First Phase III Trial of an Anti-Amyloid Drug in Alzheimer’s Disease

Also, long-term results from three other approaches

Washington, D.C., June 11, 2007

Data from clinical trials of four possible Alzheimer’s therapies raise hope for an emerging new era in treatment of the disease, according to research reported today at the 2nd Alzheimer’s Association International Conference on Prevention of Dementia in Washington, D.C.

These reports included data from:

• The first Phase III trial of an anti-amyloid therapy in Alzheimer’s, tramiprosate (Alzhemed, Neurochem).

• A six-month extension of a Phase II trial in mild to moderate Alzheimer’s of an oral drug with a novel mechanism of action (Dimebon, Medivation).

• A 4½ year follow-up data on participants from the first major Alzheimer’s immunotherapy trial (AN1792, Elan and Wyeth).

• 72-week safety and tolerability results from a diabetes drug being investigated in Alzheimer’s (rosiglitazone, GlaxoSmithKline).

While currently approved treatment options offer some relief of symptoms for perhaps a year or two, they do not change the course of the disease. It is widely believed that Alzheimer’s is associated with the accumulation of a brain protein known as amyloid ß (Aß) which, in its soluble form, is toxic to brain cells.

“Amyloid as a cause for Alzheimer’s and a primary target for therapies and preventions must be thoroughly tested,” said William Thies, Ph.D., Alzheimer’s Association vice president for Medical and Scientific Relations. “We need an answer to this question so that we can then sharpen our focus on attacking amyloid and creating better treatments, or change the focus to other areas if the theory is wrong.”

Very few drugs make it through the process from initial identification through approval for marketing, or even to Phase III clinical trials. According to the Pharmaceutical Research and Manufacturers of America, economists estimate that it takes an average of 12 to 15 years to discover and develop a new medicine and, on average, it costs as much as $800 million. On average, only five of every 10,000 compounds investigated are tested in clinical trials. Of those five, only one is ever approved for patient use. Plus, there are a variety of logistical challenges unique to conducting trials in people with Alzheimer’s.

“We’re very pleased to see several compounds in Phase III clinical trials now for Alzheimer’s disease that represent a variety of treatment strategies,” said Sam Gandy, M.D., Ph.D., chair of the Alzheimer’s Association’s Medical & Scientific Advisory Council. “The odds are quite good that we’ll have more effective new treatments for Alzheimer’s in the near future.”

18-month phase III trial of tramiprosate (Alzhemed)

Tramiprosate (Alzhemed, Neurochem) is an anti-amyloid compound in Phase III Alzheimer’s clinical trials. Tramiprosate is a small, orally-administered investigational product candidate that is known as an amyloid ß antagonist. It is believed to act by binding to the soluble Aß protein, thereby interfering with the complex cascade of events associated with amyloid deposition and the toxic effects of Aß in the brain.

At the Alzheimer’s Association Prevention Conference, lead author Paul Aisen, M.D., Professor of Neurology and Medicine, and Director of the Memory Disorders Program at the Georgetown University Medical Center, Washington D.C., presented an update from the Phase III study, which was designed to assess the safety, efficacy and disease modifying effect of tramiprosate (Alzhemed) in patients with mild-to-moderate Alzheimer’s.

A total of 1,052 patients were enrolled in the multi-center, randomized, double-blind, placebo controlled study in the U.S. and Canada. All patients were on stable doses of acetylcholinesterase inhibitors, with or without memantine. Patients were randomized to receive tramiprosate (Alzhemed) 100 mg, 150 mg, or placebo twice a day for 18 months. Safety and efficacy assessments were conducted at three-month intervals in all patients. Primary measures included the Alzheimer’s Disease Assessment Scale, cognitive subscale (ADAS-cog), and Clinical Dementia Rating-Sum of Boxes (CDR-SB) to assess clinical efficacy, and volumetric MRI to assess disease modification effect on brain volume over the course of the study. Secondary efficacy measures included the Mini-mental Status Examination (MMSE), Clinician’s Interview Based Impression of Change, plus Caregiver Interview (CIBIC-plus), Neuropsychiatric Inventory (NPI) and Disability Assessment for Dementia (DAD).

