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All Eyes on Biogen as Roche Alzheimer’s Drug Flunks Final Test

Xconomy National — 

Roche this morning added yet another failure to the ever-growing number of experimental Alzheimer’s disease drugs to crumble in late-stage human testing.

The Swiss pharma and partner AC Immune (NASDAQ: ACIU) will stop two Phase 3 studies of their drug crenezumab in Alzheimer’s early after an interim analysis by a committee of investigators showed those trials were likely to fail. No new safety concerns were seen. Roche will share detailed data from the studies, known as CREAD 1 and CREAD 2, at a future medical meeting.

AC Immune shares plummeted 60 percent in midday trading.

More than 5 million Americans have Alzheimer’s disease, most of them over 65. As the population ages, the Alzheimer’s burden will grow. The Alzheimer’s Association estimates nearly 14 million Americans will have the disease in 2050. It’s the sixth-leading cause of death.

But no failure in Alzheimer’s drug development is a surprise these days. A pair of old cognition-boosting drugs were approved to treat Alzheimer’s in 1996 and 2003. Since then, one program after another, often after thousands of patients tested and hundreds of millions of dollars spent, has shown no ability to help slow the disease.

Still, the decision to pull the plug on CREAD1 and CREAD2 a year early is eye-opening. Readouts were due to start at the end of 2019 or early 2020, AC Immune CEO Andrea Pfeifer confirmed during the J.P. Morgan Healthcare Conference earlier this month. But there was plenty of skepticism about the CREAD trials before they started.

Crenezumab, after all, showed disappointing Phase 2 results in 2014, but Roche and AC Immune pressed forward nonetheless. Their reasoning: maybe crenezumab wasn’t tested in the right patients. While crenezumab didn’t help patients with mild to moderate Alzheimer’s, perhaps a much higher dose—four times higher than the one used in Phase 2—would work in those earlier in their disease progression. CREAD 1 and CREAD 2 tested crenezumab in patients with prodromal—that is, those who show cognitive symptoms but not dementia—to early Alzheimer’s and evidence of the buildup of amyloid protein, a hallmark of the disease, on a scan.

Roche wasn’t the first to test this kind of theory. In 2016, an anti-amyloid antibody from Eli Lilly (NYSE: LLY), similarly failed a study called Expedition 3 in patients with early Alzheimer’s. Lilly started that study after digging through the data from two failed trials—Expedition 1 and 2—in later-stage patients, and seeing positive signs in those with earlier disease.

Today’s news is yet another dent in the “amyloid hypothesis” that many believe to explain the underlying cause of the memory-robbing disorder. The amyloid hypothesis holds that Alzheimer’s is caused by the buildup of bits of amyloid protein in the brain, and the longer the disease goes unchecked, the less chance to treat it. Yet drug after drug meant to break up the clumps or clear amyloid protein from the brain have failed to slow or even halt the decline of patients’ memory loss. The failures have become so commonplace that some researchers have called on their peers to look elsewhere instead. Drugmakers are also testing drugs that attack the buildup of a different protein, tau, that is implicated in the disease. Roche and AC Immune are among them: anti-tau drug RG1600, which is also part of their alliance, is in Phase 2 testing.

Yet even with today’s failure, the amyloid hypothesis lives on. Roche and AC Immune continue to test gantenerumab, another anti-amyloid drug, in two Phase 3 studies called GRADUATE 1 and 2. Data from the studies, which should include more than 1,500 patients, are expected in 2022. And one other crenezumab study is ongoing: in “cognitively healthy” patients in Colombia with a particular genetic mutation that puts them at a bigger risk of developing the disease. It’s a National Institute on Aging-funded study being run by Roche and the nonprofit Banner Institute.

Then there’s Biogen (NASDAQ: BIIB), whose anti-amyloid drug aducanumab—unlike other, similar drugs so far—has showed signs in early testing of actually slowing the decline of patients’ memory. On a conference call yesterday, Biogen executives declined to comment on the possibility of an interim look at data this year. But results from its two Phase 3 studies, ENGAGE and EMERGE, could come later this year or next.

The (multi-billion dollar) question is whether aducanumab is any different from the others to fall short, including crenezumab. Biogen has bet heavily on its fate, even announcing plans yesterday to start a third Phase 3 study in presymptomatic Alzheimer’s patients. “We do point out that crenezumab was a higher risk asset and has not shown the potential to reduce amyloid plaque burden in prior studies,” Leerink Partners analyst Geoffrey Porges wrote in a note Wednesday morning.

Biogen shares slid 3.5 percent midday Monday nonetheless.

Alex Lash contributed to this report.