EXPERT ANALYSIS FROM CTAD
BOSTON (FRONTLINE MEDICAL NEWS) – The antiamyloid antibody aducanumab continued its slide around the bases this week, revealing more positive imaging and cognitive data at 36 months into the phase 1b PRIME trial.
Patients who have been taking the highest dose of aducanumab, 10 mg/kg, for the duration of the study improved the most on two measures of cognition, the Mini Mental State Exam (MMSE) and the Clinical Dementia Rating Scale–sum of boxes (CDR-sb). On the pathology side, at least some of the 10-mg/kg patients dropped below the threshold of PET amyloid positivity by 24 months and stayed at that low level up to 36 months, Samantha Budd Haeberlein, PhD , said at the Clinical Trials on Alzheimer’s Disease conference.
During the discussion period, Dr. Haeberlein, Biogen’s vice president of clinical development, demurred when asked if the antibody was completely eliminating amyloid from the brains of the 10-mg/kg group. “I would challenge the idea that it completely removed amyloid, since I think the instrument is not perfect,” she said, reminding the audience that the drop represents a sinking below the threshold for positivity set by Eli Lilly, maker of the imaging agent florbetapir (Amyvid). “But we have to say that we’re in a different realm here, where it can be very difficult to determine whether an individual is positive or negative for amyloid pathology.”
“The aducanumab data reported at CTAD is good news for safety and good news for the signals we need to see in the phase 3 trials,” Maria Carillo, PhD, chief science officer of the Alzheimer’s Association said when asked to comment on the latest data. “These are hopeful signs, but – based on what we’ve learned from past Alzheimer’s studies – we need to wait for the phase 3 trial results.”
Aducanumab is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to Biogen. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaque in the brain.
PRIME enrolled 165 patients with prodromal or mild Alzheimer’s disease. Importantly, all of the subjects had brain amyloid proven by PET imaging. PRIME is the first randomized trial of an antiamyloid compound to enroll a purely PET-proven amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. This was followed by a 2-year open-label extension period. Patients who were randomized to placebo or 1 mg/kg were switched to aducanumab 3 mg/kg or to a 3- to 6-mg/kg titration regimen in the long-term extension. Patients randomized to aducanumab at 3, 6 or 10 mg/kg or titration in the placebo-controlled period continued in the same dose group.
Dr. Haeberlein presented only the fixed-dose data; the titration group data will be presented later in the conference.
PRIME’s primary outcomes are safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase 1b study, are exploratory. This is important to remember, Dr. Haeberlein said. She also stressed that the numbers in each dosing group are quite small. Of the original cohort, 117 entered the extension study and just 50 made it to 166 weeks, at which time 10-16 patients were in each of the dosage cohorts.
At 36 months, the mean change in amyloid plaque level was greatest for the 10-mg/kg group, which, on average, fell below the threshold of amyloid positivity on florbetapir PET scan. The 6-mg/kg group approached the threshold, but did not fall below it. The 1- and 3-mg/kg groups declined similarly to each other, although not as dramatically as the higher-dose group.
Everyone in the trial declined on both cognitive measures, the MMSE and CDR-sb. However, the decline was clearly attenuated in some of the active groups, where the best results were seen in the 10 patients who took 10 mg/kg. The average decline from baseline on the CDR-sb was 2.84 points among those patients. In the other groups, declines from baseline on the CDR-sb were:
Patients taking 10 mg/kg also fared best on the MMSE, declining 4.10 points on average. Declines in the other groups were:
During the presentation, Dr. Haeberlein said these differences were not statistically significant. In an interview, she said, “In this extension trial, we aren’t talking about statistical significance. We are beyond that.”
The incidence of ARIA (Amyloid-Related Imaging Abnormalities), however, did not follow this dose-dependent pattern. All eight cases of ARIA-E (the edematous form) in the long-term extension phase occurred in the placebo group that switched to 1 mg/kg or in the 1-mg/kg group that titrated up to 3 mg/kg. All cases occurred early in the extension phase, with no new cases during the last year, and all but one occurred in APOE4 allele carriers.
Hemorrhagic ARIA was more sporadic, occurring in two placebo switchers, five taking 3 mg/kg, two taking 6 mg/kg, and one patient taking the highest 10 mg/kg dose. Again, these cases occurred early in the trial. All of the ARIA cases, regardless of etiology, were considered mild and resolved spontaneously.
In all of PRIME, 46 patients have experienced ARIA, with 6 experiencing more than one episode.
The most common adverse events in the long-term extension phase were falls, headache, and ARIA. Two patients in the extension phase died – one taking 6 mg/kg and one taking 10 mg/kg. Neither death was related to the study medication.
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