Image source: Biogen.

Treating Alzheimer's disease costs the U.S. hundreds of billions each year, but to date there are no drugs to treat its underlying cause. Aducanumab from Biogen (BIIB 1.78%) and solanezumab from Eli Lilly (LLY -0.12%) are arguably the most promising Alzheimer's candidates ever to enter phase 3 trials -- which are ongoing. Unfortunately, Lilly's solanezumab failed its first phase 3 attempt, and winning results from Biogen's phase 3 aducanumab trial are far from certain.

Luckily, Lilly's partnership with AstraZeneca (AZN 1.19%) and Biogen's collaborations with Eisai (ESALY 0.57%) could lead these companies into what many consider the future of Alzheimer's drug development. 

Could this method of treatment be the answer to Alzheimer's?
The majority of investigators believe the formation of β-amyloid plaques in the brain is the root cause of Alzheimer's disease. Lilly's solanezumab in an injected antibody that aims at β-amyloid while it's still floating along solo, then takes it out of circulation before it can bunch together then eventually form plaques. Aducanumab is also an antibody that clings to bunches of β-amyloid and reduces their ability build up into plaques. Biogen's Eisai-partnered antibody BAN2401 appears to work along the same lines as aducanumab. However, Alzheimer's is not a well-understood disease, so it remains to be seen if this method of treatment is truly the answer.

Eisai has planned an interim analysis of BAN2401 expected to read out later this month. Biogen and Eisai investors will want to keep an eye on this and future readouts from this phase 2 study expected to fully complete in 2018. If BAN2401 shows success in both reducing β-amyloid plaque build up and slowing disease progression, then the companies at the very least have a plan B if aducanumab flops in its phase 3 trial.

Image source: Biogen.

In return for partnering with Biogen on this (along with another compound we'll get to in a moment), Eisai has an option to collaborate with Biogen on aducanumab after results for either BAN2401's phase 2 trial or aducanumab's phase 3 trial are in.

If BAN2401 fails in phase 2 to significantly reduce β-amyloid plaques, it would be upsetting, but not devastating for either company. However, if it significantly reduces plaques, but doesn't slow the rate of cognitive decline, it would cast a dark shadow on the aducanumab trial and this entire method of treatment. Remember, aducanumab is based on the idea that reducing buildup of β-amyloid plaques is the answer to slowing progression of Alzheimer's disease.

Earlier intervention
While aducanumab and BAN2401 are injected antibodies that bind to bunches of β-amyloid, orally-delivered E2609's action is directed earlier in this complex pathway to prevent the formation of β-amyloid in the first place. The idea behind this class of experimental drugs called BACE inhibitors is that simply reducing the amount of β-amyloid in circulation could slow progression of Alzheimer's disease.

In phase 1, E2609 (the previously-alluded-to other Eisai-Biogen drug) significantly lowered circulating β-amyloid in the bloodstream and -- more importantly -- in the fluid that bathes the brain and spinal cord. The reduction after two weeks compared to placebo was impressive, but it was a trial with healthy volunteers.

Image source: Pixabay.

The phase 2 trial is expected to enroll 700 Alzheimer's patients either just beginning to experience symptoms or with mild to moderate dementia. The two groups will be assessed against placebo separately, and the main goal of the test is to see how well the milder group performs on a handful of tests that assess the decline -- or hopefully maintenance -- of their cognitive abilities after a year and a half of taking the pills every day.

The partners expect to finish collecting data next summer, but some important information could become available much sooner. There's an interim analysis of safety data planned for later this month, and if the number of adverse events is low enough, they plan to meet with the FDA to discuss a path forward.

Boosting efficacy, maintaining safety
This safety data could be crucial. The phase 1b trial with four dosage levels of aducanumab produced mixed data, but patients receiving the highest dosage produced significantly improved results. Unfortunately, increasing dosage was associated with increasing incidence of brain swelling.

There's a distinct possibility that the highest dosage level considered safe in for aducanumab's phase 3 trials isn't high enough to be effective. However, if E2609 appears incredibly safe, the company might have another backup plan. In the weeks, or months ahead, what you'll want to look out for is an FDA green light for a combination trial with E2609 and aducanumab at a lower, safer dosage. Together they could form a winning combination.

Another BACE inhibitor
Of course, Biogen and Eisai aren't the only companies to consider combining antibodies with BACE inhibitors. Partners AstraZeneca and Eli Lilly are expected to report safety data from their BACE inhibitor AZD3293/LY3314814 in the second quarter.

AstraZeneca ran several phase 1 studies on AZD3293 but didn't have much to say about it until Pfizer made a bid for the company in 2014. Then Astra boasted that the phase 1 Alzheimer's candidate had peak annual sales potential of $5 billion.

That September, Eli Lilly agreed to co-develop the drug with Astra, which then claimed it significantly lowered β-amyloid in the bloodstream and fluid that bathes the brain and spinal cord, although just how significantly wasn't mentioned.

Lilly could pay up to $500 million to Astra in milestones if the drug reaches commercial stages. Also, the two intend to split costs and potential revenues going forward. With AZD3293 now in a 1500 patient phase 2/3 trial, those costs are adding up quickly.

Image source: Eli Lilly.

Lilly and Astra investors will want to keep a keen eye open for safety data from AZD3293, and the possibility of combining it with solanezumab or another β-amyloid-busting antibody.

Choosing between
While solanezumab or aducanumab could slow progression of Alzheimer's on their own, I'm not alone in thinking combinations of antibodies with BACE inhibitors could be the answer. It's difficult to estimate peak annual sales of a combination therapy that effectively slows the advance of Alzheimer's disease, but it would probably become the most successful drug of its time. The U.S. already spends about $203 billion in Alzheimer's related expenses. With an aging demographic, those figures are expected to rise to over $1 trillion by 2050.

Given solanezumab's spectacular failure in a previous phase 3 trial, and Lilly's abysmal late-stage development record, I'd say the chances of a successful combination from Astra and Lilly are extremely slim. To be fair, aducanumab or BAN2401, combined with E2609, are also moonshots -- but they're ones I'm far more hopeful for. If you want to ride the potential wave of antibody-BACE inhibitor combinations, I'd use a surfboard built from Biogen stock.