Continued Late Conversion to Complete Remission and Durability of Remission in Patients with B-cell Follicular Lymphoma (FL) Treated with Rituximab Followed by Mitumprotimut-T Immunotherapy

1
Continued Late Conversion to Complete Remission
and Durability of Remission in Patients with
B-cell Follicular Lymphoma (FL)Treated with
Rituximab Followed by Mitumprotimut-T
Immunotherapy

• Omer N. Koc, MD Charles Redfern, MD Peter H.
  Wiernik, MD Fred Rosenfelt, MD Jane N. Winter,
  MD Troy H. Guthrie, MD Lawrence Kaplan, MD
  Peter Holman, MD John Densmore, MD, PhD John
  Hainsworth, MD Thomas Lin, MD Rene A. Castillo,
  MD Nalini Janakiraman, MD and Richard G.
  Ghalie, MD
• Presented December 10, 2007, at the 49th ASH
  Annual Meeting in Atlanta, Georgia

2
Continued Late Conversion to Complete Remission
and Durability of Remission in Patients with
B-cell Follicular Lymphoma (FL) Treated with
Rituximab Followed by Mitumprotimut-T
Immunotherapy
Background

• Mitumprotimut-T is a patient-specific and B-cell
  tumor-specific idiotype (Id) protein chemically
  conjugated to keyhole limpet hemocyanin (KLH), a
  potent non-specific immunogenic protein
• Mitumprotimut-T induces a cellular and humoral
  immune response to the Id-protein expressed by
  the patients own tumor, leading to active
  immunization against the tumor while sparing
  normal B-cells

Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
3
Continued Late Conversion to Complete Remission
and Durability of Remission in Patients with
B-cell Follicular Lymphoma (FL) Treated with
Rituximab Followed by Mitumprotimut-T
Immunotherapy
Background

• Mitumprotimut-T is co-administered with
  Granulocyte-Macrophage Colony-Stimulating Factor
  (GM-CSF to further enhance anti-Id immune
  responses
• The Id protein is produced by proprietary
  recombinant technology 8 weeks from biopsy to
  final product

Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
4
Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
5
Continued Late Conversion to Complete Remission
and Durability of Remission in Patients with
B-cell Follicular Lymphoma (FL) Treated with
Rituximab Followed by Mitumprotimut-T
Immunotherapy
Objectives

• To compare the progression-free survival (PFS)
  in patients treated with Rituximab followed by
  mitumprotimut-T (Specifid, Id-KLH, FavId) and
  GM-CSF to historical data with rituximab alone
• To evaluate the safety of this combination regimen

Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
6
Continued Late Conversion to Complete Remission
and Durability of Remission in Patients with
B-cell Follicular Lymphoma (FL) Treated with
Rituximab Followed by Mitumprotimut-T
Immunotherapy
Methods

• Key Inclusion Criteria
• Histologically confirmed Grade 1 or 2 follicular
  B-cell lymphoma (WHO classification)
• Treatment-naïve (T-N), relapsed/refractory (R/R)
  to chemotherapy, or relapsed following prior
  6-month response to rituximab
• 8 weeks between completion of any prior lymphoma
  therapy and start of rituximab on study
• Measurable disease (2 cm) following node biopsy
• Performance status (ECOG) of 0, 1 or 2

Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
7
Continued Late Conversion to Complete Remission
and Durability of Remission in Patients with
B-cell Follicular Lymphoma (FL) Treated with
Rituximab Followed by Mitumprotimut-T
Immunotherapy
Methods

• Key Exclusion Criteria
• gt3 prior chemotherapy or anti-CD20 regimens
• Prior fludarabine
• Concurrent immunosuppressive therapy (e.g.,
  high-dose steroids)

Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
8
Continued Late Conversion to Complete Remission
and Durability of Remission in Patients with
B-cell Follicular Lymphoma (FL) Treated with
Rituximab Followed by Mitumprotimut-T
Immunotherapy
Methods

• Treatment Regimen
• Rituximab 375 mg/m2 weekly infusion x 4 weeks.
  Subjects with stable disease (SD) or an
  objective response (CR or PR) to rituximab were
  eligible for mitumprotimut-T
• Mitumprotimut-T 1 mg sc on Day 1 of each course.
  Courses administered monthly x6, bimonthly x6,
  and then every 3 months until disease
  progression or significant toxicity
• GM-CSF 250 mcg/day sc on Days 1-4 of each
  course same injection site as mitumprotimut-T
• CT scans Obtained every 3 months read by an
  independent radiologist blinded to clinical data

Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
9
Study Schema and Treatment Regimen
Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
10
Patient Characteristics at Study Entry
Characteristic N 89
Age Age
Median (range) 53 (30 85) years
Gender, n () Gender, n ()
Male 47 (53)
Female 42 (47)
Follicular Lymphoma WHO Grade, n () Follicular Lymphoma WHO Grade, n ()
Grade 1 47 (53)
Grade 2 38 (43)
Grade 3 2 (2)
Not reported 2 (2)
Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
11
Patient Characteristics at Study Entry
Characteristic N 89
Treatment History, n () Treatment History, n ()
Treatment-naïve (T-N) 35 (39)
Relapsed/Refractory (R/R) 54 (61)
No. of Prior Systemic Therapies (n 54 R/R) No. of Prior Systemic Therapies (n 54 R/R)
Median (range) 1.5 (1 4)
FLIPI Risk Group, n () FLIPI Risk Group, n ()
Low 16 (18)
Intermediate 26 (29)
High 20 (23)
Not evaluable 27 (30)
Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
12
Disease Response Assessment
3 Months After Start Rituximab(Before Start of Mitumprotimut-T) 3 Months After Start Rituximab(Before Start of Mitumprotimut-T) 3 Months After Start Rituximab(Before Start of Mitumprotimut-T) Any Time After Start ofMitumprotimut-T GM-CSF Any Time After Start ofMitumprotimut-T GM-CSF Any Time After Start ofMitumprotimut-T GM-CSF
Overall N 89 T-N N 35 R/R N 54 Overall N 89 T-N N 35 R/R N 54
Complete Response 2 (2.2) 0 2 (3.7) 18 (20.2) 9 (25.7) 9 (16.7)
Partial Response 41 (46.1) 24 (68.6) 17 (31.5) 37 (41.6) 18 (51.4) 19 (35.2)
Objective Response 42 (48.3) 24 (68.6) 19 (35.2) 55 (61.8) 27 (77.1) 28 (51.9)
Stable Disease 43 (48.3) 11 (31.4) 32 (59.2) 31 (34.8) 8 (22.9) 23 (42.6)
Progressive Disease 3 (3.4) 0 3 (5.6) 3 (3.4) 0 3 (5.6)
27 patients (30) had a response improvement
during treatment with mitumprotimut-T GM-CSF
11 SD converted to PR, 1 SD converted to CR, 15
PR converted to CR.Omer K et al. Abstract 3427.
Presented December 10, 2007, at the 49th ASH
Annual Meeting in Atlanta, Georgia.
13
Time Course for Achievement of Complete Response
Cumulative No. of Patients in CR
Months From Rituximab Start
Confirmation by a repeat CT scan was required to
meet the criteria for a CR
Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
14
Time to Achieving a Complete Response in Study
FavId-04 and in Rituximab Alone Trials in
Treatment-Naive Follicular NHL
Cumulative of Pts. in CR Cumulative of Pts. in CR Cumulative of Pts. in CR
Author/Reference No. of Pts. Total No. () of Pts. in CR By Mo 3 From Mo 3 - 12 From Mo 12 - 33
Study FavId-04 35 9 (26) 0 56 100
Witzig et al, J Clin Oncol 2005231103 36 13 (36) 92 100 N/A
Colombat et al, Blood 200197101 49 20 (41) 65 100 N/A

• In published single-agent rituximab trials all
  patients had achieved a CR by Month 12.
• In Study FavId-04, 44 of the CRs were achieved
  between Month 12 and 33, suggesting an added
  effect of mitumprotimut-T GM-CSF beyond of what
  is achieved with rituximab alone.

Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
15
Progression-Free Survival for All Evaluable
Patients (N89) And for Patients Who Achieved a
Complete Response (N18)

• Median follow-up 51 months (range, 47 62
  months).
• Six of 18 (33) subjects with CR have
  progressed and one (6) withdrew from study in CR.

Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
16
Continued Late Conversion to Complete Remission
and Durability of Remission in Patients with
B-cell Follicular Lymphoma (FL) Treated with
Rituximab Followed by Mitumprotimut-T
Immunotherapy
Summary

• Overall 18 of 89 (20.2) patients treated with
  rituximab followed by mitumprotimut-T achieved a
  complete response (CR), including 26 of
  treatment-naïve patients and 17 of patients with
  relapsed-refractory disease
• Of the 18 confirmed CRs, 16 have occurred during
  the mitumprotimut-T GM-CSF phase of the study

Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
17
Continued Late Conversion to Complete Remission
and Durability of Remission in Patients with
B-cell Follicular Lymphoma (FL) Treated with
Rituximab Followed by Mitumprotimut-T
Immunotherapy
Summary

• Conversion to CR has occurred as late as 33
  months from start of rituximab
• Achieving a CR is associated with prolonged
  disease-free survival 11 of 18 (61) of CR
  patients remain disease-free 47 to 62 months
  after start of rituximab therapy
• Most adverse events reported in the study were
  of severity Grade 1-2 the most common adverse
  event was injection site reaction (79.6 of
  patients)

Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
18
Continued Late Conversion to Complete Remission
and Durability of Remission in Patients with
B-cell Follicular Lymphoma (FL) Treated with
Rituximab Followed by Mitumprotimut-T
Immunotherapy
Conclusions

• The occurrence of late CRs and the durability of
  these responses suggest added anti-tumor effect
  of active immunization with mitumprotimut-T
  GM-CSF after rituximab cytoreduction than would
  be expected with single-agent rituximab therapy

Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.
19
Continued Late Conversion to Complete Remission
and Durability of Remission in Patients with
B-cell Follicular Lymphoma (FL) Treated with
Rituximab Followed by Mitumprotimut-T
Immunotherapy
Conclusions

• These findings are relevant when considering an
  ongoing Phase 3 registration trial where patients
  with follicular lymphoma randomized to receive
  mitumprotimut-T or placebo, both with GM-CSF,
  following cytoreduction with rituximab achieved a
  best CR rate of 47 in a blinded interim analysis
  (Freedman et al, Blood 20061082756.)
• Analysis of time to progression, the study
  primary efficacy endpoint, is expected in July
  2008

Omer K et al. Abstract 3427. Presented December
10, 2007, at the 49th ASH Annual Meeting in
Atlanta, Georgia.