Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study in Healthy Volunteers to Evaluate the Efficacy and Safety of CR6261 in an H1N1 Influenza Healthy Human Challenge Model

The high morbidity and mortality associated with both pandemic and seasonal influenza and the threat of new potentially pandemic strains emerging makes influenza an important infectious disease and public health problem. Mean annual estimates of influenza deaths due to seasonal influenza alone attributes up to 49,000 deaths in the US and 250,000 to 500,000 deaths in industrialized countries to influenza. Pandemics can have an even more devastating effect. Public health agencies must continue to be prepared by making attempts to reduce the public health impact of this important virus.

In the realm of influenza therapeutics, antiviral drugs are currently used to treat influenza infection in those who fail to be protected by current vaccines or those who do not receive a vaccine. Currently, only two classes of antivirals are FDA approved for the treatment of influenza A: neuraminidase inhibitors and matrix M2 channel blockers. Although these drugs have been shown to be effective in reducing influenza illness by 24-48 hours and reducing shedding in relatively healthy adults, as with vaccination, they have had limited effectiveness in high risk groups and those who have severe or complicated influenza infections. In addition, antiviral resistance has become very common in human influenza A viruses, as currently circulating H1N1 and H3N2 strains are resistant to the adamantane M2 channel blockers and many cases of neuraminidase inhibitor resistance have also been reported with strains of both subtypes. This resistance can develop quickly and in most cases only requires a single amino acid change. Given these significant issues with currently available treatments, novel therapies for influenza are clearly needed.

Live virus challenge studies have played a pivotal role in developing influenza therapeutics in the past, and they will be instrumental in the future. No novel therapeutic or prophylactic agent has been FDA-approved since the last influenza challenge studies ceased over a decade ago. In collaboration with the Crucell Vaccine Institute (part of Crucell which is in the Janssen family of Pharmaceutical Companies of Johnson & Johnson) this protocol will evaluate mAb CR6261 for possible therapeutic value. Unlike the current antivirals that are compounds which interfere with some portion of the viral replicative cycle, this agent is a mAb that targets the stem of HA, neutralizing the virus by stabilizing the pre-fusion state and preventing the pH-dependent fusion of viral and cellular membranes. Pre-clinical data suggest that this mAb has good cross-protective efficacy with a variety of HA subtypes unlike current vaccines, making it potentially effective in the event of an emerging influenza virus outbreak with a novel HA subtype. In addition, the conserved nature of the HA stem region suggests that amino acid changes conferring resistance are much less likely. We will effort to demonstrate that CR6261 leads to improved outcomes compared with placebo with respect to the AUC of virus shedding as determined by qPCR in NP swabs in all treated subjects.