For Immediate Release

Exciting Advances In Alzheimer Therapies — From Pre-Clinical to Post-Marketing

First skin patch drug tested; new immunotherapy tested in people; Leuprolide Phase II results

July 19, 2006, Madrid, Spain

There is exciting progress in new therapies for Alzheimer's disease – from the earliest stages of drug discovery through post-marketing studies, according to research reported today in Madrid at the 10th International Conference on Alzheimer's Disease and Related Disorders (ICAD), presented by the Alzheimer's Association.

Advances include positive results from the first Alzheimer "patch" and the ongoing story of immunotherapy and the Alzheimer "vaccine." Plus there are promising results from trials of a next-generation metal binding antioxidant (PBT2) and a revamped version of an existing prostate cancer drug (leuprolide).

Many of these new therapeutic strategies focus on stopping the formation of abnormal beta amyloid protein and amyloid plaques in the brain, or removing them once they are already there. Scientists regard two abnormal microscopic structures called "plaques" and "tangles" as Alzheimer's disease hallmarks. Amyloid plaques are clumps of protein that accumulate outside the brain's nerve cells. The "amyloid cascade" is considered by many scientists to be the most mature theory of the cause of Alzheimer's.

"Amyloid as a possible cause for Alzheimer's must be thoroughly tested," said William Thies, Ph.D., Alzheimer's Association vice president for Medical & 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."

"At the same time, we are very encouraged to see a diversity of approaches to treating Alzheimer's showing some level of success," said Howard Fillit, M.D., executive director of the Institute for the Study of Aging, Inc. "These include drugs with new targets, new mechanisms of action, and new methods of delivery. We must pursue every available avenue. The urgency has never been higher."

First transdermal patch for Alzheimer's uses already approved Rivastigmine Transdermal drug delivery systems (usually by drug "patches") are designed to provide controlled, continuous delivery of drugs through the skin, thereby maintaining more consistent blood levels of the drug. Patches also minimize processing of the drug in the liver, stomach and intestines. Together, this may make it easier to achieve therapeutic levels of the drug in the bloodstream with lower dosages than pills, thereby possibly reducing side effects.

Since Alzheimer's initially affects memory, reasoning and decision-making abilities, it can be a problem for people with the disease to take drugs on a regular schedule. As the disease advances, people may not know what drugs are for or even what they are. With further advance of the disease, sometimes the ability to swallow is affected. Transdermal drug delivery has the potential to eliminate issues about forgetting to take the drug or to take it at the right time, and also ease challenges associated with getting the person with Alzheimer's to take or swallow a pill. It also provides visual reassurance for the caregiver that the medication has been taken. At the same time, possible skin irritation and the presence of a new or unknown object on their body may be confusing or annoying to the person with Alzheimer's, so a skin patch may not work for everyone.

Bengt Winblad, M.D., Ph.D., of the Karolinska Institutet, Huddinge, Sweden, and colleagues at UCLA and Novartis sought to compare the efficacy, safety and tolerability of a novel, once-daily rivastigmine (Exelon, Novartis) patch with conventional, twice-daily rivastigmine capsules. Rivastigmine is an FDA and EMEA approved cholinesterase inhibitor for treatment of mild to moderate Alzheimer's disease.

IDEAL (Investigation of TransDermal Exelon in ALzheimer's disease) was a 24-week, multicenter, randomized, double-blind, placebo- and active-controlled evaluation of once-daily rivastigmine patches versus twice-daily capsules in 1,195 patients with moderate stage Alzheimer's. Patients were 50 to 85 years of age. Tested patch sizes were 10 cm2 (9.5 mg/24-hr) or 20 cm2 (17.4 mg/24-hr), and capsules were 6 mg twice-daily. Primary outcome measures were the Alzheimer's Disease Assessment Scale – Cognition (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC).

