A Possible Alzheimer’s Blood Test and Two Trials of Innovative Therapies

Washington, D.C., June 11, 2007

Positive early test results from innovative new methods for early detection and treatment of Alzheimer’s disease were reported as “hot topics” today at the 2nd Alzheimer’s Association International Conference on Prevention of Dementia in Washington, D.C.

Among the “hot topics” presentations at the Alzheimer’s Association Prevention Conference were:

• Evaluation of a new assay that measures levels of various forms of beta amyloid (Aß) protein in blood for possible use in early detection of Alzheimer’s (INNO-BIA plasma Aß forms, Innogenetics).
• A 14-week Phase II clinical trial of a compound, known as a gamma secretase inhibitor, which may prevent the formation of Aß in the brains of people with Alzheimer’s (LY450139, Eli Lilly).
• A six-month extension of a 90-day Phase II clinical trial of a drug that provides the brain with an alternative energy source as a way to inhibit brain cell damage and preserve function in people with Alzheimer’s (AC-1202, Accera).

Beta amyloid (Aß) is a protein that can abnormally collect in the brain into clumps called “plaques,” and is considered by many experts to be central to the cause and progression of Alzheimer’s.

“The diversity of research in this session is an indicator of the vigor of Alzheimer’s research, especially into treatments and early detection,” said Ronald Petersen, M.D., Ph.D., vice chair of the Alzheimer’s Association’s Medical & Scientific Advisory Council. “And we will continue to move the field forward as fast as we are given the funds to move it with. We desperately need better therapies that slow, stop and even prevent Alzheimer’s; and earlier detection of the disease, so that we can intervene with therapies when they can do the most good – before people experience Alzheimer’s symptoms.”

Petersen is Professor of Neurology, Cora Kanow Professor of Alzheimer’s Disease Research, and Director of the Alzheimer’s Disease Research Center at the Mayo Clinic College of Medicine in Rochester, Minn.

Possible blood test for Alzheimer’s measures beta amyloid levels

New diagnostic tools to help detect Alzheimer’s as early as possible, and to make early diagnosis more accurate, are vitally important to physicians, patients, and families affected by the disease. Earlier, more reliable diagnostic tools would help those who are testing new therapies to establish clear-cut treatment groups (e.g., people expected to develop Alzheimer’s versus those who will not) and give them means to monitor the effectiveness of candidate treatments. And, when disease modifying therapies are available, earlier diagnosis would enable earlier treatment.

Geert De Meyer, Ph.D., Senior Biostatistician at Innogenetics (Gent, Belgium) and colleagues are testing an assay, called INNO-BIA plasma Aß forms, to detect and measure the concentrations of various forms of Aß in blood. The company says that, at this stage, the assay is for research use only, and not for use in diagnostic procedures.

The assay was tested in samples from 556 people who had previously come to memory clinics in Sweden (173 patients) and Germany (383 patients) with early symptoms of possible dementia, including mild cognitive impairment (MCI). These patients were characterized both clinically and according to cerebrospinal fluid (CSF) biomarker patterns, and then grouped according to whether their clinical/CSF biomarker patterns suggested that they would progress to Alzheimer's or not. A single blood sample from each individual was then measured using the new assay for concentrations of beta amyloid forms including Aß1-42, Aß1-40, and other Aß forms.

The researchers found that persons at risk for developing Alzheimer’s according to their clinical/CSF biomarker profiles had significantly different Aß levels in their blood compared with those whose clinical/CSF biomarker profiles did not show risk of Alzheimer’s. Across centers and studies, the ratio of Aß1-42/Aß1-40 was significantly decreased (by about 20 percent; p<0.0001) in patients at risk for Alzheimer’s versus those who were not at risk. According to the scientists, approximately 60 percent of the patients tested could be classified by the test as having either a clearly enhanced or a decreased risk for progression to Alzheimer’s.

“Our results indicate that Alzheimer’s pathology may be reflected in blood, possibly even at an early disease stage,” De Meyer said. “If we can easily detect early markers of Alzheimer’s by simple methods such as a blood test, it will certainly help facilitate drug development efforts. While these results are very promising, more basic studies and well-designed clinical trials are now needed before such a test can be routinely used for the diagnosis of preclinical Alzheimer’s.”

Phase II trial of a gamma-secretase inhibitor as a possible disease-modifying therapy

LY450139 is currently in development at Eli Lilly and Company as a potential disease-modifying treatment for Alzheimer’s. The molecule inhibits an enzyme, known as gamma-secretase, which contributes to the formation of Aß. Earlier studies of LY450139 have investigated doses up to 50 mg given to volunteers or to people with Alzheimer’s for up to six weeks. In the study reported at the Alzheimer’s Association Prevention Conference, patients with Alzheimer’s were given 140 mg or 100 mg each day for six to 12 weeks.

