ProMIS Neurosciences Inc (PMN)

[Phoenix300]

ON THE FOREFRONT OF TECHNOLOGY

05/07/2019
By John Vandermosten, CFA

OTC:ARFXF OTC:PMN.TO

ProMIS Neurosciences Inc. holds an enviable position in the drug development universe. The scientists leading the company have been able to merge chemistry, biology and physics to optimize drug design by employing proprietary algorithms that are able to identify high probability conformations of misfolded proteins. In other words, they have used cutting edge technology to make a better drug.

This type of achievement would not have been possible years ago due to the computational burden required to solve the complex algorithm. Even now, with a network of computers, computation time takes over a week to identify the high probability epitopes used to design the complementary monoclonal antibodies. While science and technology has been advancing in one plane, trial design, the selection of the proper endpoints and how to measure them has also been evolving. In early 2018, following a spate of Phase III failures in Alzheimer’s Disease (AD), the FDA promulgated new guidance allowing for a single endpoint and the use of biomarkers for evaluating efficacy for early stage disease in registrational trials. We see the maturation of understanding the proper target, technology and regulatory environment all working together to find a cure for this debilitating and costly disease.

Evolution

The landscape for drug development for AD and other neurodegenerative diseases has advanced substantially in the last few years. The trend is largely due to an accelerated rate of learning built on a history of both successes and failures leveraged by technology. We see four factors as having a meaningful influence on current and future success to find a cure for AD and a wide variety of other diseases

1. Identifying the right target
2. Computing power and advanced analytics
3. Evolution of FDA guidance
4. Biomarkers

The Right Target

Addressing the right target is a two stage process that first ensures that it has identified the proper mark then designs a way to influence it. ProMIS scientists have performed an exhaustive review of literature addressing neurodegenerative disease and have tested these conclusions conducting experiments that illustrate the synaptotoxicity of amyloid-ß oligomers. They have performed numerous studies in the lab verifying that amyloid-ß oligomers are damaging neurons. In the following exhibit, the panels show neurons exposed to toxic amyloid-ß oligomers over a 24 hour period and compare them to a control. In the first three panels, the neuron dies over the measured period while the control neuron over the same period remains active. Neuron exposure to monomers and plaques generate results matching the control.


View Exhibit I - Synaptotoxicity of Human Amyloid-ß Oligomers on Hippocampal Neurons In Vitro

In vivo work has also been performed in mouse models to test the effect of monomers, oligomers and fibrils on memory, also illustrating the toxic effect of oligomers. In the Object Recognition Model, the mice are exposed to objects then injected with each type of amyloid-ß. Normally, mice interact longer with objects they do not recognize. After injection, the mice are again exposed to the objects, and the data collected demonstrate the oligomer-injected mice lack familiarity with the previously exposed object. This outcome suggests that the oligomers are negatively impacting the memory of the mice.


View Exhibit II - In Vivo Impairment of Recognition Memory by Amyloid-ß Oligomers1

Over the last few decades, amyloid-ß has been associated with AD and much of the research and effort employed to solve the disease has focused on this peptide. There are many configurations of Aß, from single stranded monomers, to multi-stranded oligomers and large agglomerations called plaques. As the science has advanced, the understanding of the function of each of these species of Aß has evolved as well. Either monomers or plaques at different times have been identified as the cause of AD, but as the science has advanced, consensus is coalescing around toxic oligomers as the cause of neuronal death in AD, specifically the low molecular weight oligomers such as the twelve, four and two stranded conformations. This stance was reiterated in an article2 published in Science Translational Medicine in May 2019 authored by 1997 Nobel Prize winner Stanley Prusiner among others. The research provides support that AD is a double prion disease where misfolded forms of amyloid-ß and tau are toxic and can spread and infect healthy brain tissue.

On a Thursday morning just a few short months ago, Biogen and Eisai announced the termination of the Phase III study for aducanumab, as a futility analysis concluded that it would not achieve its primary endpoint. There had been high hopes for the biologic as it had shown some effect on toxic oligomers, which have been shown in an increasing number of in vitro and in vivo studies to be the real target. However, we hypothesize that aducanumab’s higher affinity towards the more prolific amyloid plaques prevented it from achieving sufficient effect on the damaging soluble amyloid beta oligomers. This failure has accentuated the importance of targeting the root cause of AD, which is the low molecular weight toxic amyloid beta oligomers.


View Exhibit III - Various Forms of Amyloid-ß3

Because toxic oligomers are relatively rare, if a therapy is targeting all types of amyloid-ß, much of the drug may be distracted by monomers and plaques, leaving only small amounts to neutralize the toxic oligomer. Many monoclonal antibodies that also target plaques and have an IgG1 isotype are dose limited due to ARIA-E. ProMIS is able to target only the amyloid-ß oligomers with its epitope-specific monoclonal antibodies, avoiding distraction by other forms of amyloid-ß. PMN310 is not anticipated to cause ARIA-E at any dose given its sole target of amyloid-ß oligomers and IgG4 backbone.


View Exhibit IV - ProMIS Antibodies Provide Protection from Toxic Oligomers

Computer Power

Science and technology are always advancing and building on the accomplishments of predecessors. One of the most important tools to continue this building is the use of sophisticated modeling. The modeling requires vast amounts of computing power that enable data intensive calculations to be performed in a reasonable period. The increase in computing power over time4 has radically changed the approach to drug development and ProMIS’ Protein Misfolding and Collective Coordinates computational discovery platforms have been able to build on these achievements.

