Daniel M. Keller, PhD

March 23, 2015

NICE, France — After years of disappointing trials of monoclonal antibodies directed against forms of β-amyloid for the treatment of Alzheimer's disease (AD), one appears to have hit the mark, at least in early stages of the disease. The eagerly awaited trial of aducanumab (formerly BIIB037) did not disappoint, although much work still lies ahead.

Speaking here at AD/PD 2015: International Conference on Alzheimer's and Parkinson's Diseases, Jeff Sevigny, MD, from Biogen Idec reported results of this prespecified interim analysis of the PRIME trial.

"We observed a statistically significant dose- and time-dependent reduction in amyloid plaque by PET [positron emission tomography] imaging, evident as early as 6 months, out to 1 year," Dr Sevigny.

Importantly, the treatment also was associated with significant dose-dependent slowing of cognitive decline at 1 year, as measured by the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Scale-sum of boxes (CDR-sb) scores.

The randomized, double-blind, phase 1b study of aducanumab randomly assigned patients with prodromal or mild AD to 1, 3, 6, or 10 mg/kg of drug or placebo in a 3:1 fashion, with approximately 30 patients per active treatment group. Patients were 50 to 90 years of age (mean age, 70.5 to 73.7 years across the groups), had confirmed β-amyloid deposition as assessed by florbetapir (18F-AV-45) PET scans, and met clinical criteria for prodromal or mild AD by MMSE and CDR-sb. They received the drug or placebo intravenously once every 4 weeks for 52 weeks. Most patients were also taking concomitant AD medications.

A composite Standard Uptake Value Ratio (SUVR) of florbetapir was calculated from a volume of six brain regions of interest, specifically the frontal, parietal, lateral temporal, sensorimotor, anterior cingulate, and posterior cingulate regions, and compared with whole cerebellum as a reference region.

The researchers had learned lessons from past trials of monoclonal antibodies in AD that largely failed or had equivocal results, and they designed this one to be able to see a positive signal if at all possible. First, they started with patients with prodromal or mild disease. Second, they confirmed that the patients actually had AD and amyloid accumulation, thereby minimizing any "noise" from inclusion of inappropriate participants. Estimates are that up to 30% of patients in some previous trials did not have sufficient amyloid and therefore could in no way show reductions or be helped cognitively by an antiamyloid therapy.

Amyloid Plaque Reduction

At week 26, aducanumab treatment was associated with a reduction in amyloid plaque in all brain regions of interest, with even greater reductions seen at week 54.

Reductions occurred in the frontal, parietal, lateral temporal, sensorimotor, anterior cingulate, posterior cingulate, medial temporal, and occipital cortex, as well as in the striatum. In each area, plaque reduction was greater with the 10 mg/kg compared with the 3 mg/kg dose.

Table. Adjusted Mean Change in Composite SUVR From Baseline

Dose Patients (n) Change in SUVR P Value
At 26 weeks      
  Placebo 34 <–0.01 NS
  1 mg/kg 26 –.030 NS
  3 mg/kg 27 –0.087 <.01
  6 mg/kg 23 –0.143 <.001
  10 mg/kg 27 –0.205 <.001
At 54 weeks      
  Placebo 21 0 NS
  1 mg/kg 21 –0.056 NS 
  3 mg/kg 26 –0.139 <.001 
  6 mg/kg Ongoing Ongoing Ongoing
  10 mg/kg 21 –0.266 <.001

NS, not significant.

 

The mean SUVR starting values were between 1.40 and 1.50. In healthy persons, the cut-point for florbetapir is less than 1.13. By week 54, the mean composite SUVR for the 10 mg/kg dose was about 1.15.

Aducanumab slowed the rate of decline in MMSE scores at the 3 mg/kg and 10 mg/kg doses by week 54. Whereas the placebo group had an adjusted mean decline in MMSE score compared with a baseline of 3.1, the difference from placebo was 2.39 points higher for the 3 mg/kg dose and 2.55 higher for the 10 mg/kg dose (both P < .05 vs placebo). The CDR-sb adjusted mean score at 10 mg/kg was significantly lower (ie, better) than for placebo (0.50 vs 2.00; P < .05).

Good Safety and Tolerability

Three percent of aducanumab-treated patients developed antibodies against the drug, but titers were minimal and had no effect on pharmacokinetics or safety, the researchers report.

