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PMN.TO: In Alzheimer’s, It’s the Oligomers that Count

05/31/2018
By John Vandermosten, CFA

TSE:PMN.TO

OTC:ARFXF

NASDAQ:BIIB

ProMIS Neurosciences Inc. (TSE:PMN.TO) (OTC:ARFXF) is a Toronto-based, neurodegenerative disease-focused biotechnology company developing a portfolio of monoclonal antibodies (mAbs) for Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s Disease (PD). The company has shown exciting potential in its lead candidate, PMN310, for AD and is currently conducting pre-clinical development work targeting toxic amyloid β oligomers (AβOs). ProMIS’ approach is highly selective for these specific AβOs thereby avoiding dilution by not binding to the abundant, but inert monomers and fibrils (plaque).


View ProMIS Neurosciences Inc.

The last two decades have been rough for AD drug development. Only one new drug since 2002 has been approved and 99% of trials have failed. Even in 2018, we have seen disappointments from Eli Lilly’s solanezumab, Merck’s verubecestat, vTv’s azeliragon and the closure of Pfizer’s neuroscience division. Despite all of these announcements, there is a compelling body of evidence going back many years that shows that the underlying cause has not been the target in these clinical trials. Most disease modifying agent candidates have operated under the amyloid hypothesis, which attributes AD to the action of amyloid β in the brain. Studies have shown that amyloid β has been too broad of an objective as it exists in many forms. Unfortunately, the leading drug programs have targeted the wrong types of amyloid β, which has led to their failures.

However, there is hope in a competitor’s drug which could bring attention to and validate the underlying cause of the disease. This is Biogen’s (NASDAQ:BIIB) aducanumab, currently in Phase III trials which could inject a dose of confidence in the PMN310 program, validating the primary target of the mAb. Preclinical work suggests that PMN310 may be superior to Biogen’s drug due to lower likelihood of side effects and greater specificity for the intended target.

In addition to the knowledge gained from past programs, new guidance from the FDA may improve trial design and allow for faster work, expedited pathways and the use of surrogate endpoints. As ProMIS’ candidate will enter the clinic next year, we expect the company to take full advantage of all the regulatory advancements.

Research over the last decades has narrowed down the likely cause of AD-related neurodegeneration from the broad amyloid β hypothesis to a focus on amyloid β oligomers. The broad activity of previous drugs and the difficulty in specifically targeting toxic AβOs has led to the failure of numerous AD therapies in recent years. However, ProMIS has learned from recent study outcomes as well as the large body of research exhibiting the neurotoxicity of AβOs. This knowledge has been combined with the company’s algorithmic platform to create a mAb that can specifically target unique epitopes that only present themselves on the toxic oligomers that cause AD and potentially arrest the disease.

Alzheimer’s Disease

In 1906 a German neurologist named Alois Alzheimer described a patient who had memory loss, heightened suspicions and worsening psychological changes in the first clinically documented case of AD. Upon death, the patient’s brain was found to be markedly smaller than that of a normal patient and it exhibited abnormal deposits around nerve cells. Progress was slow in understanding the disease over the subsequent decades and it wasn’t until 1984 when the deposits associated with AD were identified as amyloid β. The next milestone arrived in 1987 when the first drug directed towards AD, tacrine, was placed in clinical trials. The drug failed due to safety concerns, but it did represent a concerted effort to target the root cause of AD.

Fast forward to today and the effort to address AD has ballooned. There were 105 agents in the drug development pipeline for AD in early 2017 (Cummings, Jeffrey, et al., 2017). These drug candidates were comprised of three categories: disease-modifying immunotherapy, disease modifying small molecule, and symptom reducing small molecule groups. The most promising area for an AD cure is AβO-related disease-modifying immunotherapy as it represents a way to render toxic forms of amyloid β inert.

Research has narrowed down the likely cause of AD. For decades, neurodegenerative research has been operating under the amyloid hypothesis, which proposes that the neurodegeneration in AD is caused by deposition of amyloid β peptide in brain tissue. The hypothesis posits that the accumulation of the peptide is the primary influence driving AD pathogenesis. While targeting amyloid β with a neutralizing monoclonal antibody appears to be a straightforward objective, addressing the precise cause is more complex. One of the reasons for the complexity is that there are multiple types of amyloid β, and only one of them is emerging as the culprit in causing AD. The three types of amyloid β include: monomers which are single stranded, oligomers which are multiple stranded and fibrils (plaques) which are very large aggregates of the protein.

View Exhibit I – Schematics of Aβ Monomer, Oligomer and Fibril - (ProMIS, 2016).

