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Clinical Trials

Date: 2018-08-29

Type of information: Results

phase: 1b

Announcement: results

Company: Biogen (USA - MA)

Product: aducanumab (BIIB037)

Action mechanism:

  • monoclonal antibody. Aducanumab (BIIB037) is a human recombinant monoclonal antibody selected from a population of elderly, healthy donors and cognitively stable patients using Neurimmune’s technology platform called Reverse Translational Medicine (RTM). Biogen Idec licensed aducanumab from Neurimmune under a collaborative development and license agreement. Aducanumab targets aggregated forms of beta amyloid including soluble oligomers and insoluble fibrils deposited into the amyloid plaque in the brain of AD patients. Based on pre-clinical and interim Phase 1b data, treatment with aducanumab has been shown to reduce amyloid plaque level.

Disease: Alzheimer's disease (AD)

Therapeutic area: Neurodegenerative diseases

Country:

Trial details:

  • The Phase 1b study is a randomized, double-blind, placebo-controlled, multiple-dose study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical effects of aducanumab in patients with prodromal AD or mild AD dementia. The study includes fixed dosing at 1, 3, 6 and 10 mg/kg as well as an arm with a titration regimen in which patients received a gradually increased dose of aducanumab until they reach a maximum dose of 10 mg/kg. In the Phase 1b study 196 patients received aducanumab or placebo, of which 143 patients entered the LTE.
  • The LTE cohorts were allocated across six dosing arms including: placebo switchers, 1 mg/kg switchers to 3 mg/kg, fixed doses (3 mg/kg, 6 mg/kg, 10 mg/kg) and titration. Additionally, there were discontinuations as expected in studies of 36 or more months. As a result, there are small patient numbers in the new analyses. The results for each dose arm are generally consistent with previous interim analyses. Amyloid plaque levels as measured by positron emission tomography (PET) continued to decrease in a dose- and time- dependent manner in patients from the titration cohort at 36 months and fixed-dose cohorts at 48 months. Amyloid plaque levels in the 10 mg/kg fixed-dose at 48 months remained at a level considered below the quantitative cut point that discriminates between a positive and negative scan.

Latest news:

