Alzheimer's Association Alzheimer's Disease Facts and Figures 2014
Therapies for Alzheimer's disease
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FROM THE ANALYST’S COUCH Therapies for Alzheimer’s disease Irena Melnikova Cardboard ‘Pool’ Rocker by Giles Miller, www.farmdesigns.co.uk Alzheimer’s disease (AD) is a devastating neurological disorder that affects more than 37 million people worldwide 1 . The economic burden of AD is massive; in the United States alone, the estimated direct and indirect annual cost of patient care is at least US$100 billion. However, the number of therapeutic options for AD remains severely limited. Currently marketed drugs for AD do not prevent or reverse this disease and are approved only for the management of symptoms. Driven by the clear unmet medical need and a better understanding of the biology and pathophysiology of AD, the number of drugs in development for this indication has increased dramatically in recent years. Current therapies The five drugs currently on the market — the cholinesterase inhibitors donepezil (Aricept; Eisai/Pfizer), rivastigmine (Exelon; Novartis), galantamine (Razadyne; Johnson & Johnson) and tacrine (Cognex; First Horizon Pharmaceuticals), and the N-methyl- d-aspartate (NMDA)-receptor modulator memantine (Namenda; Forest/Lundbeck) — are approved for the treatment of symptoms of AD. Despite being unable to prevent or reverse the disease progression, and being only modestly efficacious, these drugs have performed exceptionally well commercially, having collectively generated $3 billion in sales in 2006 (FIG. 1). Currently marketed drugs for the management of symptoms of AD are going to continue to be the mainstay of therapy for the next 4–5 years. Disease-modifying strategies Neurotoxic β-amyloid (Aβ) peptide and the senile plaques composed of aggregated Aβ, as well as the neurofibrillary tangles composed of tau protein, are thought to be central to the pathogenesis of AD 2 . Although both molecules present multiple opportunities to create disease-modifying therapies for AD, most of the industry’s efforts have been focused on the ‘amyloid hypothesis’ and associated targets (TABLE 1). Therapeutic strategies aimed at preventing Aβ formation, blocking its aggregation into plaques, lowering its levels in the brain, and disassembling the existing amyloid plaques might potentially slow down or stop the progression of AD 3 . The most advanced disease-modifying drug (DMD) candidate in development is Neurochem’s tramiprosate. Tramiprosate is a glycosaminoglycan mimetic designed to bind to Aβ peptides, thereby stopping the formation of amyloid plaques. Owing to the short duration (3 months) of the tramiprosate Phase II trial, no dramatic effects on cognition were observed. However, in an open-label extension study, tramiprosate showed clinically significant benefits on cognitive and global performance measures, with a stabilization of the disease in a proportion of patients with mild AD after 3 years of treatment. Tramiprosate is being investigated in two pivotal 18-month Phase III clinical trials with data expected in 2007 and 2008. Positive outcomes of these trials would be the first proof-of-concept validation of the amyloid hypothesis in humans. If proved to be safe and effective, tramiprosate could reach the market in 2009 and could become the first DMD approved for AD. Myriad Genetics’ tarenflurbil — a modulator of γ-secretase activity — is the most advanced agent in clinical development for preventing Aβ formation. In a Phase II trial in patients with mild-to-moderate AD, tarenflurbil was safe and well tolerated, and demonstrated a reduced rate of cognitive decline compared with a placebo. Tarenflurbil is currently in an 18-month pivotal Phase III study. Final data from the US sites are anticipated in the second half of 2008. Provided the trial is successful, tarenflurbil could be launched as soon as 2009/2010. Extensive animal data suggest that antibodies against Aβ, produced by the body after a vaccination (active immunization) or administered peripherally (passive immunization), can reduce amyloid deposition and produce functional improvements, thereby ameliorating cognitive deficits. Both approaches are now being tested in the clinic. The first-generation amyloid vaccine, AN-1792 (Elan/Wyeth), demonstrated a positive efficacy trend: patients with AD who developed an antibody response significantly improved over a 1-year period in a number of memory tests. However, owing to the development of aseptic meningoencepha- litis in 6% of the