According to the “amyloid hypothesis”, production of beta amyloid (Aβ) in the brain initiates a cascade of events leading to the clinical syndrome of AD. The drug that has come closest to backing up this idea is Biogen’s aducanumab, which binds to aggregated Aβ and causes it to be cleared from the body.
A couple of years ago aducanumab looked destined to join its anti-amyloid peers on the scrapheap, based on the results of two phase 3 trials which failed a futility analysis. Fast forward a few months, and a reanalysis of the data resulted in a dramatic volte face—at higher doses, and combining data across the trials, aducanumab had achieved clinical improvements that could support a regulatory filing, the company said last year.
FDA approval is far from a done deal, given that in one of the studies, placebo performed numerically better than the antibody, and changes to the trial protocols midway through make interpreting the data complex—and in the opinion of some critics exaggerate the drug’s effects. Unpicking that will be the unenviable task of an FDA advisory committee in the coming months, now that Biogen has filed aducanumab for FDA review.
There are those who question whether it will be a big step forward even if approved or whether it—like the current crop of approved AD drugs—ends up delivering minor benefits that do little to lighten the burden of AD.
Of course, that sort of shortfall didn’t stop products like Eisai and Pfizer’s symptom-treating drug Aricept (donepezil) making sales of around $2.5 billion at peak. And an aducanumab approval would inject renewed enthusiasm into amyloid as a target, particularly in combination with other drugs. Analysts have previously suggested a an approved disease-modifying AD med could be worth more than $10 billion a year.
Meanwhile, however, the negative amyloid trials continue to come in, further undermining the amyloid hypothesis, and despite its fans arguing that the answer lies in starting treatment early, even before symptoms develop.
In February, Roche and Eli Lilly reported results from the DIAN-TU trial of two drugs—gantenerumab and solanezumab respectively—that failed to deliver any improvement after at least four years of therapy in people with an early-onset, inherited form of AD.
Lilly’s solanezumab is a humanized antibody that targets the central region of Aβ, while Roche’s gantenerumab is a fully-human antibody that binds to Aβ at the center and at one end of the molecule. Researchers are now digging into subgroups of patients to see whether the combo yielded any benefits in one or more of them.
Roche says it is still committed to gantenerumab despite a separate flop in phase 3 in the broader AD population, and it has phase 3 data with a higher dose due in 2022.
Solanezumab also failed in mild AD patients a few years back, but it’s still working through a study, A4, in people with amyloid build-up but no signs of cognitive impairment.
Lilly is also looking at a higher dose of solanezumab than it used in earlier studies, with results also expected in late 2022, although a new readout from the trial has already linked high amyloid levels with early-stage disease.
Meanwhile, another Roche drug called crenezumab works similarly to aducanumab but is a little further back in development. Two phase 3 trials of the drug were abandoned last year but Roche and partner AC Immune are still testing it in cognitively healthy individuals who are at risk of developing early onset autosomal dominant AD (ADAD).
Plus, the researchers behind the investigator-led DIAN-TU trial aren’t despondent, and they are selecting additional drugs to be tested in the patient population. Right now, there’s a new generation of drugs coming through that are trying to reduce amyloid using different mechanisms, sometimes simultaneously working on other drug targets.
Among these is Lilly’s donanemab (LY3002813), an active immunotherapy designed to stimulate the patient’s immune system to attack and destroy Aβ, which is in a phase 2 trial due to read out in 2021. Pfizer and Johnson & Johnson’s AN-1792 was the first active immunotherapy drug for AD, but was dropped from development on safety and efficacy grounds years ago.
That hasn’t stopped other companies having a go, although the baton is being passed to smaller companies.
Alzheon is moving forward with a phase 3 study of its lead drug ALZ-801, a pill that blocks the formation of amyloid oligomers, or soluble amyloid molecules, in the brain—thanks to a $47 million grant from the National Institutes of Health’s National Institute on Aging (NIA).
ALZ-801 is a prodrug for an older candidate called tramiprosate which wasn’t able to show efficacy in a general AD population, but Alzheon thinks it can improve the odds of success by targeting treatment to patients with early AD who also have two copies of the APOE4 gene variant, a known risk factor for the disease. It plans to start the trial in 300 subjects early next year.
An active immunotherapy drug called ABvac40 is being tested by Spanish biotech Araclon in a phase 2 trial that started in Europe in 2017, while in the U.S., United Neuroscience is testing UB-311 in a phase 2a study due to complete in 2021. Both drugs are designed to clear Aβ without triggering inflammation in the brain.
South Korea’s AriBio, meanwhile, is focusing on AR1001, an orally-active PDE 5 inhibitor that increases the removal of toxic Aβ oligomers in the blood, but is also thought to inhibit neuronal cell death and restore synapses that are lost in AD. That drug moved into phase 2 testing last year in patients with mild to moderate AD dementia.
Elsewhere, Annovis (formerly QR Pharma) has a lead drug heading for phase 2a designed to target amyloid-precursor protein (APP) and tau in a single molecule. Targeting both inhibits the “toxic cascade” that leads to neurodegeneration in AD and other diseases like Parkinson’s, the company says.
There’s no denying that amyloid’s former crown as the premier target in AD is decidedly tarnished, however, not least because around 40% of the over-70s have amyloid plaques but no dementia. Plenty of experts think that combinations with some of the drugs in the following sections are the way forward.