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 patients to drop out of the trial, and data released Friday show one patient in the study with brain swelling also had a “seizure and loss of pulse.” While Biogen says the swelling is reversible, it remains a key issue to watch in further testing.

It now seems clear that solanezumab will not help people in decline, adding urgency to the search to treat millions of people—5.4 million in the U.S. alone—already showing symptoms of the disease. But that doesn’t mean solanezumab, or other drugs like it, can’t ever be useful.

Two major trials carry on, in part with funding from Lilly. Those trials, named A4 and DIAN-TU, are based on a more extreme version of the premise that inspired Lilly to gamble on solanezumab yet again: The earlier you intervene, the better the chance to treat the disease.

“Mild” Alzheimer’s is a misnomer, says Keith Fargo, director of scientific programs and outreach at the Alzheimer’s Association. “By the time a person can be said to have even mild dementia, the disease has already progressed fairly far along in their brain.”

A4 and DIAN-TU are going even earlier, testing people who are at high risk for the disease but have yet to show cognitive symptoms.

Because of solanezumab’s method of clearing free-floating amyloid protein, “this drug may be more appropriate for prevention rather than treatment,” says Morgan. “Ongoing studies will determine if treatment before symptoms will have greater impact, as predicted by many researchers.”

Investigators presenting the solanezumab data said Thursday night that would move forward despite the Expedition-3 results, said Snyder.

DIAN-TU is studying people with genetic mutations that almost certainly lead to Alzheimer’s at an earlier age—usually between the ages of 30 and 60. It’s easier to identify these people, because of the mutations, a luxury that researchers don’t have who are studying the more common “sporadic” form that affects people later in life.

A4, coordinated at the University of Southern California, is also testing people who aren’t yet showing cognitive decline or other Alzheimer’s symptoms. They are considered high risk because brain scans have captured amyloid buildup in their brains.

The two trials are studying very different groups of people. It’s quite possible one will produce positive data for very different reasons than the other—or not at all. As with Biogen, the A4 and DIAN-TU studies will produce final results in 2019.

If solanezumab fails to improve either group, it still won’t be the end of the amyloid hypothesis. Other research teams are studying the same high risk groups with other drugs that take aim at amyloid. For example, the same USC institute running the A4 trial is going to test drugs in people with no symptoms but signs of amyloid buildup in the brain. The drugs aim to intervene in the process that creates the amyloid fragments which form the sticky plaques.

Indeed, Snyder points out that despite all the uncertainty that remains, there is still a lot of funding for prospective Alzheimer’s treatments, and many types of drugs are being tested, data for some of which will also be presented this weekend. “There’s a lot happening in this space,” she says.

Alex Lash contributed to this report