Aduhelm™ for Alzheimer’s: Pipeline implications
Aggressive FDA stance may affect new drugs across classes
Aduhelm™ (aducanumab) is a new drug recently approved by the U.S. Food and Drug Administration (FDA) to treat Alzheimer’s. While Aduhelm is the first therapy that targets the fundamental physiology of the disease, it is not a cure and may only slow disease progression.1
In this article, we examine several ways Aduhelm’s approval could affect the broader drug market for Alzheimer’s and other neurologic conditions, such as Huntington’s disease and Parkinson’s disease.2
While the future of Aduhelm is unclear, we know Alzheimer’s will dominate the pharmacy landscape for years to come so it is important to review potential impacts stemming from the Aduhelm decision.
What’s new is what counts as success.
Aduhelm was approved through an FDA accelerated approval process. This approach allows a drug to be approved if it demonstrates an effect on a surrogate endpoint. A surrogate endpoint is a marker (e.g., laboratory measurement, radiographic image) that is believed to be reasonably likely to predict a clinical benefit. This pathway can be used when measurement of a drug’s effect is lengthy.3
However, not all surrogate endpoints are equally useful.
Savitha Vivian, senior vice president of clinical and formulary services at OptumRx, notes that validated surrogated endpoints are routinely used in drug approvals without controversy. That’s because they have undergone testing and are accepted by the FDA as evidence of a drug’s benefit.
But the Accelerated Approval program also uses reasonably likely surrogate endpoints. These may stand in for clinical outcomes but are not yet validated. According to Ms. Vivian, “The big issue with Aduhelm is that the surrogate marker used in the trials has not been proven to correlate with a clinically meaningful outcome yet.”
Available clinical trial data have not demonstrated conclusively that Aduhelm slows cognitive decline, which is the hallmark of Alzheimer’s.4 Instead, Aduhelm showed an ability to impact a reasonably likely surrogate endpoint by reducing clumps of protein in the brain called amyloid beta plaques. Some researchers think amyloid plaques cause Alzheimer’s (i.e., the amyloid hypothesis), while others have questions regarding causality.5
Now researchers are wondering whether the endpoints approach used to approve Aduhelm sets a precedent. Can other developers take a similar approach? 6
Finding effective treatments to treat neurodegenerative diseases such as Huntington’s disease and Parkinson’s disease has been challenging. In both cases, available treatments can only alleviate symptoms of the disease, but not slow its progression.7, 8
Lack of success has led several pharmaceutical companies to end their neuroscience programs for brain diseases.9
Now the FDA is saying the accelerated approval pathway for Aduhelm is a model they hope can be replicated with neurodegenerative diseases such as Parkinson’s and Huntington’s disease.10
Some researchers would welcome a revised FDA approach, arguing that as long as they can demonstrate some clinical benefit, it’s worth making the treatment available. Others are unsure. One remarked that he was not interested in having multiple drugs, but in having multiple drugs “…that work.”11
This expanded approval pathway from the FDA could open the door to new treatments for substantial patient populations. By itself, Parkinson’s disease is the second most prevalent neurodegenerative disease after Alzheimer’s, affecting approximately one million people in the U.S.12
Rapid new approvals?
If Aduhelm signals a revival of the amyloid hypothesis for Alzheimer’s, it would represent a major shift. In fact, multiple drug makers had decided to drop their Alzheimer’s research programs entirely in recent years.13
According to some researchers, the decision to move on from the amyloid approach came none too soon. By this view, once amyloid became the target, alternative approaches were abandoned, or at least found it difficult to find funding. At least until June of this year, this meant 30 years and billions of dollars wasted.14
But several anti-amyloid drugs remain in trials. Within weeks of the Aduhelm decision, the FDA granted breakthrough therapy designation to two such compounds: Eisai and Biogen’s lecanemab and Eli Lilly’s donanemab.15
Both of these drugs have experienced similarly mixed trial results as Aduhelm. They both saw some reduction of cognitive decline, with varying levels of significance. However, both were quite successful at reducing the amount of amyloid plaque in the brain.16, 17
Roche also has an amyloid reducing candidate called gantenerumab. That drug failed a phase 3 study back in 2014 when it could not demonstrate improved clinical outcomes. But now it’s being tested again specifically for effectiveness at removing amyloid plaques.18
All three of these drugs are currently in phase 3 trials. Trial results are expected by the end of September 2022 (lecanemab) or during 2023 (donanemab, gantenerumab).19, 20, 21
Experts believe that evidence of amyloid-lowering activity might now be enough for these to gain approval – regardless of their effect on cognition.22
The question now is whether potential profits stemming from the Aduhelm approval will draw a host of drug makers into the amyloid space. If the doubts about amyloid reduction prove true, the result might be that promising new development avenues could be squeezed out, while companies do nothing more than multiply the number of drugs that “don’t work.”