vaccinated people developed Aβ antibodies. The immunized group showed no increase in amyloid plaque accumulation over the observation period of 18 months or more, while the placebo group increased at a rate of 8.36 centiloids per year. Of three ARIA cases, one was symptomatic ARIA-E that did not recur with additional vaccine doses. Adverse events were mainly mild to moderate injection reactions, with one severe injection reaction reported.
In September 2019, Novartis noted that it had 'retired' the CAD106 program (see financial report, p 18).
To view all clinical trials, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
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NCT00733863 |
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| Novartis Pharmaceuticals Corporation |
NCT00795418 |
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NCT00956410 |
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NCT01023685 |
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| Novartis Pharmaceuticals Corporation |
NCT01097096 |
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Last Updated: 05 Feb 2024
Further Reading
No Available Further Reading
Overview
Name: Besipirdine HCl
Synonyms: HP 749
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Aventis Pharmaceuticals, Inc. (was Hoechst)
Background
Besipirdine was designed to address two biochemical deficits commonly observed in the AD brain: cholinergic and adrenergic activity. This drug has been shown to enhance the activity of both systems (Klein et al., 1996). Hypoactivity of the cholinergic system is a well-known characteristic of the AD brain. Similarly, AD is associated with loss of locus coeruleus neurons, degeneration of noradrenergic projections, and a decrease in cortical norepinephrine levels (Heneka et al., 2002; Bondareff et al., 1982).
Findings
Besipirdine hydrochloride, an indole-substituted analog of 4-aminopyridine, enhances both cholinergic and adrenergic neurotransmission in the central nervous system. It has been shown to have a high affinity for α2-adrenergic receptors (much lower affinity for α1-adrenergic receptors) and also to modulate cholinergic neurotransmission through unspecified mechanisms (Klein et al., 1996).
Last Updated: 10 Dec 2013
Further Reading
No Available Further Reading
Overview
Name: AZD1446
Synonyms: TC-6683
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: AstraZeneca, Targacept
Approved for: None
Background
AZD1446 selectively activates the α4β2 subtype of nicotinic acetylcholine receptor.
Findings
Acute administration of nicotine to AD patients improved accuracy of delayed recall, as well as deficits in attention and information processing (Sahakian et al. 1989; Wesnes and Warburton, 1984; Jones et al., 1992). However, nicotine has significant side effects, including tachycardia, elevated blood pressure, and gastrointestinal distress. Agonists with better selectivity for nAChR subtypes that mediate the beneficial effects could be useful. Agonist binding to the α4β2 nAChR has been shown promote sAPPα secretion and attenuate Aβ production (Mousavi and Hellström-Lindahl, 2009).
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
| Sponsor |
Clinical Trial |
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| AstraZeneca |
NCT01039701 |
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| AstraZeneca |
NCT01125683 |
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Last Updated: 10 Dec 2013
Further Reading
No Available Further Reading
Overview
Name: ABT 418
Chemical Name: 3-methyl-5-[(2S)-1-methylpyrrolidin-2-yl]-1,2-oxazole
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
Acute administration of nicotine to AD patients improved accuracy of delayed recall, as well as deficits in attention and information processing (Sahakian et al. 1989; Wesnes and Warburton, 1984; Jones et al, 1992). However, nictoine has significant side effects including tachycardia, elevated blood pressure, and gastrointestinal distress. Agonists with better selectivity for nAChR subtypes that mediate the beneficial effects could be useful. ABT-418 is a novel bioisostere of (-)-nicotine. Like nicotine, it is an agonist for nicotinic acetylcholine receptors (nAChRs), ionotropic receptors composed of five subunits arranged around a central pore. It is unclear which nicotinic receptor subtypes are preferentially activated by ABT-418.
Last Updated: 12 Dec 2013
Further Reading
No Available Further Reading
Overview
Name: Atorvastatin
Synonyms: Lipitor™ , Zarator®, Sortis®, Tahor®
Chemical Name: (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid
Therapy Type: Small Molecule (timeline)
Target Type: Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Company: Pfizer
Approved for: Hypercholesterolaemia
Background
Atorvastatin is an oral statin drug that was developed by Pfizer’s predecessor, Parke-Davis. It is marketed under different names for hypercholesterolemia worldwide, including the United States, European Union, and Japan. The original tablets and a chewable formulation are approved for children with familial hypercholesterolemia in the European Union. Generic equvalents have been available in a growing number of countries since 2010.
Statin drugs such as atorvastatin and simvastatin lower peripheral cholesterol production to prevent heart attacks and other expressions of cardiovascular disease. Atorvastatin inhibits hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, a liver enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. Statins are pleiotropic drugs. Besides lowing cholesterol synthesis, they can also alter the production of isoprenoids (Ostrowski et al., 2007), and the expression of genes related to cell growth, signaling, trafficking, and apoptosis (Johnson-Anuna et al., 2005), for example.
Atorvastatin became of interest for Alzheimer's disease when epidemiological studies began noting that chronic statin use appeared to protect against incident AD (reviewed in Shepardson et al., 2011), and subsequent cell- and animal-based studies detailed various biological pathways by which statins might benefit not only cardiovascular but also Alzheimer's disease pathogenesis.
Findings
Three clinical studies have assessed atorvastatin in Alzheimer's disease, and development of this drug for this indication has ended.
From 2000 to 2004, a Phase 2 pilot study compared a one-year course of atorvastatin to placebo in 67 patients with mild to moderate Alzheimer's disease who were also taking a cholinesterase inhibitor drug and Vitamin E. This study reported trends in favor of a benefit on cognition and function but fell short of achieving statistical significance (Sparks et al., 2005; Sparks et al., 2005).
Between 2002 and 2007, Pfizer ran a 641-patient Phase 3 trial at 99 sites in the United States, Canada, European Union, Australia, and South Africa to evaluate 80 mg/day of atorvastatin as an add-on to donepezil therapy in mild to moderate AD. Called Lipitor's Effect on Alzheimer's Dementia (LEADe), this trial assessed changes in the ADAS-Cog and ADCS-CGIC batteries as co-primary cognitive and functional endpoints, respectively, and measured rate of change in whole brain and hippocampal volume in patients who enrolled in an MRI substudy. When it read out, this large trial found no clinical benefit over 18 months of treatment (Jones et al., 2008; Feldman et al. 2010; Fillit 2010). This is considered the definitive trial on atorvastatin in symptomatic Alzheimer's disease.
In 2006, a pilot study at the University of Wisconsin, Madison, tested whether atorvastatin therapy improved brain function as measurable by MRI and ultrasound in 16 middle-aged, cognitively normal adults who had a parent with Alzheimer's disease and enrolled to take atorvastatin for four months. This study reported a benefit on the neurovascular response and cerebral blood flow for atorvastatin (Xu et al., 2008; Carlsson et al., 2012). For all clinical trials of atorvastatin in AD, see clinicaltrials.gov.
In addition to Alzheimer's disease, atorvastatin has been investigated in a Phase 2 study for clinically isolated syndrome (CIS), a term denoting the first neurological episode of inflammatory demyelnation that sometimes precedes multiple sclerosis. This trial missed its primary endpoint.
Last Updated: 10 Dec 2013
Further Reading
No Available Further Reading
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