The Pandemic Pipeline Companies Are Doing Their Best to Accelerate Experimental Drugs and Vaccines for COVID-19 Through the Pipeline
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news feature Credit: Plrang GFX / Alamy Stock Photo The pandemic pipeline Companies are doing their best to accelerate experimental drugs and vaccines for COVID-19 through the pipeline. Each faces its own set of challenges, but all agree on the need for a radical rethink of the clinical development process for pandemics. John Hodgson his week, Moderna Therapeutics’ of the mRNA vaccine could reach clinics as Approved small molecules are already in use modified mRNA vaccine for COVID- early as 2021. This will be too late for the off label as adjunct therapies for critically ill T19 began phase 1 clinical testing. current pandemic. And given that no mRNA patients (like Fujifilm Toyama Chemical’s From the first description of the novel vaccine has ever been approved, mRNA- favipiravir), with several other experimental coronavirus (SARS-CoV-2) genome on 10 1273 faces numerous challenges in clinical drugs (like Gilead’s remesdivir) under January, it took the company just 42 days development and manufacture before it has investigation. Repurposed monoclonal to produce the first batches of its vaccine the possibility of being made available for antibodies (mAbs) developed against (mRNA-1273), which encodes a prefusion- global immunization. previous coronaviruses, such as severe stabilized form of the SARS-CoV-2 spike (S) In the meantime, a host of other acute respiratory syndrome (SARS) virus protein. If it can successfully negotiate safety therapeutic modalities are being accelerated and Middle Eastern respiratory syndrome and efficacy testing on a larger scale, batches through discovery and development. (MERS) virus, promise passive immunity NATURE BIOTECHNOLOGY | VOL 38 | MAY 2020 | 523–532 | www.nature.com/naturebiotechnology 523 news feature College in London, agrees. “You need a Box 1 | Supercharging drug repurposing flu vaccine every season and that’s great commercially. But a successful outbreak Of all the approaches available to the although in silico methods are rapid, at vaccine kills the outbreak and suddenly, drug developer in the face of a pandemic, present they tend to oversimplify the there’s no market!” focused repurposing of approved small- challenge for drug design. In the case of This is certainly how things were back molecule compounds has the best favivirus proteases, they underestimate in 2002–2003 for the original outbreak promise of early returns. According to the complexity of both the initial target of SARS. A single phase 1 drug study Christian Gruber, CEO at Innophore in mechanism and the network of associated (NCT00215826) and two phase 1 vaccine Graz, Austria, having an experimentally molecular interactions. Te resulting studies ran to completion. Both vaccines determined structure of the 3CL protease compounds identifed are unlikely to were well tolerated and induced neutralizing from the original SARS virus available was provide signifcant inhibition and will not antibodies. But the SARS epidemic ended a boon to early computational drug design become clinical candidates. by the time the products were developed, so eforts against SARS-CoV-2. “Medicinal chemistry works better neither was tested under natural challenge. Although generative machine when the target is better understood,” In addition, John Rex argues that, learning approaches have been touted Behnam says. She believes that future AI since 2003, the ‘Tamiflu incident’ in the as a means for rapidly identifying lead should aim to produce more complex late 2000s set back efforts to construct the compounds, from a medicinal chemistry models that incorporate multiple factors non-market mechanisms that might have standpoint there are clear limitations afecting a target protein. helped address infectious disease outbreaks. on the ability of artifcial intelligence Behnam also thinks AI might also Fearing an overwhelming outbreak of systems to design. help identify broad-spectrum antivirals, avian influenza, health authorities in the Mira Behnam is medicinal chemist as potential frst lines of defense in United States, France, Germany, the United whose 2016 PhD with Christian Klein at emerging epidemics: “Most labs cannot Kingdom and elsewhere stockpiled Basel, the Institute of Pharmacy and Molecular cover more than a few diferent viruses, Switzerland-based Hoffmann-La Roche’s Biotechnology in Heidelberg University whereas fnding a real broad-spectrum approved antiviral Tamiflu (oseltamivir). focused on the development of inhibitors drug requires broader view of data But when the pandemic failed to materialize for the faviviral proteases from dengue, and literature. Tis is where AI can be and governments were left with warehouses West Nile and Zika