Scientists, researchers, health officials, regulatory agencies, governments, businesses, universities, and many others across the globe are searching for ways to defeat the coronavirus pandemic.
By Andrew Humphreys • [email protected]
Biopharma and biotechnology companies around the world are working with governments toward the development of vaccines and therapeutics to fight the COVID-19 pandemic. As clinical studies for COVID-19 continue to ramp up, the most promising vaccines and treatments that have the best chance to reach mass production will emerge. As of mid-April, more than 70 vaccines for COVID-19 were undergoing development and at least three were in clinical studies, according to the World Health Organization.
The early front-runner on the vaccine front was CanSino Biologics. The company’s Recombinant Novel Coronavirus Vaccine candidate Ad5-nCoV is built upon CanSinoBIO’s adenovirus-based viral vector vaccine technology platform, which has been successfully applied to develop the globally innovative vaccine against Ebola virus infection. The Adenovirus Type 5 Vector was cleared for a Phase I clinical trial in China by March 17, the first novel coronavirus vaccine for COVID-19 that reached that stage in that country. Since then, Ad5-nCoV was moving quickly toward a Phase II study expected to be performed in Wuhan, China with an enrollment of 500 healthy participants.
“It was only in mid-March when CanSino kicked off the first-in-human trial of Ad5-nCoV in healthy volunteers in the city of Wuhan, then the epicenter of the outbreak. Moving a vaccine from Phase I into Phase II in just three weeks is super fast, if not unprecedented, even with all the urgency around an ongoing pandemic, making the process look more like a Phase I/II paradigm,” according to analysis from FiercePharma.
Also leading the charge is Moderna, a clinical-stage biotechnology company based in Cambridge, Mass., that is pioneering messenger RNA (mRNA) therapeutics and vaccines to create a new generation of transformative medicines. Moderna announced on April 16 a deal for a commitment of up to $483 million from the Biomedical Advanced Research and Development Authority (BARDA) to accelerate development of the company’s mRNA vaccine candidate, mRNA-1273, against the novel coronavirus SARS-CoV-2.
BARDA is funding the advancement of mRNA-1273 to FDA licensure. A Phase I study of mRNA-1273 is being carried out by the National Institutes of Health (NIH). The Phase I open-label study, which started on March 16, has completed enrollment of the original study: 45 healthy adult volunteers ages 18 to 55 years in three dose cohorts (25 µg, 100 µg and 250 µg). The NIH amended the Phase I protocol to include an additional six cohorts: three cohorts of older adults (ages 56 -70) and three cohorts of elderly adults (age 71 and above).
If supported by safety data from the Phase I trial, Moderna planned to launch a Phase II study of mRNA-1273 under the company’s own Investigational New Drug (IND) application during second-quarter 2020. Subject to data from these clinical trials and discussions with regulators, a Phase III study could start as soon as the fall of 2020. BARDA funding will support the late-stage clinical development programs, as well as the scale-up of mRNA-1273 manufacture in 2020 to allow for potential pandemic response.
According to analysis from GlobalData, a data and analytics company, experts are cautious about mRNA-1273’s potential to trigger sufficient immunogenicity. “From using mRNA as a vaccine strategy, to the antigen choice of the virus’ spike protein, interviewed experts noted several advantages but in the same breath voiced many concerns,” according to reporting from Reynald Castañeda, Pharma Writer for the Investigative News team at GlobalData. “While mRNA vaccine manufacturing is relatively straightforward, and is an important consideration for a pandemic of this scale, the caveat is that the mRNA may code for enough irrelevant proteins that would negatively impact immunogenicity. It is also still challenging to identify how much neutralizing antibodies are needed for protection. There can be variation between assays, making it challenging to have a uniform antibody titer target.”
Castañeda continues, “The choice of SARS-CoV-2’s spike protein as the vaccine’s antigen is logical for several reasons, but as with the mRNA strategy, experts pointed to several blindspots that need to be cleared up.”
Inovio Pharmaceuticals began dosing on April 6 for a Phase I trial for the biotech company’s vaccine candidate, INO-4800. Inovio’s DNA vaccine candidate is designed to prevent COVID-19 infection. Preclinical data demonstrated promising immune response results across multiple animal models.
Biologics contract development and manufacturing organization Ology Bioservices and Inovio, which develops DNA medicines for infectious diseases and cancer, announced a partnership on March 24. The Department of Defense awarded Ology with a contract valued at $11.9 million to work with Inovio on DNA technology transfer to rapidly manufacture DNA vaccines. This work is supported by the Office of the Assistant Secretary of Defense for Health Affairs with funding from the Defense Health Agency.
The Coalition for Epidemic Preparedness Innovations (CEPI) on April 16 granted $6.9 million in funding to Inovio and the International Vaccine Institute (IVI) to conduct Phase I/II testing in Korea for INO-4800 based on their well-established DNA platform technology. IVI is performing the study in parallel to Inovio’s Phase I INO-4800 trial with 40 healthy adults receiving the vaccine candidate and eventually expanding to older adults.
