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16 February 2005

FDA Advisory Committee Meeting. 16 February 2005. Cardiovascular Safety of Valdecoxib and Parecoxib & Risk-Benefit Assessment. Valdecoxib - Background. Valdecoxib approved for OA and RA in Nov ‘01 Approved dose = 10 mg once daily

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16 February 2005

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  1. FDA Advisory Committee Meeting 16 February 2005 Cardiovascular Safety of Valdecoxib and Parecoxib & Risk-Benefit Assessment

  2. Valdecoxib - Background • Valdecoxib approved for OA and RA in Nov ‘01 • Approved dose = 10 mg once daily • >15,000 individuals studied in the registration program = celecoxib • Since the approval: • Acute pain and chronic pain conditions

  3. Valdecoxib Overall Conclusions • Valdecoxib remains a viable treatment alternative for OA and RA • Valdecoxib provides improved GI safety compared to NSAIDs • Valdecoxib CV safety database is small at present, however, emerging CV safety profile of valdecoxib is similar to NSAIDs for up to 6 months. • CV signal in CABG surgery setting does not extrapolate to the arthritis population.

  4. Clinical Effects of Valdecoxib in OA Efficacy Upper GI Safety B H 11 Placebo (n=205) 20 F B J P J Valdecoxib 5 mg QD (n=201) H Valdecoxib 10 mg QD (n=205) 10 15 F Valdecoxib 20 mg QD (n=201) P Naproxen 500 mg BID (n=204) Patients with Ulcer (%) WOMAC Pain Scorea 9 * B ** 10 † B ‡ B 8 J H P H F H 5 J J P F P F 7 0 0 0 2 6 12 Pbo 5 10 20 500 Weeks Valdecoxib (mg qd) Naproxen (mg bid) a. Scale = 0 (best) - 20 (worst) * Placebo significantly different from all treatments; p < 0.05 † Placebo significantly different from all treatments except valdecoxib 5 mg; p < 0.05 ‡ Placebo significantly different from valdecoxib 20 mg and naproxen; p < 0.05 ** Significantly different from placebo, valdecoxib 5 mg and 10 mg; p < 0.05 Kivitz et al. J Family Practice 2002:51;530-537

  5. Incidence of Ulcer Complications Pre-defined analysis of 8 RCTs (12-26 wks) & 3 open label studies up to 1 yr 2.5 * 1.95 11/563 2.0 1.5 Events/100 pt yrs) 0.68 8/1183 1.0 0.39 7/1791 0.5 0 0/146 0 Valdecoxib 5-80 mg (n=4362) Valdecoxib10-80 mg (n=2871) Placebo (n=973) NSAIDs(n=2099) Controlled Trials Open-Label * Significantly different from other treatments; p< 0.05 Goldstein et al. Alimentary Pharmacol Ther 2004;20:527-538

  6. Sources of CV Data for Valdecoxib • More limited CV safety database than celecoxib • Randomized controlled trials in arthritis • Short-term acute pain studies alone or in combination with parecoxib • No completed epidemiology studies – 3 ongoing

  7. Cardiovascular Safety of Valdecoxib: Meta-analysis • 19 randomized controlled trials and a total of 12,254 treated patients (>84% OA/RA) • 7,061 valdecoxib-treated patients • 2,235 placebo-treated patients • 2,958 patients treated with active comparators • Study duration: 2 wks – 12 months • 11 studies  3 month duration • Valdecoxib doses; 1 – 80 mg daily Valdecoxib exposure > 3 months – 2714 (50%) of patients > 6 months – 1176 (22%) of patients > 1 yr – 211 (4%) of patients

  8. CV Death, MI and Stroke:Valdecoxib vs NSAIDs n (events per 100 patient-years)

  9. CV Death, MI and Stroke:Valdecoxib vs NSAIDs Relative Risk (95%CI) 0.49 (0.21, 1.13) CV death, MI, or stroke 0.53 (0.13, 2.24) CV death 0.39 (0.11, 1.37) MI Stroke 0.43 (0.09, 2.05) 0.3 3.0 0.1 1.0 10.0 Favors NSAIDs Favors valdecoxib Valdecoxib daily dose > 10 mg

  10. Relative Risk (95%CI) vs. Placebo vs. NSAID vs. Naproxen vs. Diclofenac 0.38 (0.13, 1.09) vs. Ibuprofen No events 3.0 0.3 0.1 1.0 10.0 Favors comparator Favors valdecoxib CV Death, MI and Stroke:Valdecoxib vs Pbo, NSAIDs Combined & Individually 1.26 (0.35, 4.46) 0.49 (0.21, 1.13) 0.73 (0.18, 2.99) Valdecoxib daily dose > 10 mg

