Thanks to the pandemic caused by the SARS-CoV-2 coronavirus identified in late December 2019, 2020 was the year of COVID-19. It was a year of lockdowns and social distancing, a year of Zoom meetings and virtual conferences, and a year when donning a face mask sometimes came to signify a political rather than health decision. For the biopharma sector, the impact of COVID-19 was wide-ranging, in many cases showing the industry at its best, with the speedy mobilization of scientific efforts that spawned vaccine approvals at record rates and a host of therapeutics making their way through development. But biopharma suffered COVID-19-related setbacks as well, from a negative impact on clinical trials to the increasing politicization of science that could make the industry’s job harder as the world moves hopefully to end the pandemic in 2021.
In looking back over the past year, BioWorld has compiled the biggest trends and lessons from the year of COVID-19.
Biopharma moves into warp speed
The emergence of SARS-CoV-2 and the subsequent spread of COVID-19 proved to be watershed moments for global biopharma, which mobilized at unprecedented speed to tackle the pandemic that defined 2020. The SARS-CoV-2 virus was first identified in Wuhan, China, in December 2019 and the World Health Organization (WHO) declared a public health emergency at the end of January. By the time a pandemic was finally identified as such on March 12, the biopharma sector was well advanced into coronavirus-related R&D.
The viral genome had been sequenced in China by January, and there were multiple efforts underway to develop therapeutics and vaccines using new and innovative approaches as well as old and tested approaches. Platforms set up to enable pandemic preparedness, such as chimpanzee adenoviral vectors, were ready for immediate deployment and refinements of older technologies were used alongside novel methodologies to develop diagnostics, therapeutics and vaccines.
By March, applications for regulatory approvals of clinical trials for therapeutics and vaccines were being filed around the world. Within a matter of months, a vast arsenal was in development and, by Dec. 1, when the WHO reported almost 63 million cases of COVID-19 globally and 1.47 million deaths, there were 634 therapeutics and 187 vaccines under development – that number has since grown by four.
And it is another accolade for the industry that the two COVID-19 vaccines first approved in the U.K., U.S., Canada and the EU were mRNA vaccines, a new technology that until 2020 had not produced a single product that had made it to the market.
At the beginning of 2020, just one company, Curevac NV, had any clinical data on using mRNA against an infectious disease. On Nov. 20, Pfizer Inc. and Biontech SE’s BNT-162b2 mRNA vaccine emerged as the frontrunner in the race to get a vaccine to market in North America when it submitted and emergency use authorization (EUA) application to the FDA after just months of development, a mere fraction of the decade or so it usually takes to get a vaccine market. BNT-162b2 received the green light three weeks later. Moderna Inc.’s mRNA-1273, a second mRNA vaccine, trailed by about a week. Curevac’s mRNA vaccine candidate, CvnCoV, is in phase IIb/III trials in Europe and South America.
And then are the dozens of vaccines in development around the world using a variety of technologies, some of which also were developed in record time. Sputnik V, an adenovirus-based vaccine developed by Russia’s Gamaleya National Center of Epidemiology and Microbiology, received emergency use authorization in Russia in August, a mere nine months after the virus emerged.
And it was not just a handful of countries or companies that stepped up; instead, the quick response from biopharma was global. While China has been criticized for an initially slow response to the outbreak in December 2019 – other political pressures led to unfortunate consequences, such as muzzling medical professionals such as Li Wenliang, the Wuhan-based doctor who was initially reprimanded by police for sharing the information and who died in February from complications related to COVID-19 – the country’s early sharing of the full genome of SARS-CoV-2 with the international community kicked those global efforts into gear. After the genome was made available Jan. 12, China started shipping polymerase chain reaction (PCR) and nucleic acid test kits a few weeks later. That was a fraction of the six months or so that it took to identify and establish assays for the coronavirus that caused the severe acute respiratory syndrome (SARS) outbreak in 2002.
Genomics field rises to the occasion
Much of the industry’s speed can be attributed to advances in genomics research, which got a chance to shine in 2020. From the online publication of its gene sequence in January, to the revelation in December that a much more transmissible variant had been detected in the south of England, genomics has been at the heart of the fight against SARS-CoV-2.
The sequence of the novel coronavirus was enough for companies and academics to start vaccines development immediately, leading a mere 11 months later to the first approvals.
In 2020, technology platforms developed with pandemics in mind came into their own, with work on mRNA and viral vector-based vaccines able to start up before samples of the virus itself were available. Much credit goes to the Coalition for Epidemic Preparedness Innovations which since January 2017 has been building on the lessons of the 2015 Ebola epidemic in West Africa, to make vaccines against emerging infectious diseases shelf-ready.