Two of the world’s largest vaccines companies, Sanofi and GlaxoSmithKline, on April 14 unveiled an unprecedented collaboration to fight COVID-19. The companies have joined forces to combine innovative technologies to develop an adjuvanted COVID-19 vaccine. The vaccine candidate is anticipated to enter clinical studies during second-half 2020 and, if successful, to be available in the second half of 2021.
Sanofi is contributing the company’s S-protein COVID-19 antigen, which is based on recombinant DNA technology. This technology has produced an exact genetic match to proteins located on the surface of the virus, and the DNA sequence encoding this antigen has been combined into the DNA of the baculovirus expression platform, the basis of Sanofi’s licensed recombinant influenza product in the United States.
GlaxoSmithKline is contributing the company’s proven pandemic adjuvant technology to the collaboration. The use of an adjuvant can be of particular significance in a pandemic situation since it may reduce the amount of vaccine protein necessary per dose, allowing more vaccine doses to be produced and therefore contributing to protect more people.
Pfizer and BioNTech are jointly developing a COVID-19 vaccine based on a collaboration announced on March 17 that was publicly updated by the companies in greater detail on April 9. The partnership intends to rapidly advance multiple COVID-19 vaccine candidates into human clinical testing based on BioNTech’s proprietary mRNA vaccine platforms, with the objective of ensuring rapid global access to the vaccine, if approved. The collaboration is leveraging Pfizer’s broad expertise in vaccine R&D, regulatory capabilities, and global manufacturing and distribution network.
The two companies intend to jointly carry out studies for the COVID-19 vaccine candidates initially in the United States and Europe across multiple sites. BioNTech and Pfizer planned to initiate the first clinical trials as early as the end of April 2020, assuming regulatory clearance.
During the clinical development stage, BioNTech and the company’s partners will provide clinical supply of the vaccine from its GMP-certified mRNA manufacturing facilities located in Europe. BioNTech and Pfizer are working together to scale-up manufacturing capacity at risk to provide global supply in response to the pandemic. BioNTech and Pfizer are working jointly to commercialize the vaccine worldwide (excluding China, which is already covered by BioNTech’s collaboration with Fosun Pharma) upon regulatory clearance.
NantKwest and ImmunityBio, clinical-stage immunotherapy companies within the NantWorks family of companies, unveiled on April 14 that the companies were in active discussions with the U.S. FDA for vaccines and therapeutics to combat COVID-19. Leveraging ImmunityBio’s expertise in vaccine development and natural killer cell activation – with a broad platform of immunomodulators undergoing clinical studies for cancer and infectious diseases – and NantKwest’s extensive experience in off-the-shelf, cell-based therapeutics, the companies are combining resources to design and develop therapeutics and vaccines for COVID-19. Clinical studies were anticipated to start during second-quarter 2020.
Other companies reportedly racing ahead with vaccine trials at various stages of development include Johnson & Johnson, Dynavax Technologies, Vaxart, Heat Biologics, Translate Bio, Arcturus Therapeutics, CSL Behring, Novavax, and more.
A potentially promising treatment for COVID-19 outside the realm of new vaccines candidates is Gilead Sciences’ remdesivir, an investigational nucleotide analog with broad-spectrum antiviral activity in vitro and in vivo in animal models against multiple emerging viral pathogens, including Ebola, Marburg, MERS and SARS. Per an announcement by Gilead on Feb. 26, the Foster City-based biopharmaceutical company launched two Phase III trials to assess the safety and efficacy of remdesivir in adults diagnosed with the novel coronavirus COVID-19. The randomized, open-label, multicenter studies were to enroll 1,000 patients at medical centers primarily across Asian countries, as well as other countries globally with high numbers of diagnosed cases, starting in March. The clinical trials are assessing two dosing durations of remdesivir, administered intravenously. The initiation of these studies follows the U.S. Food and Drug Administration’s rapid review and acceptance of Gilead’s IND filing for remdesivir for treating COVID-19.
The studies expand the ongoing research into remdesivir, which includes two trials in China’s Hubei province led by the China-Japan Friendship Hospital as well as the initiated clinical study in the United States led by the National Institute of Allergy and Infectious Diseases (NIAID). Gilead has donated drug and provided scientific input for these clinical trials.
Gilead reported results on April 10 from a cohort analysis of 53 patients hospitalized with severe complications of COVID-19 who were treated with the investigational antiviral remdesivir on an individual compassionate use basis. According to the company, the majority of patients in this international cohort showed clinical improvement and no new safety signals were identified with remdesivir treatment. Compassionate use data have limitations and multiple Phase III trials continue to determine the safety and efficacy of remdesivir for treating COVID-19. The detailed results of this analysis were published in The New England Journal of Medicine on April 10.