patients, the AN-1792 programme was discontinued. A second- generation vaccine, ACC-001 (Elan/Wyeth), which was engineered to have an improved safety profile, is now in a Phase I trial. Compared to active immunization, passive immunization would be a more expensive and cumbersome approach, requiring frequent anti-Aβ monoclonal antibody (mAb) administration, but on the other hand, it might offer more control over both safety and efficacy. Three mAbs against various domains of Aβ are currently in development: bapineuzumab (Elan/Wyeth) and LY2062430 (Eli Lilly) in Phase II trials, and RN1219 (Pfizer) in Phase I. Elan/Wyeth could initially bring bapineuzumab to the market as a symptom-management drug and then secure disease-modifying claims in post- approval studies. In an 8-week Phase I study, bapineuzumab showed statistically significant improvement in cognitive function. If interim data from the ongoing Phase II trial, expected in mid 2007, confirm this result, Elan/ Wyeth could initiate a short Phase III trial (3–6 months as opposed to an 18–month study required for a DMD) and file for a cognitive improvement/symptom-management label. Improving symptom management Clinical development of symptom- management drugs is considered to be easier, faster and cheaper than that of DMDs (TABLE 2). Given the modest efficacy of approved symptom-management therapies, new agents in this area are also needed. Experts suggest that the best strategy for the development of such drugs is to focus on novel targets. Neuronal nicotinic acetylcholine receptors (nAChRs), specifically the α4β2 and α7 receptors, have attracted a lot of attention in this regard. Several nAChR agonists are currently in Phase II trials: AZD3480 (AstraZeneca/ Targacept), MEM 3454 (Roche/Memory Pharmaceuticals), and GTS-21 (CoMentis). Outlook Disease-modifying therapies that target the underlying pathogenic mechanisms represent one of the most exciting approaches to novel drug development for AD. Some of these therapies could reach the market as soon as 2009/2010. Owing to the currently limited options for treating AD, the first wave of DMDs is likely to be rapidly adopted. ▶ NEWS & ANALYSIS NATURE REVIEWS | DRUG DISCOVERY VOLUME 6 | MAY 2007 | 341 © 2007 Nature Publishing Group
Transcript of Therapies for Alzheimer's disease
FROM THE ANALYST’S COUCH
Therapies for Alzheimer’s diseaseIrena Melnikova Cardboard ‘Pool’ Rocker by Giles Miller, www.farmdesigns.co.uk
Alzheimer’s disease (AD) is a devastating neurological disorder that affects more than 37 million people worldwide1. The economic burden of AD is massive; in the United States alone, the estimated direct and indirect annual cost of patient care is at least US$100 billion.
However, the number of therapeutic options for AD remains severely limited. Currently marketed drugs for AD do not prevent or reverse this disease and are approved only for the management of symptoms. Driven by the clear unmet medical need and a better understanding of the biology and pathophysiology of AD, the number of drugs in development for this indication has increased dramatically in recent years.
Current therapies
The five drugs currently on the market — the cholinesterase inhibitors donepezil (Aricept; Eisai/Pfizer), rivastigmine (Exelon; Novartis), galantamine (Razadyne; Johnson & Johnson) and tacrine (Cognex; First Horizon Pharmaceuticals), and the N-methyl-d-aspartate (NMDA)-receptor modulator memantine (Namenda; Forest/Lundbeck) — are approved for the treatment of symptoms of AD. Despite being unable to prevent or reverse the disease progression, and being only modestly efficacious, these drugs have performed exceptionally well commercially, having collectively generated $3 billion in sales in 2006 (FIG. 1). Currently marketed drugs for the management of symptoms of AD are going to continue to be the mainstay of therapy for the next 4–5 years.
Disease-modifying strategies
Neurotoxic β-amyloid (Aβ) peptide and the senile plaques composed of aggregated Aβ, as well as the neurofibrillary tangles composed of tau protein, are thought to be central to the pathogenesis of AD2. Although both molecules present multiple opportunities to create disease-modifying therapies for AD, most of the industry’s efforts have been focused on the ‘amyloid hypothesis’ and associated targets (TABLE 1). Therapeutic strategies aimed at preventing Aβ formation, blocking its aggregation into plaques, lowering its levels in the brain, and disassembling the existing amyloid plaques might potentially slow down or stop the progression of AD3.
