UPDATED: In a setback, Biogen's mid-range dose of aducanumab flops in Alzheimer's study

Biogen CEO George Scangos

Biogen's 6-mg dose of its closely watched Alzheimer's drug aducanumab failed to deliver what the Big Biotech and anxious analysts were hoping to see, falling short of clinical significance on two key measures of efficacy that would have pointed toward a clear path ahead in a pivotal study. And the safety data on the drug also worsened, with a heightened indication of toxicity that could spell trouble for this drug's future.

On two key measures, the Mini Mental State Examination (MMSE) and the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), investigators say the 6-mg dose of the drug fell short of statistical significance. It did worse than the 3-mg arm on the MMSE rating, raising a distortion in the data that will fuel arguments over a dose-dependent response in disease modification, and failed to adequately distinguish itself on the second score.

Investors responded swiftly, driving down Biogen shares by more than 5% in a matter of minutes.

Back in March, Biogen ($BIIB) thrilled the Alzheimer's community with early-stage data from a Phase I study that had recruited 166 patients. Both the 3-mg and 10-mg dose of aducanumab (BIIB037) produced positive results, with the high dose registering statistically significant improvements on the rate of decline for both cognitive and functional measures. The 3-mg dose didn't perform on the efficacy scores as well as the top dose, though, with a 0.75 decline in the Mini Mental State Examination (MMSE) measure compared to a 3.14 decline in the placebo arm, while scoring a 1.33 worsening in Clinical Dementia Rating scale Sum of Boxes (CDR-SB) against a 2.04 decline in the placebo arm.

The 10-mg arm did distinctly better, registering a 0.58 decline in the MMSE and a worsening of 0.59 in CDR-SB. The 10-mg arm, though, was also distinctly toxic--with a higher rate of ARIA-E (brain swelling) in a dose-dependent fashion.

In a sense, Biogen is at least partly a victim of the kind of exaggerated expectations that can be triggered these days by a glimpse of positive data in an Alzheimer's study, a field where multibillion-dollar peak sales projections are a dime a dozen. And while Biogen may not have come up with a winning dose, it's sticking with the upbeat assessment that was struck when the first Phase Ib data was revealed back in March.

"Please keep in mind that this is a small study powered on changes in PET imaging, not the clinical outcomes (MMSE and CDR-SB)," says a spokesperson for Biogen. "That said, a pre-specified analysis across placebo and all doses of aducanumab, did show the slowing of clinical decline was dose-dependent, and this dose-dependence achieved statistical significance for both scales. As for the MMSE specifically, it is associated with more variability compared with the CDR-sb."

Biogen Chief Medical Officer Al Sandrock

"We are encouraged by these new results, which continue to show that treatment of prodromal and mild Alzheimer's disease patients with aducanumab resulted in a statistically significant, dose-dependent reduction in amyloid plaque, as well as a dose-dependent slowing of cognitive decline," said Al Sandrock, the chief medical officer at Biogen who took up the reins as R&D chief after Doug Williams' recent departure. "We have begun screening patients for our Phase 3 clinical trials. The results of the PRIME study gives us hope that aducanumab may one day make a meaningful difference for people with Alzheimer's disease."

These new data with the 54-week response on the 6-mg dose, though, can only add to fears about adverse events. The updated data noted that among patients in the 6-mg arm who do not carry ApoE4, a genetic risk factor for Alzheimer's, the incidence of ARIA-E was 22%, double the 11% rate reported last March. In ApoE4 carriers, the incidence of ARIA-E was 5% in the 1 mg/kg and 3 mg/kg arms, 43% in the 6 mg/kg arm and 55% in the 10 mg/kg arm.

Biogen was hoping that the efficacy of the drug would be amped up for the 6-mg dose, which had not yet matured in March, with the better tox profile allowing for a safer drug. The spokesman for Biogen noted that the worsening ARIA-E rate among non-ApoE4 carriers was the result of one case.

"When we start breaking down the treatment groups, we are getting into very small sample sizes, and those data reflect one additional patient in the additional 6 months we are reporting," he noted.

Biogen's Phase III has already begun, with investigators recruiting 1,350 patients for a 5-year study, according to ClinicalTrials.gov. Analysts, though, expect to see data around 2018 that would help determine where Biogen is headed with this drug.

- read the statement