COVID-19 has become one of the greatest challenges in medical history, and the rapid development and approval of effective and safe treatments is essential to minimise the loss of lives during the pandemic. Given the urgency of finding effective strategies, many companies are attempting to identify existing therapies with a considerable body of efficacy and safety data that could be repurposed for the treatment of COVID-19. Progress has been extraordinary, with many agents in late-stage clinical trials. At the time of writing, a search of ClinicalTrials.gov revealed almost 1,000 results for COVID-19.1 Here, we review some of the most promising therapeutic approaches.
The first clinical trials to report data have investigated traditional antiviral drugs, but early results have not been promising.2,3 There is, however, a risk of multiple small trials not generating the strong evidence needed to determine the relative effectiveness of potential treatments. To address this issue, the WHO have initiated the international Solidarity study, which involves over 100 countries and will compare four treatment options: the RNA polymerase inhibitor remdesivir, the antimalarials hydroxychloroquine and chloroquine, the combined HIV protease inhibitors lopinavir and ritonavir, and lopinavir and ritonavir in combination with the immunomodulatory agent interferon beta-1a.4 Results are expected in the coming months.
Newer antiviral agents also appear promising. An inhalation solution of ibavirin (Virazole®, Bausch Health Companies Inc., Laval, Canada), a synthetic nucleoside that exerts its effects by inhibiting viral replication, is currently approved in several countries for the treatment of infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus (RSV). An open-label, interventional trial will evaluate its safety and efficacy in hospitalised adult patients who have tested positive for COVID-19, and have significant respiratory distress.5 A similar antiviral drug, favipiravir (Avigan®, FUJIFILM Toyama Chemical Co., Ltd., Tokyo, Japan), is currently in phase II development (NCT04358549).6 In addition, preclinical and clinical data suggest that the antibiotic azithromycin (Zithromax®, Pfizer Inc., New York, NY, USA) has antiviral properties and this is expected to be investigated in patients with COVID-19 in the near future.7
Other approaches are targeting the inflammatory cascade responses to the virus. Emerging data suggest that patients with COVID-19 have elevated serum levels of pro-inflammatory cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-γ), which drive a cytokine storm, also known as cytochrome release syndrome. Infiltration of immune cells in the lungs of patients with COVID-19 as part of this exaggerated immune response leads to damage of the lungs, resulting in acute respiratory distress syndrome (ARDS).8 Preventing the cytokine storm has therefore become an important investigational strategy in the development of COVID-19 therapeutics.
Interleukin (IL)-6 is one of the excessive cytokines produced by activated macrophages as a result of COVID-19 infection.9 Antibodies such as sarilumab (Kevzara®, Sanofi, New York, NY, USA and Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA) and tocilizumab (Actemra/RoActemra®, F. Hochmann-La Roche AG, Basel, Switzerland), which can effectively block IL-6 signal transduction, have therefore been among the first agents to be evaluated in patients with complications from COVID-19 infection. Preliminary analysis of the phase II portion of Sanofi’s trial investigating sarilumab (NCT04327388) demonstrated that it rapidly lowered C-reactive protein, a key marker of inflammation. Patients were classified as “severe” if they required oxygen supplementation without mechanical or high-flow oxygenation; or “critical” if they required mechanical ventilation or high-flow oxygenation or required treatment in an intensive care unit. Sarilumab did not show clinical benefit when combining the severe and critical groups, versus placebo. However, negative trends were reported for most outcomes in the “severe” group, while there were positive trends for all outcomes in the critical group. The trial has, therefore, been amended so that only critical patients continue to be enrolled to receive treatment.10 Evidence from independent studies of tocilizumab appear more promising, but a definitive answer will not be available until the findings of the Roche global, randomised, double-blind, placebo-controlled phase II COVACTA trial (NCT04320615) are available.11
Novartis has also announced plans to initiate a phase III clinical trial to study canakinumab, an IL-1β blocker, in patients with COVID-19 pneumonia, following reports of elevated levels of IL-1β in patients with COVID-19.12
It has been suggested that regulating overactive signalling through the janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway during a cytokine storm associated with COVID-19 infection could be a useful therapeutic strategy. Ruxolitinib (Jakafi®, Incyte Corporation, Wilmington, DE, USA) is a JAK1/JAK2 inhibitor approved for polycythaemia vera, myelofibrosis and graft-versus-host disease. A global phase III study, RUX-COVID (NCT04331665), is evaluating the safety and efficacy of ruxolitinib, together with standard of care.13 Another JAK1/JAK2 inhibitor, barcitinib (Olumiant®, Eli Lilly and Company, Indianapolis, IN, USA), which is approved in many countries as a treatment for adults with moderately- to severely-active rheumatoid arthritis, will be investigated as a treatment arm in the National Institute of Allergy and Infectious Diseases (NIAID) adaptive COVID-19 treatment trial (NCT04280705).14 Results are expected within the next two months. Tofacitinib (Xeljanz®, Pfizer Inc., New York, NY, USA), a JAK1/JAK3 inhibitor used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and ulcerative colitis, is also being investigated in a phase II study (NCT04332042).7 However, some experts have expressed safety concerns around this approach, since the antiviral effects of interferons are largely mediated by the JAK–STAT signalling pathway.15
Complement is another integral component of the innate immune response to viruses, and initiates pro-inflammatory responses. Evidence from animal models of viral pneumonia suggests that complement inhibition may improve lung injury following coronavirus infection.16 Based on these data and promising findings from compassionate-use cases, Alexion are about to launch a global phase III trial to investigate the use of ravulizumab-cwvz (Ultomiris®, Alexion Pharmaceuticals, Boston, MA, USA) on survival, duration of mechanical ventilation and hospital stay of patients with COVID-19 compared to best supportive care.17 Alexion are also planning to further investigate a related drug, ecilizumab (Soliris®, Alexion Pharmaceuticals, Boston, MA, USA), in COVID-19.