The Phase III clinical trial for Alzhemed has generated an unprecedented amount and complexity of data. The company discovered there were significant and unexpected differences in the data between the study’s many sites, making it very difficult to determine the total outcome of the trial. Therefore, the company is working to account for the site differences, so it can analyze the data to determine the total results.

“At this time, we don’t have the results for the Alzhemed Phase III clinical trial,” said Gandy. “However, we have learned important lessons about how to do these types of very complex, long-term, large-scale Alzheimer’s trials, which in itself is very important because there are now so many promising Alzheimer’s therapies in the pipeline.”

12-Month Phase II Trial Results for Dimebon

Dimebon (Medivation) is an oral medication that has been shown to inhibit brain cell death in preclinical models relevant to Alzheimer's and Huntington's diseases. Dimebon appears to block a new target that involves mitochondrial pores, which are believed to play a role in the cell death that is associated with neurodegenerative diseases and the aging process.

In an already reported six-month study, 183 patients in Russia with mild to moderate Alzheimer’s were randomized to receive Dimebon 20 mg orally three times a day or placebo for six months and then offered blinded continuation of the study for an additional six months. Other anti-dementia drugs were not allowed. ADAS-cog (primary endpoint), CIBIC-plus, MMSE, NPI, and activities of daily living (ADL) were assessed at baseline and at weeks 12, 26, 39 and 52. Patients improved significantly compared to baseline and compared to placebo at six months on all five outcome measures. Dimebon was well tolerated in the study.

At the Prevention Conference, Rachelle Doody, M.D., Ph.D., Effie Marie Cain Chair in Alzheimer’s Disease Research and Professor of Neurology at Baylor College of Medicine, reported 12-month results that included the blinded, six-month extension of this trial in which patients continued treatment in their original group.

4½ year follow-up on Alzheimer’s immunotherapy with AN1792

Immunotherapy for Alzheimer’s has shown great promise, though the first major clinical trial using an active immunotherapeutic approach with a compound called AN1792 (a synthetic form of the amyloid ß protein) (Elan and Wyeth) was halted due to brain inflammation in about six percent of participants.

After treatment was discontinued, researchers continued to follow the participants from that trial. In data presented at the 2007 Alzheimer’s Association Prevention Conference, Michael Grundman, M.D., M.P.H., Senior Director of Clinical Development in the Alzheimer’s Disease Program at Elan Pharmaceuticals, Inc., and colleagues found that four and a half years after being immunized with AN1792, patients who developed antibodies to the amyloid ß protein continued to show detectable amyloid ß antibodies and less decline in activities of daily living (ADL) compared to placebo treated patients. 159 patient/caregiver pairs participated in this follow-up study (30 placebo; 129 AN1792). Of the 129 AN1792 treated patients, 25 were classified as antibody responders.

Antibody responders showed significantly slower decline on the Disability Assessment for Dementia (DAD) compared to placebo patients. The DAD is an ADL scale developed for patients with Alzheimer’s that is administered to the patient’s caregiver through an interview. This scale assesses a patient’s ability to initiate, plan and perform activities related to hygiene, dressing, continence, eating and meal preparation, telephoning, going on an outing, finance and correspondence, medications, leisure and housework. Antibody responders also showed a significant favorable difference compared to placebo patients on a dependence scale that measures disease impact on patients and caregivers.

According to the researchers, antibody responders also showed less decline on a memory test than those who received placebo. Brain volume changes were similar in antibody responders and placebo patients beyond the first year of follow-up, and no additional cases of encephalitis were observed.

“The favorable results on Activities of Daily Living among the antibody responders in this study support the hypothesis that amyloid ß immunotherapy may have long-term benefits for patients with mild to moderate Alzheimer’s and their caregivers,” Grundman said.

72-week safety and tolerability results with Rosiglitazone XR

Rosiglitazone is used to treat type 2 diabetes. It lowers blood sugar by helping cells use insulin more efficiently to remove excess sugar from the blood. It has been suggested that rosiglitazone also may influence inflammation and other brain cell processes that may be related to the development of Alzheimer's. However, a recently published meta-analysis reported that rosiglitazone use in diabetes was linked to increased risk of myocardial infarction and death from cardiovascular causes.

