FDA Approves Prophylactic Respiratory Syncytial Virus Immune Globulin
[From Antiviral Agents Bulletin, February 1996].
Respiratory Syncytial Virus Immune Globulin Intravenous (Human) from MedImmune, Inc. (Gaithersburg, MD) has received FDA approval for prevention of respiratory syncytial virus (RSV) disease, primarily pneumonia, in infants less than 24 months old having bronchopulmonary dysplasia (BPD) or a history of prematurity (² 35 weeks gestation). This is the first agent available for RSV disease prophylaxis and the first shown safe and effective for reducing the incidence and severity of pneumonia and other RSV disease. Respiratory Syncytial Virus Immune Globulin Intravenous (Human), also referred to as RSV-IGIV, will be marketed under the trade name RespiGam. Recent clinical trials with RespiGam were discussed in the August 1995 Bulletin (p. 228). Compared to controls, RespiGam reduced RSV-associated hospitalizations by 40.6%, total hospital days by 53% and total RSV-associated intensive care unit days by 44%.
The Massachusetts Public Health Biologic Labs. produces RespiGam for MedImmune and is the holder of the Product License Application (PLA). RespiGam consists of purified pooled immune globulin having high titers of RSV antibodies obtained from screened plasma donors. The immune globulin is virus inactivated and purified using the Cohn-Oncley cold ethanol precipitation process. With careful donor screening, detergent-based viral inactivation and ethyl alcohol precipitation, risk for transmission of pathogenic viruses from RespiGam is negligible. RespiGam is administered intravenously in five monthly doses, with the first dose optimally administered before the RSV epidemic season (early November-April). It may be administered in an out-patient clinic or hospital setting, and adverse effects are comparable to intravenous infusion of other immune globulins.
RespiGam will be marketed in the U.S. by Wyeth-Ayerst Labs., a subsidiary of American Home Products Corp. (AHP; Philadelphia, PA), and MedImmune. The full AHP vaccine and pediatric sales forces will co-promote RespiGam along with MedImmuneÕs own sales force. Sales in the U.S. began on January 26, and RespiGam is expected to achieve only Òvery modest salesÓ during this yearÕs RSV season. MedImmune is focusing its marketing efforts and preparing for a full product launch in the fall. The average wholesale cost for a course of treatment ranges from $3,334 to $5,251 (average, $4,543), depending on the weight of the infant. With its proven reductions in serious disease incidence and hospitalization, this compares favorably with the cost of treating an infant with serious RSV, which can cost up to $70,000. Upon approval, MedImmune received a $4.5 million milestone payment from AHP. MedImmune has an agreement with Baxter Healthcare Corp. (Chicago, IL) for marketing of RespiGam outside North America. MedImmune will be conducting a post-marketing (Phase IV) trial to provide further data regarding efficacy in certain infant populations. In related news, MedImmune recently amended its agreement with Connaught Labs. (Swiftwater, PA) to reduce its royalties on CytoGam, cytomegalovirus immune globulin, making a lump-sum payment of $2.7 million. The company recently increased its sales staff from 16 to 56 to handle RespiGam and CytoGam sales.
RespiGamÕs path to FDA approval has not been direct or simple. As discussed in the December 1993 Bulletin (p. 353), the FDA Blood Products Advisory Committee originally voted unanimously against approval of RespiGam despite a 249-infant Phase III trial (Groothius trial) and most specialists concluding that the product was safe and effective for RSV prophylaxis in high-risk infants (with bronchopulmonary dysplasia and in premature infants). An unexplainable high level of efficacy was observed at the major trial site and enrollment procedures apparently compromised blinded assignment of infants to treatment vs. placebo groups. At the time of this initial review, FDA staff concluded that available data confirmed that RespiGam reduced the frequency and severity of RSV lower respiratory tract infections. However, the review committee concluded that the design and execution of the pivotal Phase III trial was flawed and, thus, could not support approval. FDA followed these recommendations. MedImmune subsequently continued two Phase III prophylaxis trials and began another in late 1994. Altogether, clinical trial data submitted to support approval included four prevention trials involving 80 medical centers, over 1,250 children and over 2,500 infusions. During the course of clinical trials, MedImmune dropped efforts to obtain approval of RespiGam for RSV treatment indications.
RSV is the most common cause of lower respiratory tract infections in infants and children and is the leading cause of pneumonia and bronchiolitis in infants. It is responsible for over 90,000 hospitalizations and 4,500 deaths annually in the U.S. Severe RSV disease primarily occurs in infants born prematurely and those with bronchopulmonary dysplasia. RespiGam is the first preventive treatment available for RSV disease. Aerosolized ribavirin (Virazole) from ICN Pharmaceuticals Inc. (Costa Mesa, CA) is available in the U.S. for treatment of RSV disease. RSV is endemic in the general population and is commonly spread through respiratory secretions, including sneezing, coughing and hand to mouth or nose contact. Despite strict infection controls in hospitals and other nursery facilities, hospitalized and other infants are still liable to develop RSV infection that can lead to serious disease. As discussed in the October 1995 Bulletin (p. 294), a RSV monoclonal antibody (HNK20) from OraVax, Inc. (Cambridge, MA) in a nose drop formulation has shown indications of potential efficacy for prevention of RSV infections in infants. MedImmune is also working with AHP on development of MEDI-493, a humanized RSV monoclonal antibody, which may eventually replace RespiGam.