Widely-Available Corticosteroid Demonstrates Lower Mortality Rates for Some COVID-19 Patients
There are two predominantly emerging therapeutic strategies for the development of drugs to treat patients with COVID-19. The first is to target the virus (SARS-CoV2) itself. This is how Remdesivir, the most widely discussed treatment for COVID-19 works. The second therapeutic strategy is to mitigate the effect of cytokine release syndrome (or cytokine storm when it occurs very suddenly), a consequence of the viral infection and one of the main apparent causes of the virus’s high morbidity and mortality. The recent news that dexamethasone, a widely available, generic and cheap, corticosteroid anti-inflammatory drug resulted in significantly reduced mortality in patients receiving respiratory support was a huge breakthrough. A hugely positive result for patients but one that will also impact the emerging boom in COVID-19 drug development.
Treatment of Cytokine Release Syndrome
In cytokine release syndrome (CRS) the body activates white blood cells which then release inflammatory cytokines and these can in turn further activate white blood cells. While cytokines are needed for the generation of healthy immune responses, in CRS the hyperinflammatory response causes significant damage to our own bodies1. CRS is not a new concept. Coined 20 years ago it has been a recognized adverse event associated with a number of immunotherapeutic agents from the early immunosuppressive antibodies to the recently launched CAR-T therapeutics. Treatments indicated for CRS include tocilizumab and siltuximab, antibodies that interfere with the signalling of the cytokine IL-6. However, corticosteroids are also used to non-specifically reduce the inflammatory response, although their benefit/risk profile has been debated. The use of corticosteroids for SARS was already a point of debate2. Since the SARS pandemic did not generate the same tsunami of public funding and research effort that COVID-19 has generated, much of the data regarding potential therapeutics was derived from small often retrospective studies. Now the results of the RECOVERY trial, led by the University of Oxford, demonstrating the value of dexamethasone, will have put some of that debate to bed3.
Implications of the RECOVERY Trial of Dexamethasone
Dexamethasone reduced deaths by one third in patients receiving mechanical ventilation and by one fifth in patients receiving oxygen without intubation but importantly did not have a benefit in patients not requiring oxygen. The result is tremendously impactful for patient care. Indeed, given the result, it would not be reasonable to significantly delay use of dexamethasone in patients receiving respiratory support. So how does this impact COVID-19 therapeutic development more broadly? For those therapeutics targeting the virus directly, its cell entry mechanism or its intracellular replication, there may not be a significant impact. Such therapies may be complimentary or even synergistic with the use of therapies targeting a CRS hyperinflammatory response. However, for other therapeutics in development for CRA associated with COVID-19 there is now a new gold standard against which they need to compare themselves.
In addition to therapeutics already approved to treat CRS, numerous therapies targeting COVID-19 associated CRS are in development (as shown in Table 1).
|Infliximab||Celltrion Healthcare||TNF-a inhibition||Phase 2|
|Namilumab||Izana Bioscience||GM-CSF antagonist||Phase 2|
|Acalabrutinib||Astrazeneca||Bruton’s tyrosine kinase inhibition||Phase 2|
|Sarilumab||Regeneron/Sanofi||IL-6 receptor inhibition||Phase 2/3|
|Canakinumab||Novartis||interleukin-1? inhibition||Phase 3|
|Mavrilimumab||Kiniksa Pharma.||GM-CSFR inhibition||Phase 2/3|
|Lenzilumab||Humanigen||GM-CSF antagonist||Phase 3|
|leronlimab||CytoDyn||CCR5 antagonist||Phase 2|
|Gimsilumab||Roivant Sciences||GM-CSF antagonist||Phase 2|
|Otilimab||GSK||GM-CSF antagonist||Phase 2|
|Losmapimod||Fulcrum Therapeutics||p38?/? MAPK inhibitor||Phase 3 to start|
All of these products are being evaluated in clinical studies in which their effect is being compared to a placebo (best supportive care) and all of them, if eventually approved and launched, can be expected to come at a significant cost to healthcare systems. Given the dexamethasone results already reported, a few questions come to mind. If a number of the above products were to come to market which should the physician use? How would they differentiate? How will they know the relative efficacy? Will any of them be better than dexamethasone and could there be a beneficial additive effect…or the opposite? Furthermore, given the very low cost of dexamethasone, reimbursement price of these new agents would need to reflect relative value as compared to dexamethasone. Finally, since a number of these products have primary indications in oncology or immunomodulatory conditions, where they enjoy high pricing, there may be limited flexibility to reduce pricing for COVID-19 patients.
The bottom line is that novel drugs are needed and if they are safe and effective then their pricing should reflect the value that they bring to patients and healthcare systems. However, we strongly believe that developers should, more than ever in the fast moving COVID-19 space, carefully consider the costs and benefits of their therapeutic candidates. Seeking indications for moderate COVID-19, especially in more vulnerable populations, may allow earlier utilization, preventing patient progression towards more intensive respiratory support. Demonstrating beneficial comparative or additive efficacy to/with dexamethasone will provide physicians with the needed information to appropriately treat more severe patients.
Charles Gomersall et al., stated in their pros/cons review of corticosteroids for SARS “Let us hope and pray together that we never have the patient population needed to resolve the questions the two sides raise”. Today unfortunately we do and while we have answered some of the questions posed, many more remain unanswered.
- A rampage through the body. Meredith Wadman, Jennifer Couzin-Frankel, Jocelyn Kaiser, Catherine Matacic. Science 24 Apr 2020. Vol. 368, Issue 6489, pp. 356-360. doi.org/10.1126/science.368.6489.356
- Pro/con clinical debate: Steroids are a key component in the treatment of SARS. Charles D Gomersall, Marcus J Kargel and Stephen E Lapinsky Crit Care. 2004; 8(2): 105–107. ccforum.com/content/8/2/105
- Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. Peter Horby, et al. doi.org/10.1101/2020.06.22.20137273