COVID-19 has sparked an unprecedented shift in R&D. In the weeks after the novel coronavirus was identified and sequenced, businesses and academic groups around the world scrambled to identify drugs and vaccines against the pathogen, using existing molecules and novel platforms to truncate development. The question now is which pieces of the multi-front assault will work, and when.
As a novel coronavirus, SARS-CoV-2 poses some challenges to rapid-response R&D programmes. When H1N1 threatened the world, GlaxoSmithKline based a vaccine on an existing mock-up to win approval within three months of the World Health Organization (WHO) declaring a pandemic. Such shortcuts are unavailable to teams targeting SARS-CoV-2.
In the absence of an almost off-the-shelf solution, researchers are digging into the development toolkit in search of near- to longterm fixes, scouring libraries of existing molecules for ways to kill the virus and manage the symptoms while starting from scratch on products that could deliver the final blow to the pandemic.
The first wave
The most advanced programmes feature drugs that have already been tested in humans and in some cases came to market prior to the pandemic. In repositioning such drugs for use against COVID-19, organisations skipped the preclinical stage to quickly enter the clinic.
This group of drugs, which represent the best near-term chance of improving outcomes, can be split into several subcategories, notably antivirals, immunomodulators and supportive care. The antiviral subcategory is a key focal point, with drugs such as Gilead Sciences’ remdesivir being tested in tens of trials and attracting the attention of the general public and world leaders.
Remdesivir, a failed Ebola drug, is closing in on read-outs from trials, although the cessation of studies in China due to enrolment issues has extended the wait for data. The importance of the drug to a world paralysed by COVID-19 is such that a leaked report of an encouraging, incomplete snapshot of data from a remdesivir trial sent the Dow Jones Industrial Average up by 3%. A subsequent leak about the apparent failure of remdesivir in a Chinese trial then dampened expectations again.
Other antivirals including hydroxychloroquine – a drug championed by President Donald Trump – and favipiravir are also in clinical development, raising hopes that researchers will find a drug with some level of efficacy in the pre-pandemic library of molecules. Yet, it is unlikely that any of the drugs will be a panacea, with Jefferies analysts saying remdesivir “might be modestly helpful”.
In the absence of a knockout antiviral, researchers are trying to mitigate harmful effects of the virus. Roche, for example, is running a phase 3 trial to test whether Actemra improves outcomes by dampening hyperinflammation. The interleukin-6 receptor antagonist is approved for use in indications including the management of cytokine release syndrome in CAR-T patients.
A third set of studies is assessing supportive care drugs. Nitric oxide is being tested in a handful of trials on the grounds that it may counter oxygen deficiency. With regulators keen to move quickly, positive data from trials of antivirals, immunomodulators and supportive care drugs could support approvals this year.
A bigger blow
The availability of molecules that have already undergone clinical testing in other indications gives the world a shot at improving outcomes today. However, new molecules, notably virusneutralising antibodies, may ultimately prove to be more effective.
Neutralising antibodies are key to the natural immune response against all viruses. Antibodies bind to viruses to stop them entering host cells, leading physicians to use serum from previously infected patients in infectious disease treatments from more than 100 years ago. Scientists have since industrialised the concept, leading to the development of antibodies against Ebola and respiratory syncytial virus.
The same approach may work against SARSCoV-2. Regeneron Pharmaceuticals, leveraging a platform that spawned an Ebola treatment, is leading efforts to show that antibodies can neutralise SARS-CoV-2. A clinical trial of Regeneron’s drug is scheduled to start in June.
A pack of other antibody programmes involving companies including Amgen, AstraZeneca, Eli Lilly and GlaxoSmithKline is following closely behind, with multiple clinical trials scheduled to start over the summer.
If successful, the programmes could fill two gaps in the armamentarium. Firstly, an effective antibody could improve outcomes in patients infected with SARS-CoV-2, preventing deaths and helping people to recover faster or avoid mechanical ventilation. Secondly, the antibody could be used prophylactically, protecting healthcare workers and other key groups against SARS-CoV-2.
The significance of those use cases in the global effort to get a handle on COVID-19 has led to calls to bring an anti-SARS-CoV-2 antibody to market by the autumn. Doing so would make it easier for countries to lift economies out of self-induced comas without overwhelming healthcare systems or causing another spike in deaths.
Pandemic endgame
SARS-CoV-2 will remain a threat until a significant proportion of people are immune. Global lockdowns mean natural exposure to the virus is unlikely to result in herd immunity any time soon, making vaccines the best hope of achieving population-scale protection against SARS-CoV-2.
The race to get a vaccine to market is advancing on multiple fronts. Moderna was the first group to test a vaccine in humans, using its mRNA platform to enter the clinic in record time. BioNTech, CureVac and Translate Bio are also working on mRNA vaccines, while Pfizer and Sanofi are involved in those programmes through partnerships with BioNTech and Translate Bio, respectively.
Moderna thinks its vaccine could be available to healthcare professionals as early as the autumn, but the accepted timeline for widespread use runs into 2021 and beyond. The fact that many people have fairly mild symptoms means there may be reticence to use a vaccine in low-risk groups until the safety record is proven.
There is also a risk that mRNA vaccines will be ineffective. The idea of inducing immunity by delivering genetic material that encodes for viral proteins is largely untested. No mRNA vaccines are approved but with the WHO reporting that nine are in development for use against COVID-19, that could change as a result of the pandemic.
The pandemic could also serve as a proving ground for DNA plasmid vaccines. Inovio Pharmaceuticals began testing its plasmid candidate in humans in April, putting it at the head of a pack of six groups that have DNA vaccines in development. No DNA vaccines are approved.
Other groups are applying marginally more established technologies to SARS-CoV-2. China’s CanSino Biological is running phase 1 and 2 clinical trials of an adenovirus type 5 vector vaccine candidate. The same platform underpins CanSino’s Ebola vaccine that won approval in China in 2017.
Multiple groups are advancing vaccines based on similar technology. University of Oxford researchers are enrolling volunteers in a trial of its adenovirus vaccine, while Johnson & Johnson and the US government have a $1 billion adenovirus vector vaccine collaboration.
Around half the vaccines tracked by the WHO use one of the aforementioned approaches. Vaccines based on established approaches, such as the delivery of protein sub-units, are in development but are less advanced than the nucleic acid candidates. If the novel approaches confer limited immunity, there may be a role for vaccines based on established technologies in neutralising the SARS-CoV-2 threat.
Upcoming approvals
Many of the drugs now in the clinic may present underwhelming results, and the vaccines that could end the pandemic are likely to be at least a year away from widespread use and are based on unproven technology. Sceptical voices such as SVB Leerink analyst Geoffrey Porges think a 2-3 year wait is more realistic.
However, the breadth of the R&D response to COVID-19, coupled with the willingness of regulators to fast-track programmes, creates the chance that the back half of 2020 will be punctuated by a string of approvals of drugs that improve outcomes in patients infected with SARSCoV-2. Pharmacological responses to COVID-19 are coming, but it may be some time before the pharmacological fix arrives.