Chairman’s Memorandum, August 4, 2021
ProMIS Neurosciences: Chairman’s Memorandum. August 4, 2021
Notes and comments after the first AAIC meeting in the era of approved disease-modifying therapies for Alzheimer’s Disease
We are in a new era in the fight against Alzheimer’s, ALS, and other neurodegenerative diseases. ProMIS and many others have predicted this development. We believe that the Alzheimer’s community will look back on 2021 as a turning point, just as 2010 was a turning point in immuno-oncology and the fight against cancer. There were many signs of that recognition at the AAIC 2021 meeting.
As we have done after previous AAIC meetings, in this note we will comment on highlights of AAIC with relevance to ProMIS (including webinars, analyst reports, press releases, and other items timed to coincide with AAIC), summarize our two poster/presentation contributions to the meeting, and try to put it in the context of our updated corporate overview.
Key Points: Alzheimer’s
1) Alzheimer’s is seeing a dramatic increase in interest and investment, it has become an area that large pharma companies cannot afford to be left out of, akin to immuno-oncology in the last decade.
2) The FDA’s decision to approve Biogen’s Aduhelm confirmed the regulatory feasibility of Alzheimer’s disease therapies, contributing to the accelerated interest and investment.
3) The door has been opened for improved next generation therapies , that selectively target the pathogenic form of proteins like amyloid-beta.
4) Therapies that target aggregated amyloid-beta (neurotoxic oligomers and plaque) in Alzheimer’s have all shown clinical benefit; therapies that target monomer or are non-selective, targeting all forms of amyloid-beta, have failed in every clinical trial.
5) Successful clinical outcomes from the three therapies targeting aggregated amyloid, Biogen’s Aduhelm, Eisai’s BAN2401 (lecanumab) and Lilly’s donanemab, support the concept that the neurotoxic oligomer is the key target for therapy, and clinical benefit comes from neutralizing the oligomer. The simplest explanation, (Occam’s Razor), fitting all the clinical and scientific data, is that the oligomer needs to be the target for therapy. (More below).
6) ProMIS’ PMN310 is well positioned to be the best of the next generation therapies in Alzheimer’s, with extremely high selectivity for the toxic oligomer, effector function with the potential for efficacy at a low dose, and the possibility of both IV and subcutaneous delivery (More below).
ProMIS at AAIC
Conformational epitopes exposed on misfolded toxic forms of amyloid-beta, tau and alpha-synuclein directly contribute to their seeding activity
ProMIS’ unique platform uses computational approaches to predict the particular shape (or conformation) of misfolded proteins, identifying conformational epitopes exposed only on neurotoxic misfolded proteins. In our poster presentation at AAIC (available on our website) we identified a novel scientific insight into disease pathogenesis, which may suggest that ProMIS antibodies have a mechanism of efficacy that could lead to differentiated clinical benefit, in addition to their high selectivity. From the abstract: “Small misfolded regions (conformational epitopes) exposed on misfolded toxic proteins can, on their own, replicate the seeding activity of the full-length protein suggesting that they contribute to its prion-like pathogenicity. These results also indicate that these conformational epitopes represent a biologically relevant target for therapeutic antibodies.” The exposed conformational epitopes that we predict computationally are not only a target for antibodies, but also play a direct role in prion-like propagation, an important driver of disease pathogenesis. Importantly, the shape conferred on the amino acids in the epitope is key, as the same amino acid sequence lacking this specific shape does not trigger seeding. In addition to selectively binding and neutralizing those neurotoxic proteins, our antibodies may slow the rate of propagation or spread of toxicity.
Title: Selective targeting of intracellular misfolded, pathogenic TDP-43 with rationally designed intrabodies
ProMIS’ technology platform has created a large and growing portfolio of highly selective, high affinity antibodies against numerous misfolded proteins involved in neurodegenerative disease, exemplified by our TDP-43 antibodies, presented by CSO Neil Cashman at AAIC (available on our website). From the abstract: “Immunization with an NTD epitope of misfolded TDP-43 gave rise to mAbs selective for pathogenic vs physiologically important forms of TDP-43. Intrabody constructs derived from these mAbs were able to promote clearance of intracellular pathogenic TDP-43 without toxicity to the cells.” These intrabody data provide initial proof of concept for a gene therapy, vectorized antibody therapeutic, suggesting potential safety and efficacy for that approach.
Amyloid targeted therapies: PMN310 as potentially the best “next generation” therapy
– Therapies targeting aggregated amyloid (neurotoxic oligomers and plaque) show benefit
– Clinical data suggest that oligomer targeting is actually the cause of benefit (not plaque)
– “Next generation” therapies will more selectively target only neurotoxic oligomers
– PMN310 appears to have the desired profile for a “best” next generation therapy
1) The evidence suggests that Aduhelm, BAN2401, and donanemab all target both plaque and neurotoxic oligomers, (but not monomer)
– Biogen’s Aduhelm has demonstrated this in publications, and in the FDA Advisory Committee briefing package.
– Eisai’s BAN2401 was selected by BioArctic to target toxic oligomers, but has some plaque binding.
