Alzheimer's drug trials surge, suggesting new pathways for care

Chicago -- Physicians treating people with Alzheimer's disease are more confident than ever that novel, disease-modifying drugs are on the horizon.

Dozens of compounds that may delay disease onset, slow its progress or ameliorate symptoms are producing promising results in clinical trials. And such findings have triggered optimism -- voiced at the Alzheimer's Assn. International Conference on Alzheimer's Disease, July 26-31.

"The big overarching message is how robust the pipeline is, and how we're developing on all fronts and moving in some unexpected directions," said Sam Gandy, MD, PhD, chair of the Alzheimer's Assn.'s medical and scientific advisory council.

But another side to this story offers a reality check. Along with these positive signs is a sense of urgency, because as baby boomers age, the number of people with Alzheimer's is expected to swell. And therapies now available relieve symptoms for only a few years and do not change the illness's underlying course.

Researchers, therefore, are attacking this disease with pharmaceuticals aimed at an array of targets.

A 12-week trial suggested that PBT2 -- a metal, protein-attenuating compound being developed by Prana Biotechnology Limited -- reduced a toxic form of beta-amyloid in the brain.

Another 12-week investigation found that Allon Therapeutics' AL-108, a nasal spray composed of an eight amino acid peptide that reduces neurofibrillary tangles, led to improvements in those with mild cognitive impairment.

Some of the drugs are not new; rather, they are being examined for potential novel uses. An 18-month investigation of Dimebon (dimebolin hydrochloride), a decades-old Russian antihistamine that improves mitochondrial function, revealed that it preserved cognition. This research was supported by Medivation Inc. Also, an 84-week study of Methylene blue (methylthioninium chloride), a refined version of a century-old antimalarial, interfered with the accumulation of tau tangles in the brain.

Exploring other approaches

Other studies investigated the effect of various nutritional supplements, immunotherapy, insulin and blood-sugar modifying medications. But because Alzheimer's is so complex, some predict that no single answer will address the problem. A "drug cocktail" that operates from several angles may be what it takes to truly ameliorate the condition.

"I suspect we're going to have to hit the pathways at multiple steps, kind of like combination chemotherapy for cancer," Dr. Gandy said.

While experts say these studies hold much promise, they also are cautious because it is not unusual for drugs to fail as they are tested in bigger populations for extended periods.

Data presented on tarenflurbil, an anti-amyloid drug, are an example. Despite promising results in earlier studies, the therapy did not make a statistical difference in the cognition of 1,649 patients with mild Alzheimer's who were randomized to receive it or a placebo for 1½ years. Myriad Genetics Inc., the manufacturer, is discontinuing work on the drug. However, researchers said much was learned because it was the largest and longest trial of its kind.

"We've collected very valuable data on the progression of the disease in its earliest stages. We are confident that the results of this study will help researchers in their quest to develop new and better treatments," said Robert C. Green, MD, MPH, its lead author and a professor of neurology, genetics and epidemiology at Boston University School of Medicine.

Diagnostic tool needed

But investigators said their work is hampered by the lack of a definitive diagnostic test. The disease is now diagnosed and assessed by cognitive testing. This approach can lump other types of dementia in with Alzheimer's and confound results, as drugs and other interventions that address this disease's underlying mechanisms don't help those who have been misdiagnosed. In addition, current scales to measure cognition may not be sensitive enough to detect small changes in the short period covered by many early stage trials.

"This is a continuing question in Alzheimer's research. How do you monitor people's progress?" asked Donald Schmechel, MD, lead author of the paper on AL-108 and professor of psychiatry at Duke University Medical Center in North Carolina. He has received grants and research support from Allon.

To address this issue, a push is under way to identify biomarkers that may lead to more conclusive diagnostic testing and monitoring. Studies presented involved measuring various proteins associated with brain amyloid in spinal fluid and those proteins involved in lymphocyte growth in blood.

Experts hope this work will lead to tests that will enable a diagnosis before symptoms ever appear, because they usually don't show up until significant damage has occurred. Presymptomatic diagnosis also could overcome the possible cause of some clinical trial failures. The drug may have been able to benefit a patient early on, but the therapeutic window has been missed.

"There has been a focus on moving the detection threshold earlier and earlier into asymptomatic individuals. To accomplish that, we need biomarkers to tell who is at greater or lesser risk as people age," said Ronald Petersen, MD, PhD, vice chair of the Alzheimer's Assn.'s medical and scientific advisory council.

To that end, researchers also are taking a closer look at patients with the earliest form of detectable dementia: mild cognitive impairment. Not everyone in this category might progress to Alzheimer's, but it is regarded as a significant risk factor.

The number of people with this condition also is large and growing. A paper presented by Dr. Petersen found that approximately 5.3% of those older than 70 will develop mild cognitive impairment; rates are higher for people who are older or male.