Siltuximab, produced by EUSA Pharma, is an interleukin (IL)-6 targeted monoclonal antibody that binds to and neutralizes IL-6. It is currently approved in multiple jurisdictions including the US and the EU for the treatment of patients with multicentric Castleman disease.
The primary outcome of the SILtuximab in Viral ARDS (SILVAR) clinical trial, which is taking place at the Sparrow Hospital in Lansing, Michigan, in the US, is a significant reduction in 28-day mortality.
EUSA Pharma, a biopharma company focused on rare disease and oncology, said the trial is designed to confirm what it termed the “encouraging results” announced earlier this year from the SISCO study in Italy that investigated siltuximab plus standard of care in COVID-19 patients with serious respiratory complications.
Siltuximab led to a 54% reduction in risk of 30-day all-cause mortality in 30 patients treated with that drug versus 30 matched controls in that Italian study, said the company.
Unlike previous clinical trials of agents targeting the interleukin-6 (IL-6) signaling pathway, EUSA Pharma said the ‘SILVAR’ study has been rationally designed to only enroll those hospitalized patients suffering from serious viral acute respiratory distress syndrome (ARDS) in a hyperinflammatory state that will most likely benefit from the addition of an anti-IL-6 immunomodulator such as siltuximab.
Respiratory failure from ARDS is the leading cause of mortality in patients with COVID-19, it reported.
Cytokine storm
Lee Morley, CEO of the UK headquartered EUSA Pharma, explained the rationale for the company trialing the drug in respect of patients with serious respiratory complications.
“There has been a growing body of evidence highlighting that COVID-19-associated ARDS may exhibit features of systemic hyperinflammation, resulting from excessive cytokine production – the so-called ‘cytokine storm’ – with interleukin-6 (IL-6), that siltuximab neutralises, recognised as a key driver of this serious condition. We knew, however, that we needed credible data to truly understand this.
"The opportunity to support the Papa Giovanni XXIII Hospital [SISCO trial] was very timely, [as that trial] evaluated siltuximab for the treatment of patients with COVID-19 who have developed serious respiratory complications. The encouraging results from this study formed the foundation for us to move forward with the SILVAR study to potentially confirm these results in a prospective randomised clinical trial."
In terms of the likely regulatory pathway for Siltuximab to get FDA-approval for complications associated with COVID-19, the CEO told BioPharma-Reporter:
“EUSA Pharma received approval of the (randomized Phase 3) SILVAR clinical trial protocol in July of this year and, built within that, is a pre-planned interim analysis prior to the final analysis. If this study reads out positively, then we will be in a position to initiate discussions with the US Food and Drug Administration (FDA).”
The study
SILVAR is an FDA-approved, prospective, multicentre, randomized, double-blind, placebo-controlled, parallel-arm, Phase 3 clinical trial. It is designed to compare the efficacy and safety of intravenous siltuximab plus SOC to intravenous normal saline plus SOC in selected hospitalized patients with COVID-19 previously treated with corticosteroids or another respiratory virus infection associated with ARDS.
This US multicentre clinical trial will aim to enroll around 555 patients with serious viral ARDS and elevated serum levels of IL-6 as measured by its qualified C-reactive protein (CRP) surrogate.
The primary objective is to demonstrate a significant reduction in 28-day mortality with the addition of siltuximab to SOC. Secondary objectives are to compare other measures of efficacy between both treatment arms and to evaluate the safety, tolerability, exposure, and immunogenicity of siltuximab in this patient population and treatment setting.
