Seven months ago, Biogen (NASDAQ:BIIB) shocked the neurodegenerative disease community announcing that they would discontinue their two Phase III aducanumab trials for Alzheimer’s Disease (AD). The Independent Data Monitoring Committee (IDMC) reviewing the trials determined that they were unlikely to achieve their primary endpoints based on a futility analysis using preliminary data. Following the announcement, shares in Biogen collapsed by ~30% and billions in market capitalization were wiped out. More importantly, the momentum behind β-amyloid (βA) dried up and the neurodegenerative target became toxic to investors.
Timeline for Biogen’s Phase III Aducanumab Studies1
Seven months and a day later, in an even bigger surprise, Biogen announced that aducanumab does indeed work and it would be submitting a new drug application (NDA) to the FDA. Upon more thorough analysis conducted in close contact with the Food & Drug Administration, Biogen found that aducanumab did indeed have a dose-dependent effect on AD supported by amyloid-PET imaging and observations of reduced clinical decline in patients with early stage disease.
Biogen held several meetings with outside advisors and Type C meetings with the FDA to validate the updated analysis. The reason cited for the new perspective on aducanumab was attributed to the futility analysis which did not recognize the impact of earlier enrollment on exposure to high-doses of the drug and review of data that accrued later. The company also further analyzed imaging and biomarker data that included information gathered after the futility analysis which was supportive of efficacy. The regulatory filing is expected in early 2020. We believe that the favorable indication expressed by the FDA towards accepting an NDA highlights the agency’s receptiveness to promising disease modifying therapies for AD in an area where there are no alternatives which is a positive for other best in class candidates in development.
Biogen believes that this improved understanding of aducanumab has positive implications for BAN2401 and we think it has further positive implications for other βA-focused therapies including ProMIS’ (OTC:PMN.TO)(OTC:ARFXF) PMN310. When Biogen’s made its March announcement to abandon aducanumab, investor interest and capital in βA dissipated leaving stakeholders despondent. Despite the blow to βA-centered therapies, ProMIS continued to develop its impressive pipeline of neurodegenerative assets targeting not only βA, but also TAU, TDP-43, SOD1 and α-synuclein. The company’s impressive portfolio has led to numerous collaboration discussions simultaneous with the identification of additional antibody targets for tau, TDP-43 and α-synuclein.
ProMIS relies on its unique and proprietary discovery platforms that are able to predict disease specific epitopes on the surface of toxic oligomers. This platform differentiates ProMIS in an environment where many developed antibodies target like a shotgun. In this approach, all forms of a protein are hit rather than just the toxic, unwanted ones. The shotgun approach used by some of the well-known Phase III candidates relies on the hope that enough drug will bind to the disease causing proteins to have a beneficial effect overall and will not be diluted in effect by binding to non-disease related monomers and fibrils. Negative outcomes from this approach can be the requirement for doses with dose limiting toxicities and neutralizing a target with an important biological function such as βA monomers which play an important role in synaptic plasticity.
ProMIS’ approach to disease modifying therapy relies not on hope, but rather specificity. The discovery platforms known as ProMIS and Collective Coordinates employ algorithms that are able to predict unique epitopes on misfolded toxic forms of βA and other toxic proteins. This specificity allows for lower doses of drug to be used and avoids negative outcomes from binding to necessary healthy proteins.
Over the last several months, ProMIS has been sharing its exciting and unique approach to identifying specific targets with potential partners, seeking development collaborations that can advance multiple candidates through the development process. Based on our conversations with the company we see the most likely candidate to be partnered is α-synuclein, with excess upfront cash received from a deal deployed to advance PMN310 internally.
We anticipate a cash raise in the near term to support ongoing preclinical efforts while discussions with prospective partners move forward. The company has identified 5 – 10 potential partnering deals currently in discussion and anticipates from one to three deal closures in the next 12 months.
Tuesday’s resurrection of aducanumab was a big surprise and we think it could improve near term prospects for ProMIS’ PMN310 candidate. While it will take some time for stakeholders to sort through all of the details from Biogen’s announcement, an NDA filing for aducanumab is a positive for the βA approach, especially for participants such as ProMIS who are able to target the underlying cause of AD.
1. Source: Biogen Aducanumab Update slide deck; October 22, 2019. Biogen’s two aducanumab studies were designated ENGAGE and EMERGE. https://investors.biogen.com/static-files/5a31a1e3-4fbb-4165-921a-f0ccb1d64b65
2. Source: Corporate website accessed October 23, 2019. https://promisneurosciences.com/product-portfolio/
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