Alzheimer’s Disease: Part One – Another one bites the dust, but a possible glimmer of hope on the horizon
On February 14, Merck halted the Phase 3 trial of its Alzheimer’s disease drug candidate, verubecestat, after independent analysis showed that the drug had “virtually no chance of working.” This late stage failure was just the latest in a veritable cemetery of once-promising experimental drugs for Alzheimer’s disease. Merck’s decision came, in fact, just a week after Lundbeck’s news that they were halting development of their Phase 3 5-HT6 agonist idalopirdine, and a few months after the drug failure of Eli Lilly, whose antibody drug candidate, solanezumab, was unsuccessful in showing benefit in a 2,100-person study in patients with mild Alzheimer’s disease.
Merck’s verubecestat and Lilly’s solanezumab — and indeed, at least 68 more experimental compounds — target beta-amyloid or the enzymes that result in its formation. Beta-amyloid is a protein whose deposition in the brain many researchers believe to be at the heart of Alzheimer’s disease. According to their hypothesis, amyloid accumulates, aggregates, and forms plaques around neurons, gumming up the synapses and inhibiting cellular function. As the plaques slowly build and another toxic protein — tau — forms tangles in the brain, neurons die, leading to a progressive worsening of memory and cognitive function that ultimately results in dementia. In most patients, amyloid starts to accumulate at least a decade or two before the onset of cognitive problems. Giving strong support to the amyloid theory are rare genetic mutations that involve the cleaving of beta-amyloid from the amyloid precursor protein. Affecting about 500 families around the world, these mutations result in the early onset of Alzheimer’s disease, usually at age 50-60 but sometimes striking much younger people.
Solanezumb is designed to mop up free-floating amyloid to prevent further plaque formation, while verubecestat (and a number of other experimental drugs now in clinical development) is designed to block beta-secretase 1, the beta-amyloid converting enzyme (BACE) that creates the protein. While Lilly had used PET imaging to confirm that the patients in the Phase 3 trial of solanezumab indeed had amyloid deposits in their brains, the researchers speculate that patients diagnosed with “mild” Alzheimer’s disease may have had too much brain damage to be helped by the drug. It will therefore be important to understand if these drugs have any effect on patients with earlier-stage disease. Indeed, Merck expects to complete a second study of verubecestat in patients with earlier-stage disease in February 2019, and similar studies are also being conducted by Lilly/AstraZeneca and Eisai/Biogen, expected to read-out in 2019 and J&J/Shionogi in 2023.
Many have seen some optimism in another Alzheimer’s disease candidate from Biogen, an antibody called aducanumab that selectively targets and breaks up aggregated beta-amyloid. In a 165-person, double-blind, placebo-controlled Phase 1b clinical study, the patients receiving the antibody by infusion once a month for up to 54 weeks experienced a dose-dependent reduction in the amount of beta-amyloid in their brains; those receiving the highest dose were essentially free of amyloid at the end of the study, as measured by brain scan. These patients joined the study with beta-amyloid accumulation in the brain as confirmed by PET scan, and they were in the earliest stages of the disease (only mild memory deficits or no symptoms).
While the trial was primarily designed to evaluate safety, 91 of those receiving the drug for the full 54 weeks experienced statistically significant slower cognitive declines than those who received placebo.
At the same time, some patients receiving higher doses of the antibody experienced brain-swelling during the early stages of treatment — a serious adverse effect. This side-effect eventually disappeared after 4 to 12 weeks and did not result in any hospitalizations.
Given the long history of drugs that appear promising in early studies, only to fail in larger trials, we’ll have to wait to see if aducanuab can be the drug to change the face of Alzheimer’s drug development. Two larger Phase 3 studies are now ongoing, with results expected in 2020.
The recent string of failures raises a critical question on how Alzheimer’s drugs are developed going forward. In addition to investigating other mechanisms of action, these results suggest that perhaps more effort will be required to identify patients who are in the very early stages of the disease, before they become symptomatic – similar to Biogen’s approach with aducanumab. It also points to the potential importance of improving patient selection for clinical trials, using biomarkers and other characteristics (beyond beta-amyloid), just as we’ve seen in other indications like oncology.
Stay tuned for Parts 2 and 3 of this series in the coming weeks.