  11. CV Death, MI and Stroke:Valdecoxib vs NSAIDs: By Dose Relative Risk (95%CI) 0.49 (0.21, 1.13)  10 mg 0.27 (0.07, 1.04) 10 mg 0.38 (0.13, 1.17) 20 mg 1.36 (0.31, 5.94) 40 mg No events 80 mg 0.3 3.0 0.1 1.0 10.0 Favors NSAIDs Favors valdecoxib Valdecoxib daily dose > 10 mg

  12. Incidence of Cardiorenal Events n (percent of patients) NS = not significant (p>0.05) Combined analysis of RCTs

  13. Spontaneous reports of serious skin reactions received approximately 6 months after launch in the US Rate appears to be higher than celecoxib or rofecoxib Black Box warning added November 2004 Valdecoxib and Serious Skin Reactions

  14. Risk-Benefit of Valdecoxib in Arthritis - Conclusions • Efficacy similar to NSAIDs • Emerging data to establish: • GI safety benefit superior to NSAIDs • CV safety profile comparable to NSAIDs • Added warnings allow physicians to choose appropriately based on the evidence of rare although severe skin reactions.

  15. Future Plans for Valdecoxib • As with celecoxib, longer term studies are planned to evaluate the GI safety and CV safety of valdecoxib in arthritis patients.

  16. Parecoxib Sodium: Water Soluble Prodrug of Valdecoxib Parecoxib sodium Valdecoxib Water Solubility ~23 mg/ml ~0.08 mg/ml

  17. Medical Need for Parecoxib • Inadequate postoperative pain control is one of the most important factors in: • prolonging hospitalization • progression from acute pain to chronic pain • Postoperative analgesia traditionally provided by opioids • associated with complications (eg, ventilatory depression, nausea/vomiting, ileus) • inadequate analgesia upon movement • Multimodal analgesia (eg, drugs from 2 or more classes) • Earlier oral intake, ambulation, hospital discharge Parecoxib is intended to provide significant analgesia, sparing opioids without GI/bleeding risks of parenteral NSAIDs. White. Anesth Analg 2002;94:577-585

  18. Post-Operative Pain and Function Following Ambulatory Surgery Patients treated with Standard of Care Opioids Laparoscopy (n=59) 120 40 B Hernia (n=41) H 35 N=3729 100 H B 30 80 25 B 60 20 Functional Score Percent of Patients B 15 * 40 H * 10 H 20 B Mean + Std Dev p<0.05 vs pre * 5 H * * 0 0 None Mild Moderate Severe Pre-Surgery 1 day 4 days 7 days Time (post-surgery) Pain Status (day after surgery) Swan et al. Anesth Analg 1998;86:739-45 Chung et al. Anesth Analg 1997;85:808-16

  19. Background • Parecoxib was approved for short-term post-surgical pain in Europe March 2002 • > 1 million patients treated • Parecoxib NDA under review in US for management of acute pain

  20. Parecoxib Clinical Registration Program • 64 studies completed • 26 analgesia studies completed* • 10,086 patients randomized • 3,415 patients treated with placebo • 5,516 patients treated with parecoxib • 1,155 patients treated with active comparator** • 1,670 patients treated for >3 days with parecoxib • 1,183 patients treated for >10 days with parecoxib/valdecoxib * general surgery, oral and bunion surgery, renal colic trials ** morphine, ketorolac, ibuprofen, tramadol, valdecoxib

  21. Study DesignCABG Surgery Study 035 Day 3 Day 1 Day 14 Parecoxib 40 mg IV Q12h ® Valdecoxib 40 mg PO Q12h (N=311) Surgery* Extubate, baseline exam & labs; Randomize Placebo IV Q12h ® Placebo PO Q12h (N=151) Both treatment groups receive: PRN Supplemental Analgesia (PCA morphine à oral APAP+codeine) All patients received aspirin (80-325 mg daily) *89% cardiopulmonary bypass/11% off-pump cases

  22. Adjudicated Thromboembolic CV Events: CABG Surgery Study 035 * p<0.05 vs placebo; (n) percentage of patients with an event

  23. Study DesignCABG Surgery Study 071 Day 3 Day 1 Day 10 Parecoxib 40 mg IV loading dose + 20 mg IV Q12h ® Valdecoxib 20 mg PO Q12h (N=544) Surgery* Placebo IV Q12h ® Valdecoxib 20 mg PO Q12h (N=544) Randomize (Post-Op Day 1) Placebo IV Q12h ® Placebo PO Q12h (N=548) Both treatment groups receive: PRN Supplemental Analgesia (PCA morphine à oral APAP+codeine) All patients received aspirin (75-325 mg daily) *all cases were cardiopulmonary bypass

