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Amyloid Hypothesis Lives On—Solanezumab, Too, Despite “Siren Song”

Xconomy Indiana — 

When Eli Lilly (NYSE: LLY) reported the day before Thanksgiving, that its Alzheimer’s treatment solanezumab failed to significantly improve the condition of people with a mild form of the disease, some observers immediately called it a final blow for the drug.

After all, it had also failed to improve a broader range of patients with mild to moderate disease in two trials that reported results in 2012. The bad news was also considered a gut punch to the popular “amyloid hypothesis” that many believe to explain the underlying cause to the memory-robbing disorder.

But research continues on solanezumab; the situation is much more nuanced. Late Thursday, Lilly detailed results from the latest solaneznumab failure, a Phase 3 trial called Expedition 3, at the Clinical Trials on Alzheimer’s Disease (CTAD) conference in San Diego. Solanezumab appeared to produce a tiny therapeutic effect—not enough to meet the study’s goal or ask regulators for approval, the company said.

Lilly reported that Expedition 3 patients had a 11 percent reduction in cognitive decline compared to placebo. The data are consistent with earlier trials showing a “small benefit”—a 10 to 15 percent reduction, says Dave Morgan, CEO of the University of South Florida’s Byrd Alzheimer’s Institute in Tampa, FL. But that’s “probably not enough to justify approval.” Others were far more blunt. The data are “the end of [its] siren song,” wrote Leerink biotech analyst Seamus Fernandez.

But it is possible that two ongoing solanezumab trials led by academic centers will show the drug still hasn’t been tested in the right patients.

More broadly, it’s also possible that solanezumab’s modest effect is evidence that the amyloid hypothesis isn’t dead, and that a more powerful drug might succeed where Lilly’s drug failed.

Perhaps that drug is aducanumab, from Cambridge, MA-based Biogen (NASDAQ: BIIB), which provided encouraging—yet, it should be noted, early—data at CTAD. Aducanumab attacks amyloid in the brain through a different route than solanezumab. Alzheimer’s experts are waiting to see results from a much larger Phase 3 study. “You need to have a study that’s powered appropriately to see what the benefit potentially is,” says Heather Snyder, the senior director of medical and scientific operations at the Alzheimer’s Association. “Without that study, you’re guessing.”

Biogen posted a press release last night, and presented more details at CTAD on Friday. The data, from a long-running Phase 1b study, bolstered previous results that Biogen initially reported in 2015. The new data come from patients taking aducanumab long-term, or who were given a personalized dose that doctors felt would give them the best chance to improve. Previous data came from patients on a fixed dose of aducanumab. In both batches, Biogen reported the drug slowed cognitive decline and reduced amyloid levels in a meaningful way, consistent with previous testing.

But none of this will matter if Biogen’s massive Phase 3 test, now ongoing, doesn’t produce significant improvement for patients when it reads out in 2019, most likely.

Snyder also cautions that the mysteries of Alzheimer’s origins and mechanisms—not to mention the near-100 percent rate of Alzheimer’s drug failures—should give anyone pause trying to predict aducanumab’s fate based on solanezumab’s track record. Bits of protein, beta amyloid, accumulate in the brains of Alzheimer’s patients and play a role, but we don’t know what that role is, says Snyder. The amyloid hypothesis holds that the disease is caused by the buildup of those proteins, and the longer the disease goes unchecked, the less chance to treat it. But there might be other drivers, Synder says, and ultimately a combination of approaches—as with cancer or heart disease—will likely be needed to make a significant impact.

While solanezumab actually did a worse job clearing amyloid from the brain than it had in previous studies, observers and analysts were mixed as to whether the news really represented any type of change for the amyloid hypothesis.

After seeing both results, biotech analysts were uniformly encouraged with Biogen’s prospects. ISI Evercore analyst John Scotti wrote that aducanumab likely removes more than ten times more plaque than Lilly’s drug. Given Lilly hit statistical significance on at least some measures of cognition, Scotti wrote in a note, the data “bode well for… aducanumab” and “have minimal to no negative read across to the amyloid hypothesis.”

Leerink’s Geoffrey Porges wrote Biogen’s drug targets a “more relevant form” of beta-amyloid. It busts up the sticky plaques that accumulate in the brain, while solanezumab is designed to clear the free-floating protein before it forms plaques. MRI scans show all of the patients Biogen is enrolling in its big Phase 3 trial—which will wrap up in 2019—have amyloid plaques. “A better drug like [aducanumab] is more likely to work,” wrote RBC Capital Markets’ Michael Yee. Biogen’s shares climbed more than 6 percent amidst all the positive sentiment.

However, patients taking aducanumab continue to suffer from swelling caused by leaky blood vessels in the brain. The swelling has forced some … Next Page »

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