Executive Chairman’s Note: August 3, 2016
Highlights from the AAIC (Alzheimer’s Association International Conference) meeting held in Toronto July 23-28, 2016
The AAIC meeting was very positive for ProMIS Neurosciences. Most of our scientific and management team were able to attend. We shared updated data about our programs and proprietary discovery technologies, as described in our press release on July 28th. We had numerous meetings with potential large pharma partners, potential investors, and potential scientific collaborators.
In addition, many scientific sessions and speakers provided support for, and additional validation of our scientific approach and product design strategies (our Target Product Profile, creating products that selectively bind the toxic oligomer or “prion” forms of Amyloid beta and Tau). The following are select highlights from those sessions and poster presentations.
Tuesday July 26 session: The Amyloid-Tau Relationship in the Pathophysiology of Alzheimer’s Disease
This CME session included three very highly regarded speakers, David Holtzmann, MD from Washington University, William Jagust, MD from Cal Berkeley, and Dennis Selkoe MD from Harvard Medical School.
Several key points were made in the session, some emphasized by multiple speakers:
- A subset of Amyloid beta oligomers is toxic to neurons (these are what we call the “prion” forms)
- These Amyloid beta prions are directly neurotoxic – they impair memory, they facilitate synapse depression, and induce synapse loss
- In addition, there is a large and growing body of evidence demonstrating that Amyloid beta prions trigger Tau spreading and Tau toxicity
- Insoluble Amyloid cores (plaque) are largely inactive, but Amyloid plaque can play a positive role in sequestering toxic oligomers (prions).
This last point provided an additional rationale for our target product profile of binding selectively to the prion form, not monomer, and not plaque. Plaque binding is correlated with a serious side effect – neurovascular edema – seen in both Biogen’s Aducanumab and J&J/Pfizer’s Bapineuzumab clinical trial programs. Also, disrupting plaque may cause the release of sequestered toxic oligomers which can damage synapses.
In addition, Dr Selkoe mentioned during Q&A that many of the scientific analyses that led to questions about the validity of targeting Amyloid beta were based on looking at the correlation between neurotoxicity or cognitive decline, and Amyloid plaque. As more and more evidence tells us that the Amyloid plaque is inert or possibly even protective (by sequestering toxic oligomers or prions), all of those analyses need to be re-examined, since they were measuring the wrong thing – they were not measuring the toxic form of Amyloid beta.
July 27: ProMIS Poster Presentations
Throughout the AAIC meeting there were sessions and posters emphasizing the growing evidence that “toxic subspecies” of soluble Amyloid beta (Aβ) and Tau oligomers are the bad actors (what we and others are calling “prions”). That was often coupled with a recognition of the difficulty in developing drugs that could selectively target those toxic variants, or measure them accurately, a critical issue that ProMIS is in a position to address.
ProMIS’ two poster presentations exemplified what we continue to believe are the proprietary competitive advantages we are bringing to the field of Alzheimer’s therapy.
Dr. Steven Plotkin, ProMIS’ Chief Physics Officer, presented a poster describing one of our rational drug design technologies, Collective Coordinates. In the poster, he explained that: “Oligomer-specific epitope predictions are presented for Aβ. Cyclic peptides of these epitope primary sequences are both computationally and experimentally generated, which constitute antigenic targets. Clustering analysis, curvature, exposure to solvent, solubility, dihedral angle distribution, and Ramachandran angle distributions are all used to characterize the conformational properties of predicted epitopes, which quantify the distinction between the antigenic profile when presented in the context of the oligomer from that in either the monomer or fibril.”
That highly technical language from our poster presentation boils down to saying that our proprietary technology allows us to specify very precisely an epitope target – both the amino acid sequence and the conformation or “shape” – that does two important things: 1) it is immunogenic, making it possible to create an antibody therapy that specifically targets it, and 2) it is highly selective for the toxic oligomer or prion, not the monomer and not the plaque (fibrils).
