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FDA Presentation

FDA Presentation. Rafia Bhore, PhD Statistician Tan Nguyen, MD, PhD Medical Reviewer. Outline of FDA Presentation. Patient demographics Efficacy data assessment Summary of efficacy endpoint data Treatment effect on fibrosis Safety data assessment Adverse event profile

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FDA Presentation

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  1. FDA Presentation Rafia Bhore, PhD Statistician Tan Nguyen, MD, PhD Medical Reviewer

  2. Outline of FDA Presentation • Patient demographics • Efficacy data assessment • Summary of efficacy endpoint data • Treatment effect on fibrosis • Safety data assessment • Adverse event profile • Renal safety data • Viral resistance • Questions to the Advisory Committee

  3. Patient Demographics • Prevalence of hepatitis B virus infection in the US (1988-1994)*: • Black: 11.9%; Mexican American: 4.4%; White: 2.6% • African and Hispanic Americans were not well represented in the drug development program. • Study 437 US sites enrolled 15 (10%) “Black” patients and 3 (2%) “Other” patients. • Study 435 US sites enrolled 2 “Black” and 2 “Other” patients (< 4% of patients). * McQuillan, et al. Am J Public Health 1999;89:14-8

  4. Efficacy Data Assessment

  5. Primary Endpoint: Liver BiopsyStudies 437, 438 • Adefovir treatment resulted in statistically significant improvement in liver histology at week 48.* • Study 437: 67% in ADV 30 mg and 59% in ADV 10 mg versus 28% in placebo • Study 438: 69% in ADV 10 mg versus 36% in placebo • Positive treatment effect on fibrosis was evident. *  2-point decrease in Knodell NI score without worsening fibrosis.

  6. Necroinflammatory ScoreStudy 437

  7. Necroinflammatory ScoreStudy 438

  8. Fibrosis ScoreStudy 437

  9. Fibrosis Scores Study 438

  10. Secondary Endpoint: HBV DNA*Studies 437, 438 • Adefovir treatment resulted in suppression of HBV replication. • Study 437: -4.38 in ADV 30 mg and -3.52 in ADV 10 mg versus -0.99 in placebo group at week 48 • Study 438: -3.54 in ADV 10 mg versus -1.23 in placebo group at week 48 • Further decrease of -0.5 with additional 48 weeks of treatment with adefovir 10 mg daily (incomplete data). • Serum HBV DNA returned to baseline within 4 to 8 weeks following cessation of adefovir treatment. * Values shown as mean log10 copies/mL

  11. Serum HBV DNAStudy 437

  12. Serum HBV DNAStudy 438

  13. Secondary Endpoint: ALTStudies 437, 438 • Adefovir treatment resulted in a greater progressive decrease in serum ALT over time compared with placebo. • The proportion of patient with normalization of ALT at week 48 was higher in the adefovir groups compared with placebo group. • Serum ALT levels peaked in 2 to 3 months (“flare” of disease) after discontinuation of drug.

  14. Serum ALTStudy 437

  15. Serum ALTStudy 438

  16. Treatment Effect on Fibrosis Study 437 * Ishak fibrosis score: 0 to 6 (no fibrosis to cirrhosis).

  17. Treatment Effect on Fibrosis Study 438 * Ishak fibrosis score: 0 to 6 (no fibrosis to cirrhosis).

  18. Assessment of Treatment Effect on Fibrosis • Compared with placebo, adefovir treatment was associated with: • Smaller proportion of patients having progression of fibrosis. • Greater proportion having regression of fibrosis. • Consecutive liver biopsies within a year can detect treatment effect on fibrosis (i.e., disease stage). • Serum HBV DNA and/or serum ALT as endpoints in evaluating drug therapy for chronic hepatitis B will not show treatment effect on fibrosis.

  19. Comments on Ranked Assessment of Liver Biopsy • No detailed information on the degree of incremental biopsy changes • Relatively more subjective than the rigid and structured scoring systems • Results not completely concordant with the established scoring systems • For example, 23 paired biopsies in study 438 with no changes in fibrosis by both Knodell and Ishak scores were rated by ranked assessment as “worse” or “better.”

  20. Safety Data Assessment

  21. Adverse Event ProfileStudies 437, 438 • Adverse event profiles of adefovir groups, particularly the 10 mg group, were comparable to placebo group. • Fewer patients had markedly elevated ALT (shift from normal to grade 3 or grade 1 to grade 4) while on adefovir treatment. • Study 437: 2% in adefovir groups; 4% in placebo group • Study 438: 0% in adefovir groups; 4% in placebo group

  22. “Hepatic Flare”Studies 437, 438 • During treatment, 3% in placebo group compared with < 1% in adefovir groups had hepatic flare. • After switching from adefovir to placebo, 35% in study 437 and 47% in study 438 had grade 3/4 ALT elevations. • 3% had severe post-treatment hepatic flare. • A 53-y/o man coinfected with HIV/HBV died of “hepatitis flare” 1 ½ months after discontinuing adefovir (30 mg daily) because of nephrotoxicity.