  • • On August 29, 2018, Biogen and Eisai announced results from a recent analysis of the ongoing long-term extension (LTE) Phase 1b study of aducanumab, an investigational treatment for mild cognitive impairment (MCI) due to Alzheimer’s disease and mild AD dementia. The updated analyses include data from the placebo-controlled period and LTE for patients treated with aducanumab up to 36 months in the titration cohort and up to 48 months in the fixed-dose cohorts. The results are generally consistent with previous interim analyses, and there were no changes to the risk-benefit profile of aducanumab.
  • The results for each dose arm are generally consistent with previous interim analyses. Amyloid plaque levels as measured by positron emission tomography (PET) continued to decrease in a dose- and time- dependent manner in patients from the titration cohort at 36 months and fixed-dose cohorts at 48 months. Amyloid plaque levels in the 10 mg/kg fixed-dose at 48 months remained at a level considered below the quantitative cut point that discriminates between a positive and negative scan.
  • Analyses of exploratory clinical endpoints Clinical Dementia Rating Sum of Boxes (CDR-SB) and the Mini-Mental State Examination (MMSE) suggest a continued benefit on the rate of clinical decline over 36 months and 48 months, respectively. Clinical effects with titrated aducanumab in the second year of the LTE were generally consistent with findings in the 10 mg/kg fixed-dose cohorts.
  • Of the 185 patients dosed with aducanumab in the Phase 1b study, 46 patients experienced amyloid imaging abnormalities (ARIA)-E (edema). Eight patients experienced more than one episode of ARIA-E. The majority of ARIA events occurred early in the course of treatment; they were typically mild radiographically (MRI), clinically asymptomatic and resolved or stabilized within 4-12 weeks, with most patients continuing treatment. In the Phase 1b LTE, the most commonly reported adverse events were headache, fall and ARIA. Detailed results of the study will be presented at upcoming medical conferences.  
  • • On December 8, 2016, Biogen announced it will present new data from the Phase 1b (PRIME) study of aducanumab, its investigational treatment for early Alzheimer’s disease (AD), at the 9th Clinical Trials on Alzheimer's Disease (CTAD) meeting in San Diego. Data presentations include interim results from the titration cohort of the placebo-controlled period of the Phase 1b study as well as data from the first year of the long-term extension (LTE). The results support the ongoing Phase 3 studies of aducanumab for early AD.
  • Phase 1b Study: The Phase 1b study is a randomized, double-blind, placebo-controlled, multiple-dose study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical effects of aducanumab in patients (n=197) with prodromal or mild AD. The Phase 1b study includes fixed dosing at 1 (n=31), 3 (n=33), 6 (n=30) and 10 mg/kg (n=32) as well as an arm with a titration regimen (n=23) and pooled placebo (n=48). Phase 1b also includes an LTE for patients who completed the one-year placebo-controlled portion of the study. The aducanumab data presented at CTAD are consistent with previously reported analyses from this study.
  • 12-Month Titration Arm: ARIA (amyloid-related imaging abnormalities) was the most commonly reported adverse event in the fixed-dose arms of the Phase 1b study. Rates of ARIA were higher in apolipoprotein E4 (ApoE4) carriers than in non-carriers.
  • In order to explore the potential effect of titrating aducanumab, ApoE4-carrier patients were enrolled in the titration arm and titrated aducanumab up to 10 mg/kg (n=23).
  • The incidence of ARIA-E in ApoE4 carriers in the fixed-dose arms was 5 percent in the 1 mg/kg and 3 mg/kg arms, 43 percent in the 6 mg/kg arm and 55 percent in the 10 mg/kg arm. The incidence of ARIA-E in ApoE4 carriers in the titration arm was 35 percent.
  • At 54 weeks, a statistically significant reduction of amyloid plaque (versus placebo) was observed in all fixed-dose arms: 1 mg/kg [-0.050 (p<0.05)], 3 mg/kg [-0.130 (p<0.001)], 6 mg/kg [-0.206 (p<0.001)], 10 mg/kg [-0.263 (p<0.001)] and in the titration arm [-0.171 (p<0.001)]. The standardized uptake value ratio1 was virtually unchanged in the placebo group at 54 weeks.
  • Results from exploratory endpoints, Clinical Dementia Rating sum of boxes (CDR-SB) and the Mini-Mental State Examination (MMSE), were also presented.
  • The results of the CDR-SB showed that patients in the placebo group worsened by an average of 1.89 points at 54 weeks compared with the following treatment arms:
