By Manasi Vaidya in New York with additional reporting by Ayisha Sharma and Reynald Castaneda in London.
Use of repurposed antibodies already approved for other indications to effectively treat Covid-19, like those from Sanofi in partnership with Regeneron, Roche and Eusa Pharma, require early intervention in the disease, even as trials include critically ill patients. Using biomarkers to identify responders and track efficacy would also improve their chances.
While there has been an obvious thrust toward developing antivirals and vaccines to counter the Covid-19 pandemic, companies are repurposing drugs originally intended for chronic autoimmune disorders that target cytokine storm syndrome (CSS), which is also associated with Covid-19 illness. In the absence of antiviral therapy, it is important to treat the overexuberant immune responses seen in Covid-19 patients, said Dr Randy Cron, professor of Pediatrics and Medicine, the University of Alabama at Birmingham.
The protocols for Sanofi/Regeneron’s Phase II/III Kevzara (sarilumab) trial (NCT04315298), Roche’s Phase III COVACTA study (NCT04320615) of Actemra/RoActemra (tocilizumab) and Hemel Hempstead, UK-based Eusa’s Sylvant (siltuximab) trial (NCT04322188) indicate the inclusion of patients who may require oxygen through invasive ventilation, considered in critical cases.
Yet, experts emphasised the need to use anti-IL-6 repurposed antibodies before hospitalised Covid-19 patients become critically ill or require mechanical ventilation to give the therapies the best chance to be effective mechanistically. Acute lung injury and acute respiratory distress syndrome (ARDS) are common consequences of CSS, which then necessitate interventions like mechanical ventilation to help a patient breathe.
While there is no single biomarker, or a surrogate marker to gauge trial success, approved for identifying CSS, experts stressed the importance of using those already associated with it in the ongoing trials as selection and potentially secondary efficacy measures.
While trials with Kevzara and Sylvant are recruiting patients, the Actemra/RoActemra trial is not yet enrolling, as per public trial registries. Kevzara and Actemra/RoActemra are both approved for moderate-to-severe rheumatoid arthritis, while Sylvant is approved for idiopathic multicentric Castleman disease.
A Roche spokesperson said the company is doing everything possible to generate and share high-quality results as quickly as possible. A Regeneron spokesperson said initial results from the Phase II portion of the US Kevzara trial are expected by the end of April. Eusa did not respond to a request for comment before press time.
Sanofi’s market cap is $107.94bn, Regeneron’s is $54.27bn and Roche’s market cap is $ 280.1bn.
Repurposed antibodies: Early intervention key
The goal with anticytokine therapies like anti-IL-6 repurposed antibodies is to treat excessive inflammation and intervene before a patient becomes sick, said Dr Scott Canna, pediatric rheumatologist, UPMC Children’s Hospital, Pittsburgh. The best chance for such therapy is prior to intubation, before the body’s immune response does irreversible damage to the lungs, added Cron.
An antibody would likely be most effective for patients becoming breathless and could possibly delay or prevent them from having to go on a ventilator, agreed Dr Gareth Morgan, director, Multiple Myeloma Research, Perlmutter Cancer Center, New York City. The optimal time to intervene is unclear but, certainly, before a patient needs invasive ventilation, said Canna. Still, Cron reasoned, anti-IL-6s could nonetheless be explored in critical patients, considering the desperate need.
Roche’s and Eusa’s trial criteria indicate the inclusion of patients who may need mechanical ventilation. While Sanofi/Regeneron’s study does not detail hypoxemia measures, it is recruiting those with pneumonia and severe disease, critical disease or multisystem organ dysfunction.
Eusa’s study has two cohorts of Covid-19 patients with moderate-to-severe ARDS: 75% of patients will be from a non-ICU setting and treated within 48 hours from the beginning of noninvasive ventilation or continuous positive airway pressure (CPAP), while the rest will be in an ICU setting treated within 48 hours of beginning invasive ventilation. On 1 April, Eusa released interim data showing a third of 21 enrolled patients experienced clinical improvement with a reduced need for oxygen support, and nine were stabilised with no clinically relevant changes.
Roche’s COVACTA is including hospitalised patients with mild ARDS classified by the Berlin criteria. Mild ARDS patients are usually candidates for noninvasive ventilation. However, noted Dr Antonio Anzueto, professor of Medicine, UT Health, San Antonio, centres are not considering noninvasive ventilation to avoid transmission of the aerosolised virus even though that was previously standard-of-care. Additionally, he said, not all mild ARDS patients are the same; some may require mechanical ventilation while others may not.
Recruiting only the most severe patients would mean including those more likely to regress to the mean, or they will not respond because they are already too sick, noted Canna. Yet, he added, the aim to enrol patients prior to hospitalisation may be impractical, since biomarkers are likely not elevated prior to hospitalisation, he added.
Early data from China with Actemra/RoActemra indicated the vast majority of patients did well, but there was no control group and the patients received other therapies, so it is unclear what triggered their improvement, said Dr Winn Chatham, director, Rheumatology Clinical Services, the University of Alabama at Birmingham. The study’s preprint showed 19 out of 20 severely ill or critical patients were discharged after 13.5 days.
