ProMIS Neurosciences : Chairman’s Memorandum, May 20, 2020

ProMIS Neuroscience's unique technology platform

ProMIS has recently made several announcements about our progress, all of which exemplify our unique technology platform. This technology platform has become extremely rapid and cost effective after years of investment and experience. It allows ProMIS to create value in a diverse number of ways, as several recent announcements have demonstrated. Following is a description of this platform, and the many areas to which it can be applied.

The basis of ProMIS' highly efficient discovery process is the ability to identify small portions of toxic proteins,including their specific shape or 'conformation',found only on the toxic forms of that protein. We have developed proprietary patented methods and proficiency, based on years of experience, by combining biology and physics to identify these sections of proteins which can be the targets for antibodies. When exposed on the toxic protein, these sections are known as 'epitopes'. ProMIS makes exact matches of these epitopes in a precisely defined shape. These drug development tools are calledpeptide antigens, and represent the key to our efficient methods of creating potentially 'best in class' antibody therapies, vaccines, and diagnostics.

As you may know, proteins are long strings of amino acids. There are 20 common amino acids. Apeptide is a small portion of a protein. An analogy: an amino acid is aletter, a peptide is aword, and a protein is aparagraph. Changing one word (peptide) can change the meaning of the paragraph (protein) - for example changing 'is' to 'was', or 'isn't' could completely change the meaning from positive to negative, just as a toxic mis-folded protein has a negative function instead of a positive function. Our technology platform allows us to identify that one small difference on the toxic protein, and then create peptide antigens that precisely mirror its unique structure. This capability takes advantage of how the immune system works when it makes antibodies. Those antibodies fit precisely an epitope on the toxic protein, the way a lock precisely fits a key. A key is a good visual metaphor for the peptide antigens we create. It has a very specific shape which is critical to its function. In the same way, our peptide antigens, in their very specific shapes, are the key to unlocking value with therapeutics and diagnostics.

Peptide antigens used for immunization are the key to creating highly selective antibodies for toxic mis-folded proteins, like our lead program and top priority, the PMN310 monoclonal antibody for Alzheimer's disease. ProMIS was founded after Biogen published positive data on the aducanumab antibody, the first ever positive result for a disease-modifying therapy in Alzheimer's. All the scientific and clinical evidence at that time (and even more so since then) suggested that a product which was more selective for the toxic mis-folded oligomers of amyloid would avoid aducanumab's side effect (ARIA-E, or brain swelling), could dose higher, and have better clinical outcomes. PMN310 has demonstrated that scientific superiority over aducanumab (as published inScientific Reports, June 2019). After fits and starts, it appears that Biogen's aducanumab provides clinical benefit at the highest dose of 10mg/kg, and will be approved in 2021. PMN310 was created using a peptide antigen that we correctly predicted would be exposed only on toxic oligomers of amyloid, not the monomeric or plaque forms of amyloid.

We have successfully used the same approach to create selective antibodies against toxic mis-folded alpha synuclein, TDP43, and tau, as we have described in the past. Most recently, we announced progress against another mis-folded protein target, RACK1, which is implicated in numerous neurodegenerative diseases. Our highly selective antibodies have significant advantages in the rapidly growing field of gene therapy, and we recently disclosed positive data to that effect in our TDP43 program. After years of ongoing refinement our discovery process has become so efficient that we can create peptide antigens in new disease/target areas in weeks for only tens of thousands of dollars, and over the coming months we plan to substantially expand our preclinical antibody and intellectual property (IP) portfolio based on that.

Peptide antigens are also the key to making highly accurate diagnostics. Because of COVID-19, many people have become aware that serology tests are used to detect antibodies. At ProMIS we have very rapidly applied our technology platform to identify small portions of proteins or epitopes on COVID-19 that might be the target for antibodies raised by the immune system to the virus. We are creating peptide antigens that mirror them - the 'keys' that may exactly fit the 'lock' of the antibodies. With our collaborator Dr. Hans Frykman, a world expert in serology testing, we hope to create highly accurate serology tests that can determine with certainty whether an individual has immunity to COVID-19 to help manage the impact of the disease. Our highly specific peptide antigens, on the most sophisticated measurement platform (SPR, or surface plasmon resonance) may have critical advantages over many other tests on the older ELISA platform. The demand for the tests with highest accuracy will be huge, and we are exploring means of scaling up our testing if we succeed in our goal of creating highly accurate tests. As the scientific community learns more about the virus and its disease course, additional tests may be required, and we may be in a very good position to respond rapidly to that need.

The COVID-19 situation has accelerated our plans to explore diagnostic testing in neurodegenerative diseases as well. We have a portfolio of over 20 peptide antigens that have led to the generation of highly selective antibodies against toxic mis-folded forms of amyloid-beta, alpha-synuclein, tau, TDP43, and SOD1. That portfolio is expanding rapidly (e.g. RACK1). Those peptide antigens, and the selective antibodies, are proprietary reagents that can be used to create diagnostic tests in neurodegenerative diseases. There are different forms of dementia caused by different mis-folded proteins from the list above. Patients can also have mixed pathology dementia. Dementia like Alzheimer's can progress for 15+ years before symptoms arise, a window of opportunity for prevention. Our proprietary assets, which already exist and already have strong validation, could be used very rapidly to develop screening tests to determine if someone will develop symptoms and can benefit from preventive treatment. We believe that Biogen's disease-modifying aducanumab will be approved next year, and that there will be a rapid expansion of the need for this type of diagnostic testing. While our top priority in Alzheimer's and dementia remains therapeutic approaches like PMN310, we see an opportunity to take existing assets and IP and put them to a beneficial use that may have a much shorter path to revenue generation than therapeutics.

Finally, peptide antigens are also the key to making great vaccines. Therapeutic vaccines are designed to treat a disease by causing the patient's immune system to make antibodies (or T-cells, in some areas like cancer) which neutralize the toxic disease driver. Instead of using a peptide antigen to create an antibody that is made in a bioreactor and injected into patients, a vaccine prompts the body's immune system to create those antibodies. But a vaccine is only as good as its peptide antigen. Antibodies made in a bioreactor are often refined and improved substantially after the initial immunization. That is not possible with a vaccine. Our highly specific peptide antigens could have tremendous advantages in mis-folded protein diseases, where it is critical to stimulate the immune system to create selective antibodies. We have published early successful preclinical work with vaccine approaches against toxic amyloid-beta and toxic SOD1, and we are exploring ways to take this therapeutic approach in some of our programs in addition to antibody therapy. The advantage of a vaccine, if effective, is that a single course of therapy might provide benefit for many years, not requiring frequent expensive and inconvenient infusions. In preventive therapy approaches this may be particularly valuable.

Our top priority since starting ProMIS has been, and continues to be, PMN310, and we have issued numerous communications reflecting that priority. Our second highest priority has been further developing and refining our unique technology platform, knowing that it could become (and now we believe it has become) a very rapid and cost effective means to expand our portfolio of potentially valuable assets and IP in multiple areas - antibody therapy, gene therapy, vaccines, and diagnostics. Recent progress has demonstrated that productivity. We felt it would be useful to describe that platform, and the many areas to which it can be applied. We believe we have created a 'best in class' product for Alzheimer's disease: PMN310. We also believe we have created a 'best in class' technology platform which is the key to unlocking value in antibody-related treatments and diagnostics.

We look forward to sharing our future successes with you and thank you for your support.