Conference Coverage
BARCELONA—A new look at aducanumab’s phase I study data has reinforced the developer’s confidence that its newly launched phase III trials are targeting the right group: patients with very early Alzheimer’s disease.
A subgroup analysis of patients in the phase I PRIME study who had the mildest disease showed that the antibody effectively cleared amyloid plaques and that three of the four doses tested effected at least some cognitive improvement at 54 weeks, said Vissia Viglietta, MD, PhD, Senior Medical Director at Biogen, at the Clinical Trials on Alzheimer’s Disease conference.
The parsed cognitive data look slightly better in this very mild group than they did in the overall analysis, especially for the 6-mg/kg dose, which failed to confer significant benefit in either of the study’s two cognitive measures, the Mini–Mental State Exam (MMSE) and Clinical Dementia Rating scale-sum of boxes (CDR-SB). In the subgroup analysis, however, the 6-mg/kg dose significantly slowed decline, as measured by the CDR-SB. It still had no significant effect on the MMSE, compared with placebo.
The subanalysis should be viewed with the same caution as the overall PRIME data, said Dr. Viglietta. The phase I study was designed to prove safety, not efficacy. The numbers in each dosing group were small, and the numbers in the subanalysis were even smaller.
“The confidence intervals were also quite large, and it was obviously not powered to detect clinical end points,” which were investigated in an exploratory analysis that was not prespecified, Dr. Viglietta said. But the numbers provide some assurance that the phase III trials—EMERGE and ENGAGE—are targeting the right population. “We hope to be able to confirm both the safety and efficacy we saw in PRIME’s early Alzheimer’s population.”
Patients Had Amyloid Pathology
The subanalysis comprised 92 patients of the original 166-patient cohort. They had a mean age of 72. About 70% had prodromal disease, and the rest had mild disease. Importantly, all patients in the PRIME study had confirmed amyloid pathology, as measured by PET amyloid imaging, making it the first antiamyloid drug trial examining only amyloid-positive patients. The phase III studies will also employ baseline PET amyloid imaging in patient selection.
By 26 weeks, aducanumab at the 3-, 6-, and 10-mg/kg doses was associated with significant clearance of amyloid plaque; the effect was sustained at 54 weeks. The 1-mg/kg dose had no significant effect on plaque. Amyloid was removed throughout the entire brain, with no one region driving the change, Dr. Viglietta noted.
All doses except 1 mg/kg significantly slowed decline on the CDR-SB. On the MMSE, the 3-mg/kg and 10-mg/kg doses conferred significant benefit. The 1-mg/kg and 6-mg/kg doses did not.
As in the overall PRIME analysis, amyloid-related imaging abnormalities (ARIA) were the most common adverse event. ARIA can be classified as hemorrhagic (ARIA-H) or edematous (ARIA-E); all of the 15 cases were ARIA-E. None of these cases were symptomatic; all were revealed during routine imaging studies. The incidence of ARIA-E was dose-dependent. There were no cases in the 1-mg/kg group, but ARIA-E occurred in 11% of the 3-mg/kg group, 29% of the 6-mg/kg group, and 44% of the 10-mg/kg group.
ARIA-E was also more prevalent and seemed to be more serious among patients who carried the APOE4 allele. Twelve of the 15 cases occurred in APOE4 carriers. Eight patients with ARIA-E discontinued treatment (seven in the 10-mg/kg group and one in the 6-mg/kg group). Of these patients, six were APOE4 positive. The rest of the patients continued treatment either at the same or a reduced dose.
“ARIA-E was monitorable and manageable, and the majority of patients did not have a recurrence when they continued their treatment,” Dr. Viglietta said.
EMERGE and ENGAGE
The two identical phase III trials are beginning to get under way. In September, Biogen announced that the first patient had been recruited. In all, investigators aim to enroll 2,700 patients with early Alzheimer’s disease. Biogen plans to conduct the studies in more than 20 countries. The company is actively seeking patients for the trials.
In addition to a positive PET amyloid imaging study for either trial, participants must have a CDR global score of 0.5, an MMSE score of 24–30, and a Repeatable Battery for the Assessment of Neuropsychologic Status (RBANS) score of 85 or lower.
Each study will randomize patients to placebo or two active doses, depending on APOE4 status. APOE4 carriers will be randomized to either 3- or 6-mg/kg doses, and noncarriers to either 6- or 10-mg/kg doses. The 3.5-year studies will have an active randomization phase of 18 months, followed by a 24-month extension study.