By Dr. H. Michael Shepard, Co-founder, Enosi Life Sciences

The COVID-19 pandemic has created an emergency seen only once in a century. The SARS-CoV-2 virus that causes this new coronavirus has now infected over 55 million and killed over 1 million patients across the globe, with new spikes emerging as we head into the winter months. Also, as we move into the Fall and Winter months, influenza will again be a significant problem for vulnerable patients.

Much of the biology of COVID-19, including its symptoms and heavily varied impact on patients is still unknown. As of today, about 40 to 45% asymptomatic leading to further spread of this disease. For the remaining patients that are symptomatic, 80% of cases are mild and require no medical attention, 15% are moderate and 5% are severe – creating a challenge for medical professionals aiming to treat and control this disease.

While questions around the development of a vaccine, its timing and efficacy loom, one thing we have been able to determine with a high degree of confidence, however, is that in the most severe cases, uncontrolled inflammatory responses tend to be associated with the worst patient outcomes.

Inflammation’s role in COVID-19

The body is an incredible masterpiece, designed to protect itself from foreign bodies, diseases and more. Infections of the lungs, caused by viruses such as influenza, pneumonia or SARS-CoV-2 are among the many instances that will trigger the body’s defense system, releasing mediators to find and combat the infection.     

Evidence shows that interferons could play an important role early in the defense reaction. Patients with defects in interferon production or endogenous antibodies that cause interference to interferon have less than optimal outcomes1. Studies from Mount Sinai and others2, report that high levels of cytokines including IL-6 and TNF tend to correlate with poor outcomes, inducing inflammation that can result in respiratory and multi organ failure2 and death. Uncontrolled hyperinflammation is often called a “cytokine storm.” Hyperinflammation in COVID-19 cases is characterized by much higher-than-usual serum TNF, interleukin IL-6 and IL-8 concentrations, and low concentrations of IL-1 or IL-2, as in the case of influenza2. Therapies that address respiratory failure in COVID-19 offer use in the treatment of many different diseases.

Capillary leaks tend to be a driver of lung function deterioration within COVID-19 patients3. This is often the result of inflammation driven by several key cytokines: TNF, IL-1, IL-6, and vascular endothelial growth factor (VEGF). In 30% of severe cases corticosteroids may reduce inflammation and capillary leak, and lead to a better outcome, as noted in a recovery trial conducted by Oxford University.4 Some researchers are now turning their focus to explore blocking cytokines as a potential for the treatment of COVID-19.

Anti-TNF success in other treatments

Blocking TNF production could offer a more effective solution for the treatment of COVID-19. Research led by established scientists, including Enosi co-founder, Sir Marc Feldmann, showed that rheumatoid arthritis patients treated with anti-TNF monoclonal antibodies blocked TNF as well as many other pro-inflammatory cytokines5. The efficacy of anti-TNF treatments has led to its current use for multiple autoimmune inflammatory disorders, including inflammatory bowel disease, psoriasis and more. TNF inhibitors are now the largest drug class in the world since 2012.

Feldmann and his colleagues6 have now suggested that anti-TNF therapy could prove useful in COVID-19 patients as it could minimize cytokine storms and capillary leakage. As a result, it could help decrease the need for oxygen, ventilation and the mortality rate associated with COVID-19. This suggestion is supported by early empirical clinical data obtained from databases of patients already on various anti-inflammatory drugs. For example, patients with inflammatory bowel disease who develop COVID-19 do better when they are using anti-TNF therapy comparatively to those who use alternative agents.

Reports from the Global Rheumatology Alliance7 evaluating Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease, note that in patients with arthritis, those who are already on anti-TNF treatment have better patient outcomes with only 30% the likelihood of hospitalization.  Additionally, small studies have been performed evaluating IV anti-TNF infliximab which show promising results by will need bigger trials to be definitive. Thus, they have begun in hospitalized patients in UK (CATALYST, enrolling) and in US (ACCTIV-1).

More precise anti-TNF treatment

Anti-TNF therapies have had tremendous success, but there is still room to improve these therapeutics and enhance their efficacy even more. TNF is the only pro-inflammatory cytokine with two receptors; TNFR1 which promotes inflammation and TNFR2 which inhibits inflammation, promoting resolution. Existing TNF blockers block both receptors, so improving these therapeutics would require more selective inhibition.

