Drug development for Alzheimer's disease: Where are we now and where are we headed?

M.N. Sabbagh

The American Journal of Geriatric Pharmacotherapy

Drug Development for Alzheimer’s Disease: Where Are We Now and Where Are We Headed? Marwan N. Sabbagh, MD The Cleo Roberts Center for Clinical Research, Banner-Sun Health Research Institute, Sun City, Arizona

ABSTRACT Objective: The aim of this article was to provide a survey of the clinical development of pharmacotherapy for Alzheimer’s disease (AD). Methods: A search of PubMed to identify pertinent English-language literature was conducted using the terms Alzheimer’s disease AND clinical trials (2003–2008), dementia AND prevention AND clinical trials (2003– 2008), and the chemical names of all compounds mentioned in articles on new drugs for AD published since 2005. www.ClinicalTrials.gov was searched for relevant trials. Abstracts of the 2008 International Conference on Alzheimer’s Disease (ICAD) were reviewed for relevance, as were pharmaceutical company and AD advocacy Web sites. Articles selected for review were primary reports of data from preclinical studies and clinical trials. Results: A large number of drugs with differing targets and mechanisms of action are under development for the treatment of AD. Phase III trials of Ginkgo biloba, NSAIDs, phenserine, statins, tarenflurbil, tramiprosate, and xaliproden have been completed, none of them demonstrating adequate efficacy. Encouraging results from completed Phase II trials of dimebon, huperzine A, intravenous immunoglobulin, and methylthioninium chloride were reported at ICAD 2008. Nineteen compounds are currently in Phase II trials, and 3 compounds (AN1792, lecozotan SR, and SGS742) failed at this stage of development. Conclusions: Despite disappointing results from recently completed Phase III trials of several novel compounds, the extent and breadth of activity at all phases of clinical development suggest that new pharmacotherapeutic options for the treatment of AD will become available within the next decade. (Am J Geriatr Pharmacother. 2009;7:167– 185) © 2009 Excerpta Medica Inc. Key words: Alzheimer’s disease, pharmacotherapy, clinical trials, efficacy, pipeline. Accepted for publication June 10, 2009.
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M.N. Sabbagh

INTRODUCTION

PHASE III TRIALS

There was no effective pharmacotherapy for Alzheimer’s disease (AD) before the approval of the cholinesterase inhibitors (ChEIs) and memantine. These agents are associated with detectable symptomatic improvement and have a modest effect on the progression of AD from mild cognitive impairment (MCI) to disabling dementia and death.1,2 The therapeutic limitations of ChEIs and the steadily increasing prevalence of the disease have led to increased basic and clinical research aimed at developing better medications for the treatment of AD. Several drugs with widely differing targets are currently in development, some discovered serendipitously, some designed based on evolving knowledge of the pathophysiology of AD, and some identified from epidemiologic research. To date, however, no new agent has successfully passed through all phases of the clinical development process. Because it is highly unlikely that any individual agent will provide a cure for AD, future treatment is likely to involve polypharmacy, with newer medications given in combination with ChEIs and with each other. Indeed, polypharmacy for AD has already begun with the addon use of memantine. The purpose of this article was to provide an overview of the state of clinical development of AD pharmacotherapy as of the beginning of 2009. The putative mechanism of action of each agent is described, along with a summary of the pertinent clinical trials.

Completed and ongoing Phase III trials are listed in Table I. All agents are discussed in alphabetical order.

Completed Ginkgo Biloba Ginkgo biloba is a widely used herbal treatment for the prevention and treatment of aging-associated cognitive decline, including AD.3 As part of the National Institutes of Health’s complementary medicine initiative, a clinical trial was conducted at 5 academic centers between 2000 and 2008 comparing an extract of G biloba 120 mg BID with placebo in 3069 elderly community-dwelling volunteers (2587 with normal cognition, 482 with amnestic MCI [aMCI]).3 Participants were evaluated every 6 months for the primary outcome measures of incident dementia and AD (determined by expert panel consensus). The results indicated no significant effect of G biloba on the progression to AD (hazard ratio [HR] = 1.16; 95% CI, 0.97– 1.39) or all-cause dementia (HR = 1.12; 95% CI, 0.94–1.33). A subset analysis in participants with aMCI at baseline had similar results (HR = 1.13; 95% CI, 0.85–1.50). Overall, a numerically greater number of subjects treated with G biloba developed dementia (n = 277; 3.3 per 100 person-years) compared with placebo (n = 246; 2.9 per 100 person-years), but the difference was not statistically significant. The findings of this study suggested no role for G biloba in the prevention of AD.

METHODS PubMed was searched using the key words Alzheimer’s disease AND clinical trials (2003–2008), dementia AND prevention AND clinical trials (2003–2008), and the chemical name of every compound mentioned in any article on new drugs for AD published since 2005. www.ClinicalTrials.gov was searched using the key word Alzheimer’s disease. Abstracts of the 2008 International Conference on Alzheimer’s Disease (ICAD) were searched for reports of clinical trial results. The Internet was searched using the chemical name of each agent and any brand names; Internet sources were restricted to official trial registries, pharmaceutical company sites, mainstream AD advocacy group Web sites, and AD congress Web sites. For inclusion in the review, articles had to be reports of randomized, double-blind, placebo-controlled, parallelgroup clinical trials or preclinical studies published in peer-reviewed journals. All source material was obtained from the public record; no proprietary information or private opinions were sought.