The Dow Jones Industrial Average and other stock markets surged on April 17 due in part to the positive buzz created from a one-day earlier report from STAT that a Chicago hospital treating severe COVID-19 patients with remdesivir in a closely watched study saw rapid recoveries in fever and respiratory symptoms, with nearly all patients discharged in less than a week. According to the report, the University of Chicago Medicine recruited 125 people with COVID-19 into Gilead’s two Phase III studies, with 113 having severe disease. All the patients were treated with daily infusions of remdesivir, with most of them having been discharged and two reported deaths.
Industry analysts and Gilead urged caution on drawing conclusions from the STAT report that helped buoy the broader markets, according to a Reuters article. Gilead reportedly said the totality of the data from the study needed to be analyzed, and expected to announce results from the clinical trial in severe COVID-19 patients at the end of April, with clinical data from other studies emerging during May.
“The leak of anecdotal findings from a U.S. hospital participating in Gilead’s trial of remdesivir for COVID-19 has done for the sector what Gilead’s own publication in the NEJM couldn’t,” according to analysis from Evaluate Vantage. “Those earlier findings, from 53 subjects treated under compassionate use, were hard to interpret without having an idea of how these patients might have done without remdesivir, though analysts expressed cautious optimism and said the report suggested efficacy.”
Another frequent headline grabber during March and April was the drug hydroxychloroquine, which has long been used for treating malaria and certain autoimmune diseases. After being touted for weeks by many pundits and President Trump as a potentially effective treatment for COVID-19, Novartis announced on April 20 an agreement with the U.S. FDA to proceed with a Phase III study with 440 patients to evaluate the use of hydroxychloroquine for treating hospitalized patients with COVID-19 disease.
“We recognize the importance of answering the scientific question of whether hydroxychloroquine will be beneficial for patients with COVID-19 disease,” stated John Tsai, Head of Global Drug Development and Chief Medical Officer at Novartis. “We mobilized quickly to address this question in a randomized, double-blind, placebo-controlled study.”
Tarrytown, New York-based biotech company Regeneron Pharmaceuticals and French pharma giant Sanofi began a clinical program evaluating Kevzara (sarilumab) in patients hospitalized with severe COVID-19 infection, as announced on March 16. The fully human monoclonal antibody inhibits the interleukin-6 pathway by binding and blocking the IL-6 receptor. IL-6 could play a role in driving the overactive inflammatory response in the lungs of patients who are severely or critically ill with COVID-19. The role of IL-6 is supported by preliminary data from a single-arm study in China using a different IL-6 receptor antibody.
The U.S.-based study was launched at medical centers located in New York, which became the epicenter of the U.S. COVID-19 outbreak, and is evaluating the safety and efficacy of adding Kevzara to usual supportive care, compared to supportive care plus placebo. The multi-center, double-blind, Phase II/III study has an adaptive design with two parts and was anticipated to enroll up to 400 patients. The first part recruited patients with severe COVID-19 infection across 16 U.S. sites to assess the impact of Kevzara on fever and patients’ need for supplemental oxygen. The second, larger part of the clinical study will evaluate the improvement in longer-term outcomes including preventing death and reducing the necessity for mechanical ventilation, supplemental oxygen and/or hospitalization.
Regeneron reported on March 17 progress in the biotech company’s efforts to discover and develop a novel multi-antibody cocktail that can be administered as prophylaxis before exposure to the SARS-CoV-2 virus or as treatment for those already infected. Company scientists isolated hundreds of virus-neutralizing, fully human antibodies from Regeneron’s VelocImmune mice, which have been genetically-modified to have a human immune system. The company isolated antibodies from humans who have recovered from COVID-19, in order to maximize the pool of potentially potent antibodies. From this large pool of candidates, Regeneron will choose the top two antibodies for a ‘cocktail’ treatment based on potency and binding ability to the SARS-CoV-2 spike protein, along with other desirable qualities. Using a multi-antibody approach enables targeting of different parts of the virus and may help protect against multiple viral variants. Regeneron previously used these technologies to rapidly develop a successful treatment for Ebola virus infection, which is undergoing review by the U.S. FDA.
Repurposing therapies already approved for other indications to fight the SARS-CoV-2 virus is a key strategy in the race to find treatments for COVID-19, and approved antibodies that target IL-6 is one such approach, but success will depend on intervening early with these therapies, according to reporting from GlobalData Pharma Writer Manasi Vaidya. “While, there has been an obvious thrust toward developing antivirals and vaccines to counter the COVID-19 pandemic, companies are also repurposing drugs originally intended for chronic autoimmune disorders or certain infections that target the cytokine storm syndrome (CSS), which is also associated with COVID-19 illness. … Despite the potential for anti-IL-6 antibodies, interviewed experts stressed that they need to be used before hospitalized COVID-19 patients become critically ill or require mechanical ventilation to give the therapies the best chance to be effective mechanistically. Acute lung injury and acute respiratory distress syndrome—common consequences of CSS and COVID-19—necessitate interventions like mechanical ventilation to help a patient breathe.”
Other promising treatment candidates include those being developed by Amgen, Eli Lilly, Takeda Pharmaceutical, CalciMedica, Adaptive Biotechnologies, Tiziana Life Sciences, Vir Biotechnology, and more.