About one in nine Americans aged 65 or older has Alzheimer's disease, and the costs associated with caring for these patients are expected to reach more than $200 billion this year. Given the nation's rapidly aging population, the expenses are growing like weeds.
The costs to our healthcare system, and patients' families, are on the rise -- but so is our understanding of the disease. In the simplest terms, investigators are familiar with the "clutter" the disease creates inside the brain, and the most promising approaches aim to continually clean up smaller messes before they become troublesome, or preventing little messes from occurring in the first place. Recently published research suggests marijuana-derived cannabinoids may play a role along these lines as well.
No single drug has been able to safely and effectively slow the disease's progression, and experts in the field believe a combination of therapies will be necessary. However, putting two unapproved drugs into combination trials makes the Food and Drug Administration (FDA) extremely nervous, and for good reason. Most dangerous interactions and complications are discovered post-approval.
Despite the dangers of combining unknown entities, the agency has created a path for future combination studies. Approval of marijuana-derived cannabinoids from the FDA, albeit for conditions unreleated to Alzheimer's disease, could make the path a bit smoother.
Before we dig into the Agency's concerns, and a potential role for cannabis, let's look at two existing approaches to Alzheimer's disease treatment.
Amyloid beta cleanup
There's a common protein at the ends of nerve cells, called amyloid precursor protein, that is often cut by a couple of enzymes. Its function isn't well understood, but the cleaved portion, called amyloid beta, is the prime suspect for the root cause of Alzheimer's disease.
Dense plaques formed by amyloid beta are associated with Alzheimer's disease, and preventing it from bunching up is the most popular angle of attack to date. Unfortunately, Eli Lilly's (LLY 0.07%) experimental solanezumab showed it affects circulating amyloid beta levels but didn't slow the rate of cognitive decline better than a placebo in mild to moderate Alzheimer's patients. Lilly is testing the drug again in patients at an earlier stage of the disease, and results are expected this fall.
Biogen (BIIB -0.48%) has a drug similar to solanezumab, named aducanumab, that binds to amyloid beta after it's formed small bunches. It has been shown to affect amyloid beta accumulation in the brain, and significantly slowed disease progression compared to a placebo in some dosage groups, but not others, during a smaller, early stage trial. That was more than enough to move aducanumab into a larger, late-stage trial, with results expected in 2020.
Rather than cleaning up amyloid beta after it's created, this class of drugs stop an enzyme from cutting amyloid precursor protein in the first place. In partnership with Eisai (ESALY 0.07%), Biogen has one of these, named E2609, in a 700-patient mid-stage clinical trial that began in 2014.
The purpose of the study is to find a safe and effective dosage for potential use in later studies, which makes the number of patients seem outrageous. Luckily Biogen has the resources to fund larger mid-stage trials (it's sharing E2609 costs evenly with Eisai) such as this one that includes mild to moderate Alzheimer's patients, and people just beginning to show signs of impairment.
We'll have a better idea if E2609 can slow the rate of disease progression in either of these groups when this trial reports primary results about a year from now.
Regulatory roadblocks and marijuana
The trouble with aducanumab and E2609, is they might not be effective at safe dosage strengths. Combining these two, or other Alzheimer's candidates might be a way to raise the level of efficacy without increasing the risk of side effects. The FDA isn't thrilled about letting clinical trial patients receive two unapproved drugs at the same time, but has four criteria for allowing co-development:
- The condition must be serious.
- There must be a biological reason for the combination.
- Some data must suggest the combo is better than available therapies.
- There must be a compelling reason why the components cannot be developed independently.
Biogen's candidates, and many others could tick boxes No. 1 through No. 3 without much trouble, but No. 4 creates a Catch-22 situation. Further guidance from the FDA states No. 4 can be met if the individual components would be expected to have "very limited activity" when used alone. What company is going to spend a fortune trying to co-develop two drugs with "very limited activity" in a disease as difficult to treat as Alzheimer's?
It's a long shot, but marijuana could help us escape this loop of regulatory madness. Results from a laboratory study recently published in Nature suggest cannabinoids stimulate the removal of amyloid beta between nerve cells, and protect them from inflammation. Results measured in laboratory cell cultures are rarely reproducible in humans, but it might be worth a shot.
The FDA is well versed in cannabinoid side effects. Swedish pharma Meda AB (NASDAQOTH: MDABF) (soon to be acquired by Mylan) earned approval to market capsules of the cannabinoid nabilone in 1985 under the brand name Cesamet. More recently, the Agency approved an oral solution of dronabinol from Insys Therapeutics (INSY), called Syndros.
The FDA approved these cannabinoids for treatment of chemotherapy induced nausea, and AIDS related appetite loss, but their side effects and interactions are well known. There are no marijuana derived Alzheimer's candidates in mid- to late-stage human trials, but GW Pharmaceuticals (GWPH) has reported clinical success with Epidiolex (cannabidiol) in other neurological disorders. Perhaps it should take a shot at Alzheimer's disease in hopes a larger company will license it for co-development purposes.
In addition to the regulatory quandary Alzheimer's co-development presents, few companies have the resources to develop multiple candidates aimed at different targets. So far, Biogen appears best positioned.
If aducanumab trial results in 2020 lead to an approval, you can expect the company to begin testing it in combination with other drugs. If it should fail, keep your eyes open for cannabinoids entering this space.