We started the new year buoyed by the optimism of another vaccine for COVID-19 achieving regulatory authorisation, with Moderna's mRNA-based vaccine being approved by the EU. The race to develop and distribute the vaccines we need is accelerating, and it is possible to see a future unhindered by COVID-19. Yet however positive the future may appear, there remain significant present day challenges that need to be addressed.

The surge in infections and hospital admissions is putting unprecedented pressure on the health service in the UK. This increase is powered by a mutation in the virus, the variant B117, which is believed to be much easier to pass between people. Viruses constantly mutate, so multiple minor variations are to be expected, but the threat of further mutations with higher transmissibility, change in the clinical phenotype for the worse, or significant implications on vaccine efficacy are ongoing threats.

In this article I will look at what is being done by those of us in drug development to support the many challenges presented by COVID-19. In particular, I want to outline what we as an industry are doing to help clinicians as they treat hospitalised COVID-19 patients and outpatients, while awaiting the cavalry of a full vaccine rollout.

To understand the armoury of treatments available to clinicians, we need to look at the clinical spectrum of COVID-19. Categories of infection based on their severity are asymptomatic, mild, moderate, severe and critical. The first two categories do not usually require clinical support and intervention, with patients largely able to recover in their homes.

The final two categories, severe and critical, are more likely to result in patients suffering from pneumonia and being treated in intensive care. They may also develop ARDS (acute respiratory distress syndrome) and require a ventilator to help inflate their lungs. As the most extreme categories, posing the highest threat to life, there has been a focus on identifying drug treatments to assist these patients. Early enthusiasm for drugs like remdesivir has been dampened by the WHO Solidarity trial, which showed that the drug (along with hydroxychloroquine, lopinavir-ritonavir and interferon beta-1a) seemed to have little or no effect on 28-day mortality.

However, the UK's RECOVERY trial established that corticosteroids can be beneficial for COVID patients who required supplemental oxygen or mechanical ventilation. Under the trial, patients who received 6mg of dexamethasone for up to 10 days had lower mortality after 28 days than those who received the standard of care1. These results were supported by three other trials, although these stopped enrolment once the RECOVERY results were published.234This is encouraging, but COVID-19 mortality remains high and further research is still needed - such as the level of oxygen support required. Indeed, the data also indicated that dexamethasone could increase mortality in hospitalised patients who were not receiving oxygen.

At the time of writing, 279 Phase III clinical trials are recruiting to study treatments for COVID-195. Yet there remains an unmet need for effective treatments in one category – moderate infection. These are the patients who are probably hospitalised, but not in intensive care. They have a respiratory infection, with inflammation lower down their lungs, are likely to be more breathless and have a more pronounced cough but they may not yet have severe pneumonia. In focusing our energy on the more severe categories of COVID-19 infection, we may have left clinicians caring for those with moderate symptoms with a smaller arsenal of treatments. Could a renewed focus on drugs to treat moderate COVID-19 sufferers reduce the numbers who progress to critical or severe levels?

There are studies whose results could benefit patients with moderate COVID-19 infections, in particular from small, nimble biotech firms. For example, whilst the SOLIDARITY study questioned the effectiveness of interferon beta 1a when administered subcutaneously, other studies using interferon beta are showing more promising results. This year, biotech Synairgen started a global Phase III trial using an inhaled formulation of interferon beta developed at Southampton University Hospital. A dose of the protein delivered via a nebuliser to the lungs looks to trigger an antiviral response. Earlier clinical trials conducted by Synairgen have shown that it can stimulate an immune response even in patients whose immune system is already weak, which could help patients with asthma and other chronic lung conditions. The earlier Phase II trial was focused more on a moderate COVID-19 phenotype, although the latest study has a broader scope and will include hospital and home settings.

Elsewhere, the ATTRACT study was focused on supporting patients with moderate COVID-19 infections. It was a randomised, placebo-controlled trial investigating the efficacy of C21 (VP01 programme), an experimental first in class low molecular weight angiotensin II receptor type 2 (AT2R) agonist. The Phase II trial on top of standard of care, saw C21, provided as an oral capsule treatment, compared with placebo, in 106 hospitalised COVID-19 patients showing signs of an acute respiratory infection, but not requiring mechanical ventilation. These patients had an intense viral pneumonia which can develop into more critical acute respiratory failure.

Two weeks after patients were randomised, which includes seven days of treatment, only one patient in the C21 group still needed oxygen treatment compared to 11 patients in the placebo group – a 90% statistically significant reduction. The reduction in the need for supplemental oxygen was seen already at the end of treatment, with reductions of 40%, which rose to 57% at day eight and then 90% at day 14. There was also a clear trend for C21 reducing number of patients needing mechanical ventilation, with four patients in the placebo group compared to one in the C21 group. In this study, C21 was given on top of standard of care medicines such as glucocorticoids and remdesivir, and C21 had a good safety and tolerability profile, with fewer adverse events in the C21+SoC arm vs Placebo+SoC.

The need for oxygen treatment reflects progress of the infection to the lower airways, where gas exchange occurs. The angiotensin II type 2 receptor (AT2R, the target of C21) is expressed on lung type II pneumocytes that are the primary site for the viral replication, and it is possible that C21 restores lung function by acting directly on these cells. We believe that C21 could be used in an outpatient setting to reduce need for oxygen support, stopping the development of severe lung disease and bringing down hospitalisations.

The data from the Phase II study has recently been published online and submitted to a peer reviewed journal6.The next phase of the study will collect follow up data from ATTRACT, up to 24 weeks after completion of the study, and assess patient lungs using high-resolution computed tomography. Such timescales and radiographic assets could offer interesting insight into post-acute COVID-19 (or ‘Long COVID’). In particular, we are keen to see if the improvements C21 makes to hypoxia over two weeks in the acute setting, will have a knock-on effect on scarring (fibrosis) in the lungs over two-three months. C21 is an oral therapy with a favourable benefit/risk profile, so while the next stage will be a pivotal study targeting patients in hospital, we believe it could also be used for treatment in a home setting. The ATTRACT study was made possible by funding of £1.5m from LifeArc, the UK-based independent medical research charity.

If there is one positive to arise from the pandemic, it is the collective response of healthcare sectors, drug development companies, policymakers and funders like LifeArc to help reduce the threat and impact of COVID-19. If we continue to work collectively as the norm, healthcare practitioners, big pharma and smaller biotech companies could respond even more rapidly to emerging hot spots of clinical concern, ensuring the pipeline of drug development is primed to offer support as and when needed. A cross-industry forum with equal participation from big pharma and small to medium sized biotechs, fed by input from clinicians, could help to ensure that we never see the same pressure on our hospitals again.

Rohit Batta is chief medical officer of Vicore

References

1Horby P,Lim WSet al. The Recovery Collaborative Group Dexamethasone in hospitalized patients with Covid-19—preliminary report.

N Engl J Med. 2020; (published online July 17.)https://doi.org/10.1056/NEJMoa2021436

2Dequin PF, Heming N, Meziani F et al.Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial.JAMA. 2020; 324: 1298-1306

3Tomazini BM, Maia IS, Cavalcanti AB  et al.Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020; 324: 1307-1316

4Angus DC, Derde L, Al-Beidh F  et al.Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020; 324: 1317-1329

5clinicaltrials.gov 13/1/21