As early as February, vaccine candidates against SARS-CoV-2 were prepared for animal testing. At the same time, having the viral sequence made it possible to diagnose the infection with standard PCR machines. Also in February, genome sequencing had cranked up to the point where viral genomes were being released three to six days after sample collection and then shared around the world via the GISAID (Global initiative on sharing all influenza data) database. As a result, researchers could track how SARS-CoV-2 was mutating on its rapid spread from the epicenter in Wuhan, China, in a true global test of genomic epidemiology.
The first five sequences made available had little genetic variety, supporting the theory that the original source could be repeated animal to human transmission at the market in Wuhan, where live animals were on sale. But by Jan. 19, SARS-CoV-2 sequences from patients in Wuhan and Thailand indicated there was human-to-human spread, an insight that came in advance of there being evidence for that from traditional epidemiology.
Tracing the family tree of SARS-CoV-2 through its evolving genetic sequence also made it possible to refute rumors on social media claiming the virus was generated as part of a biological weapons program. The sequence data showed mutations were spread across the genome, implying natural selection, not targeted insertion, was in play. Likewise, a claim that SARS-CoV-2 had mutations with an “uncanny similarity” to key structural proteins of HIV-1, could be firmly rebutted.
As the pandemic tightened its grip, host genomics studies were set up to investigate human genetic factors influencing the wide range of responses seen to SARS-CoV-2, from asymptomatic infections to total organ failure.
In April, leading international genome sequencing groups launched the COVID-19 Host Genetics Consortium, to carry out a meta-analysis of their respective research projects, after an agreement was reached on access to anonymized patient data. More than 150 registered projects searching for genetic variation associated with severity and outcomes are contributing to the consortium. Those range from large scale genome-wide association studies, to projects focusing on human leukocyte antigen genes that influence the body’s immune response, and to the search for variants in genes coding for the ACE2 receptor via which SARS-CoV-2 enters host cells.
Other researchers are looking at specific populations, for example, fit, younger people who suffered severe disease, and patients intubated in intensive care. One of those projects, Genomicc (Genetics of Susceptibility and Mortality in Critical Care), a global collaboration set up in 2015 to study genetics in critical illness, involved a comparison of 5 million genetic variants in COVID-19 patients who were treated in intensive care, with samples provided by healthy volunteers held in genomics databanks.
That work has shed light on the mechanisms that underpin severe disease, uncovered new drug targets and highlighted approved products that could be therapies to aid recovery. Many drugs have been proposed as treatments for severe COVID-19, but it takes time to test them. This study made it possible to home in on ones that are likely to be most effective.
The first results published on Dec. 11 relate to eight variants that are more common in patients treated in intensive care. All are in genes that are known to be involved in inflammatory processes and the immune response to viruses, illustrating how genomics can separate the signal from the noise. Building on that initiative, patient genomics data are being linked to the matched sequence of the virus that infected them, enabling the study of how patient and viral genomes come together to influence an individual’s response to infection.
The power of genomics in studying zoonotic diseases was underlined when it was shown that farmed mink in Denmark were harboring a variant of SARS-CoV-2 with mutations in the spike protein. That prompted experiments which showed that mink variant was less susceptible to neutralizing antibodies from people who had recovered from COVID-19, prompting concerns that vaccines could be compromised. Sequencing showed that mink variant had spread to humans, prompting the Danish government to order a mass cull of 15 million farmed mink. In December, the U.S. Department of Agriculture reported what it claimed as the first case of SARS-CoV-2 in a free ranging wild mink, sampled in Utah. The viral genome sequence from the wild animal was indistinguishable from those obtained from farmed mink.
In March, the most intensive SARS-CoV-2 genome sequencing initiative in the world was set up in the U.K., to map how the virus evolves as its spreads from one human host to another. In December, that viral genome monitoring detected a new variant of SARS-CoV-2 with 23 distinct mutations, in patients in London and southeast England. Subsequent investigation showed that variant is more transmissible than its brethren. The first example was from a swab taken in September. By early November, the variant accounted for 28% of infections in London and, by early December, for 62%. Initial research linking back to medical records shows the variant does not appear to cause more serious disease, and research is ongoing to assess if the mutations will limit the effectiveness of COVID-19 vaccines.
As the year of COVID-19 drew to a close, this was yet another example of the central role of genomics is playing in dealing with the pandemic.
