Repurposed Drugs to Fight SARS-CoV-2, Tocilizumab and Sarilumab - Part 4

This week’s installment of drugs, we all hope can help us fight the COVID-19 pandemic, features the first biologics: tocilizumab sold under the brand name Actemra and sarilumab, which is sold as Kevzara; both are monoclonal antibodies.

Actemra was developed by Chugai, which is majority-owned by Roche, and was first approved by the FDA in January 2010 for treatment of rheumatoid arthritis and later for other indications including juvenile idiopathic arthritis and giant cell arteritis. Kevzara (sarilumab), which was jointly developed by Sanofi and Regeneron, was approved in 2017 both in the US and Europe for rheumatoid arthritis.

Both drugs are monoclonal antibodies targeting the Interleukin-6 receptor (IL-6R) with the same mechanism of action.

Actemra and Kevzara as Treatment for COVID 19

One of the jarring characteristics of COVID-19 is that seemingly mild cases can turn severe very rapidly due to a phenomenon known as cytokine storm or cytokine release syndrome. A cytokine storm can be triggered by infections: as the immune system fights the pathogen white blood cells are activated and release inflammatory cytokines, e.g. interleukin-6. These cytokines activate more white blood cells which release additional cytokines. This positive feedback loop can go into overdrive resulting in hyper-inflammation that can lead to death.

In infections of the lung, e.g. the flu, the swine flu and now SARS-CoV-2, the inflammation triggered by the cytokine storm can lead to respiratory distress that increases the mortality of patients due to secondary infections, e.g. bacterial pneumonia. The high mortality rate of the Spanish flu in 1918 that killed millions of people was also caused by cytokine release syndrome. Interleukin-6 is one of the cytokines implicated in cytokine release syndrome and blocking the binding site to its receptor has been shown to be efficacious, e.g. in cases where CAR-T cell therapies trigger cytokine storms in cancer patients.

So far, clinical evidence of Actemra’s efficacy is limited to a non-peer-reviewed study with 21 patients with severe or critical COVID-19 in China, where patients improved within a few days of being treated. A second trial is currently ongoing in China. In the US, Roche, backed with $25 million by U.S. Biomedical Advanced Research and Development Authority (BARDA) has obtained approval to treat patients with severe COVID-19 pneumonia in a phase 3 clinical trial. Several other trials are planned in Europe and China. Actemra has already been approved in China for the treatment of patients that suffer from lung damage due to SARS-CoV-2.

Kevzara is also currently undergoing clinical testing in a multi-center, double-blind, Phase 23 trial with adaptive design. Part 1 will evaluate the effect of Kevzara on patients with severe COVID-19 infection, the second part will look at long-term outcomes.

Mechanism of Action

Both Kevzara and Actemra are humanized monoclonal antibodies against interleukin-6 receptor (IL-6R). They bind specifically to IL-6R and thereby inhibit IL-6 mediated signaling via their receptors and thereby interrupt the positive feedback loop that leads to more activated white blood cells that release more cytokines.

Adverse Events

Common side effects of Actemra and Kevzara include runny or stuffy nose, sinus pain, sore throat, headache, dizziness, itching, mild stomach cramps, or urinary tract infection. A more complete list of side effects and adverse event can be found here for Actemraand here for Kevzara.

Who is Who in Tocilizumab and Sarilumab Research

The following Through the Lens will give you an overview of global academic experts and leading academic research institutions associated with Actemra or Kevzara.