The Long Wait for an Alzheimer’s Breakthrough
If you have friends or relatives with Alzheimer’s Disease (AD), you are undoubtedly hoping that some breakthrough will be made that will alleviate or even reverse this disease in your loved one. Unfortunately, recent reports might dampen your hopes that a breakthrough is right around the corner. The good news is that great progress has been made in understanding the root cause of this disease. We now know that AD is caused by the build-up of proteins into clusters that clog up nerve cells in the brain. These “plaques” break down nerve cells which results in a decrease in the ability of these cells to function, leading to the familiar AD symptoms of memory loss and an erosion of cognitive skills.
These insights have led researchers to design drugs that prevent the buildup of these plaques. This has not been trivial to do. Over the last 20 years, great work has been done to understand the multiple mechanisms on how these plaques form, develop genetically modified mice that mimic the human condition of AD, and design and synthesize compounds that could block or reverse this process in the human brain. In short, scientists are doing everything they can to try to cure the disease. A number of companies like Lilly, BMS, J&J and Pfizer have compounds in late-stage development in AD patients and the much-anticipated clinical trial data is starting to read out. But despite the knowledge of AD’s cause and the multi-tiered approach to finding a cure, early results have been discouraging.
Interestingly, this is the same place that cancer research found itself in the 1990s. At that time, a great deal of knowledge had been accrued on the genetic basis of tumor formation. The biopharmaceutical industry simultaneously created compounds to test these theories in clinical trials. These trials answered a lot of questions, disproved some theories and supported others. Eventually, this cutting edge research led to the new drugs that have been introduced in the last few years. Research in AD seems to now be in that stage.
Lilly has led the field in an area of research known as gamma secretase inhibitors. Lilly hoped its lead compound, semagacestat, would inhibit the enzyme which is believed to contribute to buildup of the amyloid protein, which in turn, forms clumps in the brain and causes AD. It was hoped that testing this compound in AD patients would slow or reverse the progress of AD. Unfortunately, Lilly halted the phase 3 trial for this compound as it led to a WORSENING of cognitive function compared to placebo in the AD patients in the study.
Was the Lilly compound flawed in some way? Or is the flaw in the hypothesis that a gamma secretase inhibitor should be of value in treating AD? That answer is not clear. More data will emerge from the study that BMS is doing with its gamma secretase inhibitor which they feel is superior to semagacestat. Will this compound behave similarly? Perhaps. But this is the nature of trying to discover a drug to treat such a difficult disease.
Another way to attack AD is to try to administer an antibody which can bind to the deposited amyloid and clear it out of the brain. Such an antibody is bapineuzumab, which is being developed by both Pfizer and J&J. Unfortunately, this antibody caused vasogenic edema – brain swelling – in AD patients. Initially, this caused a lot of worry and called this mechanism into question as well. However, subsequent studies are suggesting that such swelling MAY be an indication that the drug is working and that, theoretically, the swelling is a result of blood vessels becoming leaky when ridding the brain of the amyloid protein. Is this a side-effect or an indication of efficacy? Obviously, more studies are needed. The FDA is working closely with those running these studies to help find the answers without jeopardizing patient safety. This is yet another example of how progress is made – not necessarily with a major “aha moment,” but rather with key experiments pointing you in one direction or away from another.
There are other issues that researchers are trying to navigate. Most of the drugs in clinical trials are in patients with well-established disease. Perhaps their disease has progressed too far for any compound to show cognitive benefits. Thus, maybe trials should be done in patients for whom disease is at the earliest stages. The downside to this practice is that to see a significant effect, the trials will likely need to be of a multi-year duration, which are costly and challenging to do.
With new treatments for AD years in the future, are there steps that people who are at risk of getting AD can take? A recent NY Times article (July 26) by Pam Belluck called “Grasping for Any Way To Prevent Alzheimer’s” tried to address this. People have touted all sorts of prevention paradigms: weight loss, dietary supplements, and physical activity among them. Unfortunately, an NIH panel recently concluded that none of these has proven to be effective. The issue again stems from the fact that this is a disease that is decades in the making. Studies of any kind to prove that a new treatment or regimen is effective takes years of study and research.
Before you get too depressed by this, remember that this is the same situation scientists faced in coming up with new treatments for cancer decades ago. However, the explosion in new cancer drugs is rooted in the R&D done back then. The same process is occurring now in AD. Tremendous breakthroughs in science are occurring. It is just going to take a lot more work to cure this disease.