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PMN.TO: More Support for Toxic Oligomers

By John Vandermosten, CFA



The highlight of the 2018 Alzheimer`s Association International Conference (AAIC) was the surprise announcement a few weeks ago by Biogen and Eisai regarding their Phase II study of BAN2401. The results of this trial that were initially hinted at on July 5th, demonstrated improvements in cognition and a dose-dependent reduction in amyloid plaques that was statistically significant. The results of the trial were presented on July 25th.

Biogen’s analysis followed weak initial findings that used new approaches to evaluate efficacy. There were a few deviations from the standard approach used in other Alzheimer’s trials. One of them was the statistical approach employed. Bayesian statistics, which adapt the trial as it progresses, were used to select the target trial enrollment population as new information became available. Additionally, one of the endpoints for the trial called ADCOMS (Alzheimer’s Disease Composite Score) is a new assessment not used before in studies vetted by regulatory authorities. Another confounding factor was also thrown in the mix as the Europeans requested that APOe4 patients not receive the highest doses of BAN2401 due to concerns about ARIA-E. This population is recognized as having a higher risk for Alzheimer’s Disease (AD) and may have distorted the results.

With all of these caveats, treatment with BAN2401 produced a dose dependent reduction in brain amyloid plaque at the highest does. Compared with placebo there was a significant reduction in clinical decline using the ADCOMS methodology. Biomarkers were also used to measure efficacy and included measurements of amyloid beta using a PET scan and presence of the protein in cerebrospinal fluid.

In response to this news, Promis Neurosciences (TSE:PMN.TO) (OTC:ARFXF) published a white paper addressing the details of the Phase II trial for BAN2401. BAN2401 is an IgG1 isotype anti-amyloid beta monoclonal antibody that targets plaques and protofibrils. The ProMIS paper highlights BAN2401’s affinity for protofibrils and ability to avoid monomers. This profile allows for the drug to mute at least some toxic oligomers, which are attributed to causing neuron death and AD. Protofibrils are essentially soluble oligomers and include the aggregates that ProMIS has identified as toxic as well as other larger aggregates that have a lower or no toxicity profile. With BAN2401 binding to this entire group, some of the drug is distracted away from the oligomers, suggesting that a competitor compound that solely targets low molecular weight oligomers may show superior efficacy. Side effects in Biogen’s Phase II study included ARIA-E, which was cited in 9.9% of patients in the highest treatment dose. Patients with ARIA-E were discontinued from the study.

The combination of employing an IgG1 isotype in BAN2401 and targeting plaque have been shown to cause the ARIA-E side effect. We remind investors that Promis’ PMN310 is specifically targeting toxic amyloid beta oligomers which avoids distracting the drug on inert forms of amyloid beta. Furthermore, PMN310 employs an IgG4 isotype, which is able to avoid the inflammation associated with ARIA-E. PMN310, is expected to avoid this adverse event completely as it uses a less inflammatory isotype and does not bind to plaque.

For additional detail and explanation of our favorable thesis on Promis, please refer to our initiation. In recent years there have been numerous failures in the AD space and no drug or biologic has been approved as a cure for the disease. Despite the poor success rate, much has been learned in the last decades from unsuccessful trials and adjacent research work which has been applied in the development of ProMIS’ PMN310.

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