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With New Alzheimer’s Data, Biogen Refines Plans For Big Trial

Xconomy Boston — 

Despite the billions of dollars poured into Alzheimer’s disease research, the disorder remains a biological riddle with no cure. That’s why even hints of progress—encouraging signs in early studies, for example—garner so much attention. And that’s why an update from an experimental drug from Biogen is front and center this morning.

Today, at the annual Alzheimer’s Association International Conference in Washington, DC, Biogen (NASDAQ: BIIB) is disclosing the latest data from an Alzheimer’s drug called aducanumab, and with those data, the outlines of an upcoming Phase 3 trial—which will be one of the most anticipated biopharmaceutical tests in recent years—are starting to take shape.

These results are the latest tidbits from the Phase 1b study first disclosed in March, although Biogen executives began telegraphing positive signals from the trial late last year.

What’s new today are results from 30 patients who got a mid-level dose—6 mg/kg—of aducanumab for 54 weeks. (In March, Biogen disclosed data from the patients taking 1 mg/kg, 3 mg/kg, and 10 mg/kg doses.)

When added to the other doses, the 6 mg/kg data tell a somewhat mixed story. As the dose ramped up, aducanumab did better at breaking up amyloid plaques, the telltale protein clumps that build up in the brains of Alzheimer’s patients. These findings were statistically significant, meaning they were likely not to be due to chance.

But the results for slowing the progression of disease in these patients were murkier. On one standard cognition test, the Mini Mental State Examination (MMSE), the 6 mg/kg dose performed worse than the 3 mg dose (specifically, patients on a 6 mg/kg dose declined by an average of 1.96 points, compared to a mean 0.70 decline for the 3 mg/kg group). On another test, the Clinical Dementia Rating Sum of Boxes (CDR-SB), it fared better (a 1.11 point average decline, compared to a 1.37 point decline for the 3 mg/kg group).

In either case, the 6 mg dose didn’t hit statistical significance. Even though the patient groups for each dose were small, Biogen stressed that the effect across all doses was statistically significant. “This is a [study size] where a patient or two can move numbers pretty easily, so it’s important to look at the totality of the data,” Biogen spokesman Todd Cooper says. “We’re encouraged. The [6 mg] data reinforce the data that we saw earlier.”

That said, the results present Biogen with significant questions: Which doses, for instance, will it carry forward into further testing?

So far, the highest dose at 10 mg seems most effective, but in the Phase 1b trial it also demonstrated a big side effect: 55 percent of patients developed edema, or swelling caused by leaky blood vessels in the brain. And 35 percent of patients carrying the apolipoprotein E4 gene, a marker for higher Alzheimer’s risk, stopped treatment altogether.

Biogen also says that 20 percent of patients on its drug (compared to 5 percent on placebo) developed headaches, and that their prevalence was tied to how high the dose was cranked up. Will Biogen go with a 6 mg dose instead, even though there’s less certainty about its effectiveness? Biogen spokesman Cooper says that the company will only carry two doses into Phase 3 testing but declined to specify which ones.

The data—as well as data expected today from Eli Lilly (NYSE: LLY)—are the latest referendum on what’s known as the amyloid hypothesis: the idea that amyloid plaques are to blame for Alzheimer’s, and that clearing them from the brain should slow peoples’ cognitive decline.

Pharmaceutical companies have been trying for years to develop drugs that work in this fashion. But several drugs in the past decade have failed to prove that dispensing with these plaques actually helps curb the dementia. That’s led to more questions: Would these drugs work better on patients with earlier-stage disease—perhaps even years before they’re showing symptoms? Or are other proteins that misfold and tangle up, like tau, really central to the disease, rather than amyloid clumps?

Those questions still don’t have definitive answers, but Biogen breathed new life into the amyloid hypothesis this past year with its Phase 1b aducanumab study. The majority of the data, presented at a March medical meeting in France, added billions of dollars to Biogen’s market cap and likely emboldened other Alzheimer’s developers to raise cash: Axovant Sciences, of Hamilton, Bermuda, pulled off a massive $315 million IPO in June (NASDAQ: AXON), and North Carolina-based vTv Therapeutics is now shooting for a $125 million offering.

The prize for any success in this field is enormous. More than 5 million Americans are currently living with Alzheimer’s, and the numbers are only expected to grow (a new study presented at AAIC by researchers at the Lewin Group estimated that 28 million baby boomers will develop Alzheimer’s between now and 2050). The only approved therapies are cognitive boosters meant to help people think more clearly, but even those drugs help only a fraction of patients for a short period of time.

With the 6 mg aducanumab results released today, Biogen maintains its enthusiasm for a Phase 3 trial, the true proving ground for experimental drugs, but also where many Alzheimer’s hopefuls have fallen in the past. The company says it has begun screening patients, and the Phase 3 trial should begin later this year.

Beyond Biogen, there’s plenty of other news from this week’s big Alzheimer’s meeting. Here are some highlights so far:

—Eli Lilly is teeing up new results from solanezumab, another plaque-clearing antibody. Solanezumab failed a Phase 3 trial in 2012 in patients with mild-to-moderate Alzheimer’s, but Lilly has continued testing the drug in patients whose disease has not progressed as far. Today, Eli Lilly is offering a glimpse at the first results. The company says they suggest that early intervention, using a novel trial design, has a benefit, but as of this writing the company has not yet published data to back up its claims.

—The Wall Street Journal examined two companies—Neurophage Pharmaceuticals of Cambridge, MA, and Treventis, of Philadelphia—aiming for Alzheimer’s and other neurodegenerative diseases by targeting protein folding errors, rather than just clearing out the plaques that misfolded proteins create. Both have yet to test their drugs in humans, though Neurophage, which Xconomy profiled in early 2014, is much closer to its first clinical test.

CNN reported that researchers at the University of Alberta in Canada have developed a test to find indicators of Alzheimer’s in saliva. The test, while interesting—a tool for early detection could be critical in the fight against Alzheimer’s—hasn’t been published in a peer-reviewed journal as of yet.

—Early detection of Alzheimer’s has become an important mantra for those trying to come up with a treatment, and CBS News and NBC News examined some of those efforts here.

—Researchers have found in a study that women developing Alzheimer’s tend to progress much faster than men, as NBC reports here.

—Though the cause of Alzheimer’s remains unknown, a few studies reported at AAIC tied potential Alzheimer’s risks to lack of sleep, and too much television.

Photo “My Mother’s Hands” courtesy of Ann Gordon via a Creative Commons license.