  • 1.69 in the 1 mg/kg 1.33 in the 3 mg/kg 1.09 in the 6 mg/kg 0.63 in the10 mg/kg, p-value <0.05 versus placebo 0.70 in the titration arm, p-value<0.05 versus placebo The results of the MMSE showed that patients in the placebo group worsened by an average of 2.45 points at 52 weeks. Average clinical decline on the MMSE in the treatment arms was:
  • 2.21 points in the 1 mg/kg 0.75 points in the 3 mg/kg 1.99 points in the 6 mg/kg 0.55 points in the 10 mg/kg, p-value<0.05 versus placebo 1.00 points in the titration arm Phase 1b Long-Term Extension Patients who completed the 54-week, placebo-controlled period of Phase 1b had the option to continue in the LTE.
  • Patients who were randomized to placebo or aducanumab 1 mg/kg in the placebo-controlled period were switched to aducanumab 3 mg/kg or to a 3 - 6mg/kg titration regimen in the LTE. Patients randomized to aducanumab 3, 6 or 10 mg/kg or titration in the placebo-controlled period continued in the same dose group in the LTE.
  • In the LTE, there were no new cases of ARIA-E in patients initially randomized to aducanumab 3, 6 or 10 mg/kg who were treated up to 24 months. The incidence of ARIA-E in patients switching from placebo to aducanumab was consistent with the incidence reported in placebo-controlled portion of Phase 1b.
  • Analyses of exploratory endpoints from the first 12 months of the LTE study suggest patients treated with aducanumab for up to 24 months (n=69) continued to have beneficial effects on the reduction of amyloid plaque and the rate of clinical decline as measured by CDR-SB and MMSE.
  • * On July 22, 2015, Biogen announced new results from a prespecified interim analysis of PRIME, the Phase 1b placebo-controlled study of aducanumab (BIIB037) in patients with prodromal or mild Alzheimer’s disease. In this analysis, which includes patients treated up to 54 weeks with the 6 mg/kg dose, aducanumab demonstrated acceptable safety and tolerability, and the findings reinforce the previously reported results from PRIME. These data are being presented at the Alzheimer’s Association International Conference® 2015 (AAIC®) in Washington, D.C.
  • Consistent with previously reported results, the 54-week data from the 6 mg/kg arm demonstrated a statistically significant reduction of beta amyloid in the brain. In exploratory analyses, the 6 mg/kg dose showed an improvement in the slowing of clinical decline, as measured by the Mini Mental State Examination (MMSE) and Clinical Dementia Rating sum of boxes (CDR-SB) scales, which was not statistically significant. In a pre-specified analysis across placebo and all doses of aducanumab, the slowing of clinical decline was shown to be dose-dependent, and this dose-dependence achieved statistical significance for both scales. The previously reported results from the 1, 3, and 10 mg/kg arms showed dose- and time-dependent effects on the reduction of beta amyloid and slowing of clinical decline (as measured by MMSE and CDR-SB) compared to placebo at 54 weeks. In the same analysis, the 26-week results were available for the 6 mg/kg arm, which was shown to reduce amyloid plaque compared to placebo.
  • The new analysis presented at AAIC 2015 includes data from the 6 mg/kg dose arm and its corresponding placebo arm (n=10) up to 54 weeks. The updated results from all other fixed doses (1, 3 and 10 mg/kg) reflect a larger pooled placebo group (n=40), which now includes the placebo patients from 6 mg/kg cohort, per the prespecified statistical model.
  • Radiologic Results for Amyloid Plaque PET imaging using the radiotracer florbetapir1, which binds to amyloid plaque, was used to measure plaque levels in the brain. In the updated analysis, the standardized uptake value ratio2 was virtually unchanged in the placebo group at 54 weeks. A statistically significant reduction of amyloid plaque was observed in the 3 mg/kg [-0.135 (p<0.001)], 6 mg/kg [-0.210 (p<0.001)] and 10 mg/kg [-0.268 (p<0.001)] arms. The reduction of amyloid plaque in the 1 mg/kg (-0.055) arm was not statistically significant.
  • Clinical Results The updated results of the MMSE showed that patients in the placebo group worsened by an average of 2.81 points at 52 weeks. Clinical decline on the MMSE in the treatment arms was 2.18 points in the 1 mg/kg, 0.70 in the 3 mg/kg, 1.96 in the 6 mg/kg and 0.56 in the 10 mg/kg.
  • Relative to placebo, the 3 and 10 mg/kg doses demonstrated a statistically significant slowing of cognitive decline on the MMSE, both with p-values
  • The updated results of the CDR-SB showed that patients in the placebo group worsened by an average of 1.87 points at 54 weeks compared to 1.72 in the 1 mg/kg, 1.37 in the 3 mg/kg, 1.11 in the 6 mg/kg and 0.63 in the 10 mg/kg treatment arm.
  • The 10 mg/kg arm demonstrated a statistically significant slowing of clinical decline compared to placebo on the CDR-SB with p-value
