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A Broad Clinical Pipeline
NASDAQ: RIGL
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“safe harbor” provisions of the Private Securities Litigation
Reform Act of 1995. These statements include those regarding
clinical trial plans, business strategy and research and
development efforts. Forward-looking statements are subject to
certain risk and uncertainties that could cause actual results to
differ materially from those indicated in the forward-looking
statements due to the risk factors identified in Rigel’s Form 10-Q
for the quarter ended September 30, 2005 and other documents
filed with the Securities and Exchange Commission. The
information in this presentation is current as of this date. Rigel
takes no responsibility to update the information.
Today’s Agenda
ƒ
Introduction
James M. Gower
ƒ
Rheumatoid Arthritis:
Dr. Lee S. Simon
Current Therapies And Regulatory Review
ƒ
Rigel Product Pipeline
ƒ
Questions and Answers
Dr. Donald G. Payan
Investment Thesis:
A Broad Pipeline of Major Opportunities
Clinical Milestones Next 12 Months
R788 in Rheum. Arthritis
Phase II trial start 1H, 2006
R788 in ITP/Flt3 AML
Phase I/II trials start 2006
R763 in Oncology
Phase I/II trial start 1H, 2006
Rxxx in Transplant Rejection
Preclinical Development 2006
Ryyy in Asthma
Preclinical Development 2006
Angiogenesis/Cancer
Select Clinical Candidate, 2006
Our Business Strategy: Many
Ways to Win
ƒ Portfolio strategy for drug development
> Multiple novel products to reduce risk
ƒ Develop or co-develop by product
ƒ Partnering after proof of human efficacy provides greater value
ƒ Focus primarily on large markets
ƒ Focus programs on Immunology and Infectious Disease
> Secondary focus on oncology
ƒ Small molecule therapeutics
A History of Successful
Large Pharma Collaborations
ƒ >$140M from
collaborations to date
ƒ Focused on immunology
and oncology
ƒ Complements internal
research
ƒ Early collaborations all
expanded/extended
Asthma/COPD ‘05
Immune Diseases ‘99
Oncology ‘98
Angiogenesis ‘01
Immune Diseases ‘99
Ligase Targets in
Oncology ‘04
Ligase Target in
Oncology ‘02
Aurora Kinase
Inhibition in
Oncology ‘05
Key Financial Highlights
ƒ $127.9M total cash at end Q3, 2005
ƒ $25.0M additional cash with Serono partnership in Q4, 2005
ƒ $12M - $14M net cash burn per quarter
ƒ Sufficient cash to move products to later stages of
development
ƒ Incremental cash from future milestones and new
partnerships
ƒ 24.8 million shares outstanding, 28.7 million fully diluted
Lee S. Simon, M.D.
Associate Clinical Professor, Harvard
Medical School
ƒ Associate Clinical Professor at Harvard Medical School and
head regulatory consultant with MEDACorp, a management
consulting group that offers strategic advice to leading life
sciences and healthcare companies
ƒ Previously, Division Director of the Arthritis, Analgesic and
Ophthalmologic Drug Product Division at the FDA
ƒ Prior to his tenure at the FDA, Director of Rheumatology
Clinical Research and Associate Chief of Medicine at Beth
Israel Deaconess Medical Center in Boston, MA
Medical Need for Novel Therapeutic
Options in the Treatment of Rheumatoid
Arthritis
Lee S. Simon, MD
Associate Clinical Professor of Medicine
Harvard Medical School
Beth Israel Deaconess Medical Center
Rheumatoid Arthritis
• Affects about 1% of the US population between the ages
of 20-50
• Heterogeneous disease
• Variable course
• Systemic inflammatory disease associated with an as yet
poorly understood immune dysfunction
• Leads to the development of destructive erosive disease
in a great majority
• Treatment to date has been to alter the inflammatory
cascade to lead to decreased inflammation and
decrease in pain
• Remission rare, cure not yet observed
Rheumatoid Arthritis
• Shortens life span
• Untreated: increased risk for non-Hodgkins
lymphoma
• Most patients suffer an unrelenting course
characterized by recurrent flares over years
leading to progressive loss of functional status
and ultimately leading to significant disability; an
unfortunate few have an accelerated mutilating
course and a lucky few have either mild disease
or enter into remission early
RA Is a Progressive Disease
Early
Intermediate
Late
Severity
Inflammation
Disability
Radiographs
© ACR
0
5
10
15
20
Duration of Disease (y)
Graph: Adapted from Kirwan JR. J Rheumatol. 2001;28:881-886.
Photo: © American College of Rheumatology.
25
30
Disability in RA with Standard of
Care
Percent Maximum Disability
70
60
50
Wolfe et al
Lassere et al
Sherrer et al
Scott et al
40
30
20
10
0
7
12
Disease Duration (years)
Scott DL et al. Rheumatol. 2000; 39:122-132.
18
Joint Erosions Occur Early in
RA
Up to 93% of patients with
< 2 years of RA may have
radiographic abnormalities
• Erosions can be
detected by MRI within
4 months of RA onset
• Rate of progression is
significantly more rapid
in the first year than in
the second and third years
Maximum percent of joints affected
•
MTP
30
Total
Hand
20
10
0
0
1
Year
MRI, magnetic resonance imaging; MTP, metatarsophalangeal.
Fuchs HA et al. J Rheumatol. 1989;16:585-591; McQueen FM et al. Ann Rheum Dis. 1998;57:350-356;
van der Heijde DM et al. J Rheumatol. 1995;22:1792-1796.
2
3
Rheumatoid Arthritis
• Chronic inflammatory autoimmune disease
– Involves synovial membrane and extra-articular sites
– Associated with rheumatoid factor (autoantibody) production
• Genetic predisposition
– Familial incidence
– Genetic factor: HLA-DR4-related antigens
• Unknown environmental trigger
Impact of RA on Health-Related
Quality of Life
•
•
•
•
•
•
Pain and suffering
Decreased physical functioning
Increased psychological distress
Decreased social functioning
Increased healthcare utilization
Increased work disability
Treatment Goals for Arthritis
Patients
•
•
•
•
•
•
•
Halt progression of disease
Maximize functional independence
Optimize treatment of pain
Optimize treatment of inflammation
Enhance health related quality of life
Minimize potential for toxicity
Provide easy access to care at reasonable cost
Arthritis Management, 1892
“Many cases are greatly helped by prolonged
residence in southern Europe or southern
California. Rich patients should always be
encouraged to winter in the south and in this
way avoid cold, damp weather.”
Osler, Principles and Practice of Medicine, 1892
Evolution of RA Treatment
MTX,
Oral gold
Injectable
gold
HCQ,
Steroids
1930s
B-cell antagonists,
CTLA-4 Ig,
IL-6 receptor
antagonist
1950s
SSZ
1960s
D-Pen,
AZA
1970s
TNF antagonists,
LEF,
Cyclosporine
1980s
1990s
Remission/
Cure
2000s
Early DMARD
treatment
Treat signs and symptoms in
established disease
Aggressive
MTX dosing
Combination
therapy
AZA, azathiopine; Ig, immunoglobulin; HCQ, hydroxychloroquine; LEF, leflunomide; SSZ, sulfasalazine.
