New drug slows progression of Alzheimer's Disease in early clinical trials

Last week, the biotechnology company Biogen announced exciting preliminary Phase 1 data on their drug Aducanumab to treat Alzheimer's Disease (AD). The history of AD treatments has been marked by failure after failure (Figure 1). The new results are the most promising ever showing that the drug could slow progression of some AD symptoms. At this early stage caution is warranted given the small numbers of test subjects and the previous failures.

As described in a previous post, Alzheimer's Disease (AD) afflicts more than 5 million Americans. Approximately 13.8 million cases are expected by 2050. 1 in 3 seniors dies with Alzheimer's or another dementia. Alzheimer's disease is the sixth leading cause of death in the U.S. The disease is marked by a decline in cognitive function and memory skills. There is no cure, and so progression eventually leads to death. It may start (early-stage) as memory lapses associated with aging. Then AD can develop into mild cognitive impairment (MCI) which is characterized by mild changes in memory and thinking that are noticeable but not severe enough to disrupt day-to-day life. Finally, dementia results with symptoms such as confusion, irritability, aggression, mood swings, trouble with language, and long-term memory loss. Eventually bodily functions are lost leading to death. The life expectancy following diagnosis is approximately seven years.

According to the amyloid hypothesis, Alzheimer's Disease is caused by the accumulation of amyloid plaques (aggregates) consisting of beta-amyloid peptide. This peptide is formed from the proteolytic cleavage of amyloid precursor protein. In large quantities, beta-amyloid forms oligomers that bind to one another creating insoluble fibrils. These extracellular deposits are toxic to neurons causing cell death leading to the mental deterioration characteristic of AD. The amyloid hypothesis is still somewhat controversial but there are considerable data (including mutations in genes associated with beta-amyloid production that accelerate AD) that support this hypothesis.

Based on the amyloid hypothesis, several pharmaceutical companies have developed monoclonal antibodies that target beta-amyloid as therapeutics. The idea is that by binding the peptide, the antibody they can prevent or disrupt amyloid fibril formation slowing the production of the plaques or potentially even removing them. Unfortunately, these efforts have resulted in some high profile failures. Amyloid-clearing drugs from Pfizer, Johnson & Johnson, Eli Lilly, and Roche have all failed to show statistically significant medical effect in late-stage clinical trials.

Biogen adopted a slightly different approach from its predecessors in this area. Rather than screening for anti-amyloid antibodies in vitro (in the test tube), they examined older patients who managed to avoid AD for antibodies against beta-amyloid. Some patients possessed such antibodies, and the hypothesis was that they may have a protective effect. The anti-amyloid antibodies of one such patient was turned into the drug Aducanumab.

A second important difference from previous clinical trials was that Biogen carefully selected patients for whom their drug was most likely to work. They identified those who exhibited only mild symptoms but still presented some amyloid plaques. The idea was to pick patients that were not too early or too late in their disease progression:

"But this study also focused on treating early, when patients are only first starting to notice cognitive impairment, and on making sure that patients have amyloid plaque in their brains. Sandrock says that 30% of patients were rejected from the study because they didn’t have visible buildup of amyloid on PET scans."

In the trial, researchers examined several doses of the drug and two types of disease indicators: the amount of amyloid plaque in the brain and two tests of mental function. For the first, there was a statistically significant reduction in plaque build up over the course of one year. This reduction was dose-dependent (Forbes)"

"In the lowest dose, where patients got 1 milligram of BIIB037 per kilogram of bodyweight, the standardized uptake value ration (SUVR), the measure of amyloid, decreased by 0.03, which was not significant. In the group that got 3 mg/kg, it decreased 0.087, which was significant. At 6mg/kg, it decreased 0.143, and at 10 mg/kg, it decreased by 0.205. This is what’s known as a dose response: give more drug, and more plaque gets removed."

For the second indicator, the Biogen researchers performed tests of cognitive function on the patients and also observed a significant dose-dependent reduction in the decline compared to the placebo group (Forbes):

"What’s more exciting – and what investors and scientists will be arguing about – is that there also seems to be a dose response on tests of how well patients’ minds functioned. On one test, the Mini Mental State Examination, the placebo group’s score worsened by 3.14 points in one year. The decline was 2.21 in the 1 mg/kg arm, 0.75 in the 3 mg/kg arm, and 0.58 in the 10 mg/kg arm. Results in the 6 mg/kg arm are not ready. These results were statistically significant. The trend was similar on the Clinical Dementia Rating Scale. The placebo group decreased by 2.04 points, the 1 mg/kg group by 1.7, the 3 mg/kg by 1.33, and the 10 mg/kg by 0.59. Only the difference between the 10 mg/kg group and placebo was statistically significant."

There are several encouraging signs from the study. First, the dose-dependence of the results with a bigger effect observed at the higher doses is usually a good sign that the drug is working. Second, Aducanumab reduces both amyloid plaque build up and the decline in cognitive abilities. Third, the size of the effect was quite large.

There are important caveats to these clinical trial results. The most relevant is the small patient sample size; there were approximately 30 patients per group. These small numbers along with the considerable variation in clinical data among patients in each group make the statistical analysis more challenging. Nevertheless, the reduction in disease progression attributed to the drug was deemed to be statistically significant. Future larger trials will hopefully resolve this question beyond any doubt.

A second more concerning issue are the side-effects of the drug which can be quite serious (Forbes):

"Headaches occurred in 22% of patients given BIIB037, compared to 5% of the placebo-treated patients. But there was a more serious (and probably related) side effect as well: amyloid-related imaging abnormalities (ARIA), which can include edema, or swelling around the brain."

These side-effects were dose-dependent being more severe in patients receiving higher doses. The key in the future is finding the proper therapeutic window for every patient in which there is a significant therapeutic effect while minimizing the negative side-effects.

There is no question that Aducanumab is the most exciting Alzheimer's Disease treatment to date. Biogen is planning to go straight to Phase 3 trials (from Phase 1) in which there will be many more patients providing much greater confidence in the assessment of the drug. If all goes well, Aducanumab could hit the market by 2020. Success is far from guaranteed given the past failures and the complexity of the disease. It is also important to note that Aducanumab does not cure Alzheimer's Disease; however slowing its progression by as much as 80% would be a gigantic advance.

Figure 1. Many drugs against Azheimer's Disease have been tried but none have succeeded; Aducanumab may be the best bet.