In the early days of the amyloid hypothesis, it was thought that plaques were the cause of neuron death; however, through additional research and analysis of trial results the hypothesis has been refined to focus on a subset known as toxic amyloid β oligomers. There are volumes of research dating back over a decade (multiple citations included in our upcoming initiation) providing evidence that AβOs cause neuron death and further work showing that it is low molecular weight AβOs that are responsible. This assertion has been strengthened in the current study for aducanumab by Biogen. Aducanumab is a human mAb currently in Phase III trials that has been shown to both reduce amyloid β in the brain and slow clinical dementia (Sevigny, J. et al., 2016 The antibody aducanumab reduces Aβ plaque in Alzheimer’s disease. Nature 537: 50-56). Other AD candidates that targeted all forms of amyloid β (bapineuzumab) or monomers (solanezumab) failed to show efficacy in Phase III trials. We include a representation of why some drugs have been successful and others have not in the following exhibit called a “dot blot.” The “dot blot” illustrates the binding affinity of a drug to a form of amyloid β; the darker the dot, the greater the association between the two.

View Exhibit II – Comparison of Binding Affinities Among Selected mAbs and Aβ Forms

It is hypothesized that bapineuzumab failed because it binds to all forms of amyloid β, causing side effects and because the proportion of monomers compared to oligomers was so great, that there was little drug left to address the root cause of neuron death. Solanezumab failed for a similar reason due to its greater affinity for monomers. Aducanumab, on the other hand, has showed early efficacy due to its ability to target oligomers, despite a dose limiting safety signal.

In addition to targeting the incorrect form of amyloid β, other hurdles to success have been dose limiting toxicities and targeting the disease too late in its progression. The most common adverse event in competing therapies has been a type of cerebral edema known as amyloid-related imaging abnormalities edema or ARIA-E, which has been tied to plaque binding with higher doses of drug using the immunoglobulin G1 (IgG1) isotype.

Based on a review of the literature, further refinements that would increase the probability of success include designing mAbs that are able to specifically target AβOs and avoid distraction by monomers and fibrils. Shifting to a more efficient immunoglobulin backbone IgG4 would also confer benefits related to inflammation and ARIA-E associated with the IgG1 isotype.

ProMIS has recognized many of the shortcomings identified in other work and developed a mAb that solely targets toxic oligomers. The compound is also built on the IgG4 isotype backbone, addressing the inflammation that contributes to ARIA-E.

Biogen’s Aducanumab

A competing mAb that has shown potential is Biogen’s aducanumab, which targets the amyloid β plaques and oligomers, and avoids binding to distracting monomers. While some drug does bind to the plaques, enough remains to inhibit the existing AβOs, thereby supporting cognitive efficacy. This is an improvement over prior attempts with solanezumab and bapineuzumab whose drug substance was diverted to the more prevalent monomers that are in the brain. Success for aducanumab could be favorable for PMN310 as it validates the target of toxic AβOs and will bring substantial attention to ProMIS’ program.

Due to its targeting of AβOs and favorable data in early trials, it is likely that aducanumab will be approved after the data is submitted to the FDA in 2020. Success for Biogen’s drug will be a positive for ProMIS and PMN310 as it validates the target, provides a pathway for approval and will bring attention from investors and pharmaceutical companies. Preliminary data suggests that PMN310 can perform better than aducanumab as it is designed to avoid side effects associated with high doses of the latter, sidesteps target distraction by ignoring monomers/fibrils and has a more durable bond to toxic AβOs.

The subsequent exhibit compares aducanumab with ProMIS’ lead candidate PMN310. PMN310 uses an IgG4 backbone thereby supporting potential reduction of side effects, such as ARIA-E and thereby allowing for higher dosing. Furthermore, since the drug is able to avoid target distractions from monomers and fibrils, its full measure is directed toward AβOs. Finally, PMN310 is able to bind to toxic oligomers with higher affinity, which means the antibody will maintain a longer residence time at the binding site. While PMN310 is several years behind Biogen’s drug, its improved profile suggests that it could take market share from its larger competitor if approved.

View Exhibit III – Comparison of AD Therapy Targets

Algorithmic Platforms

ProMIS has differentiated itself from other biotechnology development companies with its discovery platforms. These platforms employ complex algorithms to model misfolded proteins and predict with a high degree of certainty specific features that will appear on the desired oligomer. The computer simulated modeling used by the ProMIS and Collective Coordinates software is able to identify epitopes which are present on the surface of toxic AβOs and also eliminate from consideration other epitopes that are exposed on non-target proteins. This specificity allows PMN310 to avoid target distraction and focus on the proper objective. The company’s research group has identified six unique epitopes that appear on misfolded AβOs which are recognized by mAbs with the PMN3xx series nomenclature. These computational models can also be used to explore characteristics of proteins for other neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Parkinson’s Disease (PD) and others.

Market Size

It is estimated that almost 6 million people in the United States and 44 million people worldwide are living with AD. This doesn’t include the population of individuals with Mild Cognitive Impairment (MCI) or prodromal AD, which, if included, could boost the population to twice this number. It is the sixth leading cause of death and about 80 to 90 thousand people die each year from the disease. This compares to stroke and diabetes where 133,000 and 76,000 die each year in the 5th and 7th leading causes of death.

The number of individuals suffering from AD is expected to double 20 years from now due largely to the increasing older population. The current treatment paradigm does not provide a cure or even stop the progression of the disease and only treats symptoms. With no approved cure, the first compounds approved will likely have a dominant market share with strong pricing power.