FDA Approval RA Threshold for US
• Signs and symptoms
– Typical show ACR 20 response is better than placebo
• Improvement in function
– HrQol improvement over placebo was 2 years as of March 5,
2003 only 1 year data required
• Altering X ray progression
– One year data required with second year for durability of
response
• Major clinical response
– An ACR 70 response on drug for 6 months to 1 year
• Remission
– No evidence of active disease off all drugs for 6 months
What We Have Achieved
• We have drugs that as monotherapy provide
benefit of improvement in signs and symptoms
in about 50% of patients
• Combination therapy at times leads to
improvements approaching 75%
• We have drugs that appear to delay x ray
progression which if patients respond include all
DMARTs
• We do not cure this disease as of this time
ACR 20
• Tender joint count
• Swollen joint count
•
•
•
•
•
VAS scale for pain
Patient global
Physician global
HAQ-DI
ESR or CRP
ACR 20 Components That are
Inter-related
•
•
•
•
•
Pain
Patient global
Physician global
HAQ-DI
Tender joint counts
Current Drug Therapy Options in
Rheumatoid Arthritis
• Non-selective NSAIDs (Rx, OTC)/ Selective
COX-2 Inhibitors
• Disease Modifying Anti-rheumatic Drugs
(DMARDs)
• Immunosuppressives
• Glucocorticoids
• Biologic agents
• Investigational agents
Drug Therapy
•
For many years it was considered standard of care to be cautious and not
expose patients to potentially toxic therapy which had not clearly been
shown to alter disease
•
Diagnosis was faulty and many early patients suffered probably viral arthritis
and not true RA; many early spontaneous remissions were likely due to a
viral etiology
•
Thus a treatment “pyramid” emphasized slow progression of therapy from
least effective modalities to palliate pain and suffering to potentially more
effective but also those therapies associated with more risk of adverse
events
The New Treatment Paradigm
Celecoxib vs Naproxen in RA
Number of Tender/Painful Joints at Week 12
00
Placebo
Placebo
(n
(n == 231)
231)
Mean Change
Change
Mean
From Baseline
Baseline
From
Fewer
-2
-2
Celecoxib
Celecoxib
100
100 mg
mg BID
BID
(n
(n == 240)
240)
-4
-4
-6
-6
-8
-8
-10
-10
-12
-12
-14
-14
--8.2
8.2
--10.1
10.1
--12.0
12.0 --12.3
12.3
**
**
Celecoxib
Celecoxib
200
200 mg
mg BID
BID
(n
(n == 235)
235)
Naproxen
Naproxen
500
500 mg
mg BID
BID
(n
(n == 225)
225)
Mean
Mean baseline
baseline values:
values: placebo
placebo == 28.7;
28.7; celecoxib
celecoxib 100
100 mg
mg BID
BID == 29.6;
29.6; celecoxib
celecoxib 200
200 mg
mg BID
BID
== 31.0;
naproxen
500
mg
BID
=
28.3.
31.0; naproxen 500 mg BID = 28.3.
*P
*P << 0.05
0.05 vs
vs placebo.
placebo.
Simon
Simon LS,
LS, et
et al.
al. JAMA.
JAMA. 1999;282:1921–1928.
1999;282:1921–1928.
Drug Therapy
•
Known “truths”
– NSAIDs were/are palliative: do not alter fundamental disease
– DMARDs
• Important for those patients with progressive disease: likely would
take 6 months to know benefit
• Highly toxic, were associated with significant risk
• Required weekly surveillance with initiation of therapy and if
tolerated would still require monthly visits
• Many patients did not have an adequate response
• Standard of care was still associated with damage evident by x-ray
and progressive loss of functional status
Drugs Used to Treat RA Prior to 1985
•
•
•
•
•
•
•
Antimalarials
IM Gold
Penicillamine
Cyclosporins
Azathioprine
Cyclophosphamide
Chlorambucil
Drug Therapy
•
Antimalarials
– Fortuitously discovered when given for either antimalarial prophylaxis or treatment in
World War II to people with RA. Is not a DMARD
•
IM gold
– previously used to treat some infections: may be a DMARD
– 1966 Empire Rheumatism Council studied IM gold therapy demonstrating significant
improvement and an occasional case of “remission” with significant risk in over 40% of
patients:
• Heavy metal induced kidney damage
• Bone marrow suppresion
• Liver effects, skin, vasculitis
•
Cyclophosphamide
– Significant benefit with decreasing disease activity and x-ray benefit
– Chronic oral therapy increased risk of urogenital cancer, leukemia,
immunosuppression, bone marrow failure, nausea vomiting, hair loss
Drug Therapy
• Methotrexate
– First studied at “low dose” in the 1960’s: concerns surrounded
use of chemotherapy agent in chronic “non-fatal” disease
– 1985 new description of use at 7.5 mgs weekly showing benefit
– Subsequently more common dose is 15-25 mgs weekly
– Better tolerated than previous DMARDS
– Some evidence of true disease modification
– Potential adverse effects included progressive liver damage
even with consistent monitoring, lung fibrosis, acute pulmonary
disease, bone marrow suppression, immunosuppression
Estimated Continuation of Initial Secondline Therapy Over 60 Months
Pincus et al. J Rheumatol 19:1885, 1992.
Disease Modifying Anti-Rheumatic
Therapies (DMARTs)
•
•
•
•
Sulfasalazine
Methotrexate
Leflunomide
Biologic response modifiers
– TNF alpha inhibitors
• Etanercept
• Infliximab
• Adalimumab
– IL-1ra
Potential Future Treatments
•
T-cell inhibitors
•
– abatacept
•
B-cell directed therapy
–
–
–
–
•
Anti-CD20
Anti-BLyS
Anti-CD22
Anti-BAFF
Other cytokine blockers
– TNF-α–converting enzyme
– IL-6 receptor antagonist
Chemokine inhibitors
– CCR2 inhibitors
•
Inhibitors of T-cell activation
– CTLA-4 Ig
– Rapamycin-like drugs
•
Intracellular signal blockade
– P38 MAPK inhibitors
– IKK inhibitors
– Other kinase inhibitors
BLyS, B lymphocyte stimulator; BAFF, B-cell activating factor; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; MAPK,
mitogen-activated protein kinase.
Shanahan JC et al. Curr Opin Rheumatol. 2003;15:226-236; Baker KP et al. Arthritis Rheum. 2003;48:3253-3265; Foey A et
al. Arthritis Res. 2002;4:64-70; Kaufmann J et al. European League Against Rheumatism (EULAR) 2004; June 9-12, 2004;
Berlin, Germany; Vaux DL. J Clin Invest. 2002;109:17-18.
