Sponsored Links: Prescription Drug Addiction     STRATEGIC BRIEFINGS  Companies Sprint toward Alzheimer's Disease-Modifying Drug By Lucy Sannes, Ph.D., Sannes & Associates December 7, 2006 The market opportunity is untapped, and the time is now. The race is on for a treatment that can modify Alzheimer’s disease (AD). As the average age of the US population rises, AD represents an ever-growing healthcare crisis. It is a devastating disease without a cure, and the economic impact to society is huge: According to the Alzheimer’s Association and the National Institute on Aging, 4.5 million Americans have AD and the cost of caring for these patients is at least $100 billion each year. Compounding the problem is the fact that although currently approved drugs can alleviate symptoms and slow progression of AD, they do not treat its underlying cause.   AD is the leading cause of dementia. As the population ages, the number of Americans with AD may grow to as many as 16 million by 2050, according to the Alzheimer’s Association. The National Institute on Aging estimates that currently, 5% of people aged 65 to 74 years have AD, and nearly half of those 85 years of age or older may have the disease. Notably, preliminary reports from a recent Mayo Clinic study suggest that approximately 12% of people over the age of 70 years have mild cognitive impairment (MCI). This fact further fuels the need for an AD treatment, as people with MCI are three to four times more likely to develop AD than those without. The market for AD drug therapy in the US , Europe, and Japan exceeded $3 billion in 2005, according to Millennium Research Group. By 2009, approximately 10 million people in this global market will suffer from Alzheimer’s disease. The Culprits: Problematic Protein Structures In the brain, the hallmark characteristics of AD are amyloid plaques and neurofibrillary tangles. Amyloid plaques are clumps of beta-amyloid, a protein fragment that is produced by abnormal processing of the amyloid precursor protein (APP). Beta-amyloid has also been called amyloid beta or Aβ. A major component of the neurofibrillary tangles is the protein tau. Development of these abnormal structures in the brain eventually results in disruptions in the transmissions between nerve cells (neurons) and death of the neuron.   FDA-Approved Drugs to Alleviate Alzheimer’s Symptoms   The Food and Drug Administration (FDA) has approved five drugs for treatment of AD (see Table 1). All of these drugs treat cognitive symptoms of the disease and can slow its progression. However, they do not treat the underlying cause of the disease. The first four drugs to reach the market were cholinesterase inhibitors (also called acetylcholinesterase inhibitors). These drugs block breakdown of the chemical messenger acetylcholine in the brain. Acetylcholine is thought to be important in memory and cognitive function, and the amount of acetylcholine produced by the brain decreases as AD progresses. Cognex, the first cholinesterase inhibitor to reach the market, is rarely prescribed now due to side effects. The leading product for treatment of AD is Aricept (donepezil), which was originally discovered and developed by Eisai ( Japan ), and is marketed by both Eisai and Pfizer. All of the acetylcholinesterase inhibitors were initially developed for treatment of mild to moderate AD. However, in October 2006, the FDA approved Aricept for treatment of severe AD, thus expanding its approved indications.   The newest drug to reach the market for treatment of Alzheimer’s disease is memantine, which is marketed in the US by Forest Laboratories under the brand name Namenda. Forest licensed memantine from Merz Pharmaceutical GmbH. Merz; its other licensees market memantine outside of the US under different brand names. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. It is currently approved by the FDA for treatment of moderate to severe AD. Forest is seeking to expand the approved indication for Namenda. In November 2004, Forest announced that the FDA had accepted a supplemental New Drug Application to expand the indication for Namenda to include treatment of mild AD. Use of memantine for treatment of AD patients is growing. However, like other AD drugs available today, memantine may help relieve symptoms, but does not treat the underlying cause of the disease.   Companies Rise to Meet Urgent Need As noted previously, AD is a large market with significant unmet needs. Numerous companies have research or clinical programs to develop new therapies for treatment of AD. According to Navigant Consulting, a new crop of drugs in development aimed at preventing and combating the characteristic buildup in the brain of amyloid plaques is expected to come to market by 2011. Selected examples of drug candidates in Phase II or later clinical development are shown in Table 2. As demonstrated by the product candidates in this table, pharmaceutical and biopharmaceutical companies are pursuing a wide range of approaches and targets in the effort to develop new treatments for AD.   