Safety and Efficacy of CR6261 in an Influenza A H1N1 Healthy Human Challenge Model

Abstract

Background It is imperative to identify new targets for improved vaccines and therapeutics against influenza and one such target is the relatively conserved stalk region of the influenza A hemagglutinin (HA) surface protein. Methods We conducted a randomized, double-blind, Phase II placebo-controlled trial of a monoclonal antibody that targets the HA stalk (CR6261) in a H1N1pdm09 healthy volunteer human challenge model. A single 50mg/kg dose of CR6261 was infused 24 hours after challenge and the primary efficacy outcome was area under the curve of viral RNA detection over time. Results Ninety-one healthy volunteers were randomized and underwent influenza challenge; 49 received CR6261 and 42 placebo. CR6261 had no statistically significant effect on AUC (AUC 48.56 log (copies/mL) x days, IQR 202 vs. AUC 25.53 log (copies/mL) x days, IQR 155), P=0.315), and no clinically significant effect on influenza disease measures including number of symptoms, duration of symptoms, or FLU-PRO scores. Preexisting anti-NA antibody titers were most predictive of reduced influenza disease. CR6261 reached a mean peak serum concentration of 1x10 6 ng/ml 15 minutes after infusion, and a mean peak of 5.97x10 2 ng/ml in the nasal mucosa 2-3 days after infusion. Conclusions The results of this study suggest that a monoclonal anti-stalk approach to prevent or treat influenza infection may be limited in efficacy. Future approaches should consider including and evaluating anti-stalk antibodies as part of a multi-faceted strategy rather than as a standalone therapeutic.

Stable nebulization and muco-trapping properties of Regdanvimab/IN-006 supports its development as a potent, dose-saving inhaled therapy for COVID-19

“…Prior studies of antiviral mAbs for treatment of ARIs have encountered substantial roadblocks in clinical translation, likely due to inefficient and inadequate transudation of systemically administered mAb into the respiratory tract. Indeed, in a clinical study of CR6261 (an anti-influenza mAb) [21], the C max in the nasal swab samples was not achieved until Day 2-3 following IV dosing, in stark contrast to peak serum concentrations of 1×10 6 ng/ml reached within 15 minutes after infusion. More importantly, the mean peak concentration of CR6261 from nasal swabs was only ~ 600 ng/ml, or ~ 1,700-fold lower concentrations in the nasal mucosa than in plasma [21].…”

“…Indeed, in a clinical study of CR6261 (an anti-influenza mAb) [21], the C max in the nasal swab samples was not achieved until Day 2-3 following IV dosing, in stark contrast to peak serum concentrations of 1×10 6 ng/ml reached within 15 minutes after infusion. More importantly, the mean peak concentration of CR6261 from nasal swabs was only ~ 600 ng/ml, or ~ 1,700-fold lower concentrations in the nasal mucosa than in plasma [21]. CR6261 is not alone in its limited distribution into the lung airways; mAbs are large molecules with generally small volumes of distribution that tend to remain in the serum and peripheral fluids in the absence of mechanisms of active transport.…”

“…Given the concentration of SARS-CoV-2 in the respiratory tract, and the resulting respiratory tract symptoms and morbidities, direct delivery of potent neutralizing mAbs to the site of infection should have been preferred. Nevertheless, every antiviral mAb that has received full approval or EUA to date is dosed either by intravenous infusion or subcutaneous/intramuscular injections, despite prior studies showing only a small fraction of systemically dosed mAb reaches the respiratory tract in animal models [17][18][19][20] and in human studies [21]. The lack of efforts advancing inhaled delivery of mAb is likely due in part to prior work suggesting mAbs can aggregate and lose binding activity following nebulization [22,23].…”

Strategies Targeting Hemagglutinin as a Universal Influenza Vaccine

“…In contrast, another study using human samples demonstrated that there was no significant correlation between stalk antibodies and protection from influenza virus infection after adjustment for head-specific antibodies [69]. In addition, a phase II trial examining the therapeutic efficacy of a monoclonal stalk-directed antibody showed no clinically significant effect on influenza disease [70]. These conflicting results draw into question the protective efficacy of these anti-stalk antibodies in humans.…”

Respiratory Viruses in Solid Organ Transplant Recipients

“…Several monoclonal antibodies targeting various hemagglutinins of influenza virus have been developed [44]. These were tested in phase two studies as monotherapy or in combination with antiviral drugs, showing mixed results [45,46].…”