Advantages of DMARTs
• Have been shown to:
– Slow disease progression
– Improve functional disability
– Decrease pain
– Interfere with inflammatory processes
– Retard development of joint erosions
Summary of ACR Response Rates* for
Leflunomide, Sulfasalzine, Methotrexate
ACR 20%
ACR 50%
ACR 70%
52.2
26.3
45.6
34.3
7.6
22.8
20.2
4.2
9.4
MN301(6 months)
Leflunomide (n=130)
Placebo (n=91)
Sulfasalazine (n=132)
54.6
28.6
56.8
33.1
14.3
30.3
10.0
2.2
7.6
Non-PlaceboActiveControlled Studies
MN302 (12 months)
Leflunomide (n=495)
Methotrexate (n=489)
51.1
65.2
31.1
43.8
9.9
16.4
Study and Treatment Group
Placebo-Controlled Studies
US301 (12 months)
Leflunomide (n=178)
Placebo (n=118)
Methotrexate (n=180)
* Intent to treat (ITT) analysis using last observation carried forward (LOCF) technique for patients who
discontinued early.
N is the number of ITT patients for whom adequate data were available to calculate the indicated rates.
p<0.001 leflunomide vs placebo
p<0.02 leflunomide vs placebo
PERCENTAGE OF PATIENTS WHO ACHIEVED
AN ACR RESPONSE AT WEEKS 30 AND 54 with
infliximab
REMICADE + MTX
3 mg/kg a
10 mg/kg a
Placebo
+ MTX
(n=88)
q 8 wks
(n=86)
q 4 wks
(n=86)
q 8 wks
(n=87)
q 4 wks
(n=81)
Week 30
20%
50%
50%
52%
58%
Week 54
17%
42%
48%
59%
59%
ACR 50
Week 30
5%
27%
29%
31%
26%
Week 54
9%
21%
34%
40%
38%
ACR 70
Week 30
0%
8%
11%
18%
11%
Week 54
2%
11%
18%
26%
19%
Response
ACR 20
a
p < 0.05 for each outcome compared to placebo
The ACR 20, 50 70 Responses with Etanercept
Placebo Controlled
Study I
Study II
Active Controlled
Study III
Placebo ENBRELa MTX/Placeb MTX/ENBRELa MTX
o
Response N = 80 N = 78
N = 30
N = 59
N = 217
ACR 20
Month 3
23%
62%b
33%
66%b
56%
b
b
Month 6
11%
59%
27%
71%
58%
Month 12
NA
NA
NA
NA
65%
ENBRELa
N = 207
62%
65%
72%
ACR 50
Month 3
Month 6
Month 12
8%
5%
NA
41%b
40%b
NA
0%
3%
NA
42%b
39%b
NA
24%
32%
43%
29%
40%
49%
ACR 70
Month 3
Month 6
Month 12
4%
1%
NA
15%b
15%b
NA
0%
0%
NA
15%b
15%b
NA
7%
14%
22%
13%c
21%c
25%
a.25 mg ENBREL SC twice weekly.
b. p < 0.01, ENBREL vs. placebo.
c. p < 0.05, ENBREL vs. MTX.
ACR Responses in Placebo-Controlled Trials of
Humira (adalimumab) (Percent of Patients)
Response
Study II
Monotherapy
(26 weeks)
Placebo HUMIRA HUMIRA
40 mg
40 mg
weekly
every
other
N=103
week
N=110
N=113
Study III
Methotrexate Combination
(24 and 52 weeks)
Placebo/MT
X
HUMIRA/MTX
40 mg
every other
week
N=200
N=207
ACR20
Month 6
Month 12
19%
NA
46%*
NA
53%*
NA
30%
24%
63%*
59%*
8%
NA
22%*
NA
35%*
NA
10%
10%
39%*
42%*
2%
NA
12%*
NA
18%*
NA
3%
5%
21%*
23%*
ACR50
Month 6
Month 12
ACR70
Month 6
Month 12
*p<0.01, HUMIRA vs. placebo
Percent of Patients with ACR Responses
of IL1-ra
Response
Study 1 (Patients on MTX)
Study 3 (No DMARDs)
TM
Placebo
Kineret TM
Placebo
Kineret
100 mg/day
75 mg/day 150mg/day
(n=251)
(n=250) (n=119)
(n=115)
(n=115)
ACR 20
Month 3
Month 6
24%
22%
34% a
38% c
ACR 50
Month 3
Month 6
6%
8%
13% b
17% b
5%
8%
10%
11%
8%
19%a
ACR 70
Month 3
Month 6
0%
2%
3% a
6% a
0%
1%
0%
1%
0%
1%
a
b
p<0.05, KineretTM versus placebo
p<0.01, KineretTM versus placebo
c
23%
27%
p<0.001, KineretTM versus placebo
33%
34%
33%
43%a
LEF: Mean Improvement in
HAQ DI Over Time
Year-2 Cohorts: 0–24 Months
Improved
HAQ DI
1.7
1.5
US301
(n = 97)
MN301/3/5
(n = 51)
MN302/4
(n = 248)
1.3
1.1
32%
46%
0.9
0.7
50%
0.5
0.3
Baseline
6 mo
Strand V, et al. J Rheumatol. 2005; in press.
12 mo
24 mo
Etanercept: Mean Change in HAQ DI
Over 2 Years (ERA)
1.7
Methotrexate
Etanercept (25 mg)
Mean HAQ DI
Improved
1.5
1.3
1.1
0.9
0.8
0.7
0.5
0.3
Baseline
Month 6
Kosinski M et al. AJMC. 2002;8,:231-240
Month 12
Month 18
Month 24
INF: Mean HAQ DI Over Time
Year-2 Patients 0–24 Months (ATTRACT)
1.7
1.7
HAQ DI
1.5
1.3
1.5
1.5
1.5
1.3
1.3
1.3
1.6
1.3
1.1
Improved
0.9
All INF + MTX
0.7
0.5
ITT
Completed 54 wk
Baseline
6 mo
(n = 340)
(n = 296)
Placebo + MTX
(n = 86)
(n = 50)
12 mo
Maini RN, et al. Arthritis Rheum. 2004;50:1051–1065; Kavanaugh AF, et al. Arthritis Rheum.
2000;43:S147.