The issue with uncontrolled studies in critically ill patients is that it is tougher to account for confounders like multiple therapies, said Canna. A large study with a randomised design will hopefully overcome the issue of background antiviral therapy use, added Cron and Canna. While Sanofi/Regeneron target to enrol 400 patients and Roche has a 330-patient goal, Eusa’s is a single-centre, 50-patient study at Papa Giovanni XXIII Hospital, Bergamo, Italy. Sylvant’s study is an observational trial where each patient will be matched with a control patient, but the Kevzara and Actemra/RoActemra trials have a randomised, double-blind design.
Yet, even in a randomised study, if comorbidities, age and gender are not balanced, that would render the results vague, Dr C Ola Landgren, hematologic oncologist, Memorial Sloan Kettering Cancer Center, New York City. Also, a degree of viremia, how critically ill a patient is and their hospital stay duration are other factors that need to be balanced, he added.
Landgren cautioned that anti-IL-6s may not be a “slam dunk.” Nonetheless, Morgan said, if there is a 50% reduction in say ICU stay, that would be clinically significant. The first part of the Kevzara study will assess the impact on fever and need for supplemental oxygen, while part two will evaluate improvement in longer-term outcomes including preventing death and reducing the need for mechanical ventilation, supplemental oxygen and/or hospitalisation, as per a 16 March press release. Roche’s and Eusa’s trial endpoints include a focus on mortality, need for ventilation and other factors.
Chatham also pointed to the potential for adaptive designs based on a patient’s response to treatment. The advantage with cytokine inhibitors is that if a patient does have CSS they respond quite quickly, and if a benefit is present it will be seen soon, he added.
Biomarkers would aid in CSS identification
C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH) and albumin are biomarkers for CSS that could help guide treatment, experts noted. Some early data from Italy and China indicates that biomarker levels do identify patients with an inflammatory response, said Canna. The Roche study is evaluating biomarker levels of IL-6, sIL-6R, ferritin and CRP as secondary outcome measures, but the Kevzara study does not mention biomarkers in their descriptions on ClinicalTrials.gov. Eusa’s interim results indicated a decline in CRP levels.
The most important measure is mortality, but if the drug is given earlier, other secondary outcomes may be key in understanding efficacy, said Cron.
It is important to have leverage biomarkers that can be evaluated at most hospitals regardless of their size, said Canna. There is no rapid diagnostic test for IL-6 levels, while hospitals can get LDH and albumin results within a day, he added.
Nonetheless, early reports have not indicated when biomarker levels start to rise or how they change from when a patient is first admitted to when they are decompensated, said Canna. While none of the aforementioned trials do so, he suggested trials could also enrich patients based on biomarkers. Cron also highlighted the importance of selecting appropriate patients, with the example of the now generic anti-IL-1 antibody anakinra, which was unsuccessful in sepsis clinical trials but retrospectively shown to double survival in patients with CSS.
Repurposed antibodies: Anti-IL-6 MOA carries mechanistic rationale
Anti-IL-6 and anti-IL-1 repurposed antibodies have been useful in treating CSS, and there is anecdotal evidence of patients with other viral infections like herpes and cytomegalovirus being successfully treated with cytokine inhibitors, said Chatham. Certain viruses like Epstein Barr, mononucleosis and the H1N1 influenza strain tend to be associated with CSS, noted Cron. However, he added, there is no research on if the virus behind Covid-19—SARS-CoV-2—affects the pathophysiology of CSS.
While inhibiting IL-6 may be of use, it may also cause harm, given it has a complicated role in the inflammatory cascade, cautioned Dr Roy Brower, medical director, Medical Intensive Unit, Johns Hopkins Medicine, Baltimore, Maryland. There is a need to treat the inflammation without affecting the body’s ability to fight the virus, added Canna. Also, with Covid-19, the luxury of incrementally increasing a dose does not exist as patients deteriorate quickly via organ failure, said Dr Bhaskar Dasgupta, consultant rheumatologist, Southend University Hospital NHS Foundation Trust, Southend-on-Sea, England.
Nonetheless, the relative risk of repurposing these anti-IL-6 drugs is low, said Cron. While they are associated with liver enzyme elevations and lower platelet counts, these are not strong enough reasons to not try them if a patient is dying, he added. Actemra/RoActemra may be a better drug, since it targets the IL-6R and not IL-6 like Sylvant and Kevzara, said Morgan. Yet the different anti-IL-6 repurposed antibodies are fairly comparable, said Chatham and Morgan.
Other targets that can also be explored in clinical trials include gamma interferon, said Cron. The FDA approved Sobi’s Gamifant (emapalumab) for hemophagocytic lymphohistiocytosis (HLH) in November 2018. In addition, on 2 April, Humanigen’s anti-GM CSF antibody lenzilumab was approved under the compassionate use program for Covid-19.
Manasi Vaidya, Ayisha Sharma and Reynald Castaneda are Reporters for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.