COVID-19 Pursuit With Interferons by Synairgen, Merck KGaA and Eiger Hinges on Early Treatment; Synairgen’s Inhaled Route Attractive for at-home Use, Experts Say

Published : 10 Oct 2020

COVID-19 studies evaluating recombinant interferon beta-1a by Synairgen (LSE: SNG) and Merck KGaA (ETR: MRK), and Eiger Biopharmaceuticals’ (NASDAQ: EIGR) peginterferon lambda, offer tantalizing mechanistic support experts said, but noted early intervention is necessary.

Intervening in nonhospitalized COVID-19 patients or those with mild disease may offer the best chance for any of the interferons to mount a successful antiviral response based on preclinical and clinical experience with interferons. Synairgen’s SNG001 Phase II (NCT04385095) cohorts are specifically focused on hospitalized patients, and experts noted strong efficacy would only be expected if the disease has not progressed enough for the patient to need oxygen support.

However, the ACCT-3 trial does allow the recruitment of those needing supplemental oxygen and excludes those who may be discharged within 72 hours. Synairgen’s hospitalized cohort excludes those who are ventilated or in the intensive care unit (ICU). The six investigator-led studies of Eiger’s peginterferon lambda enrolled a mix of hospitalized and nonhospitalized patients.

Furthermore, as these trials include more severe patients, combinatorial corticosteroid use would need to be avoided given the experience with interferons in acute respiratory distress syndrome (ARDS), one expert noted. However, given the natural production of interferons and cortisol in severe infections, their concomitant use should not be a challenge in COVID-19, another expert said.

Phase II data with Synairgen’s SNG001 in hospitalized patients piqued expert interest. On 20 July, Synairgen’s shares skyrocketed 420% after it released Phase II data from the 100-patient hospitalized cohort. The study is now enrolling 120 nonhospitalized patients, with a primary completion date in 2021. Nonhospitalized patient data from one of the peginterferon lambda studies is expected in a few weeks, this news service reported on 21 September.

The 1,038-patient ACCT-3, which was announced on 5 August, has a primary completion date is November 2023, and is evaluating Rebif with Gilead Sciences’ (NASDAQ: GILD) antiviral Veklury (remdesivir). Experts backed this potential combinatorial efficacy given the distinct mechanisms by which both would act against viral infection.

Due to the lack of data with interferon lambda, it is unclear which interferon type would be most suitable for COVID-19, but interferon lambda’s theoretical specificity to epithelial cells could afford it safety advantages, experts said. Based on available data and the short duration of exposure in the ongoing studies, the safety profile of interferon-beta-1a in COVID-19 is expected to be similar to multiple sclerosis (MS) population, said a Merck KGaA spokesperson.

Synairgen and Eiger did not respond to a request for comment. Synairgen’s market cap is GBP 240.59m (USD 311.24m), while Eiger’s is USD 236.14m and Merck KGaA's is EUR 16.37bn (USD 19.17bn).

Interferon use earlier in the course of the disease expected to have a better potential

While experts support exploring recombinant interferons in COVID-19, they emphasized the need for early intervention. It is unknown whether interferons can be effective once a patient reaches a severe disease stage, because, at such a time, the disease is not driven by only the virus, said Dr. Jordan Feld, senior scientist, Toronto General Hospital Research Institute, Canada.

Clinical experience in COVID-19 indicates the early use of recombinant interferons is beneficial in COVID-19 and using them late can be detrimental, said Ivan Zanoni Ph.D., assistant professor of Pediatrics, Harvard Medical School, Boston. In SARS-CoV-1, a 446-patient retrospective cohort showed early interferon-a2b administration was associated with reduced in-hospital mortality, late therapy-increased mortality, and delayed recovery, he noted (Wang et al. [2020] Cell Host & Microbe, 28, pp. 455–464).

As such, Synairgen’s trial cohort focused on nonhospitalized patients and could have a stronger potential compared to the hospitalized cohort or ACCT-3, experts noted. However, Synairgen’s nonhospitalized cohort is focused on high-risk patients, defined as those ages 65 years or older or 50 years and older with a risk factor like arterial hypertension, chronic lung disease, kidney disease, or continuous cough. This criterion may have been included, because most young people without risk factors have mild symptoms or none, making it difficult to assess the potential beneficial effects of interferon-beta in this population, said Dr. Sirpa Jalkanen, professor, Institute of Biomedicine, University of Turku, Finland. With most drugs, side effects tend to be worse in older people, said Feld. However, while there is not as much experience with interferons in the elderly, there is no reason to think it should be much worse than what has been observed in the younger population, he added.