24 mo
Adalimumab+MTX: Mean Change in HAQ DI over
2 years: DE019
All adalimumab treated patients
1.6
Excludes placebo-treated patients
1.4
1.2
1
0.8
0.6
0.4
0.2
At last visit, 31% of patients
had HAQ DI scores of 0
0
0
6 Mos
Keystone E, et al. EULAR 2004:FRI0098
12 Mos
18 Mos
24 Mos
ASPIRE: MTX v MTX+INF in Early RA
Demographics
Median age (years)
Median disease duration (years)
Prior DMARD Rx (%)
Corticosteroids (%)
RF+ (%)
HAQ DI [median]
DAS28 at Baseline [median]
Baseline Total Sharp Scores
Erosion score ≤0 (%)
MTX
MTX+INF
3 mg/kg
MTX+INF
6 mg/kg
N=298
N=373
N=378
51
0.6
34
37
71
1.5
6.8
5.05
20
52
0.6
28
36
73
1.5
6.8
5.15
17
49
0.6
31
39
71
1.5
6.8
5.25
16
Smolen et al. Ann Rheum Ds 2003;62:S64
Intent to Treat Analysis
Intent to Treat Analysis
TEMPO: Trial of Etanercept and Methotrexate
with Radiographic Patient Outcomes
Design:
Double-blind, randomized active controlled trial
conducted in Europe and Australia
Treatment:
MTX vs ETN vs MTX+ETN over 52 weeks
Patients:
682 patients with active RA and inadequate response
to ≥ 1 DMARD; no Rx with MTX for ≥ 6 months
1° end point:
AUC of ACR-N (24 weeks)
Change in total Sharp score at 52 weeks
2° end points: ACR 20/50/70 responses
DAS
HAQ DI
TEMPO: Demographics
MTX
N=228
Mean age (years)
53
Mean disease duration (years)
6.6
RF+ (%)
74
Mean DMARDs failed
2.3
Previous MTX use (%)
43
Corticosteroids (%)
57
Mean MTX dose (mg/wk)
17
Baseline DAS28
5.5
Baseline HAQ DI
1.7 -1.8
Baseline Total Sharp Scores
45
ETN
N=223
MTX+ETN
N=231
[<1 – 26 years]
[0 – 9]
Mean Changes in HAQ DI at Weeks 52
TEMPO RCT
Baseline HAQ DI:
1.7
1.7
1.8
-0.1
Mean Change from BL
-0.2
MCID
-0.3
MTX
-0.4
ETN
-0.5
MTX+ETN
-0.6
-0.7
-0.61
-0.66
-0.8
-0.9
-1.0
-0.97
Percentage of Patients Achieving and Not
Achieving ACR Goals: TEMPO Trial*
90
Percent of Patients
Achieving ACR Goals
Percent of patients
80
Percent of Patients
Not Achieving ACR Goals
70
60
50
40
30
20
10
0
ACR20
*Etanercept plus MTX arm.
Klareskog L et al. Lancet. 2004;363:675-681.
ACR50
ACR70
CTLA4Ig (abatacept) MOA
•
Activation of T cells requires 2 signals
– Signal 1: antigen-specific interaction with the HMC-peptide complex
– Signal 2: “costimulatory” interaction of specific receptors on T cells
(CD28) with ligands on the APCs (CD80 and CD86)
•
•
CTLA4Ig binds CD80 and CD86, which blocks the second signal
In addition to blocking costimulation, CTLA4Ig may modulate the
immune system through changes occurring in the APCs following
the binding to cell surface ligands
B7-1
(CD80)
T Cell Activation
B7-2
(CD86)
T Cell
CD28
Antigen
Presenting
Cell
B7
(CD -1
80)
B7
(CD -2
86)
g
CTLA4I
T Cell
An
Pre tigen
sen
t
Cel ing
l
CD28
By binding to CD80 and CD86,
CTLA4Ig prevents interaction with
CD28 on T-cells, preventing T-cell
activation
CTLA4Ig
ACR 20, 50 & 70 Responses @ 6 Months
Response Rate
80
ACR 20
ACR 50
ACR 70
Placebo + MTX
CTLA4Ig 2mg/kg + MTX
CTLA4Ig 10mg/kg + MTX
**
60
60
41.9
**
36.5
35.3
40
20
*
22.9
*
10.5
11.8
1.7
0
* = p<0.05; ** = p<0.001
Treatment Groups
**
16.5
Rituximab Anti-CD20 Monoclonal
Antibody
• Chimeric murine/human
monoclonal antibody
– Variable light and heavy chain
regions from murine model
– Human IgG1, kappa constant
region
RTX
• Long serum half-life
(375 mg/m2)
– Single dose t1/2 = 76 hours
– Multidose t1/2 = 206 hours
Berinstein NL et al. Ann Oncol. 1998;9:995-1001; Maloney DG et al. J Clin Oncol. 1997;15:3266-3274; Maloney DG et al.
Blood. 1997;90:2188-2195.
Rituximab: Mechanism of Action
Antibody
-Dependent Cell
-Mediated Cytotoxicity
Antibody-Dependent
Cell-Mediated
Cytotoxicity (ADCC)
(ADCC)
Rituximab
antibody
Macrophage,
monocyte, or
natural killer cell
CD20
Fcγ
Fc RI, Fcγ
Fc RII, or Fcγ
Fc RIII
Cell lysis
Complement
-Dependent Cytotoxicity
Complement-Dependent
Cytotoxicity (CDC)
(CDC)
B cell
Complement activation (C1qC1rC1s)
Membrane attack
complex (MAC)
CD20
Cell lysis
Apoptosis
Apoptosis
Anderson DR et al. Biochem Soc Trans. 1997;25:705-708; Golay J et al. Blood. 2000;95:3900-3908; Reff ME et al. Blood.
1994;83:435-445; Clynes RA et al. Nat Med. 2000;6:443-446; Shan D et al. Cancer Immunol Immunother. 2000;48:673683; Silverman GJ et al. Arthritis Rheum. 2003;48:1484-1492.
Rituximab in RA Phase IIa: Dosing
Regimen and Treatment Schedule
Rituximab 1 g
IV or placebo
Study day
1
Rituximab 1 g
IV or placebo
3
8
15
CTX
750 mg IV
or placebo
17
CTX
750 mg IV
or placebo
Methylprednisolone
(100 mg IV)
Prednisone (po)
MTX or placebo
weekly
60 mg/day
Day 2, Days 4–7
30 mg/day
Days 8–14
Continue
to 24 weeks
Preliminary data.
Adapted from Szczepański L et al. European League Against Rheumatism (EULAR) 2003; June 18-21, 2003; Lisbon, Portugal.
Rituximab in RA Phase IIa:
ACR Responses at 24 Weeks (LOCF)
Primary end point
76 †
80
73 ‡
MTX
65*
70
RTX
RTX + CTX
Percent
60
50
40
41
38
||
43
RTX + MTX
||
33 §
30
23
20
15
13
15
5
10
0
ACR20
ACR50
ACR70
*P = 0.025, †P = 0.001, ‡P = 0.003, §P = 0.059, ||P = 0.005, ¶P = 0.048. P values using Fisher’s exact test,
comparing MTX with each rituximab group.
LOCF, last observation carried forward.
Edwards JCW et al. N Engl J Med. 2004;350:2572-2581.