Several of the emerging therapies listed in Table 2 are based on disease-modifying approaches to prevent or reduce buildup of the amyloid plaques. Potential mechanisms include inhibiting beta-secretase or gamma-secretase (thus blocking cleavage of APP), blocking aggregation of beta-amyloid, and other approaches to reduce buildup of beta-amyloid and the amyloid plaques. Many companies are developing secretase inhibitors, but most of the secretase inhibitor programs are in only early-stage development, and therefore are not included in Table 2. Two of the more advanced disease-modifying agents that target buildup of amyloid plaques are Myriad Genetics’ Flurizan and Neurochem’s Alzhemed, both of which are being evaluated in Phase III clinical trials.   Myriad Genetics reports that Flurizan is a selective amyloid-lowering agent (SALA) that reduces levels of the peptide amyloid beta 43 in cultured human cells and in animal models. Results of a completed Phase II follow-on study of Flurizan in patients with mild AD were presented in July 2006 at the International Conference on Alzheimer’s Disease and Related Disorders. According to Myriad Genetics, results from this study reportedly supported the hypothesis that Flurizan may have disease-modifying effects, and that the longer patients with mild AD are treated with Flurizan, the more slowly their disease will progress. Flurizan is currently being evaluated in two Phase III clinical trials. Act-Earli-AD Global (A Clinical Trial to Evaluate Aß42 Reduction for Limiting the Impact of Alzheimer’s Disease) is a global study that includes patients in the United States and several European countries. This study, which is currently enrolling patients, will include approximately 800 patients with mild AD who will be divided into two study arms (treatment with 800 mg Flurizan twice daily or placebo). The primary objective of the study, scheduled to last 18 months, will be evaluation of changes in cognition and activities of daily living.   A second study, called Act-Earli-AD US , is being conducted in the United States only and is fully enrolled. This is also a double-blind, placebo-controlled study in which patients with mild AD receive either 800 mg Flurizan twice daily or placebo for 18 months.   Neurochem reports that Alzhemed is thought to reduce deposition of amyloid by binding to the Aß (also known as beta-amyloid) peptide. Phase II results for Alzhemed in patients with mild to moderate AD were published in the November 28, 2006 issue of Neurology. Neurochem describes positive results in that Alzhemed was safe, tolerated, and reduced levels of amyloid beta 42 in the cerebrospinal fluid of patients with AD.   Alzhemed is currently being evaluated in two Phase III clinical trials. The company’s North American trial (in the United States and Canada ) is a randomized, double-blind, placebo-controlled study in 1,052 patients with mild to moderate AD. Patients are being treated for 18 months. Following completion of the study, patients are eligible to receive Alzhemed in an open-label extension study. Neurochem reports that this study is scheduled for completion in January 2007.   A second Phase III trial of Alzhemed was initiated in Europe in September 2005. Neurochem expects to include 930 patients with mild to moderate AD in this study.   The current market opportunity for drugs to treat AD is large, and this market is expected to grow even more in the future. As demonstrated by the information in Table 1, current sales of drugs to treat AD have already exceeded $2 billion per year. The eventual success of emerging drugs for treatment of AD, including disease-modifying drugs such as Flurizan and Alzhemed, could ultimately depend on the clinical performance of these drugs. However, should such emerging therapies prove to be successful in the clinic, they have the potential to significantly penetrate this large and growing market.   For further reading:   Click here for more on Pfizer/TransTech’s potentially disease-modifying candidate for Alzheimer’s disease.   To read more about diagnostics for Alzheimer’s disease and the importance of early detection, click here. Table 1: FDA-Approved Drugs for Treatment of AD Company (Drug category appears in italics) Product Name (generic) Year of Initial FDA Approval Approved Indication(s) and Comments 2005 Worldwide Sales Acetylcholinesterase Inhibitors Eisai and Pfizer Aricept and Aricept ODT (donepezil) 1996 •For treatment of dementia of the Alzheimer’s type. Efficacy has been demonstrated in patients with mild to moderate AD, as well as in patients with severe AD. •Originally discovered and developed by Eisai. Aricept is co-promoted by Pfizer and Eisai in the US and several other countries. Pfizer has an exclusive license to market Aricept in certain countries. Reported by Pfizer: Some revenues reported separately ($346 million) and others included in total for Alliance revenue (which is $1.362 billion and includes other drugs).   