Tackling COVID-19 infection
COVID-19 therapeutics development did not see the same heroics as vaccines in 2020. But deep understanding of the biology of targets such as interleukins enabled attempts to repurpose a number of biologic drugs. Although not all such efforts were crowned by success – malaria drug hydroxychloroquine, for example, ultimately was not found to benefit COVID-19 patients – the way in which companies matched emerging knowledge of the effect of COVID-19 on the immune system with what they knew about their products and got clinical trials underway, is notable, and led to approval of remdesivir (Gilead Pharmaceuticals Inc.) in October.
Meanwhile, the use of artificial intelligence (AI) to mount drug repurposing campaigns has led to approved products being tested against COVID-19, and other companies have done de novo discovery based on viral protein structures and monoclonal antibody technologies, leading to the approval of casirivimab and imdevimab (Regeneron Pharmaceuticals Inc.) in November.
At year-end, a total of 647 therapeutics were in development for COVID-19.
Unprecedented level of public/private partnerships
Much of the industry’s speed can be attributed to collaboration, particularly with the public sector. Never before has the biopharma industry experienced such a high level of government collaboration as it has in the extraordinary year of 2020. While several countries contributed large sums to fight the deadly SARS-CoV-2 virus, the U.S. government stands out significantly with its formation of Operation Warp Speed (OWS) to accelerate development and manufacturing of COVID-19 vaccines and therapeutics.
In fact, about 84% of the $27.4 billion recorded by Christmas for biopharma industry grants and nonprofit collaborations targeted pandemic efforts. And of the total money for the year, the U.S. government and its agencies supplied about 68%, or $18.6 billion.
OWS, a partnership between the Department of Health and Human Services (HHS) and the Department of Defense, engaged with several biopharmas, signing upwards of $14 billion in contracts through early December. Four of those efforts had received emergency use authorizations (EUA) in the U.S. by December, including two therapeutics, Eli Lilly and Co.’s bamlanivimab (LY-CoV555) and Regeneron Pharmaceuticals Inc.’s antibody cocktail, REGN-CoV2 (casirivimab and imdevimab), and two vaccines, Pfizer Inc./Biontech SE’s BNT-162b2 (Comirnaty) and Moderna Inc.’s mRNA-1273. Bamlanivimab and REGN-CoV2 were the subject of OWS manufacturing deals worth $375 million and $450 million, respectively, and the U.S. government later ordered additional doses of bamlanivimab for another $812.5 million. Through OWS, both Pfizer and Moderna were contracted for 100 million doses in deals worth $1.95 billion and $1.5 billion. Those amounts doubled for each company when an additional 100 million doses were purchased from each in December. Moderna’s total funding through OWS, which included development funding, rose to $4.1 billion, and it signed another $1.97 billion contract with the Department of Defense on Dec. 29, bringing its total U.S. government funding to $6.07 billion, about 82% of the $7.36 billion calculated for all biopharma nonprofit deals and grants in 2019.
The top public-private deals not directly related to the SARS-CoV-2 virus included efforts to fight the Ebola virus or HIV-associated cancers, as well as an $812 million grant from HHS awarded to Phlow Corp. to manufacture medicines at risk of shortage during the pandemic.
The politicization of science
While industry rose to the challenge of advancing vaccines and treatments into clinical trials, a trial of another kind was playing out in the public arena. The age-old complication of science by politicking seemed to spike in 2020. Even as the practice of science shone brightly in the world's fight to overcome COVID-19, scientists themselves often suffered significant backlash.
In the U.S., President Donald Trump and his allies heaped scorn and sometimes threats on high-profile figures such as National Institute of Allergy and Infectious Diseases Director Anthony Fauci. In other clashes, senators questioned the data at the heart of disease surveillance efforts and CDC guidance borne from it. Political agendas and promises also ratcheted up pressure on the FDA, as artificial expectations for drug and vaccine approval decisions made their way into political speeches, and some states even sought to create their own local layers of drug and device review, pointing to the potential for new commercial threats ahead.
The state vs. federal government tug of war similarly broke out in Brazil, where politicians wrangled over the quality and safety of Sinovac Biotech Ltd.'s Coronavac vs. the Russia-developed Sputnik V vaccine. Chinese politicians meanwhile used COVID-19 vaccine deals and trial allowances to play favorites, suggesting certain developing nations might gain priority access to vaccines in some cases and basically stopping Cansino Biologics Inc. from trying its vaccine in Canada amid a completely unrelated political spat.
Throughout it all, an erosion of public trust in politicians and the institutions through which they govern appeared to damage public confidence in the kind of big science-driven undertakings needed to address the pandemic. Evaluating just how deep that damage runs and what steps will be needed to overcome it will fall to public health experts and, of course, more politicians in the year ahead.