Dr. Judith Silverman, from ProMIS CSO Neil Cashman’s lab, presented a detailed overview of the screening results that ProMIS announced in early June. Our rational drug design and discovery technologies have performed as planned so far. Our epitope targets induced a large number of antibody clones (they were highly immunogenic). A significant portion of those antibodies had the selective binding characteristics we were looking for – binding oligomers, not monomer. Our next step will be confirming the desired profile for our best candidates in cadaveric brain tissue, and selecting antibody therapeutics showing no binding to plaque.
July 24: Biogen’s poster analyzing the epitope and binding profile of Aducanumab
Biogen’s product Aducanumab was a very important and positive step forward in treatments for Alzheimer’s. The first positive results published in December 2014 re-energized the AD field and led to a significant increase in market value for Biogen. However, as we have described in our materials and presentations previously, Aducanumab left significant room for improvement. Among other things, there was a serious side effect, neurovascular edema, in all patients in the high dose arm.
As Biogen announced in March 2015, explaining their results:
“This is the first time an investigational drug for Alzheimer’s disease has demonstrated a statistically significant reduction on amyloid plaque as well as a statistically significant slowing of clinical impairment in patients with prodromal or mild disease”
Biogen’s poster presentation at AAIC updated their scientific rationale in a manner more consistent with the view of the “prion” scientists in neurology, including our CSO Dr. Neil Cashman and our SAB member Dr. Lary Walker. Biogen used structural analytic methods to understand the epitope targeted by Aducanumab, and its binding profile relative to other therapies that showed less efficacy. They concluded that Aducanumab was highly selective for “aggregated forms of beta-amyloid, including soluble oligomer and insoluble fibrils”, and that non-binding to monomer was also critical. They posited that the “shallow and compact epitope may contribute to its selectivity for high molecular weight Aβ forms, without targeting Aβ monomers”.
These data confirmed two important aspects of our scientific strategy and story:
- The “prion” is the problem – Biogen’s scientific analysis has provided confirmatory evidence that our target product profile of selectively binding the “prion” (or the toxic, soluble oligomer, with higher molecular weight) instead of the monomer is critical;
- Our proprietary rational drug discovery technologies, such as Collective Coordinates described by Steven Plotkin, our Chief Physics Officer (above), are a significant competitive advantage.
Biogen licensed Aducanumab in 2007. Nine years later, after expensive and complicated analyses like X-ray crystallography, Biogen has determined that the specific epitope (including its conformation or shape) is responsible for the selective binding profile that led to the efficacy of Aducanumab. Binding to plaque and its attendant adverse events however still remain a problem.
At ProMIS – in nine months – we have generated multiple product candidates that meet the desired binding profile, as Judith Silverman’s poster outlined. We achieved this by starting with precise epitope targets as described by Dr. Steven Plotkin, which were rationally designed with our proprietary science to have an optimal amino acid sequence and shape. We have the ability to identify a priori the precise targets that hopefully lead to success, while one of the largest and best resourced players in the area of neurodegenerative diseases had to come to that understanding after the fact.
Disappointing results for TauRx product LMWM
Since AAIC, there has been a great deal of press covering another late stage trial disappointment, in this case for TauRx’s product trying to block Tau aggregation. While there is an understandable attraction to finding “one size fits all” therapies, this is more evidence that the targeted precision approach may be required for complex diseases like Alzheimer’s. The phrase “systems biology” has come into wide usage. It recognizes the fact that any biologic process is part of a system – one that can be very complex. We believe that many therapies suffer from “systems biology risk”, and the TauRx product may be another example of this problem. When one tries to block a process through a single point of access, there may be other parts of the system that compensate for and produce the same negative result. There may also be unintended consequences that lead to harmful side effects. Either or both may happen in a subset of patients.
ProMIS’s view is that precision therapy has the greatest potential to lead to breakthroughs in a complex disease like Alzheimer’s. We are precise in two ways – selectively targeting and eliminating the root cause (prions, or toxic oligomers/aggregates of Amyloid beta and Tau), and being able to tailor our therapy to individual patients and the form of prions that they carry.
In Summary – a very good meeting
The ProMIS team emerged from the AAIC meeting more convinced than ever that we are on the right track to creating important breakthroughs in Alzheimer’s therapy. We will continue to move as rapidly as we can to develop precision therapeutics and demonstrate their activity in disease.