Peg lambda cuts hospitalization, ER visits in COVID-19 outpatients

Early treatment with a single dose of pegylated recombinant IL-29 type III interferon (IFN), otherwise known as peg lambda, significantly reduced clinical events in the phase III TOGETHER study evaluating mostly vaccinated, acutely symptomatic COVID-19 outpatients.

“There was a 51-percent reduction in COVID-19-related hospitalization or emergency room (ER) retention (>6 hours) with peg lambda vs placebo,” said Dr Jeffrey Glenn from the Stanford University School of Medicine, Stanford, California, US, at CROI 2023.

The risk reduction was 58 percent among patients who presented earlier (ie, within ≤3 days of symptom onset), implying that early treatment rendered a greater effect. [CROI 2023, abstract 167]

No deaths were reported among patients who received peg lambda early.

The probability of superiority of peg lambda over placebo was 99.91 percent, which surpassed the prespecified superiority threshold of 97.6 percent.

“The primary endpoint was predominantly driven by the hospitalization component. Three-quarters of the events were hospitalizations,” said Glenn. When looking at COVID-19 hospitalization alone, the risk reductions were 43 percent for those who presented within ≤7 days of symptom onset and 65 percent for those who presented earlier.

In unvaccinated participants who received peg lambda early, the reduction in the risk of hospitalization or death was about 90 percent.

“[Moreover,] peg lambda was efficacious across all variants,” said Glenn. When stratifying by variant, reduction in the risk of COVID-19-related hospitalization of ER visits was greatest when Omicron was the prevailing variant (83 percent). During the early phase of the trial wherein Gamma was predominant, risk reduction was 25 percent.

The incidences of grade 3/4 adverse events (AEs) were comparable between peg lambda and placebo (3 percent vs 4 percent).

In patients with high baseline viral loads, median viral load decline at day 7 was greater with peg lambda vs placebo (8.2 vs 5.16 log). Half of peg lambda recipients were below the limit of quantitation by day 7, whereas with placebo, only 33 percent achieved this result.

 

Potential ‘one and done’

This adaptive-platform trial randomized >1,900 high-risk*, nonhospitalized adults (median age 43 years, 57 percent female, 84 percent vaccinated) to either one subcutaneous injection of peg lambda or placebo. The most common COVID-19 variants were Delta (46 percent) and Omicron (41 percent). About 60 percent of participants presented within 3 days since symptom onset.

 

Type III IFN receptors are much less slightly distributed in the body than the classic type I IFN receptors. “[This] underlines the thesis for lambda that it is predicted to have a much better tolerability profile, because it does not have [the type I IFN receptors] yet it retains the desired antiviral activity,” said Glenn.

 

“Our hypothesis is that one dose of lambda is well tolerated and efficacious for outpatient COVID-19 … [In light of our findings, peg lambda is a] potential ‘one and done’ strategy for newly diagnosed COVID-19 outpatients,” concluded Glenn.

 

Tremendous therapeutic potential

Apart from its Orphan Drug designation by the US FDA and EMA, and Fast Track and Breakthrough Therapy designation by the FDA for hepatitis delta virus, peg lambda has not gained approval for any indication and is still investigational.

“[Nonetheless,] peg lambda has tremendous therapeutic potential, and we continue to see the emergence of aggressive variants of the virus spreading around the globe, which are less sensitive to both vaccines and treatment with antibodies,” said co-lead investigator Associate Professor Jordan Feld from the University of Toronto, Ontario, Canada, in a press release.

“Resistance due to variants or new strains of the virus could be an issue with some therapies, but this may not be a concern with peg lambda due to its mechanism of action that involves activation of multiple virus-killing pathways,” said Feld. [www.prnewswire.com/news-releases/new-england-journal-of-medicine-publishes-positive-phase-3-together-results-with-peginterferon-lambda-in-covid-19-301742477.html, accessed February 28, 2023]