168

NSAIDs There is a large and diverse body of evidence suggesting that NSAIDs may be effective for the treatment and, particularly, prevention of AD. The results of epidemiologic studies have suggested that nonaspirin NSAIDs commonly used by the elderly for relief of pain or inflammatory conditions may protect against the development of AD.4,5 These studies are supported by cell-culture and animal experiments indicating that NSAIDs reduce brain inflammatory markers such as activated microglia6,7 and may reduce brain deposits of amyloid-β (Aβ) peptide.8,9 Furthermore, in laboratory experiments, certain NSAIDs selectively lowered the more pathogenic Aβ42 species relative to the reportedly more benign Aβ40, suggesting a subtle alteration in γ-secretase activity. At least 4 prospective studies have investigated the relationship between NSAID use and AD, with results generally supporting a reduced risk of incident AD in association with NSAIDs.10–13 In the Baltimore Longi-

M.N. Sabbagh

The American Journal of Geriatric Pharmacotherapy

Table I. Phase III randomized, placebo-controlled, double-blind, parallel-group clinical trials.
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tudinal Study of Aging (N = 1686),10 the relative risk (RR) of AD in those with ≥2 years of reported NSAID use was 0.40 (95% CI, 0.19–0.84), compared with 0.65 (95% CI, 0.33–1.29) in those with <2 years of NSAID use. In a prospective, population-based cohort study in 6989 subjects aged ≥55 years who were free of dementia at baseline (mean follow-up, 6.8 years), the RR of AD was 0.95 (95% CI, 0.70–1.29) in those with <1 month of NSAID use, 0.83 (95% CI, 0.62–1.11) in those with <2 years of NSAID use, and 0.20 (95% CI, 0.05–0.83) in those with ≥2 years of NSAID use.12 However, randomized clinical trials in patients with AD or populations at high risk for AD have not found NSAIDs to be effective treatments for established AD14–16 or MCI.17 In addition, the Alzheimer’s Disease Anti-inflammatory Prevention Trial, the first prospective primary prevention trial of naproxen 220 mg BID and celecoxib 200 mg BID in at-risk subjects, failed to find a protective benefit against conversion to AD or cognitive decline after a median of 2 years of observation.18 Furthermore, lower scores on the Modi-

fied Mini–Mental State Examination (MMSE) were observed over time in both active-treatment groups compared with placebo (–0.36 points for naproxen [P = 0.02], –0.33 points for celecoxib [P = 0.04]).19

Phenserine Phenserine is a selective ChEI that was found to inhibit the formation of Aβ in animal studies, suggesting 2 potential mechanisms of action in the treatment of AD.20 In a 6-month, pivotal Phase III trial in 384 patients with mild to moderate AD (MMSE score, ≥10 and ≤26), participants were randomized to receive phenserine 10 or 15 mg BID or placebo.21 No significant differences were found between the phenserine and placebo groups on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) or the Clinician’s Interview-Based Impression of Change (CIBIC), the primary outcome measures. The AD clinical development program was terminated. In a Phase IIb study in 20 patients with mild AD, phenserine 30 mg/d reduced cerebrospinal fluid (CSF)

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levels of Aβ, as well as formation of amyloid plaques (as measured by retention of cortical Pittsburgh compound B).22 This finding has led to efforts to develop the L-isomer of phenserine, called posiphen.23

Statins Elevated midlife cholesterol levels are associated with an increased risk of AD,24 and chronic use of hydroxymethylglutaryl coenzyme A–reductase inhibitors (statins) has been reported to reduce the risk of developing AD by up to 75%.25 In addition, robust scientific data indicate that hypercholesterolemia promotes Aβ production and deposition in a variety of animal models of AD and that cholesterol reduction strategies reduce Aβ deposition.26 These observations led to the conduct of studies evaluating the clinical effects of statins on biomarkers of AD pathology. For example, a 6-month study found that probucol, a cholesterol-lowering drug, reduced levels of Aβ in CSF and stabilized cognitive deterioration in patients with mild to moderate AD.27 However, the results of clinical trials of statins have not been encouraging. Although a Phase II study of monotherapy with atorvastatin 80 mg/d in 63 patients with mild to moderate AD found that the treated group had no deterioration in scores on cognitive or functional assessment scales after 12 months of treatment,28 a larger Phase III study (N = 600) in patients also receiving donepezil, completed in 2007, found no benefit to adjunctive use of atorvastatin.29 The results of a Phase III trial (N = 400) of simvastatin monotherapy, also completed in 2007, were negative as well.30 Despite these negative findings, the epidemiologic data suggesting a protective effect (as opposed to a treatment effect) of statins in AD31 are sufficiently encouraging that simvastatin 80 mg/d is now in a Phase II trial of its potential as a preventive agent.32 This study plans to enroll 100 adults aged 35 to 69 years who have a parent with AD but who do not themselves exhibit any cognitive deficits. The primary outcome measures are CSF Aβ, inflammatory markers, and cholesterol, as well as memory and thinking skills; there is also a magnetic resonance imaging (MRI) substudy.

