COVID-19: closing in on matching therapeutic mechanism to disease stage
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In the history of infectious diseases, no single disease has had even remotely as many mechanisms or products tested at the same time as COVID-19.
With nearly 50 therapies in clinical trials due to yield data by the end of June, the needle should start to move on what works and doesn’t. The agents, all repurposed, map to a dozen different mechanisms, and the trials could help determine the disease stages at which they are most useful.
The caveat is that many of these trials are small and not placebo-controlled. Still, several are testing the same agents, enabling providing insight into whether results are replicable (see "The Dam is About to Break on Data from Repurposed Therapies").
Figure: Matching COVID-19 treatment mechanisms to disease biology
Antivirals are expected to be most beneficial early in disease, when viral replication is ramping up. Several, including remdesivir from Gilead Sciences Inc. (NASDAQ:GILD), have been shown to be more effective the earlier they are given, in animal models of COVID-19 or other infections.
However, viral load remains high in patients who progress to severe disease, and sponsors are testing antivirals across the disease spectrum. At least 14 antiviral agents are in a combined 26 trials with primary completion dates on or before June 30, according to ClinicalTrials.gov and ChiCTR.org.cn.
Immune boosting agents such as interferons could also be useful in early disease by augmenting a still growing immune response. Three trials are testing interferon α1β in the earliest disease setting, prior to exposure. The goal is to prevent development of disease in healthcare workers.
It's less clear whether immune boosters will be helpful after the disease becomes severe.
While loss of T cells has been associated with severe COVID-19, so has excess immune activation via "cytokine storm," a positive feedback loop in which in immune cells release inflammatory cytokines that activate more immune cells, stimulating additional cytokine release.
Getting the right balance of activity across immune cell types will be key.
Several cytokines, including IL-6 and TNFα, are elevated in patients with severe disease, and runaway inflammation is thought to trigger the lung pathology that results in acute respiratory distress syndrome (ARDS). Both cytokines are being targeted by molecules in testing for COVID-19.
At least 11 immune boosting and 17 anti-inflammatory therapies are in clinical trials with primary completion dates by June 30. While the studies span the disease timeline, a larger share of the anti-inflammatory trials are focused at the severe end of the disease.
Getting the right balance of activity across immune cell types will be key. At least two trials are combining an anti-inflammatory with an immune booster by pairing the IL-6 receptor inhibitor tocilizumab with an anti-PD-1 mAb. The former affects a variety of immune cell types, such as neutrophils, B cells and Tregs, while the latter is used in cancer to stimulate T cells.
Figure: COVID-19: therapeutic mechanisms by phase and disease stage
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