¶
Rituximab in RA Phase IIa: Improvement
in Patient-Reported Outcomes (24 Weeks)
MTX
(n = 40)
RTX
(n = 40)
RTX + CTX RTX + MTX
(n = 41)
(n = 40)
Global disease
activity (mm)*
−14.0
−31.1
(P = 0.004)
−31.0
−28.6
(P = 0.005) (P = 0.023)
Pain (mm)*
−13.3
−25.8
(P = 0.024)
−25.2
−26.5
(P = 0.039) (P = 0.028)
HAQ-DI*
−0.3
−0.7
(P = 0.008)
−0.5
(P = NS)
−0.6
(P = 0.026)
Preliminary data.
*Mean change (negative values indicate improvement).
HAQ-DI, Health Assessment Questionnaire Disability Index.
Pavelka K et al. European League Against Rheumatism (EULAR) 2004; June 9-12, 2004; Berlin, Germany.
Rituximab in RA Phase IIa:
ACR Responses at 48 Weeks (NRI)
80
MTX
65*
70
RTX
RTX + CTX
Percent
60
50
49
40
30
20
RTX + MTX
§
35
33
27
20
†
§
15
5
10
10
0
0
ACR20
8
ACR50
*P < 0.0001, †P = 0.003, ‡P = 0.03, §P = 0.01. P values using Fisher’s exact test, comparing MTX
with each rituximab group. NRI, Non-responder imputation.
Edwards JCW et al. N Engl J Med. 2004;350:2572-2581.
ACR70
15
‡
Rituximab in RA Phase IIa:
B-Cell Depletion and Recovery
4 Arms
3
Median CD19 (cells x 10 /µL)
500
MTX
RTX
RTX + CTX
RTX + MTX
450
400
350
300
250
200
150
100
Lower limit of normal
50
0
0
4
8
12
16
20
24
28
32
36
40
44
48
Time (weeks)
IV Steroids given on Days 1, 3, 15, and 17.
Edwards JCW et al. N Engl J Med. 2004;350:2572-2581; Emery P et al. Arthritis Rheum. 2003;48:S439 (Preliminary data).
Rituximab in RA Phase IIa: Most Frequently
Reported Adverse Events (0–48 Weeks)
All
All events*
events* 0–48
0–48 weeks
weeks
Most
Most frequently
frequently reported
reported adverse
adverse events
events
(≥
(≥ 5%)
5%)
RA
RA exacerbation
exacerbation
Hypotension**
Hypotension**
Hypertension**
Hypertension**
Nasopharyngitis
Nasopharyngitis
Arthralgia
Arthralgia
Back
Back pain
pain
Hyperglycemia
Hyperglycemia
MTX
(n = 40)
145
(85%)
RTX
(n = 40)
RTX + CTX RTX + MTX
(n = 41)
(n = 40)
169 (88%)
161 (85%)
138 (85%)
55%
18%
15%
15%
8%
8%
40%
30%
18%
10%
8%
13%
37%
29%
7%
7%
5%
7%
18%
10%
5%
7%
8%
18%
25%
15%
13%
3%
Cough
Cough
Flushing
Flushing
–
15%
5%
8%
8%
13%
5%
3%
Headache
Headache
5%
5%
7%
8%
*Number of events reported by percentage of patients.
**Hypotension/hypertension defined as > 30 mmHg change.
Edwards JCW et al. N Engl J Med. 2004;350:2572-2581.
Rituximab in RA Phase IIa:
All Serious Infection Events (0–48 Weeks)
MTX
(n = 40)
RTX
(n = 40)
RTX + CTX
(n = 41)
RTX + MTX
(n = 40)
Pneumonia
(Pseudomonal)
—
—
1
—
Bronchopneumonia*
—
1
—
—
Septic Arthritis
—
1
1
—
Septicemia
—
—
1
—
Preliminary data.
All serious infection events (SIEs) occurred within the first 24 weeks.
*Patient death.
Szczepański L et al. 67th Annual Meeting of the American College of Rheumatology, October 23-26, 2003; Orlando, FL.
Unanswered Questions About
B-Cell Therapies
• What is the role of steroids used with rituximab?
• What is the duration of clinical efficacy after a single
course of rituximab?
• Is there a risk of increased occurrence of serious
infections with B-cell targeted therapies? Opportunistic
infections?
• What role might biologics play in combination with B-cell
targeted therapies?
Unanswered Questions:
Efficacy
• Will the short- and long-term effects of different B-cell
targeted therapies differ because of different
mechanisms of action?
• What is the duration of clinical efficacy after
a single course of rituximab?
• Will combination therapy (DMARDs + B-cell therapies)
improve outcomes vs monotherapy?
• Will combinations with biologics work as or more
effectively?
Unanswered Questions:
Efficacy (cont’d)
• What is the effect and duration of a second course of
treatment?
• Should a retreatment schedule be fixed or variable?
• What are the effects on long-term radiographic damage
and long-term disability?
• What is the prevalence of human antichimeric antibodies
and clinical/safety effects?
Overview of Specific AEs with the
Available DMARTs
•
•
•
•
•
Hepatic failure and hepatotoxicity
Tuberculosis and other infections
Interstitial lung disease
Lymphoma
Demyelinating disorders
Hepatic Failure and
Hepatotoxicity
AE Reporting Rates for
ETN, INF, LEF, and MTX
Sept 1998–June 2003
Cumulative reporting rates per 100,000 pt-y (95% CI)
AE
Acute hepatic
failure
ETN
INF
6.54
(3.94,10.22)
8.55
(6.19,11.2)
LEF
MTX
7.9
0.6
(5.69,10.67) (0.48,0.73)
Denominators for exposure were estimated based on IMS data for
the use of each agent for all indications. Pt-y of exposure
calculated were 290,355 for ETN; 502,646 for INF; 531,959 for
LEF; and 15,675,396 for MTX. Reported rates of AEs per 100,000
pt-y of drug exposure were calculated by dividing the number of
AEs reported by pt-y of drug exposure.
ETN = etanercept; INF = inflixamab; LEF = leflunomide; MTX = methotrexate.
Cannon GW, et al. Presented at: Annual Meeting of the American College of Rheumatology (ACR);
October 16–21, 2004; San Antonio, Tex. Presentation 1469.
Tuberculosis and Other
Infections
AE Reporting Rates for
ETN, INF, LEF, and MTX
Sept 1998–June 2003
Cumulative Reporting Rates per 100,000 Pt-y (95% CI)
AE
ETN
Sepsis/TB
INF
LEF
102.63
136.28
33.27
(91.31,114.97) (126.26,146.88) (28.55,38.55)
MTX
4.87
(4.53,5.23)
Drug exposure during observation period (100,00 pt-y)
ETN
–
290,355
INF
–
502,646
LEF
–
531,959
MTX –
15,675,396
Cannon GW, et al. Presented at: Annual Meeting of the ACR; October 16–21, 2004; San
Antonio, Tex. Presentation 1469.