  23. Renal Safety Data • Data on treatment-emergent nephrotoxicity in studies 437, 438, and 435 will be presented. • Analyses are based on confirmed increased in serum creatinine and/or decrease in serum phosphorus. • Confirmed change: two consecutive abnormal measurements • Phosphorus: decrease to < 2.0 mg/dL (grade 2 or more) • Creatinine:  0.3 mg/dL versus  0.5 mg/dL increase from baseline

  24. Estimated Creatinine Clearance: 0.3 versus 0.5 mg/dL Cutoff *Cockcroft and Gault, 1976. † Mean baseline value, mg/dL; ‡ increase from baseline.

  25. NephrotoxicityStudy 437 * Increase from baseline. † From baseline.

  26. NephrotoxicityStudy 438 * Increase from baseline. † From baseline.

  27. Nephrotoxicity in Year 2Studies 437, 438 • By K-M estimate, 9% of patients in adefovir 10 mg daily group in study 437 and 10% in study 438 developed increase in creatinine 0.3 mg/dL from baseline by week 96. • Due to study design, no placebo control data beyond week 48 were available for comparison.

  28. NephrotoxicityStudy 435 • Study 435: open-label study of adefovir (10 mg or 5 mg) in post-liver transplantation (cohort A) and waitlisted for liver transplantation patients (cohort B) with 3TC-resistant HBV • Complicated nephrotoxicity analysis • Uncontrolled study design • Advanced liver disease/liver transplantation • Concomitant use of nephrotoxic antirejection drugs • Abnormal renal dysfunction at baseline (cohort A) • Limited data beyond week 48

  29. Estimated Creatinine Clearance: 0.3 versus 0.5 mg/dL Cutoff * Cockcroft and Gault, 1976. † Mean value, mg/dL. ‡ From baseline.

  30. NephrotoxicityStudy 435 * From baseline; † Insufficient data after week 48.

  31. NephrotoxicityStudy 435 * Insufficient data after week 48. † From baseline

  32. Profile of Patients with Creatinine Abnormality • 28 patients in cohort A had  0.5 mg/dL increase from baseline in creatinine. • 100% in cohort A were on immunosuppressive drugs. • 20 patients (71%) had renal dysfunction at baseline (creatinine clearance < 80 mL/min). • 15 patients in cohort B had similar abnormality. • 4 patients (27%) had renal dysfunction at baseline (creatinine clearance < 80 mL/min). • 12 (80%) had increased creatinine levels shortly after liver transplantation and use of immunosuppressants.

  33. Resolution of Creatinine Abnormality * From baseline; † At the last follow-up visit.

  34. Nephrotoxicity AssessmentStudy 435 • Confounding factors were present in patients with  0.5 mg/dL increase from baseline in creatinine. • Concurrent use of nephrotoxic drugs, hepatic decompensation, hepatorenal syndrome, dehydration, acute post-op renal insult, etc. • Nevertheless, the contributory role of adefovir could not be completely ruled out in: • 22 cases (85%) in cohort A. • 2 cases (13%) in cohort B.

  35. Nephrotoxicity: Case # 1Study 435 • 69 y/o man s/p liver transplant (1995) started adefovir 10 mg in 4/00. Concurrent meds: cyclosporine, 3TC, nifedipine. Adefovir was interrupted in 08/01, then restated at 5 mg. * mg/dL; † Cockcroft and Gault, mL/min; ‡ mg/dL.

  36. Nephrotoxicity: Case # 2Study 435 • 65 y/o male s/p liver transplant (1991) started adefovir 10 mg in 11/99. Concurrent meds: 3TC, cyclosporine, sirolimus, furosemide, antihypertensives, antibiotics. Adefovir was reduced to 5 mg in 5/00. Patient was hospitalized in late 11/00 with hepatorenal syndrome requiring dialysis, and died in 12/00. * mg/dL; † Cockcroft and Gault, mL/min.

  37. PK of Adefovir in Non-CHB Patients with Renal Dysfunction *ng.hr/mL † ng/mL.

  38. Adefovir in CHB Patients with Renal Dysfunction • Extrapolating from the PK study 473, adefovir 10 mg daily dose may result in significantly higher plasma levels in these patients than those with intact renal function. • The applicant has proposed various dose modifications using the 10 mg-strength tablet based on the patient’s baseline creatinine clearance. • Dose modification could be optimized with the availability of a lower strength formulation of the drug.