In many ways, solving a disease is similar to finding a key to open a lock. There are countless locks and countless keys and software can be developed that can try these combinations in silico and narrow down the likely effective combinations. ProMIS has been able to do this with its ProMIS and Collective Coordinates computational platforms. The complex algorithms that are employed by this software seek to identify epitopes that are uniquely displayed on misfolded forms of amyloid beta, providing the necessary data to develop antibodies that will neutralize them.


View Exhibit V - Grid Computing System5

ProMIS’ drug discovery platforms employ thermal dynamics and biology to predict disease specific epitopes on the surface of misfolded proteins, enabling monoclonal antibody drug design that can target the desired receptor. The ability of the algorithm to identify unique signatures for toxic misfolded proteins enables synthesis of antibodies able to ignore irrelevant proteins and focus on the intended target. Precise designs allow for lower doses of drug and fewer off-target effects, obstacles that have run competitors aground. Preclinical progress has been made identifying the root cause of Alzheimer’s Disease (AD) and validating the safety and efficacy of ProMIS’ lead candidate, PMN310. The company has used its unique platform to design precise antibodies for AD and also develop TDP43 (for ALS) and a-synuclein (for Parkinson’s disease) programs that are in active partnering discussions.

Trial Design

In February 2018 the FDA promulgated a new stance in the effort to find a cure for AD with a draft guidance document that outlines new endpoints and their measurement. As comprehension of the disease has improved, so has the understanding of how to properly measure therapies used against it. Prior to 2018, the FDA had required that registrational trials demonstrate an improvement in cognition and function in a dual-endpoint standard. However, this approach did not recognize that many AD patients in early and middle stages may show impairments in cognition, but are functionally just fine. Updated guidance will allow for studies to have a single cognitive endpoint for earlier stage disease.

The new guidance outlines the approach going forward for trial design which breaks down the assessment by stage of disease. For early stage AD, where patients do not show symptoms but do have biomarker evidence, trial endpoints can be based on biomarkers. For stage two AD, where patients have some cognitive impairment but no functional problems, a single cognition endpoint is more appropriate and may be used. For later stages of the disease where there is both cognitive and functional impairment, a dual endpoint is appropriate. The use of biomarkers is extremely important as it allows a less subjective measurement to be used and also may allow for more rapid measurement of drug efficacy.

Biomarkers

Trial design for all of the Phase III pivotal trials to date for AD employ both cognitive and functional primary endpoints that are both subjective and take a long time to measure. This has created difficulties, not only in registrational trials, but also in earlier studies that are seeking a clear signal on whether or not to pursue a specific molecule. By identifying and using biomarkers that are effective and specific, the drug development process can be accelerated and yield more precise data. We highlight several of the well-known Phase III candidates that were in human clinical trials for well over a decade: Aducanumab and Bapineuzumab were in trials for 12 years, Crenezumab for 15 years and Solenezumab a total of 17 years as time, money and resources were allocated to these programs. An effective biomarker could have rapidly and inexpensively identified the therapies that did not demonstrate efficacy allowing the reallocation of resources towards more promising endeavors.


View Exhibit VI - Leading Biomarkers for Neurodegenerative Disease6

There are a number of biomarkers that are being examined including cerebrospinal fluid (CSF) based Aß42, total-tau, and phosphorylated-tau, imaging studies, such as PET scans and MRI and blood based tests like neurofilament light chain (NfL) assay to name a few. We also list above several of the blood based biomarkers that are under consideration. Due to the ease of blood draw in contrast to the expense and discomfort of imaging studies and a spinal tap respectively, blood based biomarkers are favored. NFL has risen to the surface as a very effective biomarker that can be easily collected to measure a surrogate of efficacy. It is a measure of the rate of neuronal death. ProMIS will likely launch a dose ranging study with PMN310 and a strong supporter of the drug’s efficacy would be a dose dependent reduction in NFL.


View Exhibit VII - Level of NFL and Disease State

Summary

Developing the proper drug is only part of the battle. If the mechanism of measurement is not refined sufficiently to reflect the complexity of the disease, then even an effective medicine may take a long time to yield an inconclusive result. Much has been learned from the countless trials that have provided results in neurodegenerative disease, and the evolving landscape has been recognized by the FDA, who recently updated their guidance for AD trial design.

Advancements in science, technology and clinical understanding of AD has helped us achieve a position where we can more accurately identify what is causing the disease and develop methods to neutralize it. Improved computing power has enabled complex software algorithms to discover unique attributes of disease-causing proteins and design effective antibodies. Along with advances in discovery and drug design, we have seen a parallel development in mechanisms to measure improvement in neurodegenerative disease and the framework regulatory agencies require to test the hypothesis. It has been a difficult road forward in this problematic disease state, but never ceasing efforts built on the accomplishments of those who have gone before will eventually identify the cure for this debilitating disease.

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1. See our initiation for addition detail on the in vivo testing design, page 11 – 12.
2. Aoyagi, A., et al. Aß and tau prion-like activities decline with longevity in the Alzheimer’s disease human brain. Science and Translational Medicine, May 2019.
3. Size of blue circle indicates relative abundance of each of the amyloid-ß types.
4. Moore’s Law has held up even to present day,
5. https://commons.wikimedia.org/wiki/File:ArchitectureCloudLinksSameSite.png
6. Source: ProMIS April 2019 Corporate Presentation. MCI: mild cognitive impairment, FTD: frontotemporal dementia