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Is a new Alzheimer’s disease drug in the offing?
Posted on September 23rd, 2016 by Patrick C. May, PH.D. in Pharma R&D
A high profile paper describing a prospective new therapy for Alzheimer’s disease (AD) was being shared around the internet recently. The paper, “The antibody aducanumab reduces Ab plaques in Alzheimer’s disease,” authored by Sevigny et al., was published on-line in Nature (Sevigny et al., 2016) and describes the preclinical and early clinical development of aducanumab, Biogen’s immunotherapy approach to AD. This paper received significant play in the lay press and, as often happens, the results were over-interpreted and the conclusions over-stated, leading the public to think a cure for AD is just around the corner. In contrast, the paper landed much softer with the scientific community, in part because most of the clinical data was already presented at international conferences last year (Sevigny et al 2015 ADPD2015; Sevigny et al., 2015 AAIC15). So what’s all the fuss about?
There is much to like about the paper. It describes both the early pre-clinical data with aducanumab in aged Tg2576 transgenic mice as well as the interim results of an ongoing Phase 1b 12-month clinical trial in prodromal and mild AD patients. The preclinical data in mice document that aducanumab (or a murine surrogate antibody that can be chronically dosed in mice) can gain access to the brain parenchyma, bind to fibrillary Abeta and facilitate the removal of Abeta amyloid plaques in a dose-dependent manner. There are numerous other examples of Abeta antibodies in preclinical studies showing similar prevention of the build-up and, in some cases, removal of pre-existing amyloid plaques in transgenic mice, so this data with aducanumab is nice but not unique. The real spice in this paper comes with the demonstration of a time-dependent and dose-dependent decrease in Abeta amyloid plaque load in aducanumab-treated prodromal and mild AD patients. A positive amyloid load, determined by molecular positron emission tomography (PET) imaging with Florbetapir, was an inclusion criteria for entry into the trial. This requirement for amyloid positivity is one of the key learnings from previous AD immunotherapy trials, where it was determined that a significant percentage (up to 25%) of mildly demented patients recruited into the trials did not have amyloid (or at least a positive amyloid PET signal) in their brain. At the highest dose tested, 10 mg kg-1, aducanumab treatment for 12 months reduced the Florbetapir PET signal to a near baseline value suggesting almost complete removal of Abeta amyloid in multiple brain regions. The effect on amyloid removal was remarkably dose-dependent despite the doses being administered in essentially three separate cohorts (Placebo vs 1 and 3 mg kg-1; Placebo vs 10 mg kg-1; and Placebo vs 6 mg kg-1), suggesting a clear stoichiometric relationship between antibody and plaque removal.
Unfortunately, the dose-dependent effects of aducanumab also extended to adverse events described as amyloid-related imaging abnormalities (ARIA). Adverse events of ARIA-E (for edema) and ARIA-H (for microhemorrhage) have plagued many of the early immunotherapy trials for AD and led to dose limitations. In fact, the planned dose for the last active cohort in the aducanumab trial was a 30 mg kg-1, but after the ARIA-E adverse effects appeared at lower doses, the new dose was dropped to 6 mg kg-1. ARIA-E is thought to represent an increase in extracellular fluid due to treatment-related changes in perivascular permeability. The presentation is often clinically silent and only picked up on MRI, but nonetheless is a safety concern. While the cause of ARIA is not understood, the fact that both plaque-lowering and ARIA-E were so tightly dose-dependent suggests a relationship.
What remains to be determined is the relationship between amyloid plaque removal and cognition or disease progression in AD. This study was not powered to show statistically significant effects on cognition, but the investigators report positive data for the exploratory endpoints of CDR-SB and MMSE, two commonly used tests for cognition in AD clinical trials. This apparent positive effect on cognition is what got the lay press so excited, and at least some clinical investigators so exasperated. The 10 mg kg-1 group showed a significant difference from placebo in both CDR-SB and MMSE, but this was the dose with the highest dropout and the highest percentage of ARIA-E adverse events. Treatment was nominally dose-related when analyzed as a group, but in the MMSE analysis, the 6 mg kg-1 dose was no different from the 1 mg kg-1 dose and clearly less effective than the 3 and 10 mg kg-1 dose groups. This noise in the clinical data is not unexpected given the small numbers, but really prevents any clear conclusion being drawn about the cognitive benefit of aducanumab treatment.
The answer to the title of this blog is it’s too early to tell. Aducanumab has demonstrated remarkable effects on removing Abeta amyloid plaques from patients with prodromal or early AD. Whether it can do this in the absence of evoking ARIA-E adverse events remains to be determined. The last dosing cohort for the Phase 1b clinical trial described here is assessing whether titrating the drug over time can limit the appearance of ARIA-E. If this can be achieved or at least the ARIA-E clinically managed, aducanumab appears primed to make a strong case for accepting or rejecting the amyloid hypothesis for AD. But that won’t be known until the outcome of two phase 3 clinical trials (ENGAGE: NCT02477800; EMERGE: NCT02484547) that are currently ongoing and slated to be completed in 2022. So we are still several years away from knowing if this antibody deserves its headlines (UK Express) as a breakthrough therapy for Alzheimer’s disease.
Conflict of interest: As a former employee at Eli Lilly and Co, I was involved in the early preclinical development of solanezumab as well as other AD-related drugs discovery projects, and currently own stock in the company.
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Patrick C. May, PH.D.
President at ADvantage Neuroscience Consulting LLC
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