The risk with interferon-alpha and beta is these type 1 interferons are found in every part of the body and could cause off-target side effects, said Feld, an investigator running a clinical trial with Eiger’s interferon lambda. Type 3 interferons like lambda are specifically active on epithelial cells found in the lungs, liver, and intestine, he explained. However, no hyperimmune reaction cases were observed in the Phase II SNG001 study, said investigator Dr. Dinesh Saralaya, director, National NIHR Patient Recruitment Centre, Bradford, UK.

There is also a concern about how the use of type 1 interferons may worsen the severe cytokine storm syndrome seen in more severe COVID-19, said Feld, adding interferon lambda is not expressed on inflammatory cells. Nonetheless, interferon lambda trials in the later disease stage are still worthy, as they can pinpoint how deep into the disease interferon lambda can potentially offer efficacy, said Dr. Scott Friedman, dean for therapeutic discovery, Icahn School of Medicine, Mount Sinai, New York.

Interferons can potentially be used until a patient is likely to be transferred to the ICU or the condition progresses to the need for respiratory support, said Jalkanen. The National Institutes of Health (NIH) trial includes patients who have already had COVID-19 for any period of time even but excludes those already on or being prepared for extracorporeal membrane oxygenation (ECMO).

Antiviral combination sound, but concomitant steroid use triggers divided perspectives

Interferons are produced in response to viral infections, said Feld. Due to their nonspecific nature, there is no risk for resistance, Feld added. While not approved, interferon lambda was studied in hepatitis B and was found to be safe, but the advent of effective oral antivirals resulted in the latter’s adoption, he added. The rationale for its Phase III Rebif study and the NIH cited laboratory findings and two small randomized controlled trials.

Regarding the NIH’s approach of assessing Rebif/Veklury, the combination is rational since the former can provide a nonspecific response and the latter can be a direct antiviral, said Feld. Another role of interferon-beta is to activate CD73, which leads to adenosine production required to keep blood vessels intact, said Jalkanen. Other antivirals may act against SARS-CoV-2 but will not prevent vessel leakiness, she added.

However, clinicians will have to remember severe patients may be on other drugs, which could negatively impact interferon use. Jalkanen emphasized. A Phase III ARDS study (NCT02622724) testing Faron Pharmaceuticals’ (LON: FARN) interferon beta FP-1201 versus placebo showed no difference in a composite score, which included death or ventilator-free days (Ranieri et al; 17 February 2020, JAMA 323(8):725-733).

Later analysis indicated those who received steroids and interferon-beta had higher mortality, said Jalkanen. Further in vitro analyses indicated corticosteroids inhibited interferon-beta signaling, she explained.

If dexamethasone is part of standard care for any patient, Jalkanen advised against the use of interferons. However, Feld disagreed, noting both cortisol and interferon beta are produced naturally and usually in the context of severe infection, so steroids and interferons are unlikely to be contraindicated. Rebif’s interaction with corticosteroids has not been studied systematically, said the Merck KGaA spokesperson, adding clinical studies and practice suggest MS patients experiencing a relapse can receive Rebif and corticosteroids at the same time.

ACCT-3 excludes the use of drugs targeting cytokines or tyrosine kinases and other products like convalescent plasma, but the ClinicalTrials.gov page does not guide the use of steroids. Synairgen’s trial registry page also does not describe the exclusion of patients on specific drugs. Dexamethasone is strongly recommended for critically ill patients, defined as those on mechanical ventilation and ECMO, as per the Infectious Diseases Society of America guidelines which are based on results from the Phase III RECOVERY trial (NCT04381936).

Optimal administration route unclear, but nebulizer most attractive for nonhospitalized patients

Rebif is administered through a subcutaneous injection, while Synairgen’s SNG001 is an inhaled interferon beta delivered via an I-neb device. Friedman said it was not clear if direct delivery into the lungs will have the maximum effect. However, Jalkanen said concerns remain about how the subcutaneous route may not allow the drug to reach the lungs adequately, and an intravenous method may be preferred. 

Using a nebulizer can, however, be difficult for those already on a continuous positive airway pressure (CPAP) machine or a ventilator, said Saraya. Moreover, nebulized treatments in a closed space can put healthcare workers in the ICU at risk, but it is appealing in the outpatient setting, noted Friedman. Inhaler devices are now better controlled, so the administered dose, so home treatment is an option to consider, said Jalkanen. However, the patient’s condition may be indecisive, since those with the mild disease might have better penetration compared to those with a lot of mucus in their lungs, she added.

While Synairgen’s Phase II data in hospitalized patients note the inhaled route holds promise, the sample size was small, precluding conclusions, said Jalkanen. Among 101 patients, the risk for the development of severe disease requiring ventilation or death was reduced by 79% for patients on SNG001 compared to those on placebo (p=0.046), as per a 20 July press release. Additionally, patients were more than twice as likely to recover, defined as ‘no limitation of activities’ or ‘no clinical or virological evidence of infection’ (p=0.043).

Source: GlobalData.com