– Lilly’s donanemab was designed to target plaque, but targets pyroglutamate amyloid, which has long been associated with toxic oligomer formation. Indeed, in our hands, testing of donanemab side by side with other antibodies known to bind amyloid oligomers (all antibodies sourced from Creative Biolabs) showed that donanemab binds both synthetic oligomers and soluble oligomers from human brain homogenate at a similar level as Aduhelm and other antibodies.
2) Clinical results obtained during treatment gaps, support the view that neurotoxic oligomers are the driver of disease progression, not plaque, and that continued dosing to sustain clearance of toxic oligomers is required to maintain benefit after plaque clearance
Eisai presented data on BAN2401 at CTAD in December 2019 and drew exactly this conclusion.
Patients who had been in the Phase 2 trial stopped treatment and were evaluated for an open label extension study. Patients in high dose treatment arms had experienced both a slowing of disease progression (measured on the clinical endpoint CDR-SB, the endpoint used in both the Aduhelm and the ongoing BAN2401 pivotal trials), and a reduction of amyloid plaque, often down to normal levels.
– Plaque remained low and did not increase after stopping treatment. If plaque was the disease driver, then disease progression would be expected to stay stably reduced. In fact, the opposite happened. After treatment was stopped, plaque stayed low, but disease progression resumed at the same rate as placebo.
– Eisai concluded that: “Continued clinical progression with persistent amyloid [plaque] reduction during Gap Period suggests: a potential role for soluble amyloid aggregate species in clinical decline; continued treatment may be necessary even after amyloid [plaque] is removed.”
The Lilly donanemab Phase 2 study was designed in a way that provided some information on the same issue. The study was “treat to target”, i.e. after amyloid plaque was reduced to a target level, treatment was stopped. By week 28 of the 76-week study, 27.4% of the patients in the treatment arm were switched to placebo and had a 48 week treatment gap; by week 56 of the study, 54.7% of the patients in the treatment arm were switched to placebo and had a 20 week treatment gap.
Based on the hypothesis that oligomer binding and neutralization may have contributed to the positive outcome of donanemab, one would expect that the clinical benefit in the middle of the study might be better than at the end of the study, since by the end a majority of patients were in a treatment gap that might allow disease progression to resume. This is exactly what happened. Measured by CDR-SB, the treatment benefit vs placebo was greater at week 36 than at week 76.
3) Biomarkers results further support the oligomer hypothesis
Both Aduhelm and donanemab reduced levels of the biomarker p-tau in a dose-dependent fashion.
P-tau (for phosphorylated-tau) is toxic tau. How does an amyloid targeted therapy lower toxic tau?
Steven Strittmatter and others have published on the interaction of amyloid and tau in disease. Amyloid toxic oligomers, which are extra-cellular and can move around the brain, trigger “hyperphosphorylation” of tau, which in its normal healthy form is usually intracellular, or inside the neuron. Toxic, or p-tau, then propagates or spreads in a prion-like fashion and contributes to disease progression. The most likely explanation for the observed lowering of p-tau is a lowering of causative amyloid oligomers.
4) Next generation therapies will selectively target only amyloid oligomers, yielding greater efficacy and avoiding the side effect of ARIA-E (brain swelling)
– Current therapies targeting both forms of aggregated amyloid all have a side effect, ARIA-E, which requires complicated and expensive clinical management, including dose titration, MRI assessments, and, occasionally, gaps in treatment.
– ARIA-E has only occurred with antibodies that bind plaque.
– Acumen recently entered the clinic, after a successful NASDAQ IPO, with a single asset, the first selective antibody for amyloid oligomers, ACU193. It is an antibody with no effector function, and a relatively short half-life, that may require high dosing (the initial clinical trial is testing 10mg/kg/month – the same as Aduhelm, but also 60mg/kg/month and 60mg/kg twice a month), but the market reception has been very positive and we believe deservedly so. A recent Stifel analyst report on Acumen described “next generation” therapies as those that selectively target the pathogenic form of proteins like amyloid – we agree.
5) PMN310 could be the “best of the next generation” anti-amyloid, AD therapies
– PMN310 is extremely selective for toxic oligomers, most importantly those in human brain homogenate (the “real thing”) with high affinity binding.
– That selectivity can improve efficacy over first generation therapies like Aduhelm by not wasting dose on the wrong target, plaque.
– That selectivity will likely result in little or no ARIA-E side effect which has only been seen in therapies that bind amyloid plaque.
– PMN310 has been updated with effector function, an isotype of antibody that promotes microglial clearance, and will likely enhance efficacy at a lower dose. An antibody with this isotype (IgG1) that did not bind plaque – Lilly’s solanezumab – had little or no ARIA-E.
– PMN310 has shown stability at high concentrations, which along with high affinity binding and possible efficacy at a low dose has the potential to support development of a subcutaneous delivery form of PMN310 for maintenance therapy to avoid recurrent monthly infusions after an initial course of IV therapy to “knock down” disease.
– These combined features could give PMN310 safety, efficacy, cost, and convenience advantages over other amyloid directed therapies.