viruses. She says that quite useful.” full of unused antivirals, “there was a lot of hand-wringing,” says Rex. “Officials felt cheated, ‘ripped off’ by pharma rather than before vaccines come online. And in the clinical development process that typically being happy the pandemic didn’t occur.” wings newer experimental modalities, such takes years, sometimes a decade or more; Rex believes that governments should as small interfering RNAs (siRNAs), virus- similarly, regulators have little experience regard effective antivirals and vaccines not like particle or nanoparticle vaccines and for drug development in the context of a as a burdensome drain on limited resources, DNA vaccines, are also waiting for their pandemic. There is no accelerated pathway but rather much as householders regard chance to contribute. for COVID-19 or any other emerging insurance policies and fire extinguishers: as Every product class has different infectious disease. products we buy hoping never to have to use. strengths and faces different challenges in A second problem is that for antiviral reaching the clinic. As companies scramble R&D, funding needs to be not only available Non-market funding mechanisms to form new consortia and partnerships when the pathogenic threat is clear and Fast forward to 2020 and a few non- that meld discovery and manufacturing present but also sustained in between market mechanisms are starting to appear. expertise, tried-and-tested small molecule outbreaks. “In pharma, everything takes The Oslo-based Coalition for Epidemic and mAb development programs look the time, and it takes longer if you have to start Preparedness Innovations (CEPI), the most likely to provide the fastest route to from zero,” says John Rex, an infectious Platform for European Preparedness Against a first line of treatments. It may be that diseases physician and operating partner Re-Emerging Epidemics (PREPARE) machine learning can supercharge such with Advent Life Sciences in London. Thus, out of Antwerp, Belgium, and the US discovery programs (see Box 1). But it is novel antiviral discovery and development Defense Advanced Research Projects becoming increasingly clear that the biggest against COVID-19, or any other emerging Agency (DARPA)’s Pandemic Prevention problem for drug and vaccine makers is pathogen for that matter, faces a problem Platform (P3) program are three of the most not which therapeutic or vaccine platform of basic economics: there are no market prominent. to pursue. It is that conventional clinical mechanisms for unpredictable outbreaks. CEPI was established in 2017 and development paths are far too lengthy and Rex sees close parallels between the since then has attracted over $750 million cumbersome to address the current public situation in epidemic preparedness and his in funding from the governments of health threat. Several groups are now own preoccupation over several decades Australia, Belgium, Canada, Ethiopia, exploring how to retool the development — preventing antibiotic overuse and the Norway, Germany, Japan and the United process to find solutions. emergence of antimicrobial resistance. “Both Kingdom and from the Bill & Melinda these things,” he says, “are true honest-to- Gates Foundation and the Wellcome Trust. Arrested development God market failures. They meet the three Its original remit was to fund industry Commercial biopharmaceutical discovery is technical tests for market failure [positive and academic groups to develop vaccines a less than ideal vehicle for responding to an externalities, negative externalities and non- for emerging infections, and it came into outbreak of a new viral pathogen spreading excludability], meaning that government being after the disastrous 2014–2015 like wildfire through an immunologically intervention has to be the way you get things Ebola outbreak in West Africa, according naive population. Drug manufacturers are done.” Robin Shattock, director of the Future to director of vaccine research and accustomed to navigating a regulatory and Vaccine Manufacturing Hub at Imperial development Melanie Saville. 524 NATURE BIOTECHNOLOGY | VOL 38 | MAY 2020 | 523–532 | www.nature.com/naturebiotechnology news feature pathogen diagnosis based on RT-PCR and Box 2 | Preparing for a pathogen registered clinical trial methodologies for each center. One shortcut in preparedness for disease coronavirus and other emergent “If there was going to be a pandemic, outbreaks is to recognize the shape of the pathogens are underdeveloped, but then it was likely to be a respiratory virus,” likely threat. Tis is why one of the early rapid genome sequence technologies Goossens explained, “so our focus was acute decisions at CEPI was to lay out strategies make it plausible to broaden the scope respiratory infections in the ICU [intensive to deal with the next major infectious and frequency