  39. Deaths • Studies 437 and 438 • Four patients died after the clinical data cutoff date or after completion of 96 weeks of treatment. • Study 435 (as of data cutoff date) • Cohort A: 18 patients (9%) died. • Cohort B: 24 (19%) died. • Two of these patients (1 in cohort A and 1 in cohort B), also had treatment-emergent nephrotoxicity, in which the contributory role of adefovir could not be completely ruled out(see Appendix A, AC briefing document).

  40. HBV Viral Resistance • Genotypic analysis of DNA sequences from clinical specimens may not detect all viral variants present at < 30% of a mixture of mutant and wild-type viruses. • Resistance may be slow to emerge during treatment of HBV. • It is possible that adefovir-resistant HBV mutants may emerge during longer-term treatment (> 48 weeks).

  41. Viral Resistance Issues • Study 437 • The IC50 of H582Q, a mutant of conserved site (adefovir 10 mg group) was 3.6-fold higher than that of wild-type HBV. • Patient had -5.9 log10 HBV DNA reduction at week 48. • 2 patients with polymorphic site substitutions (E349E/Q, K487K/N) had only -1.3 and -1.8 log10 HBV DNA reduction at week 48. • No compliance issues in these patients • Other patients with 349Q (n = 9) or 487N (n = 225) substitution at baseline had adequate viral suppression. • Study 460i • 7 of 20 patients had R462G mutation in study 460i • 2 of 20 had a substitution at N470 (T or L).

  42. HBV/HIV Co-infectionStudy 460i • Historically, 2 adefovir-resistant HIV mutations, K65R and K70E, were identified in vitro. • Conferring 12-16 and 9-fold in vitro resistance, respectively. • Of 13 patients in study 460i with available HIV RT genotype data: • None harbored K65R or K70E. • 5 patients had ZDV- or d4T-associated mutations (D67N, K70R, L210W). • All had persistent M184V (3TC-associated HIV resistant) mutation.

  43. Risk-Benefit Assessment of Adefovir Treatment • Relevant benefits of adefovir (10 mg daily) treatment compared with placebo: • Improvement in liver biopsy histology at week 48 • Suppression of wild-type HBV and 3TC-resistant HBV replication (limited data on the latter) during treatment • Improvement in transaminases during treatment • Higher HBeAg seroconversion rate • Lower incidence of significant ALT/AST elevations and hepatic flare during treatment • No definitive adefovir-associated resistance mutations identified by week 48

  44. Risk-Benefit Assessment of Adefovir Treatment • Relevant risks of adefovir (10 mg daily) treatment: • Relatively low risk of nephrotoxicity in CHB patients with intact renal function and compensated liver disease by week 48, but increased risk with longer treatment duration • Potentially significant risk of nephrotoxicity in patients with pre-existing renal dysfunction • No data yet on PK, safety, and effectiveness of the dose modification scheme proposed by the applicant for CHB patient with renal dysfunction • Potentially serious “flare” of disease associated with drug discontinuation

  45. Questions to the Advisory Committee

  46. 1. Has the applicant demonstrated the safety of adefovir 10 mg daily dose for the treatment of CHB? Please discuss the safety of adefovir in patients with decompensated liver disease and patients with renal dysfunction at baseline. 2. Has the applicant demonstrated the effectiveness of adefovir 10 mg daily dose for the treatment of CHB? Please comment on the effectiveness of adefovir in patients with: compensated liver disease; decompensated liver disease; lamivudine-resistant hepatitis B virus; presumed pre-core mutation, and HBV/HIV co-infection.

  47. 3. Based on the risk-benefit profile, does the Committee recommend approval of adefovir 10 mg daily dose for the treatment of CHB in adults? 4. Are there any issues with the safety and effectiveness data that should be highlighted in the drug label? In particular, please discuss the use of adefovir in HBV/HIV coinfection and the potential risk of inducing NRTI resistance. 5. Please recommend appropriate Phase 4 (post-marketing) studies for adefovir in CHB patients. Please discuss the adequacy of the applicant’s current program to detect the emergence of adefovir-resistant HBV and the optimal strategy for long-term resistance surveillance.

  48. Adefovir Review Team Marsha Holloman, Project Manager Tan Nguyen, Clinical Katie Laessig, Clinical Team Leader Robert Kumi, Clinical Pharmacology Kellie Reynolds, Clinical Pharmacology Team Leader Rafia Bhore, Statistical Greg Soon, Statistical Team Leader Pritam Verma, Pharmacology Jim Farrelly, Pharmacology Team Leader Rao Kambhampati, Chemistry Steve Miller, Chemistry Team Leader Lalji Mishra, Microbiology Jules O’Rear, Microbiology Team Leader

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