Tarenflurbil Amyloid precursor protein (APP) is cleaved by γ-secretase to form Aβ42, and it has been hypothesized that selective Aβ42-lowering agents may be useful in the prevention or treatment of AD.33,34 Tarenflurbil, the R-enantiomer of the NSAID flurbiprofen, was the first γ-secretase modulator to reach the final stage of clinical development. Results of a Phase II trial in

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210 patients with mild AD (MMSE score, 20–26) had found beneficial effects of tarenflurbil 800 mg BID in terms of measures of daily activities and global function.35 The 18-month Phase III trial (N = 1600), conducted at 133 sites in the United States, examined the effect of tarenflurbil 800 mg TID in patients with mild AD (mean MMSE score, 23), 81% of whom were receiving a stable dosage of a ChEI, memantine, or a combination of these.36 The primary outcome measures were the ADAS-cog and ADAS activities of daily living (ADAS-ADL) scale, assessed every 3 months. There was no significant difference between the tarenflurbil and placebo groups; at the end of the study, both groups had lost a mean of 7 points on the ADAS-cog and 10 points on the ADAS-ADL. It is ironic that observation of this magnitude of decline over 18 months in patients with mild AD, the majority of whom were receiving conventional medical treatment, confirmed that adequately powered clinical trials of this duration should be able to detect an efficacy signal. One speculative explanation that has been offered for tarenflurbil’s lack of efficacy is inadequate central nervous system (CNS) penetration.

Tramiprosate Tramiprosate, a modification of the amino acid taurine that functions as a glycosaminoglycan mimetic, was designed to cross the blood–brain barrier and bind soluble Aβ peptides, thus acting as an antifibrillar agent that inhibits the formation of amyloid plaques.37 Because the amyloid cascade hypothesis is the most widely accepted theory of the pathogenesis of AD, drugs targeting Aβ are being widely investigated,38 and tramiprosate was the first of these to reach late-stage development. The Phase III trial, which was conducted in 67 centers throughout North America and enrolled 1052 patients with mild to moderate AD, compared tramiprosate 100 and 150 mg BID with placebo.39 Continued use of approved AD medications was allowed. The primary end points were the ADAS-cog, the Clinical Dementia Rating Scale–Sum of Boxes score, and change in hippocampal volume on MRI. Despite promising results in Phase II studies, tramiprosate was not significantly more effective than placebo on any of the outcome measures.40 In November 2007, the sponsor announced its intention to discontinue development of tramiprosate as a pharmaceutical and halted the European Phase III trial.41 One potential explanation for the poor results is that tramiprosate promotes the aggregation of tau,42 the primary component of the neurofibrillary tangles that are a major

M.N. Sabbagh

pathologic hallmark of AD. Another contributing factor was the unusually large placebo response rate.40

The American Journal of Geriatric Pharmacotherapy

Xaliproden was considered a likely candidate for the treatment of AD because of its nerve growth factor– like effects and its antagonism of the serotonin (5-hydroxytryptamine [5-HT]) 1A receptor.43 Consideration of 5-HT1A antagonists for AD was based on preclinical data indicating that they facilitated glutamatergic and cholinergic neurotransmission,44 and that inhibition of the 5-HT1A receptor resulted in enhancement of cognitive abilities.45 Two large 18-month clinical trials of xaliproden (monotherapy [N = 1306] and adjunctive therapy [N = 1455], respectively) in patients with mild to moderate AD (MMSE score, 16–26) were completed in 2007.46,47 Lack of adequate efficacy in both trials resulted in cancellation of the xaliproden development program for AD in September 2007.48 The drug is currently being studied as a preventive treatment for chemotherapy-induced neurotoxicity.49

6 cases, treatment was reinstated. Although 9 adverse events (AEs) occurred in ≥5% of patients and more than twice as frequently in the bapineuzumab group than in the placebo group, most AEs were mild to moderate, and there was no difference in discontinuations due to AEs between groups. As with most Phase II studies, this trial was not powered to detect efficacy. Nonetheless, there was a 2.3-point improvement on the ADAS-cog with bapineuzumab compared with placebo (P = NS). When the analysis was restricted to the 78 patients who completed the trial (both carriers and noncarriers of the apolipoprotein E [ApoE] ε4 allele), those who received bapineuzumab had a 4.3-point improvement on the ADAS-cog compared with placebo (P = 0.003). In additional post hoc analyses in which participants were stratified by ApoE ε4 status, the results suggested that noncarriers fared better than carriers. The Phase III studies of bapineuzumab, which are scheduled to be completed in April 2011, should provide answers to the safety and efficacy concerns raised by this Phase II study.

Ongoing

Dimebon

Despite the disappointing early results in the first wave of Phase III testing of new agents for the treatment of AD, several other compounds were in Phase III clinical trials at the time of the literature search and dozens more were in earlier phases of development.

Dimebon, a drug used in Russia for its antihistaminic effect for over 2 decades, is also a ChEI and N-methyl-D-aspartate (NMDA) inhibitor, the 2 mechanisms of action of existing AD drugs.59 However, it is now believed that dimebon’s primary mechanism of action in AD is stabilization of mitochondrial function.60 Dimebon is now in Phase III of clinical development. A study of dimebon 5 and 20 mg TID in patients with mild to moderate AD began enrollment in the United States, Europe, and South America in May 2008.61 Two additional Phase III trials in patients with mild to moderate AD began recruitment in 2009,62,63 and another Phase III study in patients with moderate to severe AD is scheduled to begin enrolling patients in July 2009.64 This extensive research program was undertaken after publication of the results of a 26-week, randomized, double-blind, parallel-group Phase II study in 183 patients with mild to moderate AD, in which dimebon 20 mg TID was associated with significant benefit compared with placebo at week 26 (intent to treat, last observation carried forward), as measured on the ADAS-cog (mean difference, dimebon vs placebo: −4.0; 95% CI, −5.73 to −2.28; P < 0.001).59 Moreover, patients who received dimebon had a significant improvement in the ADAS-cog at study end (mean difference: −1.9; 95% CI, −2.92 to −0.85; P < 0.001). The main tolerability finding was a higher rate of incident

