1 / 25

ONTAK ® (denileukin diftitox) Post-approval Commitments

ONTAK ® (denileukin diftitox) Post-approval Commitments. Oncologic Drugs Advisory Committee Meeting November 8, 2005 Holiday Inn Gaithersburg, Maryland. Oncologic Drugs Advisory Committee Meeting Ligand Attendees. Ligand:

hang
Download Presentation

ONTAK ® (denileukin diftitox) Post-approval Commitments

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. ONTAK® (denileukin diftitox) Post-approval Commitments Oncologic Drugs Advisory Committee Meeting November 8, 2005 Holiday Inn Gaithersburg, Maryland

  2. Oncologic Drugs Advisory Committee MeetingLigand Attendees • Ligand: • Andrés Negro-Vilar, M.D., Ph.D.Exec. Vice President, Research & DevelopmentChief Scientific Officer • James L’Italien, Ph.D.Sr. Vice President, Regulatory Affairs & Compliance • Zofia Dziewanowska, M.D., Ph.D. Vice President, Clinical Research • Elyane Lombardy, M.D. Exec. Medical Director, Clinical Research • Eric Groves, M.D., Ph.D.Vice-President, Project Management • Expert Advisor and Clinical Investigator • Francine Foss M.D. • Professor of Medicine and Oncology, Yale Cancer Center

  3. Presentation Objectives • Review structure, mechanism of action and clinical characteristics of denileukin diftitox (ONTAK®) • Review clinical basis for accelerated approval and key development milestones • Describe the outstanding clinical commitment for final approval • Progress to date • Study L4389-11 (prior to 1999, 93-04-11) • Study L4389-14 (prior to 1999, 93-04-14) • Difficulties encountered

  4. ONTAK® Structure | S | S | | S | S | Diptheria toxin Enzyme Activity • Fusion protein targets cytocidal activity of diphtheria toxin to tumor cells expressing the receptor for IL2 (IL2R) • Leukemic and lymphoma cells of T and B cell origin (including cutaneous T cell lymphoma) can constitutively express one or more subunits of IL-2R IL-2 Receptor Binding Domain RVRR Diptheria toxin Translocation Function Fusion Junction Cleavage Domain

  5. DT DT DT DT IL2 IL2 IL2 IL2 a g b Protein synthesis IL2 Denileukin Diftitox (ONTAK®) Mechanism of Action Cell exterior  = CD25  = CD122  = CD132 ONTAK INTERMEDIATE affinity IL2 receptor HIGH affinity IL2 receptor g b Cell membrane Internalization of IL2R with bound toxin CELL DEATH DT Cleavage & Toxin release Protein synthesis Terminated by toxin-mediated ADP ribosylation of elongation factor 2 Cell interior

  6. ONTAK – Clinical Characteristics • Indicated for the treatment of patients with persistent or recurrent, CD25 (+) cutaneous T-cell lymphoma (CTCL) • Acceptable safety profile • Minimal myelosuppression

  7. Clinical Data Supporting ONTAK Accelerated Approval • February 1999: accelerated approval based on data in CTCL patients from 2 clinical studies • Phase I / II study (92-04-01): • 37% response rate • Phase III study of 9 mg/kg vs 18 mg/kg (93-04-10): • 30% response rate

  8. ONTAK Clinical Commitmentsfor Final Approval • Completion of a 3 arm, blinded, placebo controlled study of 9 mg/kg and 18 mg/kg in CTCL patients 93-04-11 (now L4389-11) (n=195) • Completion of an open label study of 18 mg/kg in CTCL patients 93-04-14 (now L4389-14) (n=86) • Companion study to L4389-11, including 3 subgroups: • CD25(-) patients (target = 29 patients) • Placebo cross-over patients from study L4389-11 • Retreatment patients from studies 92-04-01, • 93-04-10 and -11 (prior to 1999)

  9. Patient Selection and Randomization Schema ONTAK 9g/kg Study 11 195 pts ONTAK 18g/kg CTCL Patients Screened (Ia to III) (≤ 3 prior therapies) Placebo CD25(+) CD25(-) Placebo Progression or 8 cycles no response Study 14 86 pts Retreatment, CD25+

