CTAD preview – Alzheimer’s hopefuls keep watch for amyloid clues


Last week’s failure of Lilly’s solanezumab heaped more doubt on the amyloid hypothesis of Alzheimer’s disease – but the theory looks set to limp on for some time yet. Many of its advocates believe that other anti-amyloid antibodies in the pipeline could be more effective than sola, but it will be a while before this will be proven either way.

Pivotal results with the next most advanced amyloid-targeting candidates, Biogen’s aducanumab and Roche’s crenezumab, are not due until 2020. Meanwhile, earlier-stage data being presented at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting in December could give some more clues on whether the approach might have some merit after all (see table below).

Lilly is now deciding whether to continue with other trials of sola in prodromal, preclinical and dominantly inherited Alzheimer’s. After the Expedition 3 flop this seems unlikely, but the group might persist in the hope that the project has an effect in even earlier-stage populations.

Imaging data

The main reason to watch out for its CTAD presentation will be for PET imaging data that could ascertain whether sola was able to reduce the amyloid plaque burden in patients’ brains.

It would arguably be better for Biogen if sola fails to show amyloid clearance, as that might at least explain why it had no clinical effect.

Biogen bulls were quick to seize on what they believe is a superior profile for aducanumab. It is thought to remove insoluble – or deposited – plaques from patients’ brains, while sola only binds soluble beta amyloid monomers, at best slowing the rate of new plaque formation.

A better trial design could also aid Biogen. The phase III studies of aducanumab include earlier-stage patients and use higher doses of the antibody, which the company hopes could help it succeed where sola failed.

Meanwhile Roche’s crenezumab has a binding profile similar to aducanumab, so analysts are also hopeful about that project.

Null hypothesis

But another possible conclusion from the Expedition 3 results is that clearing beta amyloid plaques has no effect on Alzheimer’s disease progression. If the data show that sola reduced amyloid levels but did not improve clinical symptoms, this possibility would become more likely.

It is also supported by the fact that the phase Ib Prime trial of aducanumab found a reduction in amyloid plaques in the brain with the three highest doses tested at 26 weeks, but did not show a clear dose response on one clinical efficacy measure, the Mini-Mental State Examination (All the elements of an Alzheimer’s bubble – but look out for December, September 2, 2016). 

However, there was a dose response on another endpoint, the Clinical Dementia Rating-Sum of Boxes (CDR-SB), which Biogen is using in its two phase III studies.

Biogen will report two-year data from Prime at CTAD, so things might become clearer then. Safety will also be worth watching as earlier results raised worries about brain oedema, or ARIA-E, at the highest dose.

The full CTAD abstracts will be available on December 8 at 8am Pacific Standard Time.

Selected anti-amyloid antibody CTAD presentations
Project Presentation details Abstract
Solanezumab Dec 8, 6:15pm PST Expedition 3 symposia
Aducanumab Dec 9, 8am PST OC21 – Aducanumab titration dosing regimen: 12-mth interim analysis from Prime, a randomised, double-blind, placebo-controlled phase 1b study in patients with prodromal or mild Alzheimer’s disease
Aducanumab Dec 9, 9:15am PST OC31 – Aducanumab 24-mth data from Prime
Crenezumab Dec 8, 9:45am PST OC5 – A phase Ib, randomized, double-blind, placebo-controlled, multiple dose study to evaluate the safety and tolerability of escalating doses of crenezumab in patients with mild to moderate AD
Crenezumab Dec 9, poster session Crenezumab exposure-response across AD endpoints supports a higher dose for phase III

Any concrete evidence against the amyloid hypothesis would be a blow not only to those developing anti-amyloid antibodies, but also those testing other approaches designed to reduce amyloid levels. One of these is BACE inhibition, which rather than aiming to clear amyloid is designed to prevent the production of amyloid in the first place.

The first potentially pivotal data with a BACE inhibitor, Merck & Co’s verubecestat, are due in mid-2017 (Event – All about that BACE in 2016, February 2, 2016). 

The latest sola results have reduced what little confidence remained in the theory. Despite this, and the lack of any positive readouts so far, some investors will still cling to hopes that it might not be time to sound the death knell for the amyloid hypothesis just yet. 

Companies in the Alzheimer’s space undoubtedly have a long road ahead of them – and they will hope for at least some reassurance at CTAD.

Project Study Trial ID Primary completion
Verubecestat Epoch NCT01739348 Jun 2017
Aducanumab Engage NCT02477800 Feb 2020
Aducanumab Emerge NCT02484547 Feb 2020
Crenezumab Cread NCT02670083 Aug 2020

To contact the writer of this story email Madeleine Armstrong in London at madeleinea@epvantage.com or follow @ByMadeleineA on Twitter

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