Xaliproden (SR57746A)

Bapineuzumab (AAB-001) Amyloid plaques, another of the pathologic hallmarks of AD, are abnormal, insoluble, extracellular aggregates of Aβ peptide.50 Immunotherapy employing monoclonal antibodies to Aβ has been associated with cognitive improvements in mouse models of AD.51–53 Several humanized monoclonal antibodies targeting Aβ are in clinical development. Of these, the only one to have reached Phase III trials is bapineuzumab, the subject of the largest clinical trial program to be undertaken for the treatment of AD. Four independent 18-month trials, each enrolling ~1000 patients with mild to moderate AD, will compare various doses of bapineuzumab with placebo. The primary outcome measures are the ADAS-cog and the Disability Assessment for Dementia (DAD).54–57 Results of a highly anticipated 18-month Phase II study involving 234 patients who received up to 6 infusions of bapineuzumab (1 infusion q13wk) were reported at ICAD 2008.58 The main safety concern that emerged was vasogenic edema, noted on MRI, which occurred in 12 patients and resolved in all cases; in

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M.N. Sabbagh

depression in the dimebon group compared with the placebo group (14% vs 5%, respectively).

LY450139 The neurotoxic Aβ peptide is generated by cleavage of APP by β- and γ-secretases.65 Inhibitors of γ-secretase thus present an attractive option for AD therapy.66 BMS-29989767 and LY411,57568 lowered levels of Aβ in the brain in animal studies of γ-secretase inhibitors. LY450139 is the first selective γ-secretase inhibitor for the treatment of AD to reach Phase III testing. Enrollment is under way in 2 long-term trials (≥18 months’ duration) comparing LY450139 with placebo in patients with mild to moderate AD, with enrollment targets of 1100 patients in one study (LY450139 140 mg/d vs placebo)69 and 1500 in the other (LY450139 100 and 140 mg/d vs placebo).70 A Phase II study in 51 patients (n = 22, LY450139 100 mg; n = 14, LY450139 140 mg; n = 15, placebo) found a clinically significant reduction in plasma (but not CSF) levels of Aβ in both active-treatment groups.71 Although there were no significant differences in cognitive outcome measures between groups, the trial was not powered to detect such differences and had a duration of only 14 weeks. Safety concerns included 1 case of transient bowel obstruction and 3 cases of possible drug rash.

the placebo group (P = 0.001 and P = 0.013, respectively).75 Recent concerns about the safety of rosiglitazone (and pioglitazone) in patients with or without a history of heart failure, particularly when used in conjunction with insulin, do not seem to have affected the clinical trial program for rosiglitazone in patients with AD, in part because a diagnosis of diabetes is among the exclusion criteria for clinical trials. The Phase III clinical development program for rosiglitazone extended-release oral tablets in AD consists of 1 just-completed monotherapy trial (N = 863) with active-comparator (donepezil) and placebo arms76 and 2 adjunctive-therapy trials.77,78 In each of these trials, the primary outcome measures are the change from baseline to week 24 in ADAS-cog total score and CIBIC plus Caregiver Input score, by ApoE ε4 status. This prespecified stratification by ApoE ε4 status was based on the results of the successfully completed Phase II trial (N = 511),79 in which there was no significant difference between rosiglitazone and placebo at any of the doses studied (2, 4, and 8 mg/d) in the population as a whole, although there was a significant interaction between ADAS-cog and ApoE ε4 status (P = 0.014). Exploratory analyses found significant improvement in ADAS-cog with rosiglitazone 8 mg among those who were not carriers of ApoE ε4 (P = 0.024, unadjusted for multiplicity). No serious safety concerns were reported.

Rosiglitazone Insulin, insulin receptors, and insulin-sensitive glucose transporters are abundant in the medial temporal regions of the brain that support the formation of episodic memory.72 Insulin signaling is now known to play a role in memory functions and may also play a part in the regulation of APP and Aβ.73 In addition, Aβ accumulation in the brains of patients with AD may be the result of impaired clearance of Aβ by Aβ-degrading enzymes, including insulin-degrading enzyme.74 These findings suggest that insulin-related CNS abnormalities may cause or exacerbate cognitive impairment, and that treatment of insulin resistance may reduce the risk of AD or delay its development.73 Rosiglitazone, a peroxisome proliferator–activated receptor-γ agonist originally developed and marketed for the management of diabetes, is the leading drug in clinical development for AD based on the insulin resistance hypothesis. In a double-blind, placebo-controlled pilot study of rosiglitazone 4 mg/d in 30 patients with mild AD or aMCI, measures of delayed recall and selective attention after 6 months of treatment were significantly better in the rosiglitazone group compared with

172

PHASE II TRIALS Completed and ongoing Phase II trials are listed in Table II. Again, all agents are listed alphabetically.