Following this research around COVID-19 and inflammation, Feldmann, Shepard and their team at Enosi Life Sciences are now working to create second-generation TNF inhibitors which, based on understanding of the TNF pathways, are likely to be more effective. The two new TNF-blocking therapeutic candidates, each of which is intended for different use include EN1001, a TNFR1-binding protein inhibiting TNFR1 without compromising TNFR2’s healing capabilities, and EN2001 which inhibits growth of the cells that produce TNF.  EN1001 blocking TNFR1 could prove more effective as it spares regulatory T cell function9, an important component as insufficient T regulatory cell function is involved in COVID-1910.

Anti-TNF deserves consideration for COVID-19 treatment

We are still months away from having an effective and safe COVID-19 vaccine on-hand and available to quell the spread and stop the pandemic. Thus, we need to focus on treatments for severely ill COVID-19 patients with COVID-19. We know a connection exists between the SARS-CoV-2 virus and inflammation, and we know that anti-TNF therapeutics for other diseases have offered success. In the coming months, we will have a clearer understanding of whether or not current generation anti-TNFs are effective in reducing severe COVID-19 symptoms. Most importantly, we need to continue developing next generation therapeutics with more precise TNF-blocking capabilities, that can be used for multiple diseases.

Sir Marc Feldmann

About the authors

Sir Marc Feldmann is Co-founder and Board Member of Enosi Life Sciences. He is a preeminent immunologist, and an Emeritus Professor at the University of Oxford. With Sir Ravinder Maini, he identified TNF as a target. They led the successful trials of the first anti-TNF antibody called Infliximab (or Remicade), and prompted J&J’s $4.9B USD acquisition of Centocor. Total Remicade sales so far amount to more than $50B USD globally. Professor Sir Marc Feldmann is a Fellow of the Royal Society of Australian Academy and a Foreign Member of the US National Academy of Sciences; he was knighted in 2010 and received the Australian equivalent. He has received many accolades including the Lasker~DeBakey Clinical Medical Research Award., the Crafoord Prize, the Canada Gairdner Award, the Paul Janssen Award, and the Ernst Schering Award.

H. Michael Shepard

Dr. H. Michael Shepard is a serial entrepreneur and also serves as CEO, CSO, Co-founder and Board Member of Enosi Life Sciences. Dr. Shepard led the research at Genentech that resulted in Herceptin/trastuzumab, an antibody therapy now used for HER2-positive breast and gastric cancers. About 3 million women have been treated with Herceptin, many of them very successfully. Dr. Shepard has been recognized by his peers and by the Harvard Medical School Warren Alpert Prize (2006) and by the Lasker~DeBakey Clinical Medical Research Award (2019).

 

1 Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020; 369(6504): 718-24.

2 Del Valle DM, Kim-Schulze S, Huang HH, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med2020. 

3 Wu MA, Fossali T, Pandolfi L, et al. COVID-19: the key role of pulmonary capillary leakage. An observational cohort study. medRxiv2020.

4 Group RC, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 – Preliminary Report. N Engl J Med 2020.

5 Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 1989; 2(8657): 244-7.

6 Feldmann M, Maini RN, Woody JN, et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet 2020; 395(10234): 1407-9.

7 Gianfrancesco M, Hyrich KL, Al-Adely S, et al. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis 2020; 79(7): 859-66.

8 McCann FE, Perocheau DP, Ruspi G, et al. Selective tumor necrosis factor receptor I blockade is anti-inflammatory and reveals immunoregulatory role of tumor necrosis factor receptor II in collagen-induced arthritis. Arthritis Rheumatol 2014; 66(10): 2728-38.

9 Tseng WY, Huang YS, Clanchy F, et al. TNF receptor 2 signaling prevents DNA methylation at the Foxp3 promoter and prevents pathogenic conversion of regulatory T cells. Proc Natl Acad Sci U S A 2019; 116(43): 21666-72.

10 Meckiff BJ, Ramírez-Suástegui C, Fajardo V, et al. Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4+ T cells in COVID-19. Cell 2020.