Reported by Eisai: Global product sales (Eisai territory sales) of 196.5 billion Yen (approximately $1.7 billion) for fiscal 2006 (ended 3/31/06). Novartis Exelon (rivastigmine) 2000 •For treatment of mild to moderate dementia of the Alzheimer’s type, and for treatment of mild to moderate dementia associated with Parkinson’s disease. $467 million Ortho-McNeil Neurologics (Part of Johnson & Johnson) Razadyne (galantamine) 2001 •For treatment of mild to moderate dementia of the Alzheimer’s type. •Originally sold under the trade name Reminyl. Not Available Sciele Pharma (Formerly First Horizon Pharmaceutical) Cognex (tacrine) 1993 •For treatment of mild to moderate dementia of the Alzheimer’s type. •Originally developed by Warner-Lambert (which has since been acquired by Pfizer). Not Available N-methyl-D-aspartate (NMDA) Receptor Antagonist Forest Laboratories Namenda (memantine) 2003 •For treatment of moderate to severe dementia of the Alzheimer’s type. •Forest Laboratories licensed US rights to memantine from Merz Pharmaceuticals GmbH. •Merz and its partners market memantine outside the US under different brand names. Reported by Forest : US-only sales were $508 million for fiscal 2006 (ended 3/31/06); compared with $333 million for fiscal 2005.   Reported by Merz in 2004/2005 Annual Report: Total sales (Merz and license holders) were $600 million for 2004/2005. Source: Sannes & Associates, Inc.   Table 2:  Selected Companies with Late-Stage Candidates for Treatment of AD Company (Drug category appears in italics) Product/Technology Status Comments Disease-Modifying Agents Targeting Amyloid Plaques Eli Lilly LY2062430 Phase II •Reportedly may influence beta-amyloid production. Eli Lilly LY450139 Phase II •Gamma secretase inhibitor. •For mild to moderate AD. Myriad Genetics Flurizan  (MPC-7869) Phase III •Selective amyloid-lowering agent (SALA) that reduces levels of the Aβ 42 peptide in cultured human cells and in animal models. •Being evaluated in two Phase III trials in patients with mild AD. Neurochem ( Canada ) Alzhemed  (tramiprosate) (3-amino-1-propanesulfonic acid [3APS]) Phase III •Binds to Aβ peptide and maintains this peptide in a non-fibrillar form. Prana Biotechnology ( Australia ) PBT-2 10/06 – Approved to start Phase IIa in Sweden •Reduces levels of Aβ protein. •For early AD. TorreyPines Therapeutics phenserine Phase III (Did not achieve statistical significance over placebo in Phase III trial where it was evaluated for improvement in memory and cognition.) •Dual mechanism of action: Acetylcholinesterase inhibition and lowering levels of Aβ 42 peptide. •For treatment of mild to moderate AD. •Acquired through a reverse merger with Axonyx. •Licensed to Daewoong, which has rights for South Korea . TransTech Pharma TTP488 Phase II •Small molecule. •Reduces amyloid burden. Wyeth and Elan bapineuzumab  (AAB-001) Phase II •Humanized monoclonal antibody to Aβ; designed to bind to and clear Aβ peptide. •Passive immunization approach. Wyeth and Elan AAC-001 Phase II (Reported by Elan) •Immunoconjugate. •Aβ-related active immunization approach. Other Agents in Development for AD Accera Ketasyn  (AC-1202) Phase II •First-in-class therapeutic agent that Accera reports addresses the energy deficit observed in the brains of AD patients. •Phase IIb trial for AD complete. Accera expects to have results available by end of 2006, and expects that results of a six-month open-label extension will be available during the first quarter of 2007. •Start of Phase II trial for age-associated memory impairment announced August 2006. AstraZeneca AZD3480   Phase II •Neuronal nicotinic receptor agonist. •For cognitive disorders/AD. •12/05: Agreement with Targacept granted AstraZeneca rights to Targacept’s TC-1734 (now AZD3480). Cortex Pharmaceuticals CX717 Phase II: Released from clinical hold 10/06 •AMPAKINE compound—AMPAKINE drugs increase the activity of the AMPA receptor. Dainippon Sumitomo AC-3933 Phase II  (US)   Phase I ( Japan ) •Partial inverse agonist of benzodiazepine receptors; reportedly activates cholinergic neurons by enhancing release of acetylcholine, and also stimulates glutaminergic neurons. •Being developed for treatment of dementia. •Phase II trial in US for treatment of mild to moderate AD; sponsored by Dainippon Sumitomo Pharma America . Debiopharm Debio-9902 SR  (ZT-1 SR) Phase II •Acetylcholinesterase inhibitor. Forest Laboratories neramexane Phase III •NMDA receptor antagonist for moderate to severe AD. •Licensed from Merz. GlaxoSmithKline rosiglitazone XR (extended-release tablets) Phase III (AD)   (Avandia [rosiglitazone] is on the market for diabetes.) •Peroxisome proliferator-activated receptor (PPAR) gamma agonist. •Rosiglitazone XR is in Phase III development for mild to moderate AD. It is also being evaluated in clinical trials for rheumatoid arthritis. •Avandia (rosiglitazone) is FDA approved for use as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Avandia may be used either as a monotherapy or in combination with sulfonylurea, metformin, insulin, or sulfonylurea plus metformin. Medivation Dimebon Phase II •Oral drug that has been on the market since 1983 for treatment of allergic rhinitis and allergic dermatitis. •In Phase II for AD and in preclinical development for Huntington’s disease. •Has a potential neuroprotective activity, e.g., inhibits brain cell death. Memory Pharmaceuticals MEM 1003