2020 was a tremendously challenging year on many dimensions, dominated by an unprecedented global pandemic. Economies were threatened, governments were threatened, many lives were lost. The biopharma industry rallied to help. It seemed that every company with the ability to make a contribution pitched in to do what they could (including ProMIS and our partner BCNI) and we as an industry should be proud of what has already been and will be accomplished.
However, that progress against COVID-19 has had a cost – labs have been shut down or restricted (the Cashman lab supporting ProMIS at the University of British Columbia was shut down for several months), clinical trials have been slowed or halted, programs other than those targeting COVID-19 have been deprioritized. Just as society is looking to 2021 with strong optimism that we will get out from under the pandemic, we believe that the biopharmaceutical industry will move back toward normal, and that ProMIS will be able to capitalize on the progress we were able to achieve this year.
PROGRESS IN THE PROMIS “RARE DISEASE” PORTFOLIO
As we have disclosed previously, our strategy for all of our non-amyloid programs has been to focus initially on rare disease indications for clinical proof-of-concept. These diseases represent great unmet need, and are often rapidly progressive, enabling a rapid and cost- effective path to validating clinical data that can serve as a strong catalyst. Many of the ProMIS management team and Board members spent decades at Genzyme, the innovator in the rare disease space, and our discussions with third parties are strongly supportive of this strategy. Accordingly, the alpha-synuclein program will focus first on multiple system atrophy (MSA) and the tau program on rare tauopathies, like progressive supranuclear palsy (PSP).
A growing portion of our portfolio will be focused on ALS. Our Chief Scientific Officer and founder, Dr. Neil Cashman, has been a leading researcher in the ALS field for decades, as well as a dedicated clinician, who like other physicians in the field, has had to tell patients and their families that there is very little that can be done. That is changing, and ProMIS is positioned to make a potentially significant contribution. “With advances in the science developed by the research community, accelerated by programs like the ice bucket challenge, I am convinced that we will see effective treatments for ALS in the next few years, and ProMIS programs focused on selectively targeting the toxic misfolded forms of the proteins implicated in ALS are poised to be an important part of that,” according to Dr. Cashman.
The ProMIS portfolio has expanded to four protein targets in ALS that can misfold and play a role in ALS pathology. Misfolded forms of these proteins are also implicated in other diseases with great unmet need, like FTD (frontotemporal dementia), LATE (limbic-predominate age-related TDP-43 encephalopathy). and Huntington’s disease (HD).
ALS can serve as a proof of concept strategy for a broad portfolio of products that may have benefit in other diseases, driven by the same pathogenic proteins.
In ALS, biomarkers are elevated, and can be used in early, proof of concept trials
Further, the selectivity of our antibodies makes them excellent candidates for vectorization in gene therapy. A growing number of large pharma companies are making significant investments in gene therapy for rare diseases – Pfizer, Novartis, Roche, recently Bayer and UCB. This represents an area of opportunity for ProMIS.
PROMIS COLLABORATION IN DIAGNOSTICS
ProMIS entered into the diagnostics field in 2020 through a collaboration with a high-quality accredited diagnostics laboratory, BC Neuroimmunology (BCNI), run by lab director Dr. Hans Frykman. In part due to the fact that our partner is a private company, we have agreed to limit public announcements to major items like regulatory approval or revenues. Since initiating our collaboration over the summer, we have made and continue to make progress scientifically validating both existing assays and our own proprietary assays and are actively pursuing potential revenue opportunities for 2021.