The researchers found that the rivastigmine patch showed statistically significant benefits versus placebo on both of these measures and the ability to perform activities of daily living. The recommended target dose 10 cm2 patch showed similar efficacy to the highest doses of rivastigmine capsules with three times fewer reports of nausea (7.2 percent vs. 23.1 percent) and vomiting (6.2 percent vs. 17.0 percent), which are well-known side effects of cholinesterase inhibitors. The 20 cm2 patch showed improved cognitive scores versus capsules and similar tolerability to capsules. Local skin tolerability was good. Abnormal redness of the skin was present at moderate or severe levels in only 7.6 percent and 6.2 percent of patients receiving 10 and 20 cm2 patches, respectively.

"The rivastigmine patch provides similar efficacy to the highest capsule doses, and both formulations were superior to placebo," Winblad said. "The smaller patch had three times fewer gastrointestinal side effects than the capsule. A transdermal patch may prove to be the best way to deliver rivastigmine to treat Alzheimer's."

"We also gave a questionnaire to more than 1,000 caregivers whose loved ones with Alzheimer's were in the IDEAL study. The caregivers significantly preferred the patch to capsules for ease of following the treatment schedule, overall ease of use, and less interference with daily life," Winblad said.

Phase II Trial of Leuprolide Acetate for Alzheimer's Leuprolide acetate, which is in a class of drugs known as gonadotropin-releasing hormone agonists, is being tested for its ability to stabilize cognition in people with Alzheimer's. It is used now to treat symptoms of advanced prostate cancer in men, endometriosis and uterine fibroids in women, and early onset of puberty in girls and boys.

Results of an earlier subgroup analysis of 50 female participants in a 109-patient Phase II clinical study suggested that treatment with leuprolide in conjunction with acetylcholinesterase inhibitors (AChEIs) may stabilize cognitive functioning in mild to moderate Alzheimer's for up to 48 weeks.

At ICAD, Christopher W. Gregory, Ph.D., of Voyager Pharmaceutical Corporation, Raleigh, NC, reported preliminary results of a similar Phase II study in 119 men with mild to moderate Alzheimer's. Patients aged 65 and older were randomized to receive leuprolide acetate (22.5 mg and 33.75 mg) or placebo every 12 weeks for 48 weeks. Treatment with AChEIs was allowed, but not required. Efficacy was assessed by measuring change from baseline in scores on several standard measures of cognitive function and ability to perform daily activities for leuprolide plus or minus AChEIs compared to placebo. Safety was also assessed.

In a pooled analysis of Voyager's Phase II clinical trials in women and men with mild to moderate Alzheimer's, patients received concomitant acetyl cholinesterase inhibitor (AChEI) treatment and either 22.5 mg leuprolide acetate or placebo. Patients receiving leuprolide acetate and AChEI performed significantly better on the ADCS-CGIC compared to patients receiving placebo (AChEI only) (p=0.048). Patients treated with leuprolide acetate and AChEI also performed 1.87 points better than placebo (AChEI only) patients on the ADAS-cog although this difference was not statistically significant.

"Based on these results, we're enrolling patients for two Phase III clinical trials of VP4896, which is our proprietary formulation of leuprolide, as adjunctive therapy with cholinesterase inhibitors in mild to moderate Alzheimer's," Gregory said.

New Alzheimer immunotherapy promising in Phase I Trial in humans

Immunotherapy for Alzheimer's, sometimes referred to as a "vaccine," has shown great promise, though the first major clinical trial using an active vaccination method was marked by side effects of brain inflammation in about six percent of participants. An active vaccination strategy is treatment or prevention by marshalling the body's own disease fighting mechanism to attack the disease. This is usually done by giving the person a low level of the disease against which the body produces substances called antibodies (proteins made by the immune system) that fight the disease. A passive immunization strategy is based on treating patients with antibodies that are manufactured.

In Alzheimer's, immunotherapy has been directed at abnormal beta amyloid protein and amyloid plaques – one of the hallmark lesions found in Alzheimer's brains. Many researchers are working on improving Alzheimer's immunotherapy, either by developing active vaccination methods that eliminate the previously seen side effects or by developing passive immunization methods using laboratory created antibodies.