Serious Infection Rates in Patients Receiving
Biologic Therapy in the UK: BSRBR
ETN
2602
2508
INF
2781
936
ADA
915
641
132
205
40
52.6
/1000 pt-yrs
52.1
/1000 pt-yrs
62.4
/1000 pt-yrs
TB cases
2
9
0
Septic Joints
3
0
0
[n]
patient yrs
All Serious
Infections
Dixon WG, et al. EULAR 2005, #OP0094; Dixon WG, et al. ibid, #SAT0053;
Dixon WG, et al. Rheumatol 2005;44(suppl 1):i11
Serious Infection Rates in Pts
Receiving Biologics in the UK
ETN
Pt y
ADA
936
641
132 (52.6)
205
(52.1)
40
(62.4)
Lower respiratory
42 (16.7)
85
(21.6)
12
(18.7)
Skin and soft tissue
26 (10.4)
Bone and joint
15 (6.0)
21 (5.3)
3 (4.7)
Urinary tract
12 (4.8)
13 (3.3)
6 (9.4)
All serious infections
2508
INF
37(9.4)
Entries presented as no. of infections (rate/1000 pt y).
Dixon WG, et al. EULAR; June 8–11, 2005; Vienna, Austria. Abstract OP0094. [Evidence Level B]
8
(12.5)
Interstitial Lung Disease (ILD)
AE Reporting Rates for
ETN, INF, LEF, and MTX
Sept 1998–June 2003
Cumulative Reporting Rates per 100,000 Pt-Y (95% CI)
AE
ETN
INF
LEF
MTX
ILD
24.8
(19.4,31.23)
33.42
(28.56,38.88)
15.41
(12.26,19.13)
2.26
(2.03,2.51)
Denominators for exposure were estimated based on IMS data for the use of each agent
for all indications. Pt-y of exposure calculated were 290,355 pt-y for ETN; 502,646 pt-y
for INF; 531,959 pt-y for LEF; and 15,675,396 pt-y for MTX. Reported rates of AEs per
100,000 pt-y of drug exposure were calculated by dividing the number of AEs reported by
pt-y of drug exposure.
Cannon GW, et al. Presented at: Annual Meeting of the ACR; October 16–21, 2004; San
Antonio, Tex. Presentation 1469.
Lymphoma
AE Reporting Rates for
ETN, INF, LEF, and MTX
Sept 1998–June 2003
Cumulative Reporting Rates per 100,000 Pt-Y (95% CI)
AE
ETN
Lymphoma
INF
LEF
MTX
27.55
29.25
5.26
1.38
(21.85,34.29) (24.71,34.37) (3.50, 7.61) (1.21,1.58)
Drug exposure during observation period (100,00 pt-y)
ETN
–
290,355
INF
–
502,646
LEF
–
531,959
MTX –
15,675,396
Cannon GW, et al. Presented at: Annual Meeting of the ACR; October 16–21, 2004; San
Antonio, Tex. Presentation 1469.
Demyelinating Disorders
Demyelinating Reports*/100,000 Pt-Y
Demyelinating Disorders:
AERS Reporting Rates
*FDA/IMS data. Pt-y of exposure were 290,355 for ETN, 502,646 Pt-y for INF, 531,959 Pt-y
for LEF, and 15,675,396 Pt-y for MTX.
Cannon GW, et al. Presented at: Annual Meeting of the ACR; October 16–21, 2004; San
Antonio, Tex. Presentation 1469.
Summary
• AEs continue to be a concern for pts and clinicians
• Hepatotoxicity/ALF is a concern, especially with MTX,
but careful monitoring can prevent this from becoming
a problem
• TB rates in RA pts on TNF-α blockers seem to be
higher than normal, but screening can decrease risk
• Other opportunistic infections still seem to be of
concern, so strong suspicion may prevent serious
issues arising
(cont)
Drug Therapy
• Paradigm shift
– Inversion of conservative standard of care
– DMARTs clearly improve patient outcomes by
improving signs and symptoms decreasing pain and
inflammation
– DMARTs have been shown to retard x-ray
progression
– Thus the standard of care is to start aggressive
therapy as soon as a certain diagnosis of progressive
disease has been made
– Includes combination chemotherapy as the best
ongoing approach
Drug Therapy
• Even so
– There is still no cure, real remissions are very rare
– Ideally would prefer robust ACR 50 and 70 responses: not yet seen with
monotherapy
– The data from clinical trials really only approximate what may happen in
the “real world”: is a 1 or 2 year data set reasonable to predict long
term results over 20-30 years
– Most patients need access to many possible therapies since there is no
way to predict who might respond to any one therapy: thus it is
important to have available as many potential therapies as possible with
an acceptable benefit/risk ratio
Treatment of RA
•
•
•
•
•
Clearly aggressive therapy with combinations of drugs is becoming
standard of care
Safety of these approaches is a significant issue
The DMARTs are all good therapies with similar efficacy in
monotherapy and in some patients even in combination
There are still patients who are not adequately treated
There is a significant safety signal with DMARTs including risk for
infection, liver toxicity, ILD, lymphoma etc which require careful
monitoring
Summary
• Many choices when selecting DMARDs (newly
diagnosed and treated patients)—considerable body of
data on which therapy/combination is most appropriate
• However, close monitoring and early intervention,
particularly with combination therapy, generally makes
more clinical difference than the specific therapy chosen
• While ACR20, and more recently ACR50 and 70 are
good indicators of efficacy, other methods including
SF36, HAQ and XR data are gaining in popularity as
important tools for judging efficacy and measuring
patient outcomes
The Future
• Limited by our successes
– We have begun to believe our own press! Difficulty in recruiting
patients who have done reasonably well on therapy; do we want
to relegate studying new therapies only in those patients that fail
the presently available therapies, are their results going to be
broadly applicable to the general population with RA?
– Many patients thus who will be available for study in the US will
be those on the margin of society: those who cannot pay for
drugs or are uninsured
– Many studies will have to be done in Eastern Europe or
elsewhere, given our inability to better define RA are we dealing
with the same disease?
– Why are there some pts who derive benefits regarding structural
improvement but have few improvements in signs and
symptoms?
Trial Designs
• Superiority trials against placebo, lower
dose of test drug, active comparator
• Equivalence trials, actually non –inferiority
trials
• effective comparative agents desired
• more patients generally needed
• Define margins of non inferiority
• Other types of trials
• induction
Efficacy Outcomes
• Efficacy must be “clinically meaningful”
– Defined a priori
– Raises question as to what is meant
• Change in Sharpe score of two points
• Clinicians like to talk about ACR 50 and 70 but regulatory
approval threshold is ACR 20, but can you market a drug
without a 50, 70?
• Remission?
