BioProtection Systems Corp.

As Merck and regulators around the world race to get molnupiravir approved for the treatment of COVID-19 - a U.S. Food and Drug Administration expert panel will deliberate its fate on November 30 – it may be important to look at just how this potential “miracle drug” came to be. Emory University has a program called DRIVE LLC, which stands for Drug Innovation Ventures at Emory. It operates as a not-for-profit biotech company and is dedicated to developing drugs and vaccines that have limited applications. In March 2020, DRIVE partnered with Ridgeback Biotherapeutics to further develop a promising oral COVID-19 treatment (then known as EIDD-2801). Two months later, Merck joined the development party when it entered into a collaborative agreement with Ridgeback to develop the drug that would later become known as molnupiravir. The journey, Joe Allen, executive director of the Bayh-Dole Coalition, said, “really shows how our system works.” Between 2013 and 2020, the Emory Institute for Drug Development (EIDD) was awarded an estimated $35 million in grants by the U.S. government. Importantly, this placed EIDD-2801 under the purview of the Bayh-Dole Act of 1980. The purpose of this act is to encourage the private-sector investment necessary to turn basic government-funded research into tested and approved products. It empowers universities, small businesses and non-profit institutions to take ownership of inventions made during federally-funded research, so they can license them for further applied research and development and broader public use. In November 2019, Emory realized this experimental drug could have significant potential in respiratory viruses such as COVID-19. So they took EIDD-2801 to the Biomedical Advanced Research and Development Authority (BARDA) and made their case for the drug. According to Allen, they were turned down twice. The Bayh-Dole Act states that when hoping to commercialize drugs borne of government-funded research, the academic institution must give preference to a small company. Allen said this is because “small companies traditionally are willing to take risks that large companies won’t take.” So, when Emory was approached by Ridgeback, it seemed like a perfect union. Particularly because Ridgeback has experience in fighting pandemics. In December 2020, the FDA approved Ridgeback’s Ebanga™ for the treatment of Ebola. True enough, Ridgeback did not give up on the drug. Under the leadership of CEO Wendy Holman, the company struck out on its own and began to conduct preliminary clinical trials. Holman was in the middle of applying for government funding when she appeared on a Bayh-Dole Coalition webinar Allen was hosting. “I can see how frustrated she is, because she's like, this could really be breakthrough she can’t get anybody to listen to her,” Allen said, adding that BARDA turned Ridgeback down as well. But they persevered and found Merck. “To its credit, after Merck got involved, the government did come back and partner with them and they did help on some of the later stage trials,” Allen noted. “And the Biden administration has already negotiated with Merck to go ahead and say, if this is cleared by FDA, we’ll start purchasing it, which is what they did for the vaccines.” On June 9, the U.S. government committed to procuring approximately 1.7 million courses of molnupiravir pending emergency use authorization (EUA). At this point, Allen said, “the company knows it is full steam ahead because [they’ve] actually got people who are going to use it.” The real heroes, though, Allen said, are Emory and Ridgeback. “The most important thing in commercialization is passion, and if you hadn't had the passion at Emory and hadn't had the passion at Ridgeback, this thing would never have even been developed. They persisted when the whole system was basically telling them they were wrong, turning them down even in the midst of a crisis,” Allen said. Credit must also be given to Merck – whether from a social good or business savvy standpoint is irrelevant – because this isn’t the first time in recent history it has been at the end of the R&D pipeline for a drug to treat a pandemic. In 2019, the FDA approved its first vaccine for Ebola, Merck’s rVSV-ZEBOV (Ervebo). This breakthrough came at the end of a winding 20-year odyssey that began at Canada’s National Microbiology Laboratory in Winnipeg, Manitoba. Ervebo was then licensed by Iowa State University start-up BioProtection Systems Inc. (BPS), now Lumos Pharma, and underwent early manufacturing at IDT Biologika GmbH in Germany When the West African Ebola crisis struck in 2014, Merck came in to finish the development job.

