Biogen Points to Enrollment and Dosing to Explain Alzheimer’s Results

Xconomy National — 

Biogen revealed detailed results from its Alzheimer’s trial to a jam-packed room of eager conference attendees this week—and while some described it as a major advance in the field, others were less convinced.

Samantha Budd Haeberlein, Biogen’s vice president of clinical development, took the stage Thursday morning in San Diego at Clinical Trials on Alzheimer’s Disease (CTAD) to reveal data the company says supports its plan to ask the FDA to review its experimental Alzheimer’s drug, aducanamab. If approved, the drug would be the first marketed to change the course of the neurodegenerative disease.

The potentially multi-billion dollar question that underpinned the presentation was why, of the two studies Biogen (NADSAQ: BIIB) conducted of aducanamab, did one meet the primary endpoint of reducing clinical decline while the other failed—and what that dichotomy reveals about the drug’s efficacy and its chances for approval.

Thursday was the first time the company shared detailed data from results it analyzed following the trials’ untimely end in March, a decision made after a futility analysis showed disappointing results.

“That larger dataset showed a different outcome from futility, and formed the basis for the subsequent analysis that we have conducted to understand the difference from futility and the difference between the two studies,” Budd Haeberlein said.

Patients in the EMERGE trial saw clinical decline reduced by 22 percent on the high dose of the drug and by 15 percent on the low dose compared to a placebo. In the ENGAGE trial, patients saw clinical decline accelerate by 2 percent on the high dose and slow by 12 percent on the low dose.

The Biogen presentation looked to convince industry watchers that ENGAGE failed while EMERGE succeeded because more patients in EMERGE were on the higher dose regimen, and for longer, as a result of a confluence of factors.

EMERGE enrolled patients more rapidly than ENGAGE, having, for example, about 800 patients signed up as of March 2017 compared to 600. And, in that month, Biogen amended the trial to permit patients with ApoE e4—a form of a gene believed to increase the risk of Alzheimer’s—to begin receiving the high dose of the medication, after previously having restricted them to the low dose.

The restriction was in place due to concerns that the group was more likely to experience one of the most common side effects in the trial at a higher dose. But investigators believed those patients could handle the higher dose via titration, in which a medication’s dose is slowly adjusted upward.

However, the analysis that ended the trial included patients through June of 2017—close to the time when the higher dose was first allowed for that subset of patients, Budd Haeberlein said.

An analysis of those patients in EMERGE and ENGAGE who moved to the higher dose shows a respective 30 percent and 27 percent reduction in clinical decline compared to placebo. Patients on that post-amendment high-dose regimen received a median cumulative dose of 153 mg/kg. Before the amendment, the median cumulative dose was 116 mg/kg, the data show.

As part of the presentation, Paul Aisen, director of the University of Southern California’s Alzheimer’s Therapeutic Research Institute in San Diego, was among a small group that shared their takeaways, all bullish, from the stage.

Aisen called the discordance between that study and ENGAGE “challenging,” but said he was convinced of the studies’ consistency by enrollment differences and the timing thereof related to the amended protocol Budd Haeberlein had delineated.

“I think that the futility decision was highly unfortunate, and puts us in this situation of interpreting complex data, but clearly the EMERGE final analysis is positive…and the analysis of all the key secondaries was consistent and positive, and as important, the biomarker evidence supports the mechanism… I think that is a hugely important result, and it represents a major advance for the field,” he said.

Others were less convinced.

Howard Fillit, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, said while the presentation indicated the drug is having an effect, more work is needed to determine whether it is a clinically meaningful one.

He compared the effect size revealed in the data on aducanamab to that of donepezil (Aricept), a cognitive booster approved for patients with Alzheimer’s disease: “We all know that donepezil, even though it does work in clinical trials, is perceived in the clinical community as a drug that doesn’t have much of a clinically meaningful effect.”

Fillit said while it’s clear “there’s a signal in this work,” another study should be done to learn more about the effect of aducanamab on patients.

“The driver here has got to be the science,” he said.

Trading of Biogen shares was halted for the presentation, but the company’s stock price rose about 3 percent afterward to about $300 apiece from $289.52 per share at market close Wednesday.

“Aducanumab excitement” among patients and providers is likely to heighten further “despite its questionable statistical basis,” wrote SVB Leerink analyst Geoffrey Porges in a research note.

“We share the reservations about drawing inferences from subsets within subsets, particularly non pre-specified ones, but this is conceptually close enough to our expectations for the drug’s effect and performance that it is likely to be generally endorsed by most non-statistician specialists and physicians,” he said.

Budd Haeberlein said Biogen’s additional analyses were conducted in “close consultation” with external advisors—and the neurology division of the FDA. Those regulators are who Biogen will ultimately need to convince that the difference between the studies can be explained, and that the explanation reveals that the drug does indeed work.