PROMIS ALZHEIMER’S PROGRAMS TARGETING TOXIC OLIGOMERS OF AMYLOID BETA
The ultimate goal of therapy in Alzheimer’s disease is prevention. Alzheimer’s disease pathology progresses for ~20 years prior to symptoms of cognitive decline. By age 80, 30% of the population exhibits symptoms, suggesting that well over 30% of the population over 60 has pathology progressing to symptomatic Alzheimer’s disease. The model often cited is cardiovascular disease, where tremendous progress has been made with therapy and lifestyle changes reducing heart attacks and strokes. With the emergence of blood-based biomarkers that will allow to detect pre-symptomatic Alzheimer’s disease and monitor response to lifestyle or drug therapy, we believe we are entering the era of Alzheimer’s prevention. Many experts have suggested that for the prevention market, infusion antibody therapies, while potentially effective, will be too expensive and inconvenient, and that it is critical to develop therapeutic vaccines.
In this respect, ProMIS has initiated an updated anti-amyloid vaccine program. We published positive preclinical results two years ago with an initial anti-amyloid vaccine made with the peptide antigen that gave rise to our very first amyloid-directed antibody, PMN300. Working with VIDO-Intervac, the same vaccine specialist collaborator, we are now creating a multivalent vaccine incorporating the peptide antigens that were used to raise the PMN310, PMN330, and PMN350 antibodies, in addition to PMN300. Those antibodies all protect neurons by selectively targeting different sites on toxic oligomers. The goal of the multivalent vaccine is to induce the patient’s immune system to make its own antibodies against all these targets simultaneously, hopefully resulting in protective immunity capable of preventing or significantly delaying symptom onset.
The most impactful development of 2020 for our best-in-class antibody PMN310 was the FDA Medical Review document followed by the Advisory Committee meeting on Biogen’s aducanumab antibody therapy on Nov 6. It can best be described by borrowing the words of one of the greatest craftsman of the English language Charles Dickens – “it was the best of times, it was the worst of times.” The negative advisory committee vote will most likely impact the AD field for some time in 2021, including the very challenging capital formation environment that we and others have faced in this field since Biogen’s mistaken suspension of the aducanumab program in March 2019. We and others will be monitoring closely developments over the coming weeks and months. Various experts have forecasted a host of different scenarios: perhaps a delay of the PDUFA date from March 2021 to the summer, to allow for consideration of additional data from the ongoing aducanumab high dose extension study; perhaps approval with restrictions conditional on a confirmatory Phase 4 clinical study; perhaps a smaller study of high dose 10mg/kg vs placebo prior to approval; potentially Q1 2021 approval as scheduled, in line with the FDA’s clearly positive view of the data; perhaps Biogen abandoning aducanumab to focus with Eisai on BAN2401, expected to complete its pivotal program in mid 2022. Any of these is possible.
The FDA Briefing document released November 4th, however, could not have been more positive from our perspective. The scientific rationale offered was in line with and supportive of the arguments we have been making around the importance of selectively targeting toxic oligomers. Prior failures in the amyloid field tell us that targeting the correct form of amyloid matters a great deal. Targeting amyloid monomer leads to failure since there is so much monomer in the vasculature that it “distracts” the treatment from being effective in the brain. These are the arguments we have cited as to why aducanumab is differentiated from previous therapies that failed in the amyloid area, and why PMN310 which is completely selective for the toxic form of amyloid, may have better clinical results. The FDA was clear that it was a mistake to discontinue the aducanumab trial for futility in March of 2019. We believe, and the FDA seems to concur, that had the trial completed as planned, the positive outcome would have been clear. We would add that it is unfortunate that Biogen initially started the trial with nearly 70% of the “high dose” arm receiving the low dose of 6mg/kg, not the intended high dose of 10mg/kg. That design was corrected in March of 2017 with the V4 protocol amendment, but in much of the data the “high dose arm” combines data from patients receiving the high dose of 10mg with others receiving the low dose of 6mg. The table below from the FDA briefing document provides data with numerous clinical endpoints, including but not limited to the primary endpoint of CDR-SB, for patients who completed the EMERGE study (study 302). We have added our “estimate” calculated from public sources of what the results might be for only those patients in the high dose arm who actually received the high dose of 10mg. Since that is the dose that would be used on the market if aducanumab is approved, we believe it is the best data available to judge whether aducanumab would provide a meaningful clinical benefit.