Intellectual property. It controls the written word, the musical world and every work of art. It also controls science and medical innovation. Will it control our response to the next pandemic too? The first vaccine for Ebola, Merck’s rVSV-ZEBOV (Ervebo), was given the green light by the U.S. Food and Drug Administration (FDA) in December 2019. After a winding 20-year odyssey that began at Canada’s National Microbiology Laboratory in Winnipeg, Manitoba, Ervebo was licensed by Iowa State University start-up BioProtection Systems Inc. (BPS), now Lumos Pharma, and went through early manufacturing at IDT Biologika GmbH in Germany before its development was finally accelerated when the West African Ebola crisis struck in 2014. Why the 20-year trek to commercialization? “The problem is, there’s no commercial interest in some of these diseases. Ebola is not unique in suffering from what is essentially a market failure we see for a lot of what are called neglected tropical diseases,” said Jason Nickerson, Humanitarian Affairs Advisor at Doctors Without Borders/Médecins Sans Frontières (MSF) Canada. “There are quite literally a billion people on the planet who are at risk of developing these diseases or who have them, but most of them live in developing countries that are not viewed as being profitable by a profit-oriented pharmaceutical industry,” he said. “Ebola fell into that category until the world was afraid for its own security interests in 2014. There’s just a failure of the model of drug development for these kinds of diseases.” Against this backdrop, exactly what was the value proposition for BPS? According to Professor Matthew Herder, Director of the Health Law Institute, Schulich School of Law at Dalhousie University, the draw was the funds the IP could net them from the U.S. government for a bioterrorism contract. “My theory is that they were interested in getting access to the patent because then they could use that as part of their argument for more funding from the government, to basically exist. The company didn’t actually do anything with the IP that they came to control. All of the scientific work continued in Winnipeg, so it was kind of like, what’s the point of this deal at all?” said Herder, who used Canada's Access to Information Act to obtain hundreds of documents to track the development of the vaccine. Herder found that of the promises BPS made during the negotiation process, which included manufacturing and experimentation assistance, the company only fulfilled one, in soliciting technical advice from the FDA. “We came down pretty hard on this company in terms of what value add. They got the worldwide license to use this vaccine and in turn got tens of millions of dollars from Merck because they controlled the IP, and they got even more money from the U.S. government because they controlled the IP. We show in the paper that they got well over $100 million from the Department of Health and Human Services [HHS],” he said. In a paper published in the Journal of Law and the Biosciences, Herder Et. al. argue that this case challenges the assumption of university labs doing the discovery and preclinical work before relinquishing the IP to a more solvent pharmaceutical company for the challenging downstream development work. “For me, the structural intervention became about rethinking how we support public sector science. What the Ebola vaccine story shows is that a lot of that downstream work was done by the public sector as well,” he said. “They give away the control of it, the IP, even though the work is really being done by the precariously employed public sector lab in Winnipeg, and this one scientist in particular.” The name of the scientist was Judie Alimonti, a researcher working on contract at the NML. The documents Herder obtained show that the vaccine project was very nearly abandoned in 2010 for lack of funding, until Alimonti offered to take over the file. Herder explained that this unsung hero not only shepherded the vaccine to the finish line, but took part in a lot of the downstream development work herself. “The company in Germany was running into big problems in manufacturing this, and someone from the lab in Winnipeg went over there to help them. Judy, you can see it in the records, she had the technical knowledge required. She problem solved a ton of it,” he said. The story of how the Ervebo came to be is not just an account of a broken contract, but also a cautionary tale. In 2018, the World Health Organization (WHO) published a list of infectious diseases that pose the most serious threat to public health. Among the top five are the Ebola virus, Crimean-Congo haemorrhagic fever, and Lassa Fever, three diseases that originate predominantly in developing nations. All three also feature prominently on Gavi, The Vaccine Alliance’s list of 10 infectious diseases that could be the next pandemic. “We’ve known for decades about coronaviruses. There was tons of money in research for some therapeutic candidates ready. Did anyone pick them up? Hardly at all before this. It’s not actually a deep critique of industry as evil; they’re responding to the incentives that work in light of their commitments to shareholders,” Herder said. “They have to, it’s the logical thing to do. So, I think we should be playing with these alternative approaches for health problems that aren’t – cancer.” Of course, the private sector will need funding to take on more of the downstream development required for innovative vaccines and treatments. “There’s probably very clearly a role for the public sector and the not-for-profit sector to be taking the reins on an alternative model of research and development,” Nickerson said. “It requires either public funding to directly support clinical trials, or charitable philanthropic funding to support the clinical trials. It’s just not a viable path to consider commercialization as being a strong enough incentive for these things to get developed.” From Herder’s perspective, the diseases on the WHO and Gavi lists are the perfect place to begin experimenting with different public-private IP models. “If we’re going to get some experimentation in how innovation works, I think infectious diseases are our prime candidate. Particularly infectious diseases that are primarily happening in the global south,” he stated. “It’s sad that we approach innovation the same way again, and again, and again.”