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 International Alzheimer’s Conference Reveals Latest Amyloid Antibodies Clinical Trial Results

Researchers and patients advocates are cautiously optimistic that a new focus on proteins known as amyloids may yet solve the ongoing puzzle of Alzheimer’s disease.
Scientists, executives, and advocates met by the thousands here in Washington this week for the Alzheimer’s Association International Conference 2015, and researchers here unveiled three promising clinical trials aimed at the build up of amyloids in the brains of sufferers.
Alzheimer’s disease, which makes up 60-80 percent of dementia cases, is a triple threat: it has a huge prevalence, enormous healthcare costs, and no preventive measures and cures. Six drugs have been approved by the Food and Drug Administration (FDA) that temporarily improve Alzheimer’s symptoms, but none so far have proven to slow or stop the nerve damage that causes the disease, and death.
The FDA approved the sixth drug in December 2014. Before that, the last approval of an Alzheimer’s drug was in 2003—the only drug of 244 tested in clinical trials from 2002-2012.
Difficulties of developing effective treatments for Alzheimer’s include the long time to disease progression, and what scientists call the blood-brain barrier, which makes it difficult for drugs to access the brain.
Compounding the problem are the monetary and time costs of drug development. It costs $4 billion-$11 billion to develop one drug and takes an average of 12 years for it to travel from bench to bedside, according to the InnoThink Center For Research In Biomedical Innovation. Only 5 in 5,000 drugs that enter preclinical or animal testing progress to human testing—of those 5 drugs, only one is approved, according to the FDA.
Yet hope springs eternal. A bevvy of recent studies have shown that the build up of beta amyloid and tau proteins—Alzheimer’s grim calling cards—begin attacking patients’ brains up to 20 years before the disease reveals itself. That has some scientists hopeful that they can intervene early, before Alzheimer’s symptoms show.
Now, three separate trials by big drug companies are underway, testing whether antibodies that bind and destroy amyloid proteins—solanezumab (Lilly), gantenerumab (Roche), and aducanumab (Biogen)—show any prospect of preventing Alzheimer’s disease.
The Phase III solanezumab study used and published a “delayed-start” approach: Patients are randomly assigned to start active treatment at the beginning of the study or are placed in a group that received placebo for a period of before being given the active experimental therapy. If the experimental treatment merely reduces Alzheimer’s symptoms, both the early-start and the delayed-start participants should experience the same benefit. However, if the treatment actually slows disease progression, both groups would benefit, but the late starters would not “catch up” to the early starters, researchers say.
“The delayed-start patients did not catch up, which is encouraging to us. It suggests that the treatment effect seen is consistent with a disease-modifying effect. It also suggests that solanezumab should be started earlier rather than later,” study author and research advisor at Lilly Hong Liu-Seifert, Ph.D., tells Provider. “This analysis method is also planned for the ongoing …. study.”
Gantenerumab’s experienced a revival of becoming a viable drug as a result of a Phase III study that showed reductions of amyloid and tau levels. In December 2014, a 2-year, Phase trial of people with early symptoms of Alzheimer’s was halted due to preliminary results indicating that those treated with the drug did not experience any cognitive benefit compared to patients on placebo.
The latest findings, says principal investigator, Philip Scheltens, M.D., Ph.D., “are consistent with brain amyloid clearance… They also suggest that the gantenerumab dose in the Phase 3 SCarlet RoAD trial likely was too low. Future trials should examine higher doses of the drug.”
The new drug on the block, aducanumab, showed great promise in March, when Biogen showed that after one year, a dose-response effect was seen: In a pre-specified analysis across placebo and all doses of aducanumab, treatment of prodromal and mild Alzheimer’s disease patients with aducanumab resulted in a statistically significant, dose-dependent reduction in amyloid plaque, as well as a dose-dependent slowing of cognitive decline. But one hitch was seen: the 10 milligram dose, while being the most effective, also carried the serious side effect of ARIA (amyloid-related imaging abnormalities) that results in dangerous brain swelling. Biogen revealed today the results of its Phase IB study that included a fourth dose, 6 milligrams, which it hoped to fall into the dose-dependent response previously seen: highly effective yet without too many side effects. This dosage fell between that of 3 and 10 milligrams—ARIA was seen but at a lowered and more tolerated level.
“It all comes down to that one dose may not fit all subjects. One may need to find a trial dose that fits best for each patient,” principal Biogen investigator Jeff Sevigny, M.D., tells Provider. His research team are now moving to a Phase III trial in which a low- and a high-dose will be given to APOE4 gene carriers (those who have a high risk of developing ARIA) and APOE4-non-carriers.
Once stagnant, the field is now experiencing tremendous growth and promise.
Maria Carrillo, Ph.D., chief scientific officer of the Alzheimer’s Association, echoes this sentiment: “The data from these new analyses present exciting possibilities, and we look forward to the results of future studies in these experimental drugs.”
Jackie Oberst is Provider’s Managing Editor. Email her at Follow the magazine on Twitter @ProviderMag.
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