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1 Page 2 Medlmmune, Inc. Name ofactive Ingredient: PROTOCOL SYNOPSIS Title: A Phase II Study ofthe Safety, Tolerance,Phannacokinetics,and Effect on Viral Load in Tracheal Aspirates ofmedi-493, a Humanized Monoclonal to Respiratory Syncytial Virus, in Children on Mechanical Ventilation for Respiratory Syncytial Virus Infection Investigators: Study Centers: See Appendix Six investigators participated. See Appendix Six clinical centers participated. Publication (reference): None Studied Period: Date offirst enrollment: 12/19/96 Date of last completed: 05/05/97 Phase ofdevelopment: Phase II Objectives: Primary: To measure the effect ofa single intravenous dose of 15 mg/kg MEDI-493 on quantitative RSV cultures oftracheal secretionsfrom intubated infants with RSV infection and to evaluatethe safety ofmedi-493 comparedto placebo. The effect on quantitative RSV cultures was determined by comparing the change in the mean log plaque forming units from baseline to day 1 between the MEDI-493 and placebo groups. Secondary: To obtain preliminary data regarding the effect of MEDI-493 treatment on the duration of hospitalization for RSV and on the duration ofmechanical ventilation. To compare the results obtained from an experimental quantitativeelisa for RSV with those obtained from quantitative RSV cultures of specimens from the upper and lower respiratory tracts. To conduct initial exploratory evaluations of measures of inflammatory response in pulmonary secretions. To detennine the levels ofmedi-493 in pulmonary secretions ofrsv-infectedpatients after a single intravenous dose and to relate those levels to serum levels ofmedi

2 Page 3 MedImmune, Inc. Methodology: This was a randomized, double-blind, placebo-controlled, single-dose clinical trial. Number of Patients: Planned number of patients: 36. Thirty-five patients were enrolled and analyzed. Diagnosis and Main Criteria for Inclusion: Children less than 24 months of age at randomization, with RSV detected from respiratory secretions within 48 hours prior to randomization, and intubated and receiving mechanical ventilation for less than 24 hours prior to randomization were included. Those with hemodynamically significant cardiac abnormalities or who had required oxygen for the management ofbronchopulmonary dysplasia for more than seven days in the three months prior to randomization were excluded. Test Product, Dose and Mode of Administration, Batcb Number: Drug: HumanizedRespiratory SyncytialVirus Monoclonal (MEDI-493,palivizumab) Dose and form: MEDI-493 is suppliedas a sterile liquid fonnulatedin phosphatebufferedsaline without preservativeat a concentration of 10 mglml in a 10 ml vial. Patients received a single infusion of 15 mglkg. Lot number: L95KOl7 Administration: Intravenous infusion Duration oftreatment: Participants received a single intravenous dose (15 mg/kg) on the day ofrandomization. They were followed for 30 days after the infusion for safety parameters and clinical outcome. Reference Therapy, Dose and Mode ofadministration: Drug: Placebo Dose and form: 0.9% normal saline Administration: Intravenous infusion 2239

3 Page 4 Medlmrnune. Inc. Criteria for Evaluation: Safety: Safety was evaluated by examining adverse events, laboratory parameters, infusion history, vital signs and measures ofduration and severity ofhospitalization including total hospital days, days ofmechanical ventilation and days of supplemental O 2, Activity: The effect of MEDI-493 treatment on RSV levels in tracheal aspirates was assessed by quantitative culture. The change in mean log plaque forming units from baseline was compared between treatment groups. The primary endpoint assessmentwas comparison between groups of the mean change from day 0 to day 1. MEDI-493 Levels: MEDI-493 levels were determined by ELISA. Immunogenicity: Anti-MEDI-493 binding activity was determined by ELISA. Statistical Methods: All randomized patients were included in all analyses. Data were analyzed by either enumeration of patients displaying distinctive characteristics within each dose group, or, for continuous measures, by descriptive statistical summaries such as means, standard errors and ranges. Tests ofsignificance were by the Wilcoxon rank sum test or Fisher's exact test as appropriate. Summary and Conclusions: Study Conduct: This Phase II, randomized, double-blind, plac~bo-controlledstudyin children being mechanically ventilated for respiratory disease due to RSV was conducted to determine the safety and effect of MEDI-493 on levels ofrsv in tracheal aspirates. Children hospitalizedwith RSV infection and intubated and started on mechanical ventilation less than 24 hours before enrollment were randomized to receive a single infusion of 15 mglkg of MEDI-493 or an equivalent volume of placebo (normal saline). A total of35 children(l8 placebo and 17 MEDI-493) were randomized at six study centers. Randomization began on December 19, 1996 and ended on April 6, The median age at study entry was 1.7 months in the placebo group and 3.2 months in the MEDI 493 group. Study participants had a mean gestational age of35.9 weeks in the placebo group and 34.1 weeks in the MEDI-493 group. Only one child, in the placebo group, had a history of BPD. No children were currently being treated for BPD. 2240

