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Placebo Enrolled Group vs All UPMC Unenrolled Who Survived > 30 Days Posttransplant

Chiron Briefing Document Figure 4.3.1.2-1. Placebo Enrolled Group vs All UPMC Unenrolled Who Survived > 30 Days Posttransplant. 100. 90. 80. 70. 60. P = .9908. Survival (%). 50. 40. 30. Placebo (n = 30) Screen failures > 30 days (n = 45). 20. 10. 0. 0. 6. 12. 18. 24. 30. 36.

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Placebo Enrolled Group vs All UPMC Unenrolled Who Survived > 30 Days Posttransplant

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  1. Chiron Briefing Document Figure 4.3.1.2-1 Placebo Enrolled Group vs All UPMC Unenrolled Who Survived > 30 Days Posttransplant 100 90 80 70 60 P = .9908 Survival (%) 50 40 30 Placebo (n = 30) Screen failures > 30 days (n = 45) 20 10 0 0 6 12 18 24 30 36 42 48 54 60 Time posttransplantation (months) UPMC = University of Pittsburgh Medical Center.

  2. Chiron Briefing Document Figure 3.2.3-2 Representative Gamma Scintigraphy in a Double-Lung Transplant Recipient Mouth Trachea andesophagus Left lung Right lung Stomach Esophagus

  3. FDA Analysis of BOS • FDA censors death in their BOS analysis • Informative censoring = flawed methodology • All time-to-event techniques assume reason for censoring independent of endpoint • All deaths disease related; thus, FDA analysis biased • Contrary to April 2005 FDA-issued guidance • The effect of CyIS is significant on BOS-free survival (P = .019) and OB/BOS-free survival (P = .001)

  4. Changes in FEV1 • FEV1 was investigated by a number of methods: • Change from baseline to final, change from posttransplant peak to final, time-adjusted AUC, and slopes • Using both liter values and percent predicted • All FEV1-based endpoints showed directional effects favoring CyIS • None reached statistical significance • Example: Mean and standard errors of change from baseline to final: • Placebo: +0.15  0.09 L • CyIS: +0.40  0.13 L • P = .45 in an ANOVA model controlling for transplant type

  5. Changes in FEV1 • Limitations of the FEV1 data: • Informative censoring occurred. Over time more FEV1 missing from Placebo due to higher mortality • FEV1 is highly variable and confounded with transplant type • CyIS did demonstrate a statistically significant effect (P = .019) on BOS-free survival

  6. Chiron Briefing Document Figure 1.3.2-1 Survival All CSI—Rather Than CyIS Random ie, Including the Pilot-Phase Patients 1.0 0.9 0.8 0.7 0.6 Survival probability 0.5 Relative risk = 0.349 P = .018 0.4 0.3 CyIS Placebo 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 Time (months)

  7. SS-7

  8. Chiron Briefing Document Figure 1.3.2-1 Time to OB—Deaths Censored 1.0 0.9 0.8 0.7 0.6 OB-free probability 0.5 P = .060 0.4 0.3 CyIS Placebo 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 Time (months)

  9. PG: Long-term Safety • Defined versus objective clinical endpoint (survival) with matched controls in UNOS versus PG (placebo) CyIS 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 Survival probability 0.5 0.5 0.4 0.4 0.3 0.3 CyIS UNOS matched controls ACS001 placebo UNOS matched controls 0.2 0.2 0.1 0.1 0.0 0.0 0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60 Time (months) Time (months)

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