  • Pharmacokinetic activity and exposure were linear with dose. Treatment-emergent immunogenicity, which occurred in three percent of aducanumab treated patients, was transient and without an apparent effect on aducanumab PK.
  • Safety Results Aducanumab demonstrated an acceptable safety and tolerability profile in this analysis that was consistent with previously reported analyses from this study. 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 E4- (ApoE4) status-dependent. 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 continued treatment at a lower dose.
  • In ApoE4 carriers, the incidence of ARIA-E was 5 percent in the 1 mg/kg 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, the incidence of ARIA-E was 9 percent in the 3 mg/kg, 22 percent in the 6 mg/kg and 17 percent in the 10 mg/kg aducanumab arm; no cases were reported in the 1 mg/kg arm.
  • In ApoE4 carriers, the incidence of patients who developed ARIA-E and discontinued treatment was 5 percent in the 1 mg/kg arm, 10 percent in the 6 mg/kg arm and 35 percent in the 10 mg/kg arm. There were no discontinuations in the 3 mg/kg arm. In ApoE4 non-carriers, the incidence of patients who developed ARIA-E and discontinued treatment was 11 percent in the 6 mg/kg arm and 8 percent in the 10 mg/kg arm. There were no discontinuations in the 1 mg/kg and 3 mg/kg arms. Overall, 56 percent of subjects who developed ARIA-E continued treatment at the same or lower dose and none developed recurrent ARIA-E.
  • Headache occurred in 20 percent of patients receiving aducanumab compared to 5 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.
  • * On March 20, 2015, Biogen Idec announced data from a 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 or mild Alzheimer’s disease. These data are being 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. 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.
  • 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) and 10 mg/kg (n=32) dose arms, and up to week 30 data for the 6 mg/kg (n=30) dose arm.
  • Radiologic Results for Amyloid Plaque:  In patients receiving aducanumab, a dose- and time-dependent reduction of amyloid plaque was observed over 54 weeks of treatment. PET imaging using the radiotracer florbetapir1, which binds to amyloid plaque, was used to measure plaque levels in the brain. A composite standardized uptake value ratio (SUVR) of six regions of the brain –frontal, parietal, lateral temporal, sensorimotor, anterior and posterior cingulate – was calculated at baseline, at 26 weeks and at 54 weeks using whole cerebellum as a reference.
  • In the placebo arm, the SUVR was virtually unchanged at 26 and 54 weeks. 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.
  • Clinical Results: The effect of aducanumab on AD-related impairment was measured using the MMSE and Clinical Dementia Rating sum of boxes (CDR-SB). The MMSE is used to assess a patient’s cognitive status and the CDR-SB characterizes a patient’s cognitive and functional performance.
  • 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 10 mg/kg doses 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 arm. Relative to placebo, the 10 mg/kg showed a statistically significant slowing of clinical decline on the CDR-SB with p-value <0.05.
  • Pharmacokinetic activity and exposure were linear with dose. Treatment-emergent immunogenicity, which occurred in approximately 3 percent of patients, was transient and without apparent effect on aducanumab PK.
  • Safety Results: 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).
  • on MRI scans, the incidence of ARIA-E (edema) was dose- and apolipoprotein E4-(ApoE4) status-dependent. 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 continued treatment and did so at a lower dose.
  • In ApoE4 carriers, the incidence of ARIA-E was 5 percent in the 1 mg/kg 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, the incidence of ARIA-E was 9 percent, 11 percent and 17 percent in the 3 mg/kg, 6 mg/kg and 10 mg/kg aducanumab arms, respectively; no cases were reported in the 1 mg/kg arm.
  • In ApoE4 carriers, the incidence of patients who developed ARIA-E and discontinued treatment was 5 percent in the 1 mg/kg arm, 10 percent in the 6 mg/kg arm, and 35 percent in the 10 mg/kg arm. There were no discontinuations in the 3 mg/kg arm. In ApoE4 non-carriers, the incidence of patients who developed ARIA-E and discontinued treatment was 11 percent in the 6 mg/kg arm and 8 percent in the 10 mg/kg arm. There were no discontinuations in the 1 mg/kg and 3 mg/kg arms.
  • Headache occurred in 22 percent of patients receiving aducanumab compared to 5 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.

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