At ICAD, Eric R. Siemers, M.D., of Eli Lilly and Company, Indianapolis, IN, and colleagues reported on investigations of safety and biomarker changes for a passive immunization strategy using a humanized monoclonal antibody directed at the central domain of beta amyloid.

Nineteen people with Alzheimer's were given a single intravenous infusion over approximately 30 minutes. Four groups of people each were given doses of 0.5 mg/kg, 1.5 mg/kg, 4.0 mg/kg and 10 mg/kg respectively; three controls of similar age and level of dementia received placebo. Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) samples were obtained at baseline and 21 days after treatment. The Alzheimer's Disease Assessment Scale - cognition (ADAS-cog) was administered at baseline and at three and 21 days after dosing. Multiple plasma samples were taken for pharmacokinetic and beta amyloid analyses.

The researchers found that reports of side effects were similar among the four groups except that two of the participants receiving 10 mg/kg reported mild shaking and dizziness lasting less than two hours after the infusions. The ADAS-cog scores showed no consistent changes. Plasma levels of a type of beta amyloid called A§1-40 at baseline were 226 +/- 40 pg/mL, 249 +/- 85 pg/mL, 135 +/- 31 pg/mL, and 163 +/- 83 pg/mL for subjects receiving antibody treatment at doses of 0.5, 1.5, 4.0 and 10.0 mg/kg respectively. These values increased to maximum values of 32,900 +/- 9,150 pg/mL, 52,675 +/- 8,882 pg/mL, 85,600 +/- 26,533 pg/mL, and 81,700 +/- 5,370 pg/mL respectively. The effect of the antibody on beta amyloid in blood was present for more than two months after the infusion.

"While we did not see a change in cognitive function from this single dose of the antibody, there was a very substantial increase in the amount of beta amyloid that we saw in plasma, which we believe was bound to the antibody," Siemers said. "These single treatments were well tolerated up to a dose of four milligrams of drug per kilogram of body weight. This gives us confidence to study this drug in larger populations of people with Alzheimer's."

Next generation metal complexing agent (PBT2) targets Alzheimer's amyloid in mice

There is evidence that abnormal handling of essential brain metals (copper, zinc and iron) may cause beta-amyloid to become sticky, leading to the formation of beta-amyloid oligomers (assemblies) and neurotoxicity in Alzheimer's disease.

Ashley Bush, M.D., Ph.D., of the Mental Health Research Institute of Victoria and consultant to Prana Biotechnology Ltd, both of Parkville, Australia, and colleagues previously showed that clioquinol, a discontinued antibiotic drug, binds to metals in Alzheimer's plaques and reduces beta-amyloid build up in the brains of transgenic mice. Further, clioquinol was well tolerated and slowed cognitive decline in a pilot Phase II clinical trial of people with moderate stage Alzheimer's, but was not further developed due to a manufacturing difficulty.

At ICAD, Bush and colleagues reported results on Prana's successor to clioquinol, PBT2, which they believe has a similar but enhanced mechanism of action.

In the brains of 15 month old transgenic Alzheimer's mice treated orally for nine weeks with 30 mg/kg PBT2, insoluble and soluble beta-amyloid, as well as the number of plaques, were reduced to about 50 percent of the levels in mice that were given placebo. Soluble beta-amyloid in brains of the transgenic mice dropped by 60 percent within 24 hours of the oral PBT2 dose. Rodent pharmacokinetic studies show that the brain concentration of PBT2 is about 50 times greater than clioquinol for an equivalent dose.

The researchers also reported that, in test tube studies, PBT2 stops the formation of soluble beta-amyloid oligomers and blocks harmful radical production by amyloid. In addition, PBT2 prevents beta-amyloid from inhibiting memory formation activity in living mouse brain tissue. Safety studies in animals and healthy humans (Phase 1 A & B), which were referenced by the researchers, indicate that PBT2 is well tolerated at doses proposed for Alzheimer's treatment.

