麻豆传媒

WASHINGTON -- A monoclonal antibody for Alzheimer's disease reduced amyloid plaque and slowed cognitive decline in an early trial of patients with prodromal and mild disease, researchers reported here.

In the phase Ib PRIME trial -- some results of which were reported at an Alzheimer's meeting in France last month and were much heralded by the financial press -- patients on either the 3 or 10 mg/kg dose of Biogen's aducanumab (aka BIIB037) had a significant reduction in amyloid plaque over 1 year compared with placebo, according to , of Biogen, and colleagues.

Both groups also had less worsening on the Mini Mental State Exam (MMSE), and the higher-dose group had less worsening on the Clinical Dementia Rating sum of boxes (CDR-SB) during that time, they reported at the American Academy of Neurology meeting here.

However, patients on higher doses of the drug had a greater incidence of brain swelling -- which was also worse for ApoE4 carriers, the researchers said.

Sevigny's presentation provided some additional data beyond the European presentation, including 26-week data from the 6 mg/kg group and analyses by subgroups including ApoE4 status and disease severity.

The monoclonal antibody targets aggregated forms of beta amyloid, including soluble oligomers and insoluble fibrils deposited into amyloid plaque in brains of Alzheimer's patients, according to Biogen.

Investigators looked at 188 patients -- a large number for a phase Ib study -- with prodromal or mild Alzheimer's disease who were randomized to one of four doses of the drug. They used Eli Lilly's florbetapir (Amyvid) to assess amyloid plaques and measured cognitive decline and function with MMSE and CDR-SB.

Sevigny and colleagues found that patients on placebo had no changes in plaque levels, and that patients on two doses of the drug had significantly greater reductions in plaque over a year than those who didn't get any drug (P<0.001):

• 3 mg/kg: -0.139
• 10 mg/kg: -0.266

They also reported the first data on the 6 mg/kg group, which saw a significant reduction in plaque levels over 26 weeks (-0.15, P<0.001). This dose group did not yet have 54-week data available.

Another new finding was that reductions in plaque with aducanumab were consistent and dose-dependent across stages of disease and ApoE4 status, Sevigny reported.

As for clinical outcomes, placebo patients had significantly greater worsening on the MMSE at 1 year (3.14) than the two higher-dose drug groups (P<0.05):

• 3 mg/kg: 0.75
• 10 mg/kg: 0.58

On the CDR-SB, placebo patients had significantly greater worsening at 1 year compared with those in the 10 mg/kg group (2.04 versus 0.59, P<0.05).

Sevigny said the drug demonstrated an acceptable safety and tolerability profile, although there was more brain swelling in drug-treated patients -- which appeared to be mediated by ApoE4 status and disease severity.

In ApoE4 carriers, incidence of ARIA edema rose with dose:

• 1 mg/kg: 5%
• 3 mg/kg: 5%
• 6 mg/kg: 43%
• 10 mg/kg: 55%

And it was generally higher than in noncarriers:

• 1 mg/kg: no cases
• 3 mg/kg: 9%
• 6 mg/kg: 11%
• 10 mg/kg: 17%

Headache was also more common with the drug, at 22%, compared with 5% on placebo.

There were three deaths -- two in the placebo group and one in the 10 mg/kg aducanumab group -- but none were determined to be treatment-related.

Neurologists at the meeting expressed cautious optimism about the early results. Alzheimer's has seen its fair share of similar drugs produce stellar early results, only to bomb in subsequent large trials -- as was the case with bapineuzumab.

Aducanumab will now move directly to phase III trials.

"All told, I think this is probably some of the more encouraging data we've had on the therapy front for Alzheimer's in a while, albeit very early, so we're very cautious," , of the Mayo Clinic in Rochester, Minn., who was not involved in the study, told 麻豆传媒. "We have to remain cautiously optimistic, because we've been here before."

Petersen said he'd like to see additional data on measures of cognition and function beyond the MMSE and CDR-SB data, as well as neuropsycological data.

He also flagged the edema findings. Swelling would be expected, particularly in the ApoE4 carriers, he said. "This is perfectly reasonable and tells me the drug is probably doing what it's supposed to be doing."

But he questioned whether that would be limiting in clinical use, noting that it is still unclear whether the edema is symptomatic.

"With the higher incidence of headache ... was that in the people who had [edema]?" Petersen told 麻豆传媒. "We don't know."

, of Massachusetts General Hospital in Boston, who was not involved in the study, added that the findings are novel because they specifically target early stages of disease.

"This is important as we start to explore the concept of brain health as opposed to disease," Rost said. "We are trying to better understand the state of the brain earlier and earlier to catch the inklings of disease development. I think the fact that they included prodromal patients and those with very mild symptoms and perhaps an early burden of amyloid plaques is really a tidal change in the way we approach disease."

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