The most advanced disease-modifying drug (DMD) candidate in development is Neurochem’s tramiprosate. Tramiprosate is a glycosaminoglycan mimetic designed to bind to Aβ peptides, thereby stopping the formation of amyloid plaques. Owing to the short duration (3 months) of the tramiprosate Phase II trial, no dramatic effects on cognition were observed. However, in an open-label extension study, tramiprosate showed clinically significant benefits on cognitive and global performance measures, with a stabilization of the disease in a proportion of patients with mild AD after 3 years of treatment. Tramiprosate is being investigated in two pivotal 18-month Phase III clinical trials with data expected in 2007 and 2008. Positive outcomes of these trials would be the first proof-of-concept validation of the amyloid hypothesis in humans. If proved to be safe and effective, tramiprosate could reach the market in 2009 and could become the first DMD approved for AD.
Myriad Genetics’ tarenflurbil — a modulator of γ-secretase activity — is the most advanced agent in clinical development for preventing Aβ formation. In a Phase II trial in patients with mild-to-moderate AD, tarenflurbil was safe and well tolerated, and demonstrated a reduced rate of cognitive decline compared with a placebo. Tarenflurbil is currently in an 18-month pivotal Phase III study. Final data from the US sites are anticipated in the second half of 2008. Provided the trial is successful, tarenflurbil could be launched as soon as 2009/2010.
Extensive animal data suggest that antibodies against Aβ, produced by the body after a vaccination (active immunization) or administered peripherally (passive immunization), can reduce amyloid deposition and produce functional improvements, thereby ameliorating cognitive deficits. Both approaches are now being tested in the clinic.
The first-generation amyloid vaccine, AN-1792 (Elan/Wyeth), demonstrated a positive efficacy trend: patients with AD who developed an antibody response significantly improved over a 1-year period in a number of memory tests. However, owing to the development of aseptic meningoencepha-litis in 6% of the patients, the AN-1792 programme was discontinued. A second-generation vaccine, ACC-001 (Elan/Wyeth),
which was engineered to have an improved safety profile, is now in a Phase I trial.
Compared to active immunization, passive immunization would be a more expensive and cumbersome approach, requiring frequent anti-Aβ monoclonal antibody (mAb) administration, but on the other hand, it might offer more control over both safety and efficacy. Three mAbs against various domains of Aβ are currently in development: bapineuzumab (Elan/Wyeth) and LY2062430 (Eli Lilly) in Phase II trials, and RN1219 (Pfizer) in Phase I. Elan/Wyeth could initially bring bapineuzumab to the market as a symptom-management drug and then secure disease-modifying claims in post-approval studies. In an 8-week Phase I study, bapineuzumab showed statistically significant improvement in cognitive function. If interim data from the ongoing Phase II trial, expected in mid 2007, confirm this result, Elan/Wyeth could initiate a short Phase III trial (3–6 months as opposed to an 18–month study required for a DMD) and file for a cognitive improvement/symptom-management label.
Improving symptom management
Clinical development of symptom-management drugs is considered to be easier, faster and cheaper than that of DMDs (TABLE 2). Given the modest efficacy of approved symptom-management therapies, new agents in this area are also needed. Experts suggest that the best strategy for the development of such drugs is to focus on novel targets. Neuronal nicotinic acetylcholine receptors (nAChRs), specifically the α4β2 and α7 receptors, have attracted a lot of attention in this regard. Several nAChR agonists are currently in Phase II trials: AZD3480 (AstraZeneca/Targacept), MEM 3454 (Roche/Memory Pharmaceuticals), and GTS-21 (CoMentis).
Outlook
Disease-modifying therapies that target the underlying pathogenic mechanisms represent one of the most exciting approaches to novel drug development for AD. Some of these therapies could reach the market as soon as 2009/2010. Owing to the currently limited options for treating AD, the first wave of DMDs is likely to be rapidly adopted. ▶
N E W S & A N A LY S I S
NATURE REVIEWS | DRUG DISCOVERY VOLUME 6 | MAY 2007 | 341
© 2007 Nature Publishing Group
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THERAPIES FOR ALZHEIMER’S DISEASE | MARKET INDICATORS
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Figure 1 | US sales of marketed AD drugs. Source: IMS Health.
