Eli Lilly has reported that its Alzheimer’s drug solanezemab failed to slow cognitive decline in a large phase 3 clinical trial. The news is particularly disappointing because it’s been over a decade since a new Alzheimer’s drug was approved, and all current drugs only treat symptoms. Alzheimer’s patients desperately need effective drugs to slow down the progression of the disease, and this failure means their wait continues.
Lilly persevered with its solanezumab clinical trials despite earlier setbacks. When a phase 3 trials fails, it is a serious, often fatal blow to a drug development program. Lilly made the highly unusual decision to conduct a third phase 3 trial after two previous failures. Since a single phase 3 trial in Alzheimer’s costs about $400 million, and it had already failed twice, why would Lilly continue?
In planning the first two trials, Lilly indicated several analyses it intended to do after the trials ended. These analyses don’t count toward the success or failure of the trial (though they do have to be declared before the trial starts). The predetermined analyses showed some positive trends in patients’ cognition and function, and some relevant findings in PET amyloid imaging data. While not everyone in the study was required to get a PET scan to enter, a smaller sample of patients did. In those PET scans, Lilly found that up 35 percent of patients did not have beta-amyloid plaques in their brains, and thus did not have Alzheimer’s disease. These patients would likely have skewed the results of the trials. How could you benefit from a drug that targets plaques if you don’t have them in the first place?
So it is somewhat understandable why Lilly wanted to try again. In the third trial, every patient got an Amyvid™ PET scan to ensure they had plaques in their brain and other tests to ensure they were in a mild stage of Alzheimer’s, which the earlier analyses has indicated would yield the best results. Lilly even changed its primary goal during the trial to just benefits for cognition (instead of cognition and function), which should have increased the odds of success. And yet, solanezumab still failed to improve patient’s cognition compared to a placebo.
Like most Alzheimer’s drugs in late-stage clinical trials, solanezemab targeted a specific region in the beta-amyloid proteins deposited in plaques in patients with the disease. So far, every drug targeting these beta-amyloid plaques has failed. But not every drug targeting beta-amyloid is the same, so it is still possible some of the drugs currently under study in late-stage clinical trials, such as aducanumab from Biogen, may work. Nevertheless, Lilly’s failure raises further questions about the “amyloid hypothesis,” and highlights the need for a diverse drug pipeline.
The Alzheimer’s Drug Discovery Foundation stopped offering funding for drugs targeting beta-amyloid because the pharmaceutical industry was pursuing many drugs in this class, and questions arose about this hypothesis of Alzheimer’s progression. Our strategy is to fund drugs targeting other known contributors to Alzheimer’s disease, including inflammation, vascular disease, genetics and epigenetics, and mitochondrial dysfunction. We also fund neuroprotective drugs that help neurons evade damage from all of these causes. By taking this more strategic approach to the disease—based on the knowledge that aging is the leading risk factor for Alzheimer's—the ADDF believes we will develop drugs to effectively treat and prevent Alzheimer’s disease.
Howard Fillit, MD is the Founding Executive Director and Chief Science Officer at the ADDF.