View Exhibit IV – Projected US Population with AD

FDA Position on AD Trials

Since the 1990s, the FDA has provided guidance that calls for pivotal trials in AD indications to have dual primary endpoints on both cognitive and funtional axes. The double mandate has created additional hurdles for approval and needs an update. Critics argue that focusing on a single endpoint is adequate because improvements in cognition are more important for this group. They contend that approving a drug that helps on only cognitive or functional objectives is sufficient if safety is acceptable and there are no other drugs to treat the disease.

Another concern regarding trial design is that the major clinical studies have enrolled patients that exhibit evidence of mild or moderate AD. This may be too late in the progression of the disease for a preventative treatment. With improvements in diagnostic tests and better identification of biomarkers indicating the onset of AD, it may be easier to locate earlier stage enrollees for trials.

Over 400 trials have been conducted for AD and none of them has been able to show pivotal results supporting safety and efficacy. The lack of success has prompted this proactive change by the FDA to simplify the trial design in order to promote improved success and stimulate investment in this therapeutic area. The Alzheimer’s Association notes that AD is the only disease among the top ten causes of death in the United States “that cannot be prevented, cured or even slowed” highlighting the critical state of patients suffering from the disease (Alzheimer’s Association, 2016).

With drug development for AD in crisis, the Food and Drug Administration responded. In February 2018, the FDA published draft guidance that defined six stages for patients for AD, and potentially acceptable endpoints for earlier stage disease. The most notable factor was the acceptability of biomarkers for determining efficacy. The agency also recognized that using a single endpoint for cognitive impairment would be a satisfactory trial goal. Sensitive neuropsychological measures were recommended to serve as primary endpoints to support marketing approval. Later stage endpoints were not updated, as this was not the focus of the guidance. In conjunction with the pharmaceutical aspect of treatment, the diagnostic approach is equally important. Biomarker evidence is critically important in identifying patients with the disease. The FDA also wants sponsors who are co-developing diagnostic devices for AD to engage with the Division of Neurology Products or the Center for Devices and Radiological Health in the advancement of their device.

This shift in approach is a substantial positive for the design of new clinical trials for Alzheimer’s Disease. ProMIS may be able to obtain expedited consideration from the FDA based on biomarkers and surrogate endpoints and can also use the pathway established by Biogen to efficiently construct their trial design. With knowledge gained from previous failures and the mutual interest of the FDA and the drug development processes it regulates, we see an easier path forward for new AD compounds entering clinical trials. Applying a single endpoint and employing surrogate markers could potentially eliminate two to four years of clinical trial work through more efficient trial design and expedited pathways.

Pipeline

ProMIS’ pipeline is divided into multiple categories of target proteins: Toxic amyloid β oligomers, tau proteins, SOD1, TPD43 and α-synuclein. The most advanced and primary category is the toxic amyloid β oligomers. ProMIS has identified six epitopes that appear on toxic oligomers, which allow for the development of mAbs that will specifically bind to them.

View Exhibit V – ProMIS Pipeline

Summary

ProMIS has developed an impressive portfolio of product candidates that have been generated on their development platforms. Its lead candidate, PMN310, is able to selectively target toxic amyloid β oligomers and potentially address one of the most difficult diseases that we face today. The mAb is able to selectively bind to low molecular weight oligomers implicated in AD and render them inert. The company has been able to learn from prior trial failures and the body of existing research to develop a drug that specifically targets the root cause of the disease without being distracted by non-toxic forms of amyloid β. ProMIS has been able to achieve this specificity with its proprietary algorithms that allow it to identify unique epitopes expressed on the toxic oligomers and develop mAbs that neutralize them before doing damage. The AD therapeutic area has faced many difficulties in recent years, and the disease represents a tremendous burden on society. Recognizing this burden, the FDA has updated its guidance on trial design which should allow for shorter and more efficient trial construction as well as the potential for expedited regulatory pathways and the use of surrogate markers. PMN310 is expected to go into the clinic next year and take advantage of this new pathway. With few competitors in this immense market and early success with this drug, there could be strong demand from multiple pharmaceutical companies who desperately need to fill holes in their declining portfolios.

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Full Citations

Cummings, J., et al. Alzheimer’s disease drug development pipeline: 2017. Alzheimer’s & Dementia: Translational Research & Clinical Interventions 3 (2017) 367-384. Retrieved from here.

ProMIS Poster presentation at 2016 Annual AAIC, July 28, 2016. A Computational Method to Predict Disease-Specific Epitopes in Aβ, and Its Application to Oligomer-Selective Antibodies for Alzheimer’s Immunotherapy.

Sevigny, J. et al. (2016). The antibody aducanumab reduces Aβ plaque in Alzheimer’s disease. Nature 537: 50-56.

Healy, M. (2018, January 09). One of the most promising drugs for Alzheimer's disease fails in clinical trials. Retrieved from here

2016 Alzheimer’s Disease Facts and Figures, Alzheimer’s Association, 2016.

Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry. Retrieved from here.
 
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