SAN FRANCISCO — A company hoping to market an inhalable formulation of interferon beta for viral lung diseases isn’t dissuaded by phase III trial results in 623 hospitalized COVID-19 patients, which showed no statistically significant benefit for its prespecified efficacy endpoints.
The findings “provide a strong clinical rationale” for additional trials because most outcomes in the randomized, placebo-controlled study trended in the product’s favor, said Philip Monk, PhD, chief scientific officer for Synairgen in Southampton, England, at the American Thoracic Society annual meeting.
But Monk acknowledged that the current trial results were disappointing, insofar as a previous phase II study had shown a clear benefit for the nebulized interferon beta-1a therapy called SGN001.
In the phase II study, odds that patients hospitalized with non-severe COVID-19 would suffer severe progression or death were reduced by more than 80% with active treatment versus placebo plus usual care (P=0.041); odds of hospital discharge were greater by 63%, though this fell short of statistical significance.
Monk explained that the rationale is that viruses tend to suppress interferon beta production that would otherwise interfere with their replication, and local delivery would both increase interferon’s activity at the site of infection (notably, a trial of injected interferon in COVID-19 showed no benefit) and minimize its notorious systemic side effects.
For the phase III SPRINTER trial, Synairgen chose time to hospital discharge as the primary endpoint. In contrast to the phase II findings, close to 90% of patients in both the active-treatment and placebo groups had recovered by day 28, with little separation in Kaplan-Meier curves over time in an intention-to-treat (ITT) analysis. No significant benefit was seen either for secondary endpoints including risk of severe disease, intubation, or death, and this was true both in ITT and per-protocol analyses.
The phase II study was conducted in 2020, whereas SPRINTER ran from January to November 2021, and Monk said that may be a factor in the disparate results. About 25% of patients in the new trial were vaccinated, and of course “usual care” had changed considerably over time. As a result, the placebo group did better in SPRINTER — fewer than 40% of the phase II placebo group had recovered by day 28.
While the finding that nearly 90% of patients in SPRINTER recovered with placebo may suggest diminished need for additional therapy in COVID-19, Monk argued that there could still be a role for inhaled interferon in this and other viral lung diseases.
He pointed to post-hoc analyses of the SPRINTER data that did suggest benefit. For one thing, differences between groups did increase in per-protocol analysis versus ITT. About 10% of each group did not receive at least two full doses of interferon in the first 3 days of treatment as prescribed, and another 5% left the hospital for reasons other than recovery from COVID. When those patients were excluded, patients receiving the treatment showed 32-41% reductions in risk of severe progression, intubation, and death.
“Subgroup analyses increase confidence that SGN001 is having a beneficial effect with respect to prevention of progression,” Monk said.
Kaplan-Meier curves indicated that recovery was faster with interferon therapy, with clear separation between active treatment and placebo for most outcomes during days 10-20. The gap closed again by day 28.
One unquestionably favorable finding from the study was that SGN001 appeared safe. Serious treatment-emergent adverse events were more common in the placebo group, including those related to infections and respiratory/thoracic symptoms as well as overall.
Synairgen hasn’t yet publicly committed to another phase III study for hospitalized patients. However, one of the ongoing “adaptive” treatment trials for COVID-19 outpatients, called ACTIV-2, now includes SGN001 as one of the therapies being tested. Monk also emphasized that SGN001’s hypothesized mechanism should give it potential in many if not all viral lung diseases.
Patients were eligible for the study if they were adults with PCR-confirmed COVID-19, hospitalized with supplemental oxygen through masks or nasal prongs but without more aggressive respiratory support. Those with previous SARS-CoV-2 infection or evidence that the current infection had lasted more than 3 weeks were excluded, as were those in intensive care.
SGN001 was to be administered once daily via nebulizer for up to 14 days, at doses of 15.6 MIU. Patients were randomized 1:1 to the active treatment and placebo arms.
Mean patient age was about 53, two-thirds were men, and just over 70% were white. Half the patients had at least one comorbidity; roughly 40% were obese. The study was conducted in 17 countries in Europe, North America, India, and South America.
Background treatment included systemic steroids for about 87% of participants, and remdesivir (Veklury) for some 20%.
SPRINTER was funded by Synairgen. Monk and some other co-authors are company employees.