- Roche will not continue two late-stage studies of its Alzheimer's drug crenezumab, disclosing Tuesday that a data monitoring committee had concluded the anti-amyloid therapy was unlikely to yield a cognitive benefit for patients with early forms of the neurodegenerative disease.
- The Swiss pharma's decision marks another high-profile setback in a research field consistently confounded in efforts to find a disease-modifying treatment for Alzheimer's. Crenezumab's apparent lack of efficacy also raises questions about the logic of targeting beta-amyloid — a protein which forms the characteristic sticky plaques that have commanded the attention of researchers and drugmakers alike.
- Roche's announcement also carried implications for AC Immune, the pharma's partner and original developer of crenezumab, as well as Biogen, which is in late-stage testing with another anti-amyloid drug called aducanumab. Shares in both companies fell Wednesday, with AC Immune seeing a particularly steep 65% stock drop.
A major pharma drops further study of a late-stage drug for a disease affecting millions and all Wall Street analysts want to talk about is what it means for a competitor.
Wednesday's reaction to Roche's decision on crenezumab is indicative of just how important aducanumab has become for Biogen and its future growth prospects.
While the biotech has a portfolio of blockbuster drugs for multiple sclerosis and a fast-rising rare disease treatment, aducanumab and Alzheimer's are the linchpin of its pipeline.
Two Phase 3 studies of the drug in early Alzheimer's disease began in 2015 and are currently slated to wrap up early next year. Wall Street has been anxious for an update, and questions of whether Biogen plans to hold an interim analysis were a focus of the company's fourth-quarter earnings call Tuesday.
Analysts from Jefferies calculate aducanumab's value to be worth between $60 and $80 per share of Biogen, which currently trade above $320 apiece. The drug's success, therefore, is a major variable in Wall Street's estimations of Biogen.
Crenezumab's setback also leaves Biogen alone at the front of the industry's much-battered pipeline of anti-amyloid Alzheimer's therapies.
"There is essentially no first-to-market competitor left," wrote Mizuho analyst Salim Syed in a Jan. 30 note to investors.
"The therapeutic options that were once in the race for first-to-market with [aducanumab] are no longer in the running," Syed added, referring to crenezumab and Eli Lilly's twice-failed solanezumab.
That begs the question of whether those setbacks have bearing on the likelihood for aducanumab to succeed. Biogen, as might be expected, has argued forcefully that differences between the two molecules precludes any read-through from crenezumab to aducanumab
"These are not the same antibodies," Biogen's Chief Medical Officer Al Sandrock said Tuesday in response to a question on how aducanumab differs from Roche's molecule. Sandrock noted that aducanumab and another investigational Alzheimer's drug from Biogen and Eisai, BAN2401, are highly selective for soluble and insoluble forms of aggregated beta-amyloid proteins.
"[C]renezumab doesn't have that same level of specificity," he argued during Tuesday's earnings call.
Biogen appears to have succeeded in messaging these differences to analysts on Wall Street, many of whom cautioned against drawing conclusions about aducanumab from Roche's Tuesday setback.
"In our minds today's crenezumab disclosure was not all that surprising and significant read-through to aducanumab or BAN2401 would be a mistake," wrote Christopher Raymond, an analyst at Piper Jaffray, in a Jan. 30 investor note.
Longer list of failures
While that defense may have legs, crenezumab's failure adds to an ever-lengthening list of once promising anti-amyloid Alzheimer's therapies that have come up short.
Last year alone, molecules from Merck & Co., Johnson & Johnson, vTv Therapeutics and the team of AstraZeneca and Eli Lilly were discontinued from late-stage development, leaving only a handful of Phase 3 programs remaining.
The steady drumbeat of trial setbacks in Alzheimer's has led drugmakers to study treatments in earlier and earlier settings.
Roche, for example, studied crenezumab in people with prodromal-to-mild forms of the disease, launching the now discontinued CREAD 1 and CREAD 2 studies in 2016 and 2017 — several years after the drug failed in a Phase 2 study of patients with mild-to-moderate Alzheimer's.
Rather than call defeat after that mid-stage miss, Roche moved study of the drug earlier and increased the dose of crenezumab by four times over what was studied in Phase 2.
The pharma didn't disclose specific data from either CREAD trial on Wednesday. But it did note that an independent data monitoring committee concluded crenezumab was unlikely to hit the primary endpoint measuring change from baseline in Clinical Dementia Rating-Sum of Boxes Score, a standard measure of the disease's cognitive effects.
Roche isn't giving up all of its Alzheimer's research efforts, however.
"We remain dedicated to the Alzheimer’s community and will continue our Phase III GRADUATE trials with gantenerumab and Phase II TAURIEL trial with the anti-tau molecule RG6100, as well as our imaging and fluid-based diagnostic solutions," said Sandra Horning, the company's chief medical officer, in a Wednesday statement.
GRADUATE isn't expected to read out data until 2022, however, and RG6100 has yet to be studied in late-stage study.
For the next few years at least, all eyes will be on Biogen.