  10. R Up to 8 courses of A placebo S N C Primary D R Up to 8 courses of Endpoint: O E 9 g/kg/day Response M E Rate I N Up to 8 courses of Z 18 g/kg/day E L4389-11 Study Design • 5 daily treatments every 21 days; • Tumor burden is assessed at Baseline and Day 1 of each course after Course 1

  11. Study L4389-11Randomization Scheme Original 120 pts (1:1:1) Revised 195 pts (1:2:2) Placebo (40 pts) (39 pts) Study 11 CD25(+) 9 g/kg (40 pts) (78 pts) 18 g/kg (40 pts) (78 pts)

  12. Challenges Encountered inConduct of L4389-11 • Small population size (CTCL annual incidence – 4 per million; 1,100 new U.S. cases per year) • Few clinical research centers in each country see significant numbers of patients appropriate for this study • Impact of the placebo arm in a symptomatic patient population • Impact of number of prior therapies on eligibility

  13. Site Enrollment Efforts to Complete Protocol L4389-11 From 1999 Through October 2005

  14. Patient Enrollments for CTCL Studies Largest Prior Prospective CTCL Trial Prior to NDA Approval Post Approval Studies Number of Patients/Trial 3 1 2 1 Saleh et al. J Am Acad Dermatol 1998 39:63 2 Olsen et al. J Clin Oncol. 2001 19:376 3 Kaye et al. NEJ Med 1989 321:1784

  15. Patient Enrollments for CTCL Studies Largest Prior Prospective CTCL Trial Prior to NDA Approval Post Approval Studies Number of Patients/Trial 3 1 2 1 Saleh et al. J Am Acad Dermatol 1998 39:63 2 Olsen et al. J Clin Oncol. 2001 19:376 3 Kaye et al. NEJ Med 1989 321:1784

  16. Patient Enrollments for CTCL Studies Largest Prior Prospective CTCL Trial Prior to NDA Approval Post Approval Studies Number of Patients/Trial 3 1 2 1 Saleh et al. J Am Acad Dermatol 1998 39:63 2 Olsen et al. J Clin Oncol. 2001 19:376 3 Kaye et al. NEJM 1989 321:1784

  17. Site Enrollment Efforts to Complete Protocol L4389-11 in 2000 # of Active Sites 12 # of Pts. Enrolled 9 Cumulative # of Pts. 82 France: 6 Canada: 2 Germany: 3 UK: 2 USA: 3 Australia: 2

  18. Site Enrollment Efforts to Complete Protocol L4389-11 in 2003 # of Active Sites 25 # of Pts. Screened 48 # of Pts. Enrolled 16 Cumulative # of Pts. 114 Netherlands: 1 Germany: 4 Canada: 3(1) UK: 3 Austria: 2 Poland: 5(1) USA: 1 Russia: 5 Australia: 1

  19. Site Enrollment Efforts to Complete Protocol L4389-11 in 2004 # of Active Sites 23 # of Pts. Screened 70 # of Pts. Enrolled 14 Cumulative # of Pts. 128 Germany: 3 UK: 3 Austria: 2 Canada: 2 Poland: 5(1) Russia: 6(1) Australia: 2(1) Brazil: 9 Argentina: 7

  20. Site Enrollment Efforts to Complete Protocol L4389-11 in 2005 # of Active Sites 25 # of Pts. Screened 31 # of Pts. Enrolled 9 Cumulative # of Pts. 137 Switzerland: 1 Germany: 3 UK: 3 Canada: 2 Austria: 2 Poland: 5 Russia: 5 Australia: 4(2)

  21. Summary of Patient Recruitment Efforts Since 2003 26% 25% 21%

  22. Summary of Patient Recruitment Efforts Since 2003 26% 26% 21%

  23. Post-approval Commitment For Protocol L4389-14 Status:Enrollment goals met

  24. Summary With Ligand’s intensive efforts: • L4389-11 • Total accrual to date is 137 patients • Enrollment averages about 12 pts/year or 0.5 pts/site/year • L4389-14 • Met enrollment goal (86 targeted, 90 enrolled) • Continues to accrue, offering L4389-11 placebo patients the therapeutic option of receiving ONTAK

  25. Next Steps Ligand intends to open a dialogue with the FDA to discuss strategies to satisfy the requirements of our post-approval commitments, including the possibility of achieving an earlier study closure following an evaluation of total patient accrual from both the L4389-11 and L4389-14 studies.

More Related