Keeping to the deep dive nature of my writing goal, I want to focus on the recent news that Biogen (BIIB) exercised their license on the Denali (DNLI) ATV-Aβ program. There were no disclosed payments, although there was a fee payable to Denali as well as milestones with continued successful development, and neither stock reacted to the news (as would be expected).  Why focus on such an early-stage program?  I think it speaks to some critical questions in the Alzheimer's space and is likely a program useful to follow going forward.

The Aβ thesis on Alzheimer's disease is well established, debated, and analyzed.  There is nothing in this program that is likely to sway people’s opinions.  The success and approval of lecanemab is the most validating series of events for the thesis but debate rages as to the ultimate implication of the lecanemab data and approval.  How does this deal have implications for the Aβ thesis?

The ideal approach to treating Alzheimer's (or frankly any disease) comes down to the efficacy and safety and the potential trade off of those characteristics.  This also interacts with the target population, where the more acute and life threatening the disease the more one is willing to accept higher side effects for efficacy.  In contrast, the frailty and overall health of the target population matters, where safety becomes more important.

If we assume for a moment that the Aβ thesis is accurate and clearing the plaques improves outcomes, then we still run into the efficacy/safety issue in what is generally a frail population.  The problem is that increases in the clearing of plaques tend to come with increased rates of side effects with ARIA being the most troubling.  This is where the press release of this deal becomes interesting.  Joseph Lewcock, Ph.D., Chief Scientific Officer of Denali specifically notes that “our ATV:Aβ program is designed to safely increase exposure of the therapeutic antibody in the brain and potentially lead to improved efficacy and/or safety.”

The Denali platform technology is designed to more efficiently transport large molecules (like the monoclonal antibodies being developed to treat Alzheimer's) to cross the blood brain barrier (BBB).  I think there is a clear rationale that getting more of the treatment into the brain would increase the plaque clearance capacity of the treatment, but would this not then logically increase the risk of ARIA, which seems to be driven by plaque clearance.

It would be ideal to find a way to increase the clearance of plaques with the concurrent benefit with patients, while also decreasing the most concern side effect.  A large analysis of the EMERGE and ENGAGE trials, however, shows a clear increase in ARIA with treatment with most of the side effects occurring during the dose titration period, which is where the levels of plaque would be highest.  There was also a meta-analysis that found that plaque clearance was highly correlated with both increased efficacy and higher rates of ARIA-E.

If we assume these findings are accurate, then why would more efficiently moving antibodies across the BBB lead to both an increase in efficacy and safety.  Would that increase in efficacy not simply come with increased rates of ARIA-E?  That would be the logic, but I go back to the press release, which specifically calls out safety.  Are there reasons to think it could also increase safety?

To be clear, without any data this is all speculation and there will ultimately be data to analyze at some point, but I can think of two potential paths for this approach to increase both efficacy and safety.  First, the ability to get the antibody more efficiently across the BBB allows for a more fine-tuned dose titration.  If it is the quick initial rate of plaque clearance that generates the ARIA-E, then the ability to keep that initial rate slow and steady might keep it below an ARIA triggering level.

The second possibility is related to the first but slightly different.  In order to get enough drug into the brain requires a higher dose without the Denali technology.  The drug that does not get through the BBB still circulates for awhile and perhaps this circulating drug is related to the onset of ARIA (likely by not allowing for a precisely controlled level of drug in the brain).  If you more efficiently pass the BBB, then you require lower doses.

There may be a third or fourth reason that is not clear at this point but the above two seem the most plausible (I would lean towards the first if forced to choose one).  This, however, is exactly why I found this announcement and the asset interesting.  We will likely learn a lot about the relationship between plaque clearance, ARIA, and efficacy with a drug that can more efficiently cross the BBB.  As I said, it is not going to fundamentally change anything in the near term, but I would file it away as an asset to track over the coming years as we get data.

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