Trial Designs
• Placebo controlled with active comparator
– Probably unethical for longer than 4 weeks
– Last real development program to use: leflunomide
• Classic “add-on” design
– Used for cyclosporin, infliximab, adalimumab, abatacept, part of
etanercept development program
• Full factorial
– Will define full benefit of study drug as well as safety also will
reveal potential for synergy
• Withdrawal design
– Popular with pediatric trials
– Variant of step down trials
RA trials (safety)
• Safety considerations may be different for drugs,
biologics and devices
• Cumulative incidences tend to be better
• In new world of FDA, longer term exposures prior to
approvals for safety
• Use of comparator trials rather than observational
experiences
• Need to understand informed consent
• Patient numbers; proposed 300 patients at highest dose
for 6 months, 100 patients at highest dose for 1 year
Some Possibilities
• Approval Trials could be performed as non inferiority
trials against presently available therapy since it is hard
to imagine we will find drugs which are profoundly
superior to the effect of those DMARTs presently
available: BUT will marketing appreciate that?
• Withdrawal trials of one drug vs another could be done
as powerful tests of benefit, but companies and investors
appreciate simpler superiority trials: they make better
copy.
Unmet Needs in RA
• Reliable predictors of response to guide
therapeutic decision making
• Firm definition of therapy goals and
clinically useful response markers
• Effective therapy for current biologic
failures or inadequate responders
• Durable response (remission/cure)
Unmet Needs (cont’d)
• Reversal of pre-existing damage or earlier
intervention to prevent damage
• More affordable therapies
• Best combination of agents is unknown
• Safety concerns remain
• Immunopathogenesis is not completely
understood
Donald G. Payan, M.D.
Rigel’s Chief Scientific Officer and EVP
ƒ Dr. Payan is one of Rigel’s co-founders and a member of the
Board of Directors
ƒ Dr. Payan has held senior level positions at numerous
biotechnology companies, including AxyS Pharmaceuticals,
Inc. and Khepri Pharmaceuticals, Inc
ƒ He is also an Adjunct Professor of Medicine and Surgery at
the University of California, San Francisco, is a former
investigator in Howard Hughes Medical Institute, and is
Board Certified in Allergy-Immunology and Infectious
Diseases
Rigel Product Pipeline Update:
December 2005
R112: Allergic Rhinitis
R343: Asthma (with Pfizer)
R406/788: Rheumatoid Arthritis (and other immune diseases)
R763: Oncology (with Serono)
R017 Series: Transplant Rejection (and other immune/inflammatory
diseases)
Future Product Candidates
Dr. Donald G. Payan
101
Rigel Product Pipeline Review
December 2005
Build a strong and broad technology platform
directed at the biology of disease mechanisms
Focus on chronic illnesses that reflect
significant diseases with large markets
Leverage knowledge and expertise for
each program across multiple clinical
opportunities
102
Rigel R&D Goals
Each year going forward:
A First in Human (FIH) clinical study initiated /
IND filing with a Rigel small molecule drug for a
new target in an important disease
2004: R406/788 oral for Rheumatoid Arthritis
(and other autoimmune diseases)
2005: R763 oral/IV in Oncology
Going forward…
103
Rigel R&D Goals - Going Forward
We have established the systems and organization
to deliver one new molecule each year for an
important FIH study initiated / IND filing
2006
Additional indications for
R406/788 (ITP/AML/MS/SLE)
R017 series for chronic
transplant rejection
2007/08
R343 for Asthma w/Pfizer
Rxxx for Axl Kinase in
oncology/endometriosis
104
Rigel Product Pipeline
December 2005
CLINICAL STAGE
PHASE I
PHASE II
R112
inhaled Syk kinase
inhibitor for Allergic Rhinitis
R406/788 oral Syk kinase
inhibitor for Rheumatoid Arthritis
R763
oral/IV Aurora kinase
inhibitor for Oncology
PRE-CLINICAL IND-ENABLING PROGRAMS
2006
IND YEAR
PROGRAM
2007
ƒ R017 series Oral JAK3
Inhibitor for Transplant
Rejection
ƒ R343 Inhaled Syk Kinase
Inhibitor for Asthma
(with Pfizer)
ƒ 2nd Indication for
R406/788
(ITP/AML/MS/SLE)
ƒ Oral Axl Kinase Inhibitor
for Oncology and
Endometriosis
DISCOVERY
(ongoing lead molecule optimization)
ƒ Virology - Hepatitis C (NS2 cysteine protease inhibitor; IRES inhibitor)
ƒ Immunology/Inflammation - (TRAF-6 ligase inhibitor; PAK2 kinase inhibitor)
ƒ Oncology - (PRK-1 kinase inhibitor)
105
ƒ Metabolism - (Adiponectin mimetics)
PHASE III
Rigel Pipeline Connections
R406/788
R112 / R343
Airway Mucosal inflammation
/ atopic diseases
Same target different cellular activities
Chronic Tissue inflammation /
destruction
Allergic Rhinitis/Asthma
Rheumatoid Arthritis/MS/SLE/ITP
• 1º mucosal mast cells
• Fcε - Syk kinase signaling
• Multiple inflammatory mediators
released
• B Cells/macrophages/T cells
• Fcγ - Syk kinase signaling
• Multiple inflammatory mediators
Same cells different cytokine target
R017 series
Chronic tissue rejection
Transplant rejection
• Bcells/Tcells - MLR
• Jak3 kinase/cytokine signals
• Specific immune cell proliferation
106
R763
Different growth factors and
cellular responses
Tumor Growth / progression
Leukemia/Lymphoma/Solid
tumor growth
• Inhibit Transit through:
• Specific phase of cell cycle
• Selective growth factor
responses
• Aurora kinase inhibitor
Allergic Rhinitis and Asthma:
Common Mechanisms of Disease
107
IgE Production, Mast Cell Activation by Allergens,
and Action of Mast Cell-Derived Mediators
Singulair
Lipid mediators
(Leukotrienes, PGD2)
Allergens
Pollen
Parasite
Antigen presenting cell
(Dendritic cell)
Xolair
CD4+ T cell
B cell
Plasma cell
Acute allergic reaction
(vasodilation,
bronchoconstriction, mucus
secretion)
Antihistamines
Th2 cell
IL-4 (IL-13)
Preformed
mediators
(Histamine,
Proteases)
Specific IgE
production
Basophil/Mast cell
Late phase reaction
(Lymphocyte, eosinophil,
basophil, macrophage
recruitment and activation)
Chronic allergic
inflammation
(Structural and functional
changes in tissue)
108
R112
R343
Allergen-induced
receptor
crosslinking
Cytokines and
chemokines
(IL-4, TNF, IL-6, et al)
Rigel’s Topical Syk Inhibitor in Allergic Rhinitis
Primary Human
Mast Cell Culture
System
Cell-based HTS IgE Signaling
(200K cmpds)
Med Chem
MOA
R112
Phase Ib
• R112 appears
effective
Multiple Dose Safety
Phase II Park Study
• R112 is safe
• R112 is fast and effective
Allergic Rhinitis
109
Phase II 7-day
comparative study
Conclusions:
R112 Park Study
ƒ R112 is a selective inhibitor of Syk kinase
- Discovered in a primary human mast cell HTS screen
ƒ Blocks allergen triggered mast cell degranulation, leukotriene and
prostaglandin secretion, and cytokine synthesis and release in the
airway
ƒ Desirable chemical and pharmaceutical characteristics
- Ease of synthesis
ƒ Shown to be safe with no adverse events
ƒ The Phase II Park Study demonstrated efficacy (24% relative to
placebo, p=0.0005) against all nasopharyngeal symptoms of allergic
rhinitis when administered every 4 hours over 8 hours for 2 days as a
nasal spray
ƒ Rapid onset by 30 min with duration lasting throughout the study
ƒ Complete study reported in JACI - April 2005 issue
110
Questions Raised by R112 Park Study
ƒ How long does the beneficial effect of R112 last?
