LONDON – Izana Bioscience Ltd. has become the third company to supply an anti-GM-CSF antibody for compassionate use against COVID-19, announcing namilumab, currently in phase IIb testing in the treatment of rheumatoid arthritis and ankylosing spondylitis, will be used to treat 20 patients with severe respiratory symptoms.

The trial, at two centers in Italy, shows how increased understanding of the pathology is shifting the focus of clinical development in COVID-19. Following the first rush to test approved and advanced-stage antiviral drugs against the coronavirus infection, a second wave of trials is being set up, with the aim of blocking the immune cascade that is now known to cause severe respiratory failure in patients with advanced disease.

“Evidence suggests that anti-GM-CSF therapy has the potential to change the way patients’ immune systems respond to the virus,” said Someit Sidhu, chief executive and co-founder of Oxford, U.K.-based based Izana.

The mounting number of case studies shows there are two distinct, but overlapping phases of COVID-19 pathology. The first phase of viral infection causes the sore throats, coughs and fatigue from which most people recover. In the second phase, viral pneumonia takes hold and can lead to the development of acute respiratory distress syndrome (ARDS), sepsis and organ failure.

The first phase of illness is triggered by the virus itself, the second by the host immune response. It has been shown that inflammatory cytokines, including interleukin-2, IL-6, IL-7, tumor necrosis factor and granulocyte-colony stimulating factor (GM-CSF), are significantly elevated in the blood of COVID-19 patients suffering from hyperimmune inflammation.

Those observations form the basis for repurposing immunomodulatory drugs approved for indications including rheumatoid arthritis and the prevention of cytokine storms associated with CAR T cancer immunotherapy, and for the approval of compassionate use of drugs in late-stage development in conditions including ankylosing spondylitis and giant cell arteritis, a chronic inflammation of the arteries.

Data published by the Chinese Centers for Disease Control and Prevention on 72,314 COVID-19 cases show that 5% of patients progressed to respiratory failure, septic shock and multi-organ dysfunction, of whom half died. Given the current state of the pandemic, arresting development of ARDS and avoiding the need for mechanical ventilation would make the biggest contribution to reducing morbidity and relieving the strain on hospitals.

The significant increase in IL-6 levels in the blood of patients with severe respiratory symptoms provides a rationale for FDA’s approval of a phase III trial of Roche Holding AG’s IL-6 inhibitor, Actemra (tocilizumab), in the treatment of COVID-19 patients with serious lung damage. The rheumatoid arthritis treatment showed positive effects in patients with severe respiratory symptoms in a small-scale study in China.

In Italy, currently one of the worst affected countries with 14,681 deaths recorded by April 3, the Italian Medicines Agency has approved an independent phase II study of Actemra.

Sanofi SA also has started a trial of its IL-6 inhibitor, Kevzara (sarilumab), in the prevention of ARDS, while Novartis AG announced a phase III trial of its myelofibrosis therapy, Jakavi (ruxolitinib), a JAK inhibitor, which also modulates IL-6 signaling.

But while IL-6 has a role in prolonging inflammation, it is a bit player compared with GM-CSF, which is known to induce the inflammatory cascade that sets in train the release of other pro-inflammatory cytokines, including the interleukin family, TNF-alpha, et al.

Levels of GM-CSF-expressing cells have been found to be significantly higher in the blood of COVID-19 patients treated in intensive care, compared both to healthy controls and to COVID-19 patients who do not require ventilation.

“GM-CSF is an initiator, while IL-6 is a prolonger; GM-CSF is earlier in the cytokine cascade and patients are showing it is overactivated,” Sidhu told BioWorld.

Timing is everything

Alongside Izana, Kiniksa Pharmaceuticals Ltd, of Hamilton, Bermuda, and Humanigen Inc., of Burlingame, Calif., have supplied anti-GM-CSF antibody drugs on a compassionate-use basis.

There is some initial indication of a benefit in six patients experiencing a steep decline in pulmonary function who were treated with Kiniksa’s mavrilimumab. According to the company, none required mechanical ventilation, and they all showed an early resolution of fever and improvement in oxygenation in one to three days. Three of them were discharged within five days.

Kiniksa is developing mavrilimumab for the treatment of giant cell arteritis, but under the previous ownership of Astrazeneca plc, it successfully completed phase IIb development in a 326-patient trial in rheumatoid arthritis.

Humanigen said on April 2 the FDA approved the compassionate use in COVID-19 patients of its anti-GM-CSF antibody, lenzilumab. The company also is planning a U.S. phase III trial in the prevention of ARDS.

Both lenzilumab and mavrilimumab are in phase II trials sponsored by Kite Inc., in the prevention of cytokine storms prompted by treatment with its approved CAR T therapy, Yescarta (axicabtagene ciloleucel).

The call for immune-modulating drugs to be used in treating ARDS has come from specialists in rheumatology and immunology. In the case of Izana, the approach came from Carlo Selmi, professor of internal medicine at Humanitas University, Milan.

“He knows the GM-CSF rheumatoid arthritis story,” Sidhu said. Selmi has identified an initial algorithm that indicates which patients are likely to progress to ARDS, but the selection of patients also will be based on his experience of treating patients.

Sidhu said that given the overlapping nature of the two phases of disease, it is important not to treat with anti-GM-CSF drugs too early or too late. “GM-CSF is the bridge between the adaptive and the innate immune response. You’ve got to get it at the right point,” he said.

“It’s why we are doing the trial with a very experienced principal investigator. Patients will be selected based on biomarkers and clinical judgment,” said Sidhu. “Patients will be on the path to ventilation; the aim is to intervene to prevent the need for mechanical ventilation.”

Izana is now talking to regulators about staging a randomized trial. Sidhu did not want to comment, but given namilumab has completed phase IIb study in rheumatoid arthritis, this will likely be a phase III study.

“We have clinical supplies and a lot of data to leverage in this scenario – we can launch a large trial,” Sidhu said.

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