In the next 5–10 years, the AD market is expected to undergo a major expansion driven by the ageing population, improvements in diagnostic testing and by the approval of novel therapeutics (TABLE 1). However, given the upcoming patent expirations (rivastigmine going off-patent in 2007, galantamine in 2008, donepezil and memantine in 2010) and the likely entry of generics, the total value of the AD market might decline around 2010–2011. But with the launch of the first wave of novel drugs occurring potentially as soon as 2009, the AD market could resume growth by 2011–2012 when new agents could achieve widespread market penetration.
Irena Melnikova, Ph.D., is a director at MEDACorp, a division of Leerink Swann,
One Federal Street, Boston, Massachusetts 02110, USA.
e-mail: [email protected]
doi:10.1038/nrd2314
1. Mount, C. & Downton, C. Alzheimer’s disease: progress or profit? Nature Med.12, 780–784 (2006).
2. Klafki, H.-W. et al. Therapeutic approaches to Alzheimer’s disease. Brain 129, 2840–2855 (2006).
3. Masters, C. L. & Beyreuther, K. Alzheimer’s centennial legacy: prospects for rational therapeutic intervention targeting the Aβ amyloid pathway. Brain 129, 2823–2839 (2006).
Competing interests statementThe author declares no competing financial interests.
Table 1 | Selected Alzheimer’s disease drugs in development
Drug Company Target/mechanism Status
Disease-modifying therapies
AL-108 Allon Therapeutics Stabilizes microtubules, blocks Aβ aggregation Phase II
LY450139 Eli Lilly γ-Secretase inhibitor Phase II
MK 0752 Merck γ-Secretase inhibitor Phase II
TTP488 TransTech Pharma/Pfizer Blocks RAGE/Aβ interactions, reduces brain amyloid load Phase IIa
E2012 Eisai γ-Secretase inhibitor Phase I
NGX267 TorreyPines Therapeutics M1 muscarinic agonist, α-secretase activator Phase I
AZD-103 Transition Therapeutics/Elan Inhibits Aβ fibrillization and disassembles preformed amyloid fibrils Phase I
ATG-Z1 CoMentis BACE1 inhibitor Preclinical
Symptom-management therapies
Xaliproden Sanofi–Aventis 5-HT1a receptor agonist Phase III
Lecozotan Wyeth 5-HT1a receptor antagonist Phase II/III
PRX-03410 Epix Pharmaceuticals/GlaxoSmithKline 5-HT4 receptor agonist Phase II
Dimebon Medivation Cholinesterase and NMDA-receptor inhibitor, mitochondrial permeability transitory pore modulator
Phase II
MEM 1003 Memory Pharmaceuticals l-type calcium-channel blocker Phase II
5HT, 5-hydroxytryptamine (serotonin) receptor; BACE1, β-site APP cleavage enzyme 1; RAGE, receptor for advanced glycation endproducts; NMDA, N-methyl-d-aspartate. Sources: company documents, MEDACorp documents.
Table 2 | Factors in pivotal trial design for novel Alzheimer’s disease therapies
Factor Symptom-management therapies Disease-modifying therapies
Trial duration
• 24–30 weeks • 18 months or longer
Number of patients
• 150–250 per treatment arm • 350–800 per treatment arm
Primary endpoints
• ADAS-cog, ADCS-ADL-severe, SIB • ADAS-cog, ADCS-ADL-severe, SIB• Demonstration of a change in a
relevant biomarker
Patient selection
• In some cases, a true placebo arm might be required (that is, no concurrent use of CI drugs or memantine)
• Under such conditions, enrolling patients into a 6-month trial might be challenging; however, if currently approved drugs are allowed, demonstrating added benefit of a drug candidate could be more difficult
• Tendancy to enrol patients with the mildest form of Alzheimer’s disease
• Concurrent use of approved symptom-management drugs is allowed
• Biomarkers that could identify patients at risk will be highly desirable to improve patient selection
Cost • US$15–30 million • US$30–50 million
ADAS-cog, Alzheimer’s disease assessment scale — cognitive; ADCS-ADL, Alzheimer’s disease cooperative study — activities of daily living; CI, cholinesterase inhibitors; SIB, severe impairment battery. Source: MEDACorp documents.
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