AstraZeneca are also investigating approaches targeting the inflammatory cascade. Acalabrutinib (Calquence®, AstraZeneca, Cambridge, UK), a highly selective Bruton’s tyrosine kinase (BTK) inhibitor currently used to treat chronic lymphocytic leukaemia, is about to enter the phase II CALAVI trial (NCT04346199), following evidence supporting the role of the BTK pathway in the production of inflammatory cytokines and encouraging early clinical data.18 In addition, Medicinova are planning a study of investigational drug ibudilast (MN-166, Medicinova, Inc., La Jolla, CA, USA), a small-molecule inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE) -4 and -10, which is known to suppress the production of pro-inflammatory cytokines and promote neurotrophic factors.19
Tradipitant (Vanda Pharmaceuticals Inc., Washington, DC, USA), an investigational neurokinin-1 receptor (NK-1R) antagonist that is being developed to treat gastroparesis, motion sickness and atopic dermatitis, has entered the ODYSSEY phase III clinical trial (NCT04326426) to investigate its efficacy and safety in people with severe COVID-19 pneumonia.20 The NK-1R receptor is the main receptor for substance P, a key component of the neuroinflammatory processes that leads to significant lung injury following a viral infection.21
Antibody-based therapies may also be a promising approach to COVID-19 treatment. A preliminary study on 10 Chinese patients suggests that immunotherapy with neutralising antibodies present in convalescent plasma improved clinical symptoms, higher levels of blood oxygen and lymphocytes, lower C-reactive protein levels and undetectable viral loads; two patients were weaned from ventilators. Treatment was particularly successful if the plasma was given within 14 days of symptom onset and no adverse effects were observed.22 This finding needs investigation in larger studies.
Kiniksa Pharmaceuticals (Bermuda) recently announced preliminary evidence of treatment response with mavrilimumab, an investigational fully-human monoclonal antibody that targets granulocyte macrophage colony stimulating factor receptor alpha (GM-CSFRα), in six patients with severe pneumonia and hyperinflammation resulting from COVID-19 infection. All patients showed an early resolution of fever and improvement in oxygenation within 1–3 days. None of these patients have progressed to require mechanical ventilation. Further studies are being initiated.23
Eli Lilly and Company has also initiated a phase II study (A study of LY3127804 in participants with COVID-19; NCT04342897) of LY3127804, an investigational selective monoclonal antibody against angiopoietin 2 (Ang2), in patients with pneumonia hospitalised with COVID-19 who are at a higher risk of progressing to ARDS. Ang2 levels are known to be elevated in the alveolar components of patients with ARDS. It is hoped that inhibition of Ang2 will reduce the progression to ARDS or the need for mechanical ventilation in patients with COVID-19.14
Given the unprecedented pace at which trial information and findings are emerging, it is essential to track clinical trials, and avoid unnecessary duplication of efforts. A COVID-19 clinical trials registry, the Global Coronavirus COVID-19 Clinical Trial Tracker, has been produced, which is collating all trials.24
There is an urgent need for new strategies to help hospitalised patients with COVID-19, many of whom will progress to respiratory failure. With new studies being announced on a daily basis, this short article cannot provide a comprehensive account of all the potential therapeutics in clinical development. Despite the rapid rate of progress, large gaps exist in our understanding of the immunopathology of COVID-19. Collaborative efforts between pharmaceutical companies are bringing hope of effective therapies; however, these are unlikely to yield a “quick fix”. Nevertheless, every possible effort must be made to halt the epidemic as soon as possible and bring our life back to normal.
- ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/results/details?cond=COVID+19&draw=1&rank=46 (accessed April 29, 2020).