Eric Siemers, M.D., Medical Director, Alzheimer's Disease Team at Eli Lilly and colleagues conducted this Phase 2 study in collaboration with an academic group of investigators known as the Alzheimer’s Disease Cooperative Study (ADCS). The safety and tolerability of LY450139 was assessed, as well as the effect of the drug on Aß levels in blood and CSF. Cognitive function was measured using the Alzheimer’s Disease Assessment Scale – cognition (ADAS-cog), which is a standard instrument in Alzheimer’s trials.

Fifty-one participants with mild to moderate Alzheimer’s were randomized; 43 completed the study. According to the researchers, a number of side effects were reported, but they were generally mild in severity and the drug was generally well tolerated. Safety assessments showed:

• Possible side effects involving the skin – five rashes that may have been related to drug treatment. Additionally, three patients reported a lighter hair color.
• Of the patients given LY450139, 38.9 percent complained of mild fatigue or sleepiness, compared to 13.3 percent in the placebo group.
• There were three adverse event related discontinuations; 1) small bowel obstruction (resolved spontaneously), 2) hemoglobin positive stool, and 3) diarrhea.
• There was a mean prolongation of “QTcF interval” of 16.8 msec (corrected for baseline values) on electrocardiograms in the 140 mg group. These changes are considered small and were not accompanied by any symptoms, but they will require additional evaluation, according to Siemers.

Aß1-40 concentrations in blood were reduced substantially by LY450139, by 58.2 percent for the 100 mg group and by 64.6 percent for the 140 mg group. Aß1-40 concentrations in cerebrospinal fluid were variable, but showed a trend for decreased values that did not reach statistical significance. No differences were seen in cognitive measures.

“No other gamma-secretase inhibitor has reached this stage in the drug development process,” Siemers said. “This study is valuable in that higher doses were utilized and we saw an even more robust effect on plasma amyloid. There were no clinical cardiac effects that accompanied the changes in electrocardiograms, though in future studies, electrocardiograms, rash and other skin or hair changes, fatigue, and gastrointestinal symptoms will be monitored closely. After considering both the potential risks and potential benefits, a large Phase III clinical trial of LY450139 is being planned.”

Alternative energy source for the brain may help treat Alzheimer’s

A sugar called glucose is the primary energy source for brain cells. In people with Alzheimer’s, scientists have detected a dramatic decrease in glucose use in certain brain areas that may begin 10 to 20 years before any visible symptoms appear. Deprived of their primary energy source, neurons suffer irreparable damage. The cause of decreased glucose metabolism remains uncertain.

Scientists at Accera have developed a compound called AC-1202 (Ketasyn™) that provides these glucose-deprived neurons with an alternative energy source known as ketone bodies, which can be metabolized even when glucose cannot. Accera’s hypothesis is that increased availability of ketone bodies will improve memory problems and other functional losses that occur in Alzheimer’s.

At the Alzheimer’s Association Prevention Conference, Lauren Costantini, Ph.D., vice president, Clinical Development at Accera, reported results of a double-blind, placebo-controlled Phase IIb clinical trial with 152 subjects with probable mild to moderate Alzheimer’s. AC-1202 was taken as a drink each morning (20 grams). Most study participants continued taking other Alzheimer’s drugs such as acetylcholinesterase inhibitors, so this study was measuring the efficacy of AC-1202 on top of existing therapy.

Treatment lasted for three months, followed by a two-week washout, then an additional six-month follow-up where all subjects, including both placebo and AC-1202-treated patients, were given the opportunity to receive AC-1202 in an open-label extension study. The main clinical outcome for efficacy was improvement in the ADAS-Cog.

The researchers found that, after 45 days of treatment, participants who took AC-1202 showed statistically significant improvement compared with placebo with the highest response in subjects not carrying the E4 variant of the apolipoprotein gene (ApoE4(-)),which occurs in half of all Alzheimer’s patients. These effects in ApoE4(-) subjects were maintained for the duration of the initial study treatment (90 days). In contrast, patients carrying the E4 variant of the ApoE gene (ApoE4(+)) showed no differences between AC-1202 and placebo.

Forty-nine study participants entered the six-month open label extension; 34 completed the study. According to the researchers, subjects taking AC-1202 for nine months showed very little disease progression (mean change in ADAS-cog score from baseline to day 294 = 0.8).

Ketasyn was generally well tolerated by study participants. Some gastrointestinal side effects occurred more frequently in subjects taking AC-1202 compared with placebo.

“We’re very pleased with these results for a new approach to Alzheimer’s, especially the rapid onset of efficacy,” Costantini said. “Considering that the safety profile is equal to or better than existing Alzheimer’s drugs, we believe that further testing will show AC-1202 to be an ideal candidate for a co-therapy approach to 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.

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