Completed AN1792 Based on the amyloid cascade hypothesis, the therapeutic strategy of active immunization targeting Aβ has generated widespread interest. The first-generation Aβ vaccine, AN1792, underwent a large Phase I trial (N = 80) in which 4 intramuscular injections of 2 doses of AN1792 with adjuvant QS-21 and 2 doses without adjuvant QS-21 were administered during the first 24 weeks, and a polysorbate 80–modified formulation was used in up to 4 additional injections from weeks 36 to 72.80 One case of meningoencephalitis was diagnosed postmortem on follow-up (day 219) and was not attributed to study drug. Overall, AEs were reported in 23.9% of those treated with AN1792, with no relationship noted between dose and the occurrence of AEs. Exploratory efficacy analyses identified an efficacy signal on the DAD (P = 0.002, all treated patients vs placebo), but not on

M.N. Sabbagh

The American Journal of Geriatric Pharmacotherapy

Table II. Phase II randomized, placebo-controlled, double-blind, parallel-group clinical trials. "HFOU
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3 other outcome measures. Despite the apparently acceptable safety profile of AN1792 in this study, the subsequent Phase II study (n = 300, AN1792 225 μg IM + adjuvant QS-21 50 μg; n = 72, IM saline) was discontinued because 6% of participants developed aseptic meningoencephalitis.81 Immunization was stopped after 1 (2 patients), 2 (274 patients), or 3 (24 patients) injec-

tions, at which point only 59 patients (19.7%) had developed the predetermined antibody response. Although no significant differences were found between antibody responders and the placebo groups on the ADAS-cog, DAD, Clinical Dementia Rating scale, MMSE, or Clinical Global Impression of Change (CGIC), a post hoc analysis of the z score composite across all tests found a

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difference favoring antibody responders (mean [SD], 0.03 [0.37] vs –0.20 [0.45], respectively; P = 0.020). In a recently published report of a study performed 6 years after completion of the Phase I study, 8 of 9 patients who received AN1792 and who gave permission for postmortem examinations were assessed neuropathologically.82 The key finding was that the degree of plaque removal varied significantly with the mean antibody response attained during the treatment period (P = 0.02, Kruskal-Wallis test), and 2 of 8 patients had nearly complete clearance of plaques. However, there was no evidence that the AN1792 group had improved survival (HR = 0.93; 95% CI, 0.43–3.11; P = NS) or a reduced time to severe dementia (HR = 1.18; 95% CI, 0.45–3.11; P = NS) compared with the placebo group. Although the 6% incidence of aseptic meningoencephalitis led to discontinuation of the AN1792 development program, many active immunization strategies are now being pursued in Phase I trials.

open-label trial in 8 patients with mild AD.88 The study comprised a 6-month dose-finding phase, a 3-month discontinuation phase, and a 9-month treatment phase. Transient improvements on both cognitive and global clinical measures were observed during the initial phase, a return to baseline in the second phase, and stabilization in the final phase. A Phase III clinical trial is planned.

Lecozotan SR Lecozotan sustained release (SR) is a potent, selective 5-HT1A–receptor antagonist that was found to have cognition-enhancing properties in several primate models.45 Two 6-month, Phase II/III dose-ranging studies of lecozotan SR (2, 5, and 10 mg/d) as add-on treatment to a ChEI were completed in June 2008 (N = 250).89 No study data have been published, and the compound is no longer included on the manufacturer’s comprehensive list of drugs under development.90

SGS-742 Huperzine A Huperzine A, derived from the Chinese herb Huperzia serrata, was identified by Chinese scientists in the 1980s as a potent, reversible, and selective acetylcholinesterase inhibitor. More recently, a variety of potential neuroprotective effects have been reported that may be of benefit in the treatment of AD.83 In a Phase II study conducted in the United States and completed in November 2007, 210 patients with mild to moderate AD received huperzine A 200 μg or 400 μg PO BID for 16 weeks.84 Approximately half of the patients were also receiving memantine. Results for the primary end point, the ADAS-cog, indicated significant cognitive enhancement at the 400-μg BID dose (P = 0.03), but not at the 200-μg dose.85 There were no significant differences between either dose of huperzine A and placebo on the secondary end points, the Alzheimer’s Disease Cooperative Study–CGIC, and the Neuropsychiatric Inventory. Huperzine A was well tolerated, particularly given that many of the patients had been unable to tolerate at least 1 previous trial of treatment with a marketed ChEI. A Phase III trial is anticipated.

Intravenous Immunoglobulin There is evidence suggesting that intravenous immunoglobulin (IVIg) may be useful as a treatment for AD, as it contains antibodies against Aβ.86 A 6-month, openlabel pilot study of IVIg in 5 patients with mild AD, all of whom were receiving stable doses of ChEIs and, in some cases, memantine, reported improved cognition.87 This finding was confirmed in a Phase II, 18-month,

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SGS-742, a phosphoamino acid–derivative, orally active, selective γ-aminobutyric acid type B (GABAB)– receptor antagonist,91 was considered as a potential treatment for AD because activation of GABAB receptors had been found to inhibit memory/learning in certain animal models.92 It was hypothesized that GABAB antagonists might reverse this effect by reducing glutamatergic excitotoxicity via indirect effects on NMDA receptors. In the first Phase II trial, SGS-742 was well tolerated at a dose of 600 mg TID for 8 weeks in 110 patients with MCI.93 However, in a Phase IIb monotherapy trial in 280 patients with mild to moderate AD, SGS-742 failed to meet the efficacy end points.93

TRx0014 (Methylthioninium Chloride) TRx0014 is a proprietary formulation of an old and well-known drug, methylthioninium chloride (MTC), or methylene blue, a deep-blue dye used as a tissue stain in biology, as well as in analytical chemistry and numerous industrial products (eg, ink). Its investigation as a potential treatment for AD was based on its reported ability to interfere with tau aggregation by acting on self-aggregating truncated tau fragments. Data from unpublished preclinical studies suggested that MTC dissolved tangle filaments isolated from the brain at a 50% effective concentration (EC50) of 0.15 μmol/L and stopped tau aggregation in cells at an EC50 of 0.56 μmol/L.94 The report of a highly successful Phase II trial of TRx0014 was unexpected.94 In this trial, 323 patients with mild to moderate AD who were not receiving any