Development delays: The pandemic’s negative impact on biopharma
Even as work moved full speed ahead against COVID-19, other biopharma efforts were suffered delays and setbacks, most often caused by restrictions of business and travel. From clinical trial delays to company reorganizations, the negative effects of the pandemic will be felt by biopharma for years to come. When lockdowns restricted travel and physicians and companies shifted priorities, the development of hundreds of therapies was either placed on hold or continued at a snail’s pace.
According to Cortellis, well over 1,600 clinical trials have been impacted by the COVID-19 pandemic, and BioWorld has directly reported on more than 400 trials involving biopharma therapeutics that were either stopped, delayed or terminated.
Company executives have grown increasingly frustrated by the inability to bring therapeutics to the patients who need them. A supply disruption was expected in December for Horizon Therapeutics plc’s thyroid eye disease drug Tepezza (teprotumumab-trbw) due to “dramatically restricted capacity” as a result of government-mandated COVID-19 vaccine production. Biologics license applications for Spectrum Pharmaceuticals Inc.’s Rolontis (eflapegrastim) for chemotherapy-induced neutropenia, Bristol Myers Squibb Co.’s lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma, and Revance Therapeutics Inc.’s daxibotulinumtoxinA for moderate to severe glabellar lines, are still awaiting approval, more than a month past their PDUFA dates, and all because the FDA is unable to inspect manufacturing facilities.
Early science is also suffering setbacks. A scientist survey by the Institute of Cancer Research in London suggested that the loss of 10 weeks of laboratory time due to global lockdowns will translate into a 17-month delay in cancer research.
While keeping the research going is one thing, staying afloat is quite another. Several companies have struggled this year to make ends meet. Eyepoint Pharmaceuticals Inc., Intelgenx Technologies Corp. and Alligator Bioscience AB have all reduced headcounts. Nervgen Pharma Corp. has suspended external consulting contracts and temporarily reduced employee compensation. Polarityte Inc. has cut payroll by 10%. Assertio Holdings Inc. announced a restructuring in December, with both the CEO and chief operating officer stepping down.
Lessons from COVID-19: Remote clinical trials and greater diversity
COVID-19 clearly changed the way biopharma – and other industries – did business in 2020. Whether those changes will continue as we move into 2021 is anyone’s guess. But sometimes crisis moments bring about much-needed opportunities for improvement. Regulators, for example, have been discussing the possibility of running clinical trials virtually for years. It took COVID-19 to finally move forward an idea that has long been made possible by technology.
One of the biggest lessons to come out of the COVID-19 pandemic for the biopharma industry and those that regulate it is that clinical trials can be effectively run remotely by taking advantage of digital health technologies, including telemedicine-based physician visits and exams or hybrid models that include at-home nursing visits. There has been talk of that shift for years, but with scant movement. COVID-19 made it necessary.
Adoption of new models and technologies also has been slow over the last few decades, but the pandemic supercharged forward progress by forcing halts to many trials. Randomizing of patients, a laborious process that often requires travel, had to be stopped as lockdowns took effect virtually everywhere.
On March 12, Science 37 published a white paper encouraging virtual clinical trials. The FDA endorsed the idea less than a week later.
This newfound willingness to run – and allow trials to be run – remotely should have positive implications for the future of the industry and it should also help address another longstanding problem: the lack of diversity in clinical trials.
The year saw a clear push toward greater diversity in trials, which is expected to also help address downstream disparities in health care, with new FDA guidance issued in November on enhancing diversity in clinical trials and the Pharmaceutical Research and Manufacturers of America (PhRMA) releasing industrywide principles that focus on building trust within Black and ethnic communities, reducing barriers to trial access, using real-world data to boost information on diverse populations, and boosting information about diversity and inclusion in trial participation. These principles take effect in April 2021.
The need for speed and transparency in approving COVID-19 vaccines helped with that push. The sheer speed of vaccine development created doubts about the efficacy of products, particularly among underrepresented patient groups and among patients in countries that may not have the capacity to manufacture their own vaccines or other essential drugs, APIs and devices. That lack of capacity was a wakeup call for many countries, including wealthier countries like Canada and less wealthy countries like Colombia or just about every country in the Caribbean. COVID-19 brought that lesson home. It is a lesson that will serve well beyond the pandemic.
– Jennifer Boggs, Anette Breindl, Karen Carey, Michael Fitzhugh, Nuala Moran, Alfred Romann