Ontak denileukin diftitox post approval commitments
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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:

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ONTAK ® (denileukin diftitox) Post-approval Commitments

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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

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


Presentation objectives

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


Ontak structure

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


Denileukin diftitox ontak mechanism of action

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


Ontak clinical characteristics

ONTAK – Clinical Characteristics

  • Indicated for the treatment of patients with persistent or recurrent, CD25 (+) cutaneous T-cell lymphoma (CTCL)

  • Acceptable safety profile

  • Minimal myelosuppression


Clinical data supporting ontak accelerated approval

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


Ontak clinical commitments for final approval

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)


Patient selection and randomization schema

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+


L4389 11 study design

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


Ontak denileukin diftitox post approval commitments

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)


Challenges encountered in conduct of l4389 11

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


Ontak denileukin diftitox post approval commitments

Site Enrollment Efforts to Complete Protocol

L4389-11 From 1999 Through October 2005


Patient enrollments for ctcl studies

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


Patient enrollments for ctcl studies1

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


Patient enrollments for ctcl studies2

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


Ontak denileukin diftitox post approval commitments

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


Ontak denileukin diftitox post approval commitments

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


Ontak denileukin diftitox post approval commitments

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


Ontak denileukin diftitox post approval commitments

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)


Summary of patient recruitment efforts since 2003

Summary of Patient Recruitment Efforts Since 2003

26%

25%

21%


Summary of patient recruitment efforts since 20031

Summary of Patient Recruitment Efforts Since 2003

26%

26%

21%


Post approval commitment for protocol l4389 14

Post-approval Commitment For Protocol L4389-14

Status:Enrollment goals met


Summary

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


Next steps

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.


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