M.N. Sabbagh

pharmacotherapy for AD were randomized to receive TRx0014 30, 60, or 100 mg PO TID, or placebo.95 The primary efficacy end point was ADAS-cog at 24 weeks. Although stratification by AD severity may not have been prespecified in the statistical analysis plan, the results were presented by subgroups of patients with mild and moderate AD. Only the group with moderate AD had a significant improvement in ADAS-cog scores at 24 weeks compared with placebo (effect size for 60 mg TID, –5.5 points).96 At 50 weeks, the combined mild and moderate AD groups receiving TRx0014 60 mg TID had a decrease in ADAS-cog score of 1.0 point, compared with increases of 3.5 points in the groups receiving TRx0014 30 mg TID and 7.8 points in the groups receiving placebo (effect size, –6.8 points; P < 0.001). At 81 weeks (preliminary data from the openlabel extension study), the TRx0014 60 mg TID group appeared to have stabilized. A Phase III trial is scheduled to begin in 2009.

Ongoing ACC-001 Although active immunization with AN1792 failed to show efficacy or safety in Phase I and II trials, the rationale for this therapeutic approach remains strong. ACC-001, a second-generation vaccine designed to have an improved safety profile, is undergoing evaluation in 3 separate Phase II studies with a combined enrollment target of 360 patients with mild to moderate AD, including a small study in Japanese patients. Three dosages of ACC-001, with and without adjuvant QS-21, are being compared with adjuvant alone and placebo.97–99

AZD3480 Evidence that neuronal nicotinic receptors (NNRs) may play a role in the pathophysiology of AD arose from several sources. Loss of NNRs has been observed postmortem in the cortex and striatum of brains from AD patients.100,101 When the brains of AD patients who had smoked were compared postmortem with the brains of those who had never smoked, less loss of NNRs, as well as less plaque formation, was observed in those with a history of smoking.102 In vitro studies have found that nicotine protects against cytotoxicity induced by excitotoxins and Aβ103 and prevents aggregation of monomeric Aβ peptides into β-pleated sheets.104 In addition, a short-term clinical study of the effect of nicotine administration via transdermal patch in patients with AD found significant improvements in attention (P < 0.05), although not in other areas of cognition.105

The American Journal of Geriatric Pharmacotherapy

AZD3480, an α4β2-selective NNR agonist,106 was the first drug of this class to be evaluated for the treatment of AD in a Phase IIb trial, with inconclusive results.107 Patients with mild to moderate AD (N = 659) were randomized to receive 1 of 3 doses of AZD3480, a fixed dose of donepezil, or placebo for 12 weeks. Although AZD3480 was comparable to placebo in terms of its overall safety and tolerability profile and was associated with fewer gastrointestinal-related AEs than donepezil, neither AZD3480 nor donepezil met the criteria for statistical significance on the primary outcome measure (ADAS-cog). Future development of AZD3480 for this indication is uncertain.

CAD106 CAD106 is an active immunization agent. Results for the first patient cohort to complete the Phase I, 52-week, double-blind, placebo-controlled safety and proof-of-concept trial were presented at ICAD 2008.108 Overall, CAD106 50 μg SC (n = 24) administered at weeks 0, 6, and 18 was not associated with any study withdrawals or serious AEs compared with placebo (n = 7). An antibody response was achieved in two thirds of those receiving CAD106, compared with none of those receiving placebo. Two small Phase II studies (N = 30 each) are in progress.109,110

CX717 CX717 belongs to a therapeutic class known as ampakines, which are positive allosteric modulators of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)–type glutamate receptors.111 Although ampakines have been found to reduce age-associated memory deficits in animal models,112 clinical development of the first ampakine to be evaluated in humans (CX516) was discontinued in Phase II.113 Two different doses of CX717 are being tested in a Phase II pilot study in patients with mild to moderate AD.114 Each patient is undergoing psychometric testing and positron emission tomography scanning at various times during receipt of active drug or placebo.

ELND005 ELND005 (formerly AZD 103) is a cyclohexanehexol stereoisomer, scillo-inositol. Inositol has 8 possible stereoisomeric forms, of which 3 are found in the human brain. Among these, the most common form is myoinositol, which is available as a nutraceutical. Only scilloinositol has been found to reduce the accumulation of soluble Aβ oligomers and reverse memory deficits in the brain of transgenic mice.115 ELND005 has successfully

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completed Phase I trials, and a Phase II trial (N = 340) of the safety and efficacy of 3 doses of ELND005 is under way, with results expected by mid-2010.116

disorder and that lithium may reduce the incidence of AD relative to that in the general population.125

LY2062430 (Solanezumab) Intranasal Insulin Reduced brain insulin signaling and low CSF-toplasma insulin ratios have been observed in patients with AD.72 After intranasal administration, insulinlike peptides follow extracellular pathways to the brain within 15 minutes.117 In a 3-week, randomized, double-blind, placebo-controlled pilot study, 25 patients with early AD or aMCI received intranasal insulin 20 IU BID (n = 13) or placebo (n = 12).117 Cognitive and laboratory testing was performed at baseline and after 21 days of treatment. The insulin group had significantly better scores on measures of working memory (P = 0.037), attention (P = 0.011), and functional status (P = 0.041). Insulin was also associated with a significant increase in the Aβ 40/42 ratio (P = 0.021). Given the promising findings, 2 Phase II trials of intranasal insulin aspart are currently in progress: a university-based trial of 40 IU/d (N = 36)118 and a larger trial of 10 or 20 IU BID for 16 weeks conducted at the National Institute on Aging (N = 90), appropriately named SNIFF 120 (Study of Nasal Insulin to Fight Forgetfulness [120 days]).119