4 PaQe 5 Medlrnmune, Inc. Serum MEDI-493 Levels: Serum concentrations one day after infusion of 15 mglkg ofmedi-493 were well above those (25-30 J.LglmL) which result in a 2 log reduction ofpulmonary RSV in the cotton rat prophylaxis model ofrsv. The mean serum concentration one day after infusion was J.LglmL. Thirty days after the infusion, the mean serum concentration was 34.9 J.LglmL. Quantitative RSV Cultures: Treatment with 15 mglkg MEDI-493 intravenously was associated with a significant reduction ofthe amount ofrsv in tracheal secretions. For patients who had both a day 0 and day 1 result, the mean loglo pfulml in the placebo group declined from 4.7 on day 0 to 4.1 on day 1, and in the MEDI-493 group from 4.8 on day 0 to 3.1 on day 1. The mean decline in log pfu from day oto day 1 was 0.6 in the placebo group and 1.7 in the MEDI-493 group, which is a 1.1 log greater decline in the treated patients (p=o.004 Wilcoxon rank sum test). The result was not influenced by gender, race, age or weight at study entry, or gestational age. The effect of MEDI-493 on RSV load in nasal aspirates was also evaluated. In contrast to the effect seen on RSV in tracheal secretions, there was no significant difference between groups in the change from baseline to days 1, 3, 7 or 30 of log,o pfu in nasal aspirates. Safety: MEDI-493 appearedto be safe inthispopulationofchildrenwho requiredmechanicalventilation for RSV infection. Twenty-sevenof35 patients in the study had a total of76 reported AEs. The AEs were generally those expected in children hospitalized with RSV lower respiratory tract infection ofsufficientseverity to require mechanical ventilation. The AEs were balanced between treatment groups. No AEs werejudgedby the blinded study investigatorsto be possibly, probably or definitely related to study drug. There was one death, from progressive respiratory failure and ARDS, in a child in the placebo group. Thirteen SAEs, six in the placebo group and seven in the MEDI-493 group, were reported among 11 children: six placebo and five MEDI-493. Two children in the placebo group (including the fatality) and four children in the MEDI-493 group had reported SAEs in the respiratory system. There were no clinically relevant trends in chemistries, vital signs, or physical findings. Laboratory AEs were balanced between the placebo and MEDI-493 groups. Evaluation of RSV hospitalization parameters did not demonstrate statistically significant differences between the MEDI-493 and placebo groups in mean days of hospitalization, n-tean days ofmechanical ventilationor mean days ofsupplemental02. A Kaplan Meier analysis ofthe time to discharge from hospital, time to end ofmechanical ventilation, and

5 Page 6 MedImmune, Inc. ofthe time to cessation of supplemental O 2 also did not show any significant difference benveen the placebo and MEDI-493 groups for these parameters. Conclusions: In summary, treatment with 15 mglkg MEDI-493 intravenouslywas associated with a significant reduction amount of RSV in tracheal secretions. After a single intravenous infusion of 15 mglkg MEDI-493, the 10g\0 pfu in tracheal aspirates declined from 4.8 to 3.1 from day 0 to day 1 compared to a decline from 4.7 to 4.1 in the placebo group. This is a difference of 1.1 (p=o.004). No significant effect was observed on RSV titers in nasal aspirates. MEDI-493 appeared to be safe and well tolerated in these children. Date of Report: October 9, 1997