Any Light at the End of the Tunnel for Alzheimer's Disease?

Few diseases have frustrated researchers like Alzheimer's disease. First identified in 1906, the disease still has no cure and strikingly little real progress in helping patients. Is there any hope for light at the end of this long, dark tunnel?

Dead ends
The history of dead ends in Alzheimer's research isn't encouraging. For years, scientists thought that the disease could be caused by lowered levels of a neurotransmitter in the brain called acetylcholine. Early drugs for treating Alzheimer's disease were based on this hypothesis. Unfortunately, those medications haven't been very effective. As a result, most experts no longer think the disease is caused by acetylcholine deficiencies.

In the early 1990s, another theory emerged. The amyloid hypothesis suggested that Alzheimer's disease could be caused by beta-amyloid protein deposits. Several findings seemed to support this hypothesis.

However, so far therapies focusing on targeting amyloids have met with across-the-board failure. Last August, Johnson & Johnson and Pfizer threw in the towel on a late-stage clinical trial of experimental drug bapineuzumab after finding the drug didn't improve cognitive function for Alzheimer's patients.Only a few weeks later, Lilly announced that two late-stage studies of experimental Alzheimer's drug solanezumab failed to meet primary cognitive and functional endpoints.

Baxter became the latest drugmaker to hit a dead end earlier this month. The company's drug Gammagard, an immunoglobulin therapy, is approved for treating other diseases, but some physicians have prescribed it as an off-label treatment for Alzheimer's disease. However, Baxter discontinued a late-stage trial of Gammagard in treating Alzheimer's after no significant improvement was obtained in patients taking the drug.

Glimmers of light
Some scientists think that the reason for the string of failures thus far is a result of focusing on the wrong area. They suggest that a more likely cause of Alzheimer's disease stems from tau protein tangles inside the brain's nerve cells. Dr. Claude Wischik, a prominent supporter of this tau hypothesis, conducted research with others that found brains of Alzheimer's patients contained tau tangles, while both healthy brains and Alzheimer's brains showed heavy deposits of amyloid plaque.

While many researchers still think the amyloid hypothesis holds the most potential for treating Alzheimer's, a few companies are also now focusing on reducing tau tangles. Lilly announced in April that it had purchased special equipment for imaging tau tangles in brains as part of a combined research effort including both anti-amyloid and anti-tau approaches. Roche spent more than $400 million last year for rights to an anti-tau drug developed by Swiss firm AC Immune.

Privately held TauRx Therapeutics, where Dr. Wischik serves as chairman, is the only company with a large late-stage study under way using tau inhibitors as a potential treatment for Alzheimer's disease. The company's phase 2 results claimed to show the first evidence of slowing down progression of Alzheimer's rather than just addressing symptoms of the disease.

Perhaps the most promising glimmer for Alzheimer's stems from renewed efforts to better understand the function of the human brain. The European Union began an initiative a few months ago called The Human Brain Project to map the brain. President Obama also recently called for funding of a U.S. effort to map the human brain, which has received support from both sides of the political spectrum.

Forging ahead
In the meantime, private companies continue to forge ahead. While Johnson & Johnson and Pfizer discontinued their program for intravenous bapineuzumab, the pharmaceutical partners are moving forward with a study testing the drug as a shot. There are some hints from earlier research that bapineuzumab could be more effective for patients with early stage Alzheimer's disease.

Johnson & Johnson has also teamed up with Japanese drugmaker Shionogi on a new class of drugs targeting amyloid production. Shionogi developed compounds known as BACE inhibitors, which block creation of beta-amyloid by inhibiting beta-secretase enzymes in the brain.

Lilly and Merck are also moving ahead with BACE inhibitor programs. Merck initiated a phase 2/3 trial of experimental drug MK-8931 in late 2012. Earlier research found that Merck's drug reduced cerebral spinal fluid beta-amyloid by more than 90%. MK-8931 represents Merck's only effort targeting Alzheimer's disease beyond early stage discovery and testing.

Meanwhile, Lilly has its BACE inhibitor, known as LY2886721, in a mid-stage study. The company has also committed to study solanezumab further after examining data showing significant slowing of cognitive decline in patients with mild forms of Alzheimer's.

Is there a light at the end of the tunnel for this frustrating disease? Nothing is yet shining brightly, but several glimmers of hope are available. Most importantly, governments and pharmaceutical firms keep moving ahead. The end of the tunnel for Alzheimer's will only be reached one step at a time.

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