Going (anti)viral

Time pressure in any laboratory, is a poor vector for good quality science but these are far from normal conditions.

There are many questions repeated daily in the media. How long before we devise a vaccine? Can we possibly design a therapeutic response? Why is it taking so long to create reliable and efficient across-the-board testing regimes?

We were caught like of a nest of ants whose universe has been turned over by a gardener’s spade. It seems like chaos and confusion in all directions. Fake news, rumours and gossip are as repulsive an enemy as the virus itself. For the world’s health and economy, the pandemic is a disaster setting the biosciences sector its biggest ever challenge, but the counter offensive is operating on many levels.

What are we to make of various reports of a treatment or potential therapeutic tools that appear to bring improvements to clusters of victims?

Tocilizumab success in Covid-19 patient

Last month, the respected OncLive forum reported that the cancer supportive care agent, tocilizumab (Actemra) had treated Covid-19 in a patient with multiple myeloma. The case emerged, coincidently from Wuhan, and appeared in a research paper in Blood Cancers.^1,2

The researchers concluded tocilizumab could be effective against cytokine storm caused by Covid-19, and that this benefit could potentially be expanded to other patients. 

The cytokine storm is the colourful description for a type of severe immune overreaction causing life-threatening respiratory complications. Cytokines are small proteins important which function in cell signalling and are especially relevant to immune response mechanisms. The term cytokine storm describes the malfunction of that signalling process to the detriment of the patient. Effectively the immune system is somehow triggered to turn on the patient; the biological equivalent of friendly fire.

Tocilizumab is a drug that emerged from the Interleukin family of agents during the search for auto-immune system boosting treatments in HIV research. Subsequently it became adopted as a drug for treatment for rheumatoid arthritis. In the US it had a bed press for a series of alleged side effects, including heart failure, in some patients. 

Nevertheless, lead researcher Changcheng Zheng, at the University of Science and Technology of China went public last month. He reported tocilizumab apparently successfully resolved Covid-19 symptoms in a man already diagnosed with multiple myeloma. 

Zheng emphasised that the patient did not have the standard Covid-19 symptoms of cough and fever. He said this could mean that patients with hematologic malignancies may not typically have these clinical symptoms of the coronavirus. 

The case study involved a man aged 60 with multiple myeloma diagnosed in 2015. He was receiving maintenance therapy for myeloma at the time of his hospitalisation on 1 February 2020, for chest tightness and shortness of breath. He tested positive for Covid-19 that was considered severe, despite not displaying the standard symptoms of cough or fever. 

Antiviral and corticosteroid therapies were initially used but did not completely resolve his symptoms. A chest CT scan on his second day in hospital revealed that there were ground glass opacities in his lungs, a characteristic of pneumonia. Additionally, he had high levels of the pro-inflammatory cytokine IL-6.  

The patient was dosed with 8mg/kg of tocilizumab intravenously on day 9 in the hospital, which was day 24 of his having COVID-19.

His IL-6 levels went down after the single dose and continued to decrease over the next 10 days (121.59 to 20.81pg/mL). The levels then started to increase rapidly, peaking at 317.38pg/mL, but eventually settled to 117.10pg/mL. After 19 days in hospital the patient was released as ‘cured’.

Zheng wrote: “The transient rebounding of the IL-6 level to the peak does not mean Covid-19 relapse. Instead, this might be attributed to the recovery of the normal T cells.”

He hoped the tocilizumab would inspire more extensive research. It already has.

A sign of the rapid reaction forces at work in the pandemic is that the US Federal Drug Administration has already approved the start of a double-blind, randomised phase III clinical trial of tocilizumab for use in combination with standard of care for the treatment of hospitalised adult patients with severe Covid-19 pneumonia.³

Genentech (Roche) is said to be collaborating with the Biomedical Advanced Research and Development Authority (BARDA), to evaluate tocilizumab combined with standard of care versus placebo plus standard of care.⁴

Enrolment is expected to begin soon, with a target cohort of 330 patients spread across the US and other countries. Patients will be monitored for 60 days after randomisation and early proof of efficacy will be assessed at an interim analysis. Key study factors will be clinical status, mortality, mechanical ventilation, and intensive care unit variables.

Remdesivir waiting in the wings

At the same time clinical trials have begun with California-based Gilead Sciences’ experimental antiviral remdesivir.

Remdesivir is said to mimic an adenosine nucleotide and interferes with viral RNA replication. It was originally developed to treat Ebola and has shown promise in animal models of Middle East respiratory syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), both caused by coronavirus derivatives.

In an open letter, CEO Daniel O’Day said Gilead has speeded up production of the coronavirus therapeutic candidate. Remdesivir's manufacturing timeline has been halved from one year to six months.

In one remdesivir trial, with 400 participants, patients with severe Covid-19 are receiving treatment for either five or 10 days. Similar trials are underway in China.

Gilead says it plans to donate 1.5 million doses of remdesivir to on-going clinical trials through its expanded access and compassionate use programs.

The search for weapons against Covid-19 is likely to throw up many false leads.

The anti-coronavirus vaccine is the Holy Grail and hopefully it is not too distant, but therapies may have a vital role to play too and rapid reaction to experimental work, such as that described here will continue to be an option.

References:

1 Treating COVID-19 in a Patient with Multiple Myeloma. Published online April 3, 2020. Accessed April 3, 2020.

2 Zhang X, Song K, Tong F, et al. First case of Covid-19 in a patient with multiple myeloma successfully treated with tocilizumab. Blood Adv. 2020;4(7):1307-1310. 

3 https://www.statnews.com/2017/06/05/actemra-rheumatoid-arthritis-fda/

4 Genentech Announces FDA Approval of Clinical Trial for Actemra to Treat Hospitalized Patients With Severe Covid-19 Pneumonia. Posted March 23, 2020. . Accessed March 23, 2020.