Lithium Glycogen synthase kinase–3 (GSK-3) activity has been associated with AD because of its role in the phosphorylation of tau and regulation of the production of Aβ.120,121 Lithium has been found to inhibit GSK-3 activity122 and to provide a significant and dosedependent reduction in the expression of GSK-3b, but not GSK-3a, that was specific to hippocampal cells (mean [SD] 32% [20%] at a lithium concentration of 0.02 mM [P < 0.05]; 50% [7%] at a lithium concentration of 2 mM [P < 0.001]).123 Despite this suggestive basic science, no further clinical development of lithium has been pursued since the 2005 completion of a small Phase II trial (N = 35).124 Ongoing concerns about the safety, tolerability, and monitoring requirements associated with clinical use of lithium constitute a serious impediment to its further development for the prevention of AD.123 Nonetheless, a case–control study reported a significantly reduced incidence of AD in patients with bipolar disorder treated with lithium compared with a matched population not receiving lithium (5% vs 33%, respectively [background incidence, 7%]; P < 0.001), suggesting that there may be an increased incidence of AD in patients with bipolar

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LY2062430 is a monoclonal antibody against Aβ peptide that has completed 1 Phase II trial.126 A second Phase II trial in Japanese patients is ongoing.127 On the basis of unpublished results from the completed trial, 2 Phase III trials were initiated in May 2009 to evaluate the safety and efficacy of LY2062430 400 mg IV administered every 4 weeks for 80 weeks.128,129

MK-0952 Phosphodiesterases (PDEs) are an important family of proteins that regulate intracellular levels of cyclic adenosine monophosphate. Compounds that inhibit PDE4 are neuroprotective, neuroregenerative, and antiinflammatory, and preclinical studies have indicated that PDE4 inhibitors may counteract deficits in longterm memory caused by overexpression of mutant forms of human APP.130 A Phase II trial of the PDE4 inhibitor MK-0952 in patients with mild to moderate AD was completed in late 2007,131 although the results have yet to be published.

PBT2 PBT2 is a metal protein–attenuating compound that affects the Cu2(+)- and Zn2(+)-mediated toxic oligomerization of Aβ seen in AD. As such, it is considered an antifibrillar agent with a unique mechanism of action. In a Phase IIa trial in 78 patients with early AD that was completed in December 2007, PBT2 reduced CNS Aβ42 levels in a dose-dependent manner (P = 0.023; difference in least squares mean change from baseline, PBT2 vs placebo: –56.0 pg/mL [95% CI, –101.5 to –11.0], P = 0.006).132 No serious AEs were reported in relation to use of PBT2, and 95% of patients completed the study. Cognitive testing, which included the ADAS-cog, MMSE, and a battery of neuropsychological tests, indicated significant improvement on only 2 components of the neuropsychological test battery in the PBT2 250-mg group compared with placebo (category fluency: 2.8 words [95% CI, 0.1 to 5.4], P = 0.04; trail-making part B: – 48 seconds [95% CI, –83 to –13], P = 0.009), but the trial was not powered for efficacy end points and was only 12 weeks long.

PF-04360365 Like bapineuzumab and LY2062430, PF-04360365 is a monoclonal antibody against Aβ. Although Phase I studies are not scheduled to be completed until late

M.N. Sabbagh

2009 or early 2010, recruitment for a Phase II trial (N = 100) evaluating the safety, tolerability, and pharmacokinetics of 5 dosages of PF-04360365 began in December 2008.133

PF-04494700 The receptor for advanced glycation end products (RAGE) has been found to bind to Aβ and mediate its transport across the blood–brain barrier.134 A series of elegant experiments in mouse brain slices of entorhinal cortex (the first area of the brain to exhibit damage in AD) indicated that the RAGE–Aβ complex suppresses long-term potentiation, at least in part via activation of p38 mitogen-activated protein kinase.135 Thus, the evolving science suggested that an inhibitor of RAGE might have therapeutic benefit in AD. A large (N = 400) Phase II safety and efficacy trial is now under way to examine 2 dosages of PF-04494700 (formerly TTP488), an orally bioavailable small-molecule RAGE antagonist, in patients with mild to moderate AD.136

PRX-03140 PRX-03140 is a highly selective, small-molecule agonist of 5-HT4, a specific G-protein–coupled receptor.137 In preclinical studies, PRX-03140 was found to improve cognitive function by increasing levels of acetylcholine, soluble APP, and brain-derived neurotrophic factor in regions of the brain known to be important for memory.137 In Phase IIa clinical trials of PRX03140 alone and in combination with donepezil in patients with mild AD, those receiving PRX-03140 150 mg/d PO as monotherapy had a mean 3.6-point improvement on the ADAS-cog, compared with a 0.9point worsening in those receiving placebo (P = 0.021). PRX-03140 was well tolerated as monotherapy and in combination with donepezil, with no reports of serious drug-related AEs.137 PRX-03140 has entered Phase IIb development, with a 6-month combination-therapy trial begun in April 2008138 and a 3-month monotherapy trial begun in May 2008.139

