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Biogen Idec says its investigational candidate is the first drug to both reduce amyloid plaque in the brain and slow cognitive decline.
Biogen Idec is presenting detailed interim Phase Ib data for its Alzheimer’s drug, aducanumab (BIIB037) on Mar. 20, 2015 at the 12th International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders in Nice, France. According to preliminary results, the experimental drug is said to clear amyloid plaques from the brains of prodromal or mild Alzheimer’s disease (AD) patients, and more importantly, is thought to improve cognitive function in trial participants.
“This is the first time an investigational drug for Alzheimer’s disease has demonstrated a statistically significant reduction on amyloid plaque as well as a statistically significant slowing of clinical impairment in patients with prodromal or mild disease,” said Alfred Sandrock, MD, PhD, group senior vice-president and chief medical officer at Biogen Idec, in a press release. “Based on these results, we are advancing the aducanumab clinical program to Phase III with plans to initiate enrollment later this year.”
The reduction of amyloid plaque in the brains of study participants was dose- and time-dependent, meaning that the 166 participants in the trial were split up to receive placebo (n=40), 1 mg/kg (n=31), 3 mg/kg (n=33) and 10 mg/kg (n=32) doses for up to 54 weeks, or 6 mg/kg for up to 30 weeks. Compared with placebo, aducanumab treatment resulted in a statistically significant reduction of amyloid plaque in the 3 mg/kg, 6 mg/kg, and 10 mg/kg dose arms at 26 weeks. At 54 weeks, a statistically significant reduction of amyloid plaque was observed in the 3 mg/kg and 10 mg/kg dose arms, but not in the 1 mg/kg arm. The 6 mg/kg arm has not reached 54 weeks yet and is still ongoing.
Based on Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scales, improvements in cognition also occurred in patients receiving aducanumab in doses more than 1 mg/kg. The placebo group’s scores on both of these tests worsened the most in one year, while most of the cognition scores worsened less quickly as the dose of aducanumab increased, although results from the 6 mg/kg were not ready by press time. According to calculations by Marc Schoenebaum of Evercore ISI, this translates to improvements in MMSE scale of 30–82%, depending on dose.
Although the amyloid-clearing medicine shows promise as a treatment option for AD, the most common adverse effect was edema, which was determined to be dose-dependent as well, and the incidence of edema was higher (as high as 55% for the 10 mg/kg arm) for those carrying the ApoE4 gene. As dose increased beyond 3 mg/kg, the rate of discontinuation due to edema increased as well in ApoE4 carriers. Biogen Idec says in the press release, however, that the “majority of patients” with edema continued treatment at lower doses. Headache was also reported by 22% of the participants treated with aducanumab compared with 5% in the placebo group. There were three deaths throughout the duration of the trial-two in the placebo group and one in the highest treatment group (10 mg/kg) -although researchers say none of the deaths were related to treatment.
Aducanumab is a monoclonal antibody that Biogen licensed from Neurimmune. Neurimmune used its Reverse Translational Medicine platform to develop human recombinant monoclonal antibodies from cognitively stable, elderly donors. Elderly donors were used because these individuals reached old age without developing AD and appear to make anti-amyloid antibodies, Sandrock told CNBC. "The hypothesis is that maybe these people have antibodies to bad proteins or protein aggregates and that's why they're doing so well.”
Neurimmune has a total of four collaborative antibody programs with Biogen Idec, including preclinical-stage development agreements for therapeutic antibodies targeting Parkinson’s disease, tauopathies, and fronto-temporal dementia.
Rather than prevent the formation of plaques, many of the therapies for the treatment of AD have focused on a medication’s amyloid-clearing ability. Early detection of Alzheimer’s-before symptoms are evident or there are obvious signs of neurodegeneration-has been the primary area of focus for researchers trying to identify appropriate candidates for clinical trials. In 2013, FDA proposed relaxed guidelines for the approval of medications to treat AD, stating in a draft guidance that in early–stage patients with no obvious symptoms, it may be feasible to require proof of minute changes in cognition alone. It is more challenging to assess “milder functional and/or global impairments especially for patients early in the spectrum of the illness,” FDA wrote. “Therefore, although the principle behind the co-primary outcome measure approach still holds, the application of this approach in practice may be impractical in these cases and clear evidence of an effect on delaying cognitive impairment may provide sufficient evidence of effectiveness.” Patients closest to the onset of overt dementia (i.e., prodromal AD or MCI due to AD) are likely to have relatively mild but noticeable impairments in their daily functioning, FDA stated in the guidance, and for these patients, it is still “important to demonstrate that a drug favorably affects these deficits, in addition to showing an improvement in cognition, to establish the clinical value of a given treatment."
During a webinar on Mar. 20, 2015 led by Schoenebaum, a specialist noted that aducanumab had a different mechanism of action than Lilly's solanezumab, which was deemed to show no clinical benefit. Aducanumab’s superiority to other antibodies in development for AD, such as crenezumab and gantenerumab, is based on the data showing aducanumab’s high affinity to bind to its target, the physician said during the webinar. Biogen’s aducanumab targets aggregated forms of beta amyloid, including soluble oligomers and insoluble fibrils deposited into the amyloid plaque in the brain of AD patients.