  24. Adjudicated Thromboembolic CV Events • Myocardial events: • MI, severe myocardial ischemia, • cardiac arrest, or sudden cardiac death • Cerebrovascular events: • Acute ischemic or hemorrhagic stroke, hemorrhagic infarction or TIA • Peripheral vascular events: • Vascular thrombosis (venous or arterial) • Pulmonary embolism

  25. Adjudicated Thromboembolic CV EventsCABG Surgery Study 071 Significantly different from placebo; p<0.05 -- p > 0.20 n (percent of patients)

  26. IV Study Medication Discontinued 3.0 ORAL 2.5 2.0 1.5 1.0 0.5 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 Adjudicated Thromboembolic CV EventsCABG Surgery Study 071 Time to Event Analysis Treatment Log rank test pbo/pbo vs pbo/valde, p=0.311 pbo/pbo vs pare/valde, p=0.030 Parecoxib/Valdecoxib (n=544) H H H Percent of Patients H H Valdecoxib only (n=544) J H J H J Placebo (n=548) J B H J B H J B H B J H Days

  27. Adjudicated Thromboembolic CV Events:CABG Surgery Study 071 * p<0.05 vs placebo; n (percentage of patients with an event)

  28. CABG Surgery • Limited data to evaluate the effects of NSAIDs in this setting • Mechanism for increased CV risk with parecoxib/ valdecoxib is not known: • CBP results in activation of platelets, leukocytes and endothelial cells • Aortic cross-clamping; ischemia reperfusion injury and emboli • Complex time course of changes in PGI2/TXA2 • High degree of platelet aspirin resistance These factors are largely confined to the CABG surgery setting Wan et al. Chest 1997;112:676-92Faymonville et al. J Thorac Cardiovasc Surg 1986;91:858-66Zimmerman et al. Circulation 2003;108:542-7

  29. Study DesignGeneral Surgery Study 069 Day 3 Day 1 Day 10 Parecoxib 40 mg IV loading dose + 20 mg IV/IM Q12h ® Valdecoxib 20 mg PO Q12h (N=525) Surgery Randomize (within 6 hr of surgery) Placebo IV Q12h ® Placebo PO Q12h (N=525) Both treatment groups receive: PRN Supplemental Analgesia (PCA morphine à oral APAP+codeine)

  30. Adjudicated Thromboembolic CV Events:General Surgery Study 069 n (percentage of patients with an event)

  31. ORAL Study Medication Discontinued 3.0 2.5 2.0 1.5 1.0 0.5 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 Adjudicated Thromboembolic CV EventsGeneral Surgery Study 069 Time to Event Analysis Treatment Log rank test placebo vs parecoxib/valdecoxib, p=0.999 IV/IM Placebo (N=525) B H Parecoxib/Valdecoxib (N=525) Percent of Patients B H B H B H B H B H H B Days

  32. Thromboembolic CV EventsCombined Parecoxib General Surgery Studies n (percentage of patients with an event)

  33. Daily Summed Pain Intensity Scoresa General Surgery Study 069 35 Placebo (n=525) Parecoxib / Valdecoxib (n=525) 30 25 * Mean Scorea 20 * * * 15 * * * 10 * * Less Pain 5 0 2 3 4 5 6 7 8 9 10 Days * Significantly different from placebo; p<0.05 a. Scale ranges from 0 to 72. Larger number indicates more pain

  34. p<0.001 -35%, p<0.001 0.6 75 0.59 66.2 0.39 0.4 50 43.2 Morphine Equivalents (mg) Morphine Equivalents (mg/hr) 0.2 25 p=0.085 0.11 0.08 0 0 IV Phase PO Phase Supplemental Opioid UseGeneral Surgery Study 069 Placebo (n=519) Parecoxib / Valdecoxib (n=520) Combined IV/PO

  35. Modified Brief Pain Inventory - Function:General Surgery Study 069 3.5 Placebo (N=525) 3.0 Parecoxib / Valdecoxib (N=525) 2.5 * 2.0 Mean Scorea 1.5 * * * 1.0 * * improved function * * * 0.5 0 2 3 4 5 6 7 8 9 10 Days * Significantly different from placebo; p<0.05 a. Scale ranges from 0 to 11. Larger number indicates greater interference with function Composite score: general activity, walking, sleeping, deep breathing, coughing, concentration, mood, relations with others

  36. Risk-Benefit of Parecoxib - Conclusions • Parecoxib offers unique benefits over existing parenteral analgesic medications and a favorable risk benefit ratio in surgical settings other than CABG/ revascularization • Parecoxib administered in controlled settings under physician observation • CV risk found only in CABG surgery setting; not observed in other surgical settings • other revascularization procedures not assessed

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