Almost all patients had some adverse event. Serious adverse events occurred in 10% to 13% of patients at lower doses, in 38% of those in the highest dose group, and, curiously, in 38% in the placebo group. Six percent to 10% discontinued the study in the placebo and lower dose groups, but 31% stopped in the 10 mg/kg group. Three patients died — two in placebo group and one in the 10 mg/kg group — but no deaths were considered treatment related.

Amyloid-related imaging abnormalities with edema and effusion (ARIA-E) on MRI were the main safety and tolerability signal. ARIA-E occurred in a dose-dependent manner, affecting 33% and 41% of patients at the 6 mg/kg and 10 mg/kg doses, respectively. It was more prevalent in ApoE ε4 carriers.

Most cases occurred within the first five doses; 65% of cases were asymptomatic, and the rest were generally mild. Signs of ARIA-E resolved within 4 to 12 weeks after the drug was stopped. Patients could resume dosing at the next lower dose once ARIA resolved.

Headache occurred in 22% of patients receiving aducanumab compared with 5% in the placebo groups and appeared to be dose-dependent, a company statement noted.

On the basis of these encouraging phase 1b results, Dr Sevigny said the plan is to go directly into a phase 3 trial.

"Compelling" Approach

In the days leading up to the aducanumab presentation, some attendees expressed pessimism about how the trial would come out, based on certainly less than stellar earlier results with other monoclonal antibodies against forms of β-amyloid. However, just before the session, John Trojanowski, MD, PhD, professor of geriatric medicine and director of the Institute on Aging at the University of Pennsylvania in Philadelphia, told Medscape Medical News that he thought the trial would be a success, and he was right, calling the approach "very compelling" after seeing the data.

"The biomarker changes that were shown — abeta [β-amyloid] clearance coupled with the improvement in MMSE and CDR sum of boxes… there was a dose-dependent improvement in the biomarkers and improvement of cognition, so I think the…study looks very promising," he said. He added that replication will be needed, and many candidate drugs fail after initial encouraging results.

Dr Trojanowski mentioned that it may be good that the antibody does not recognize amyloid monomers, which may help to clear aggregates through the action of microglia. And in line with much of the opinion at the conference, he believes a multitargeted approach that attacks plaques, tangles, and Lewy bodies will be needed.

Even with these reservations, "I want to end on an upbeat note by saying that this is really amazing, really exciting, it's what the field needs, a signal as robust as this that progresses on to an FDA [US Food and Drug Administration] approval," he said, "but at the end of the day, we're going to need combination therapy as well."

Nonetheless, "this is just so far beyond where the field has been with earlier immune therapy efforts. It was a very exciting morning," he stated with a smile.

 
This is just so far beyond where the field has been with earlier immune therapy efforts. It was a very exciting morning. Dr John Trojanowski
 

Session moderator Colin Masters, MD, senior deputy director of the Florey Institute of Neuroscience and Mental Health in Victoria and a laureate professor at the University of Melbourne, Australia, commented to Medscape Medical News that what distinguishes this antibody from previous ones, according to Biogen, is that it recognizes aggregated β-amyloid.

"Because it is derived from a human [B cell] clone, it's recognizing an epitope which is there in real life, whereas all the other antibodies are being created against artificial constructs," he explained, with the implication that those epitopes may not be as relevant.

Furthermore, he called it a "reasonable supposition" to think that if monomeric amyloid has a beneficial function in the body, as Dr Trojanowski alluded to, in terms of clearance of amyloid aggregates through microglia, aducanumab should allow those functions to continue.

On the downside, Dr Masters said, "there are a lot of ARIA in the Biogen study, and that's a big problem, but it can be managed…it needs to be investigated much more, and obviously they can't push the dose too high."

Aducanumab is a human recombinant monoclonal antibody that selectively binds aggregated forms of β-amyloid, including soluble oligomers and insoluble fibrils, but does not bind β-amyloid monomers, according to its developers. It was developed by a novel method of reverse translational medicine, taking memory B cells from healthy elderly and cognitively stable patients and screening for ones that produced antibody against aggregated β-amyloid.

The study is funded by Biogen Idec. Dr Sevigny is an employee of Biogen Idec. Dr Trojanowski has received research funding from Biogen Idec for work not related to amyloid. Dr Masters is a consultant on the global advisory board for Lilly and has an interest in an unrelated company.

AD/PD 2015: International Conference on Alzheimer's and Parkinson's Diseases. Abstract #269. Presented March 20, 2015.

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