- Mullard A, Flooded by the torrent: the COVID-19 drug pipeline. 2020;395:1245–6.
- Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;NEJMoa2001282.
- “Solidarity” clinical trial for COVID-19 treatments. Available at: www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments (accessed 28 April 2020).
- Bausch Health. Bausch Health initiates VIRAZOLE® (ribavirin for inhalation solution, USP) clinical study in patients with COVID-19. 2020. Available at: https://ir.bauschhealth.com/news-releases/2020/04-13-2020-120008693 (accessed 28 April 2020).
- Clinical Trials Arena. Fujifilm commences phase III trial of Avigan for Covid-19. 2020. Available at: clinicaltrialsarena.com/news/fujifilm-avigan-covid-19-trial-japan/ (accessed 28 April 2020).
- Pfizer advances battle against COVID-19 on multiple fronts. 2020. Available at: www.pfizer.com/news/press-release/press-release-detail/pfizer_advances_battle_against_covid_19_on_multiple_fronts (accessed 28 April 2020).
- Zhou Y, Fu B, Zheng X, et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. bioRxiv. 02.12.945576; doi: https://doi.org/10.1101/2020.02.12.945576
- Liu B, Li M, Zhou Z, et al. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun. 2020;102452.
- Sanofi and Regeneron provide update on U.S. phase 2/3 adaptive-designed trial in hospitalized COVID-19 patients. 2020. Available at: www.sanofi.com/en/media-room/press-releases/2020/2020-04-27-12-58-00 (accessed 28 April 2020).
- Roche initiates phase III clinical trial of Actemra/RoActemra in hospitalised patients with severe COVID-19 pneumonia. 2020. Available at: www.roche.com/media/releases/med-cor-2020-03-19.htm (accessed 28 April 2020).
- Novartis announces plan to initiate clinical trial of canakinumab for patients with COVID-19 pneumonia. 2020. Available at: www.novartis.com/news/novartis-announces-plan-initiate-clinical-trial-canakinumab-patients-covid-19-pneumonia (accessed 28 April 2020).
- Incyte announces initiation of phase 3 RUXCOVID study evaluating ruxolitinib (Jakafi®) as a treatment for patients with COVID-19 associated cytokine storm. 2020. Available at: https://investor.incyte.com/news-releases/news-release-details/incyte-announces-initiation-phase-3-ruxcovid-study-evaluating (accessed 28 April 2020).
- Lilly begins clinical testing of therapies for COVID-19. 2020. Available at: https://investor.lilly.com/news-releases/news-release-details/lilly-begins-clinical-testing-therapies-covid-19 (accessed 28 April 2020).
- Favalli EG, Biggioggero M, Maioli G, Caporali R. Baricitinib for COVID-19: a suitable treatment? Lancet Infect Dis. 2020;10.1016/s1473-3099(20)30262-0.
- Gralinski LE, Sheahan TP, Morrison TE, et al. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. mBio. 2018;9:e01753-18.
- Alexion announces plans to initiate phase 3 study of ULTOMIRIS® (ravulizumab-cwvz) in hospitalized patients with severe COVID-19. 2020. https://ir.alexion.com/news-releases/news-release-details/alexion-announces-plans-initiate-phase-3-study-ultomirisr (accessed 28 April 2020).
- AstraZeneca initiates CALAVI clinical trial with Calquence against COVID-19. 2020. www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-initiates-calavi-clinical-trial-with-calquence-against-covid-19.html (accessed 28 April 2020).
- MediciNova announces plans to initiate a clinical trial of MN-166 (ibudilast) for COVID-19 acute respiratory distress syndrome (ARDS). 2020. Available at: https://investors.medicinova.com/news-releases/news-release-details/medicinova-announces-plans-initiate-clinical-trial-mn-166 (accessed 28 April 2020).
- Clinical Trials Arena. Vanda Pharmaceuticals starts phase III Covid-19 trial of tradipitant. 2020. Available at: clinicaltrialsarena.com/news/vanda-tradipitant-covid-19-trial/ (accessed 28 April 2020).
- O’Connor TM, O’Connell J, O’Brien DI, et al. The role of substance P in inflammatory disease. J Cell Physiol. 2004;201:167–80.
- Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020;117;9490–6.
- Kiniksa announces early evidence of treatment response with mavrilimumab in 6 patients with severe COVID-19 pneumonia and hyperinflammation. 2020. Available at: https://investors.kiniksa.com/news-releases/news-release-details/kiniksa-announces-early-evidence-treatment-response-mavrilimumab (accessed 29 April 2020).
- Global coronavirus COVID-19 clinical trial tracker. 2020. Available at: www.covid-trials.org/ (accessed 29 April 2020).
Disclosures: Katrina Mountfort is a Senior Medical Writer for Touch Medical Media.
Support: Developed and supported by Touch Medical Media.
Published: 30 April 2020