By Sy Mukherjee
January 18, 2019

Few spaces in the life sciences have fathered failure to the extent that experimental Alzheimer’s drugs have. In the past year alone, at least a half-dozen Alzheimer’s drug hopefuls from major pharmaceutical companies bit the dust. What’s more, there’s an ongoing debate about what should be the main focus area—amyloid plaque, some other biological marker, or a combination strategy? Here are some of the notable flameouts—and ongoing studies—in the field.

Read: Could This Radical New Approach to Alzheimer’s Lead to a Breakthrough?

• Lilly

Indianapolis-based Eli Lilly may have experienced the biggest heartbreak in the field—both financially and in unfulfilled promise—with the demise of solanezumab. Data released in early 2018 confirmed that solanezumab couldn’t slow cognitive deterioration even in patients with the mildest forms of Alzheimer’s. Various disappointments related to the drug, in part, led Lilly to lay off some 3,500 workers, or 8% of its global staff. The firm also shuttered several other mid-to-late-stage trials of BACE inhibitors (drugs that target amyloid) last year, including a project with partner AstraZeneca.

• Axovant

Axovant has taken a very different approach to drug development relative to the conventional pharma players. Part of parent company Roivant Sciences’ federation of drugmakers, Axovant picked up experimental treatments that had been cast off by other bio­pharmas in an attempt to carry them across the regulatory finish line. Unfortunately, the novelty hasn’t panned out so far. Intepirdine, Axovant’s first marquee treatment (and licensed from British drug giant GlaxoSmithKline), failed in late 2017. The company’s new CEO is now focused on a gene therapy strategy for Alz­heimer’s and dementia.

• Merck

Yet another of 2018’s high-profile “BACE drug” failures came from Merck. The firm’s experimental verubecestat proved ineffective in ­early stage trials at treating “prodromal” patients—i.e., the patients showing the earliest symptoms of the disease. The treatment had already failed in earlier trials of patients with more advanced forms of the disease, and its demise raised open questions about whether or not beta-amyloid, at least by itself, should be the focus of treatment.

• Biogen

Despite the amyloid-centric roster of the dismal record of Alzheimer’s treatments, not all companies are ready to give up hope on targeting the plaque-causing protein. Biogen and Japan-based partner Eisai are forging on with studies of BAN2401, aducanumab, and elenbecestat. The hope is that at least one of these treatments will show enough of a slowdown in cognitive impairment to justify an FDA approval, which would be the first Alzheimer’s medicine green-lit since 2003.

New Approaches

The failures listed here are far from the only big-name recent disappointments for Alzheimer’s R&D. Japan’s Takeda crashed and burned with pioglitazone in early 2018; Johnson & Johnson has had multiple setbacks in the space; Pfizer has ditched the neuroscience field altogether.

But newer companies are hitching their wagon to fresh approaches, as our understanding of Alzheimer’s evolves. For instance, Denali Therapeutics and partner Sanofi are testing out a drug that uses a different biological pathway to halt brain deterioration; other companies, including the upstart United Neuroscience, are focused on even earlier stages of Alzheimer’s, before symptoms begin to develop, acknowledging that prevention may be more effective than medication after the fact.

A version of this article appears in the February 2019 issue of Fortune with the headline “A Trail of Disappointment.”

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