The FDA’s position from the briefing document stated: “Study 302 provides the primary evidence of effectiveness of aducanumab. The effect of aducanumab in Study 302 is robust and exceptionally persuasive on several of the instruments used to evaluate efficacy. In fact, the effects observed for the primary and secondary endpoints encompass two acceptable approaches to establish effectiveness: (1) primary endpoint of CDR-SB and (2) co-primary endpoints of ADAS-Cog 13 and ADCS-ADL-MCI.”
Our interpretation of the FDA’s position is that ultimately aducanumab is likely to be approved, not certain, but likely. In addition, as we have disclosed before, we believe that scientifically BAN2401 shows a similar, but slightly improved profile compared to aducanumab. It has lower plaque binding and ARIA-E side effect than aducanumab, and it has a stronger binding signal to the toxic oligomer enriched portion of brain homogenate (nevertheless, BAN2401 is unlike PMN310 that is far more selective for the toxic oligomer). The ongoing BAN2401 pivotal trial is dosing patients at 20mg/kg per month which is twice the 10mg/kg high dose of aducanumab. The Phase 2 results reported were positive but might have been much more so if not for what appeared to be a slower than average rate of placebo progression.
Despite the Advisory Committee vote, the data shared by the FDA and the FDA’s clearly positive view leave us more convinced than ever that we are on the right track with PMN310, and that in the clinic it could demonstrate safety and efficacy advantages consistent with “best-in-class”. While there is no certainty, we anticipate that over the next 12-24 months there will be at least one, if not two approved disease-modifying products for Alzheimer’s disease (aducanumab and BAN2401) which will facilitate the progress of improved, second generation therapies like PMN310. We remain committed to moving PMN310 forward and continuing to overcome external challenges to that goal.
In 2021, we will make it a priority to rapidly advance our rare disease portfolio. After years of investment, our discovery process is extraordinarily rapid and cost-effective. We see a convergence between our expertise, progress in ALS, and growing market interest.
- 2020 was a tremendously challenging year on many dimensions, dominated by an unprecedented global pandemic;
- The most impactful development of 2020 for our best-in-class antibody PMN310 was the FDA Medical Review document followed by the Advisory Committee meeting on Biogen’s aducanumab antibody therapy on November 6. The negative advisory committee vote will most likely impact the AD field for some time in 2021, including the very challenging capital formation environment that we and others have faced in this field since Biogen’s mistaken suspension of the aducanumab program in March 2019;
- ProMIS has made significant progress in the rare disease field in 2020 and we plan to focus most of our R & D efforts in the near term on further advancing our ALS program selectively targeting toxic misfolded proteins implicated in the development of ALS.
Furthermore, ALS can serve as a proof-of-concept strategy for a broad portfolio of ProMIS antibody candidates that may have benefit in other diseases, driven by the same pathogenic proteins;
- Since initiating our diagnostic JV collaboration with BCNI over the summer, we have made and continue to make progress scientifically validating both existing assays and our own proprietary assays and are pursuing potential revenue opportunities for 2021.
- IN 2020 ProMIS initiated an updated Alzheimer’s disease anti-amyloid vaccine program. Working with VIDO-Intervac, we are creating a multivalent vaccine incorporating the peptide antigens that were used to raise the PMN310, PMN330, and PMN350 antibodies;
- The data shared by the FDA and the scientific rationale offered by the Agency was in line with and supportive of the arguments we have been making around the importance of selectively targeting toxic oligomers. We are more convinced than ever that we are on the right track with PMN310, and that in the clinic it could demonstrate safety and efficacy advantages consistent with a “best-in-class” profile;
- We anticipate that over the next 12-24 months there will be at least one, if not two approved disease-modifying products in Alzheimer’s disease (aducanumab and BAN2401) which will facilitate the progress of improved, second generation therapies like PMN310. We remain committed to moving PMN310 forward and continuing to overcome external challenges to that goal.