Raloxifene Raloxifene, a selective estrogen-receptor modulator, is approved for the treatment and prevention of osteoporosis in postmenopausal women. A cognitive outcome substudy (n = 5386) was conducted as part of a trial of raloxifene 60 and 120 mg/d in 7705 postmenopausal women at risk for osteoporosis in which the primary outcome measures were fractures and bone mineral density.140 After 3 years of treatment, the 120-mg dose, but not the 60-mg dose, was associated with a

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reduction in risk for MCI (RR = 0.67) or AD (RR = 0.52). This finding, supported by evidence suggesting that estrogen may have a protective effect against dementia,141 led to the clinical development of raloxifene for the treatment of AD. A 1-year Phase II trial is currently comparing raloxifene 120 mg/d with placebo in 72 patients with early AD.142

RO5313534 (Formerly MEM 3454)

RO5313534 is a partial nicotinic α7–receptor agonist. Three doses of RO5313534 were evaluated (as MEM 3454) in a Phase IIa trial in 80 patients with mild to moderate AD.143 The 2 lower doses (5 and 15 mg/d) were associated with significant improvements compared with placebo on several efficacy measures (P ≤ 0.05). Constipation was the only AE that was found to occur substantially more frequently in the MEM 3454 groups compared with the placebo group (43% vs 5%, respectively); no serious AEs were attributed to study drug. A second Phase II trial was initiated in April 2009 to assess the safety and efficacy of 4 dosages of RO5313534 as adjunctive therapy to donepezil 5 or 10 mg/d in patients with mild to moderate AD.144

SB742457 SB742457, a small-molecule antagonist of 5-HT6, is in the second round of Phase II testing.145 In preclinical studies, antagonists of 5-HT6 were found to variably enhance cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission; in human studies, they were associated with benefit in terms of several tests of learning and memory.146 SB742457 has successfully completed a dose-ranging safety study in patients with mild to moderate AD.147 Two Phase II trials of SB742457, one as add-on therapy to donepezil (N = 672)148 and the other as monotherapy (N = 576),149 were begun in 2008.

SK-PC-B70M SK-PC-B70M is composed of the oleanolic glycoside saponin–enriched fraction of Pulsatilla koreana (Korean pasque flower), which has been found to have neuroprotective and cognition-enhancing effects in animal models.150 A Phase II study that compared SK-PC-B70M monotherapy with placebo in 188 patients with mild to moderate AD was completed in January 2009.151

T-817MA Potent neuroprotective effects of T-817MA against Aβ- or oxidative stress–induced neurotoxicity have been found in vitro, as well as promotion of neurite

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outgrowth in rat hippocampal slice cultures.152 These neuroprotective and neurotrophic properties suggest that T-817MA may be useful in the treatment of AD. A large Phase II study in patients with mild to moderate AD (N = 316), initiated in April 2008, is assessing the safety and tolerability of T-817MA and is powered to detect an efficacy signal using the ADAS-cog as a primary outcome measure.153

ZT-1 (Formerly DEBIO-9902 SR) ZT-1 is a long-acting implantable formulation of the ChEI huperzine A. It is being evaluated in a Phase II trial (BRAINz [Better Recollection for Alzheimer’s patients with the ImplaNt of ZT-1]) that completed enrollment in October 2008.154 A concurrent study is under way to assess the bioequivalence of a tablet formulation and the implantable formulation.155

PHASE I TRIALS As of January 2009, a wide variety of compounds were in Phase I trials, including agents with presumptive mechanisms of action similar to those of compounds in more advanced stages of development and a number of agents with novel mechanisms of action (Table III). However, because Phase I trials are designed almost exclusively to assess safety in humans and because there is a long time span from Phase I testing to the potential introduction into clinical practice of a new treatment, these agents will not be discussed in detail.

CONCLUSIONS The clinical development of new agents for the symptomatic and disease-modifying treatment of AD has resulted in both promise and disappointment. Despite the fact that no new compound for the treatment of

Table III. Agents in Phase I trials.


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M.N. Sabbagh

AD has been introduced since the approval of memantine in 2002, the breadth and depth of development activity, the variety of drug targets and mechanisms of action, and the total number of compounds under investigation make it highly likely that important new pharmacotherapeutic options will become available for the treatment of AD over the next decade. Moreover, research into the underlying etiology and pathophysiology of AD is likely to facilitate identification of additional targets for future drug development. Many agents in clinical development for the treatment of AD are being evaluated in samples in which the majority of patients are receiving at least 1 ChEI. Because the use of concurrent therapy is not an exclusion criterion in most trials, patients can often enroll in trials while receiving a ChEI and/or memantine. Informing patients and caregivers of clinical trials taking place in their area is an important component of providing optimal clinical care and may help accelerate advances in treatment. It is too soon to predict which therapeutic strategy or agent will be the next to expand the treatment options for patients with AD. However, it is not unrealistic to hope that several medications may emerge from the crowded pipeline of novel compounds that will help revolutionize the treatment of AD, transforming it from a relentless progressive and devastating illness to a manageable chronic disease.

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ACKNOWLEDGMENTS Dr. Sabbagh received an honorarium from Eisai Inc. and Pfizer Inc. in connection with the development of this manuscript. Editorial support was provided by K. Jambor, MA, and B. Kadish, MD, of PAREXEL, Stamford, Connecticut, and was funded by Eisai Inc. and Pfizer Inc. Support was also provided by National Institute on Aging grant P30 AG019610 and the BannerSun Health Research Institute.

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Address correspondence to: Marwan N. Sabbagh, MD, The Cleo Roberts Center for Clinical Research, BannerSun Health Research Institute, 10515 W. Santa Fe Drive, Sun City, AZ 85351. E-mail: [email protected]

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