Neurimmune has announced that Biogen Idec has presented data from its pre-specified interim analysis of PRIME, the Phase 1b study of aducanumab (BIIB037), in which aducanumab demonstrated an acceptable safety profile and positive results on radiologic and clinical measurements in patients with prodromal and mild Alzheimer’s disease (AD). These data were presented at the 12th International Conference on Alzheimer's and Parkinson's Diseases and Related Neurological Disorders in Nice, France.
Treatment with aducanumab produced a dose- and time-dependent reduction of amyloid plaque in the brain, which is believed to play a key role in the development of the symptoms of AD. In exploratory analyses, a dose-dependent, statistically significant effect of slowing clinical decline was observed on the Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scales.
PRIME is an ongoing Phase 1b randomized, double-blind, placebo-controlled, multiple-dose study evaluating safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of aducanumab in patients with prodromal or mild AD.
This interim analysis of PRIME reflects data for 166 patients, up to week 54 in the placebo (n=40), 1 mg/kg (n=31), 3 mg/kg (n=33), 10 mg/kg (n=32) dosing arms and at least week 30 data for 6 mg/kg (n=30) dosing arm.
In patients receiving aducanumab, a dose- and time-dependent reduction of amyloid plaque was observed over 54 weeks of treatment. Aducanumab treatment resulted in a statistically significant reduction of amyloid plaque in the 3 mg/kg [average change of -0.087, p<0.01)], 6 mg/kg [-0.143 (p<0.001)], and 10 mg/kg [-0.205 (p<0.001)] dose arms compared to placebo at 26 weeks. Amyloid plaque levels were reduced by -0.030 in the 1 mg/kg arm, which was not significant.
At week 54, a statistically significant reduction of amyloid plaque was observed in the 3 mg/kg [-0.139 (p<0.001)] and 10 mg/kg [-0.266 (p<0.001)] dose arms. The reduction of amyloid plaque in the 1 mg/kg (-0.056) arm was not significant. The 6 mg/kg arm is ongoing and the week 54 data will become available at a later date.
Results from the MMSE and CDR indicated a slowing of cognitive decline associated with aducanumab treatment. On the MMSE, patients in the placebo group worsened by an average of 3.14 at one year, whereas the decline was 2.21 in the 1 mg/kg arm, 0.75 in the 3 mg/kg arm, and 0.58 in the 10 mg/kg arm. Relative to placebo, the 3 mg/kg and the 10 mg/kg demonstrated a statistically significant slowing of cognitive decline on the MMSE both with p-values <0.05.
On the CDR-SB, patients in the placebo group worsened by an average of 2.04 at one year. In comparison the worsening was 1.70 in the 1 mg/kg arm, 1.33 in the 3 mg/kg arm and 0.59 in the 10 mg/kg group. Relative to placebo, the 10 mg/kg showed a statistically significant slowing of cognitive decline on the CDR-SB with p value <0.05.
Aducanumab demonstrated an acceptable safety and tolerability profile in this analysis. The most frequently reported treatment-related serious adverse event (SAE) and adverse event (AE) was ARIA (amyloid-related imaging abnormalities).
Based on MRI scans, the incidence of ARIA-E (edema) was dose- and apolipoprotein E-e4-(ApoE4) status-dependent. ApoE4 is a gene associated with a higher risk of developing AD. In ApoE4 carriers incidence of ARIA-E was reported in five percent of patients in the 1 and 3 mg/kg arms, 43 percent in the 6 mg/kg arm and 55 percent in the 10 mg/kg arm. In ApoE4 non-carriers, ARIA-E was seen in nine percent, 11 percent and 17 percent of patients in the 3, 6 and 10 mg/kg aducanumab arms, respectively; no cases were reported in the 1 mg/kg arm.
In general, the onset of ARIA-E was observed early in the course of treatment and was asymptomatic or with mild, transient symptoms. The majority of patients with ARIA-E were able to resume treatment at a lower dose once the ARIA-E resolved.
Headache occurred in 22 percent of subjects receiving aducanumab compared to five percent in the placebo groups and appeared to be dose-dependent. Three deaths were reported in the time period of this analysis, two in the placebo group and one in the 10 mg/kg study arm; none were considered to be treatment related. Other AEs and SAEs were consistent with what is typically observed in the study population.
“We are pleased about the consistent nature of the Phase 1b interim data obtained with aducanumab that originated from Neurimmune’s RTM technology platform,” said Roger Nitsch, co-founder and President of Neurimmune. “The dose- and time-dependent reductions on brain amyloid levels in addition to the slowed cognitive decline and an acceptable safety profile are encouraging results for aducanumab. We are looking forward to the planned Phase 3 clinical trials.”