Scientists at GlaxoSmithKline studied Alzheimer’s patients treated with rosiglitazone XR, an extended-release form of the drug, to evaluate its tolerability and safety during 12 months of treatment. This study was a follow-up, open-label, extension study to a randomized, controlled trial that suggested rosiglitazone may be effective in some patients depending upon their APOE genotype – APOE e4-negative subjects showed improvement, whereas e4-positive subjects showed either no improvement or a decline.

Three hundred thirty-seven (337) patients with mild-to-moderate Alzheimer’s were enrolled in the study; 82 percent completed it. Seven percent withdrew due to adverse events (AEs). Forty-eight (48) percent of subjects experienced =1 AE, most commonly peripheral oedema, which is accumulation of fluid, usually in the legs or sacral region (6 percent), and nasopharyngitis, which is inflammation of the nasal passages and upper part of the pharynx (5 percent). 9 percent experienced =1 severe adverse event (SAE); each SAE except fractures (2 percent) occurred in = 1 percent of subjects. Few subjects exhibited clinically significant changes in heart rate (<1 percent), or clinically significant abnormal ECG readings (2 percent) during the study. Changes in insulin sensitivity and glycemic control measures were within expected ranges and typical of an older population with a low level of insulin resistance.

“Rosiglitazone XR appeared to be generally well tolerated in subjects with Alzheimer’s for up to 72 weeks,” said Michael Gold, M.S., M.D., Global Clinical Vice President, Neurology, at GlaxoSmithKline. “Rosiglitazone use in Alzheimer’s appears to have a safety profile comparable to that established in type 2 diabetes.”

Recent reports have raised concerns about increased risk of heart attack and death from cardiovascular causes during use of rosiglitazone in diabetes. The issue continues to be investigated in ongoing studies and data analyses.

“There is value in continuing to study rosiglitazone in Alzheimer’s. We need to attack the disease through multiple mechanisms, and the only way we can learn with certainty about issues of safety and efficacy in Alzheimer’s is through clinical trials,” Thies said. “There are risks involved in clinical studies, and we do need to ensure that all risks are thoroughly described and explained to study participants and family members. That’s why we have informed consent, and why the process is so important.”

Large-scale clinical trials are underway to investigate the effectiveness of rosiglitazone as a potential new treatment for Alzheimer’s. Rosiglitazone is not currently approved for treatment of Alzheimer’s.

About the Alzheimer’s Association Prevention Conference

The Alzheimer’s Association International Conference on Prevention of Dementia is the world's only multidisciplinary forum to convene professionals from the fields of bench research, drug discovery, medicine, care and public policy. More than 1,000 dementia experts from around the world will gather to present and discuss the latest detection, treatment and prevention research, and address how together we can prevent Alzheimer's from becoming a global health crisis. The 2007 Alzheimer’s Association Prevention Conference will be held June 9-12 at the Marriott Wardman Park Hotel in Washington, D.C.

About the Alzheimer’s Association

The Alzheimer’s Association is the leading voluntary health organization in Alzheimer’s care, support and research. Our mission is to eliminate Alzheimer’s disease through the advancement of research, provide and enhance care and support for all affected, and reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer’s. For more information, visit www.alz.org.

• Paul Aisen – A Phase III Study of the Efficacy, Safety and Disease Modification Effect of Tramiprosate in Mild-to Moderate Alzheimer’s Disease, (Funder: Neurochem)
• Rachelle S. Doody – Results of a One-Year, Randomized, Placebo-Controlled Trial of Dimebon for the Treatment of Mild to Moderate Alzheimer’s Disease. (Funder: Medivation)
• Michael Grundman (first author, Leon Thal (deceased)) – Long Term Follow Up of Patients Immunized with AN1972(QS-21): Reduced Functional Decline in Antibody Responders. (Funder: Elan)
• David Hosford – Long-Term Safety and Tolerability of Rosiglitazone XR in Alzheimer’s Disease. (Funder: GlaxoSmithKline)

Contact:
Alzheimer's Association media line: 312.335.4078 or media@alz.org
Prevention Conference press room, June 9-12: 202.745.2108