Efficacy, Safety, and Pharmacokinetics of a New 10 % Liquid Intravenous Immunoglobulin Containing High Titer Neutralizing Antibody to RSV and Other Respiratory Viruses in Subjects with Primary Immunodeficiency Disease

Wasserman, Richard L.; Lumry, William; Harris, James; Levy, Robyn; Stein, Mark; Forbes, Lisa; Cunningham-Rundles, Charlotte; Melamed, Isaac; Kobayashi, Ai Lan; Du, Wei; Kobayashi, Roger

Among the viral infections that cause substantial morbidity, respiratory syncytial virus is a particular problem, especially in patients with coexistent pulmonary disease [19, 20] . In 1996, an anti-RSV hyper-immune globulin product, RSV-IVIG (RespiGam®), was approved for the prevention of severe respiratory syncytial virus infection in premature infants whose gestational age was less than 32 weeks. Studies suggested that RSV-IVIG reduced disease severity in infants who became infected with RSV, shortening hospital stays compared to age-matched controls [15, 16, 21] . Despite these beneficial effects, RSV-IVIG was voluntarily removed from the market by the manufacturer in favor of an intramuscularly administrated monoclonal anti-RSV antibody palivizumab (Synagis®). There are no direct head to head clinical studies comparing the efficacy of RSV-IVIG to palivizumab [17] . While both appear comparable in their ability to prevent RSV infections in low birth weight infants, there appear to be certain clinical advantages of the polyclonal antibody [17] . In the PREVENT study, not only was RSV-IVIG able to prevent RSV infections but it also reduced the incidence of other, non-RSV-related upper respiratory diseases [15] . Another study demonstrated that high-risk infants receiving RSV-IVIG had a statistically significant reduction in the overall frequency of otitis media compared with placebo-treated subjects, also suggesting that polyclonal antibody activity to other pathogens may have contributed to this reduction observed in the incidence of otitis media [21] . Interestingly, in the current study, there was only one single reported case of otitis media, an exceedingly low incidence for this population of subjects in the study. Recently published studies in the cotton rat demonstrated that RI-002 can not only reduce the viral load in normal and immune suppressed cotton rats that have been infected with RSV, but that it can dramatically reverse the intense inflammatory changes that are observed in their pulmonary tissue [22] . Because of the historical data suggesting the potential value of a polyclonal anti-RSV, IG product for the immunecompromised patient population, a new Ig formulation was developed. The new product, RI-002, is an IVIG that is manufactured and standardized to contain elevated levels of anti-RSV neutralizing antibody and, in this regard, is comparable to RespiGam® [22] [23] [24] . However, this new product has the added advantage that it is manufactured to comply with the FDA guidance for IG products for the treatment of patients with PIDD [18] . Similar to other IGs, this IVIG (RI-002) was made from plasma collected from more than 1000 plasma donors and was manufactured using an FDAapproved fractionation and purification process [25, 26] . Unlike other IGs, the plasma that was used to produce RI-002 was collected from donors who were identified and selected to have high neutralizing antibody titers to RSV. The selection was based on testing results obtained utilizing a validated RSV live-virus microneutralization assay. There was as great as a 6.79-fold increase in the levels of anti-RSV neutralizing antibody that was measured in subjects who were on the dosing regimen of greater than 500 mg/kg. Interestingly, the lots of IVIG produced from RSV hyperimmune donors were also found to have significantly elevated antibody titers to other respiratory viruses (parainfluenza type 1 and 3, influenza, coronavirus, and metapneumovir