"PBT2 may facilitate the clearance of beta amyloid from the brain, or prevent its accumulation," Bush said. "On the basis of the encouraging results so far, Prana is initiating a Phase II, double-blind, placebo-controlled trial of PBT2 in Alzheimer's patients who are early in the natural history of the disease."

Acumen drug discovery focuses on novel target in Alzheimer's – ADDLs

Amyloid §-derived diffusible ligands (ADDLs) are small protein assemblies that attach to nerve cells. Researchers have identified ADDLs as a possible molecular cause of learning and memory problems in Alzheimer's. ADDLs form from the same protein – beta amyloid – that is found in Alzheimer's plaques, and they turn on the nerve cell signals that create Alzheimer's tangles from the tau protein. ADDLs may explain many features of Alzheimer's that cannot be explained by plaques or tangles. Grant Krafft, Ph.D., and colleagues at Acumen Pharmaceuticals have identified small molecules that target ADDLs as potential therapies for Alzheimer's.

The researchers assembled a library of 100,000 small molecules that, based on initial assessment of their properties, seemed most likely to block the formation of ADDLs or inhibit them from binding to brain cells. The team used high capacity, automated screening systems to test these initial compounds. Several ADDL assembly blockers were identified for further refinement, and the first ADDL binding inhibitor hits were characterized.

"A number of the ADDL blocker lead compounds effectively prevent assembly and reduce ADDL binding at synapses of cells from the hippocampus, which plays a key role in learning and memory," Krafft said. "We believe that several of these leads may represent the most potent ADDL or amyloid-directed compounds ever described."

About ICAD

The 10th International Conference on Alzheimer's Disease and Related Disorders (ICAD), presented by the Alzheimer's Association, is the largest gathering of Alzheimer researchers in history. At ICAD 2006, more than 5,000 researchers will share groundbreaking information and resources on the cause, diagnosis, treatment and prevention of Alzheimer's and related disorders. As a part of the Association's research program, ICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community. ICAD 2006 will be held at IFEMA Feria de Madrid, Centro de Convenciones, North Section - Hall 9 and 10, IFEMA Convention Center, Madrid, Spain.

About the Alzheimer's Association

The Alzheimer's Association, the nonprofit world leader in Alzheimer research and support, is the first and largest U.S. voluntary health organization dedicated to finding prevention methods, treatments and an eventual cure for Alzheimer's. For more than 25 years, the donor-supported Alzheimer's Association has provided reliable information and care consultation; created supportive services for families; increased funding for dementia research; and influenced public policy changes. For more information, call (800) 272-3900 or visit www.alz.org.

* Bengt Winblad – IDEAL: A 24-week placebo-controlled study of the first transdermal patch in Alzheimer's disease – rivastigmine patch versus capsule (Funder: Novartis)

* Christopher Gregory – Efficacy and safety of leuprolide acetate for the treatment of Alzheimer's disease (Funder: Voyager Pharmaceutical Corporation)

* Eric Siemers – Safety assessments and biomarker changes following a monoclonal A§ antibody given to subjects with Alzheimer's Disease (Funder: Eli Lilly and Company)

* Ashley Bush – Oral treatment of APP Transgenic mice with the second-generation 8-OH quinoline, PBT2, decreases soluble brain ABeta within 24 hours (Funders: Prana Biotechnology Ltd., Australian Research Council)

* Graft Krafft – Discovery of ADDL-targeting small molecule drugs for Alzheimer's disease (Funder: Acumen Pharmaceuticals)

ICAD 2006 press room
July 15-20
+1-312-622-4779

Alzheimer's Association
Media Line
+1-312-335-4078 media@alz.org

Voyager was founded in 2001 and is headquartered in Raleigh, N.C. For more information go to www.voyagerpharma.com.

###

Contact:
Brian Reynolds, Ph.D.
Director of Medical and Scientific Information
Voyager Pharmaceutical Corp.
(919) 846-4880

Erica Gregory
Euro RSCG Life PR
(202) 772-1054