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PMN.TO: Aducanumab Failed. What Does This Mean for Amyloid Beta?

By John Vandermosten, CFA


On Thursday, Biogen (BIIB) announced that it will discontinue its Phase 3 ENGAGE and EMERGE trials for Alzheimer’s Disease (AD) drug aducanumab. The Independent Data Monitoring Committee (IDMC) advised that the trial was unlikely to achieve its primary endpoints based on a futility analysis. Management noted that the trial was not stopped due to safety concerns and that the company will present detailed data at future medical meetings.

This is disappointing news for both patients, who were anticipating a disease modifying drug to become available in the next few years and, at first glance, for proponents for amyloid-β. Biogen’s ENGAGE and EMERGE trials were launched in 2015 and since that time there have been substantial advancements in the understanding of what causes AD. Understanding of what is damaging neurons has evolved and a consensus has emerged that it is toxic oligomers rather than plaques and monomers that cause the disease. ProMIS Neurosciences (PMN.TO) (ARFXF) has conducted in vitro work demonstrating the damage that toxic Aβ oligomers can have on neurons, as we illustrate below.

View Exhibit I – Effect of Aβ Oligomers on Neurons

Prior to Biogen’s announcement, there was general consensus that aducanumab would be approved. Even though aducanumab’s main target was plaques, it also bound to toxic oligomers which provided hope there would be sufficient drug to neutralize sufficient amounts to be effective; however, it was not specific enough. It had also generated proof of concept data that demonstrated a positive effect on AD patients, in contrast to other AD candidates that did not do well in in this stage and also failed in Phase III. The absence of any other approved disease modifying therapies also contributed to the environment, creating the impression that the FDA would apply a lower threshold for approval for this unmet need. However, with Biogen’s abandonment of aducanumab, it appears that the drug was not selective enough to provide a favorable outcome.

Despite aducanumab’s poor showing, we see ProMIS’ program as different and not negatively implicated by the futility demonstrated in the ENGAGE and EMERGE trials.

One of the more compelling slides that ProMIS presents in support of this assertion is one that illustrates the binding capability in some of the best known candidates for AD. While bapineuzumab, solanezumab, aducanumab all demonstrated binding to oligomers, they also bound to monomers and/or plaques which exist in greater volumes that the toxic species that PMN310 targets. Even aducanumab, which held hope for many, did have a substantial binding affinity to plaques, as shown by the dark dot under the aducanumab heading.

View Exhibit II – Binding Affinity to Monomers, Plaques and Oligomers

There is a broad body of independent literature and research performed by ProMIS identifying toxic oligomers as the source of neuron death as we discuss in our initiation. Despite the failure of aducanumab, which primarily binds to plaques, we have confidence that the specificity of ProMIS’ PMN310 will eliminate the toxic oligomers that have been shown to damage neurons. The emergence of blood based biomarkers is also a valuable tool which will allow an early read for in-human drug trials to measure whether or not the drug is working. Based on our discussions with the ProMIS science team, we believe that within three to six months of first dosing there may be a detectable signal. One of the key biomarkers that ProMIS has mentioned and we have discussed is Neurofilament Light Chain (NfL). Blood based tests can detect small changes in NfL and determine the rate of neuron death. These biomarkers can provide an early read as to whether or not a candidate demonstrates efficacy.

Despite this disappointing news for both Biogen and AD patients that need a cure, we maintain our positive view on ProMIS Neurosciences.

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