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Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
BIIB037 is a high-affinity, fully human IgG1 monoclonal antibody against a conformational epitope found on Aß. It was originally derived by the biotech company Neurimmune in Schlieren, Switzerland, from healthy, aged donors who were cognitively normal. The rationale was that these donors' immune systems had successfully resisted Alzheimer’s disease and that the operative antibodies could be turned into therapeutics by a process called "reverse translational medicine." BIIB037 binds aggregated forms of Aß, not monomer. In the brain, BIIB037 preferentially binds parenchymal over vascular amyloid. Thirteen-week chronic dosing in old APP-transgenic mice reduced plaques of all sizes; vascular amyloid stayed unchanged. Brain-exposure studies in mice suggest that microhemorrhages start at 500 mg/kg, more than 100 times the minimally effective dose for plaque clearance, 3 mg/kg (see Apr 2013 conference news).
A Phase 1 safety and pharmacokinetics study began with a single-ascending-dose trial of 0.3 mg/kg to 30 mg/kg intravenous BIIB037 in 56 people with mild to moderate AD. Participants were assessed at 10 time points up to two years after dosing. Amyloid-related imaging abnormalities (ARIAs) were monitored with four MRI scans, read both locally and by a central reader at an imaging CRO. Side effects included headache, diarrhea, and dizziness. They were mild or moderate, some possibly related to the study drug but not to the dose. No new ARIA developed during the trial beyond age- and AD-related baseline ARIA. In dose-ranging studies, a new dose is given once the safety monitoring board has deemed the previous dose safe. Because BIIB037 seemed safe at 30 mg/kg, 60 mg/kg was added. This amounts to 4 grams in a 150-pound person. (For comparison, the multiple sclerosis antibody natalizumab [Tysabri®] is administered as a 300-mg infusion.) BIIB037 exposure changed in a linear fashion across doses, with little variability from person to person. Consistent with preclinical work, the antibody generated no plasma spike.
In summer 2012, Biogen Idec started PRIME, a multicenter, multiple-dose study in 166 people with prodromal or mild AD. Besides aducanumab, this trial evaluates the performance of proposed research diagnostic criteria (see Dubois et al., 2010; Albert et al., 2011). Prospective participants must score more than 19 on the MMSE, between 0.5 and 1 on the Clinical Dementia Rating, and 27 or lower on the Free and Cued Selective Reminding Test (FCSRT). They then undergo amyloid PET and MRI scans; a positive amyloid scan is required for entry.
Nineteen imaging centers using 12 different scanner models participate in the aducanumab prodromal trial and send the scan data to a central reading CRO, where a binary classification method and quantitative standardized uptake value ratios (SUVRs) are compared to establish best methods of interpreting an amyloid scan. Of the first 80 patients scanned, 44 had been diagnosed as prodromal, 36 as mild AD. Of those, the visual read confirmed the clinical diagnosis in 60 percent and the quantitative analysis confirmed the diagnosis in 55 percent of the subjects. The visual read produced no false positives. The false negatives were prodromal cases with a mean MMSE of 27 and an SUVR near the cutoff (Apr 2013 conference news).
In December 2014, Biogen announced it would move into Phase 3 based on interim data suggesting target engagement and a cognitive benefit (Bloomberg news).
In March 2015, an interim analysis of the first data cut pre-specified in the protocol was reported at the AD/PD conference (Mar 2015 conference news). Aducanumab dose-dependently reduced amyloid deposition in six cortical regions of the brain. The effect was large: After one year, the highest dose appeared to have reduced cortical amyloid close to the cutpoint of positivity. ARIA-E occurred with increasing dose and ApoE4 genotype; about a third of cases were symptomatic, with mild headache and confusion reported in retrospect. Two exploratory signals were reported, as well: aducanumab appeared to reduce decline on the MMSE and CDR-SB in dose-dependent fashion, although only the 1, 3, and 10 mg/kg doses were reported at AD/PD. The PRIME study will continue collecting data until 2016.
In July 2015, one-year data for the 6 mg/kg dose were presented to have reduced brain amyloid levels and, in exploratory analyses, to have slowed decline on the CDR-SB in accordance with a dose-dependent effect. On the MMSE, the 6 mg/kg group numerically was closer to the 1 mg/kg than the 3 or 10 mg/kg group, but overall dose dependence remained significant. Instances of ARIA-E increased with dose and ApoE4 carriage, up to 55 percent among ApoE4 homozygotes on 10 mg/kg. Most instances occurred early in the trial, about a third were symptomatic; all resolved (Aug 2015 conference news).
In May 2015, development began in Japan with a Phase 1 study of increasing doses up to 6 mg/kg in 25 patients with mild to moderate AD.
In August 2015, Phase 3 began with two efficacy trials. The 221AD301 ENGAGE study will enroll 1,350 people with MCI due to AD or mild AD as ascertained by a positive amyloid PET scan. It will compare monthly infusions of one of two undisclosed doses of aducanumab or placebo over an 18-month treatment course; the primary outcome measures cognitive and functional decline per the CDR-SB; secondary outcomes include the MMSE, ADAS-cog13, and the ADCS-ADL mild cognitive impairment version. The trial is set to run until 2022, in 150 centers in North America, Europe, Australia, and Asia. The 221AD302 EMERGE study is identical to ENGAGE but will be conducted in 1,350 additional patients at 131 other sites in North America and Europe.
In 2016, Biogen formally published the PRIME data (Sevigny et al., 2016), presented data suggesting that a dose titration schedule mitigated ARIA-E, and announced it would be used in phase 3 (Dec 2016 conference news).
In 2017 and spring 2018, 2- and 3-year data from the long-term open-label extension phase of the PRIME study were being reported at conferences as continuing to show dose-dependent amyloid removal by up to 70 centiloids, and also as slowing cognitive decline as per exploratory analysis. ARIA in the open-label extension was reported to be similar to ARIA the placebo-controlled phase of the trial (see Dec 2018 and May 2018 conference news).
To view all clinical trials on BIIB037, see clinicaltrials.gov.