ƒ Will it work in a less “disciplined” environment?
(Fewer measurements; no supervision)
ƒ How does it compare to IN Steroids?
111
Comparative Phase IIb R112 Trial in Allergic
Rhinitis
ƒ Initiated in August 2005
ƒ Randomized, double-blind study comparing R112 to placebo and
Beconase AQ® nasal spray
ƒ Primary Endpoints:
• Efficacy as measured by total nasal symptom severity (TNSS) rating
• Safety
• Direct Steroid comparison in Allergy
• Locations: 25 sites across the US
• Patients: 396 verified to suffer from allergic rhinitis
• Protocol: 7 days, twice a day treatment with R112, placebo or Beconase
112
Change from baseline in TNSS
AM measurements
Comparative Phase IIb R112 Trial in Allergic Rhinitis:
Effects of R112 and Beconase on Total nasal symptom score
(*TNSS)
0
-1
-2
-3
-4
-5
-6
-7
-8
0
1
2
3
4
5
6
7
Days of Treatment
Twice/day:
113
R112
(n=139)
Placebo
(n=131)
Beconase
(n=63)
*TNSS= sum of symptoms of congestion/runny nose/sneezing/itchy nose/post-nasal drip
8
Conclusions from Comparative Phase IIb R112
Trial in Allergic Rhinitis
ƒ R112 did not significantly inhibit TNSS in allergy patients over a
7 day treatment period
ƒ The positive control therapy with Beconase performed as
expected
ƒ An R112 follow-on in Allergic Rhinitis will need a longer duration
of action (greater potency, slower dissolution rate)
114
Next Steps in Rigel Allergic Rhinitis Program
ƒ Detailed evaluation of R112 clinical data and comparison of both
Phase II studies
ƒ Discussion with Pfizer regarding AR option (per contract)
ƒ Potential selection of follow-on molecule with 100X> potency and
slower dissolution rate (longer residency time in nose)
115
Rigel Pipeline Connections
R406/788
R112 / R343
Airway Mucosal inflammation
/ atopic diseases
Same target different cellular activities
Chronic Tissue inflammation /
destruction
Allergic Rhinitis/Asthma
Rheumatoid Arthritis/MS/SLE/ITP
• 1º mucosal mast cells
• Fcε - Syk kinase signaling
• Multiple inflammatory mediators
released
• B Cells/macrophages/T cells
• Fcγ - Syk kinase signaling
• Multiple inflammatory mediators
Same cells different cytokine target
R017 series
Chronic tissue rejection
Transplant rejection
• Bcells/Tcells - MLR
• Jak3 kinase/cytokine signals
• Specific immune cell proliferation
116
R763
Different growth factors and
cellular responses
Tumor Growth / progression
Leukemia/Lymphoma/Solid
tumor growth
• Inhibit Transit through:
• Specific phase of cell cycle
• Selective growth factor
responses
• Aurora kinase inhibitor
Syk Inhibitors: Potential Modulation
of Both IgE or IgG Fc Receptor Signaling
Anti-IgE
Anti-IgG
IgG
IgE
FcγR
FcεR
β
Lyn
P Syk
Mast Cell Activation
117
FcRγ
FcRγ
Lyn
P Syk
Macrophage, B-lympocyte
and Mast Cell Activation
Rheumatoid Arthritis: A Progressive Debilitating
Disease with Poor Current Treatment Options
Swelling and inflammation
118
Rheumatoid Arthritis: A Progressive Debilitating
Disease with Poor Current Treatment Options
Swelling and inflammation
Destruction of cartilage
119
Rheumatoid Arthritis: A Progressive Debilitating
Disease with Poor Current Treatment Options
Swelling and inflammation
Destruction of cartilage
Bone deterioration
DMARDs (Disease-Modifying
Anti-Rheumatic Drugs) introduced
120
Rheumatoid Arthritis: A Progressive Debilitating
Disease with Poor Current Treatment Options
Swelling and inflammation
Destruction of cartilage
Bone deterioration
DMARDs (Disease-Modifying
Anti-Rheumatic Drugs) introduced
Destruction slows
121
R406/788 for Rheumatoid Arthritis
R406/788
122
Designed to prevent bone
and cartilage damage
R406/788 Inhibits Several Steps that Initiate and
Maintain RA Disease Activity
Periphery
Joint Synovium
Bone/Cartilage
R406
I
3
,1
0
1
4,
L
B
Immune Complex
BCR
R406
CD40
CD40L
T
FcγR
R406
Mast
MMP
Synovial Fibroblast
TCR
PGE2
H+
CatK
MHC
FcγR
FcγR
TNF
IL-1
R406
Osteoclast
FcγR
IL-6
Macrophage
O2-
IL-17
IL-8
FcγR
PMN
KC
VEGF
Pannus
Disease Initiation
Disease Propagation
Tissue Damage
R406 Has Demonstrated Efficacy in Three Different
Animal Models of Rheumatoid Arthritis
1) Mouse Collagen Antibody Induced Arthritis (CAIA)
2) Rat Collagen Induced Arthritis (CIA)
3) Mouse K/B x N Spontaneous Autoantibody Induced Arthritis
ƒ All three models display tissue swelling and bone destruction in
and near affected joints resulting in loss of mobility and function
ƒ R406 reversed all these changes in all three models
124
R406 Pharmacology: Efficacy in the Rat Collagen
Induced Arthritis (CIA) Model
Radiographs
8
Vehicle Control - Day 28
Hind Paw clinical score
a
c
i
n
i
l
C
w
a
P
d
n
i
H
7
6
5
Vehicle
10 mg/kg b.i.d
30 mg/kg b.i.d
4
3
R406 - Day 28
2
1
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19
Days Post Arthritis Onset
Immunization Day
Day-post onset
125
Collagen
type II+IFA
i.d.
CII/IFA
boost
0
7
Treatment with R406
b.i.d. from onset
(clin. score>1)
*
10-18
0
Clinical score/histology, Hind-paw thickness,
Body weight, Cytokine/chemokine
Radiographic score
18
R406 Prevents Joint and Bone Destruction in Rat
Collagen Arthritis Model
Rheumatoid Arthritis
No Treatment (Vehicle)
126
Data from E. Brahn, MD, UCLA
Rheumatoid Arthritis
Treated with R406 30 mg/kg
R406 Phase I Clinical Study Overview
(in normal volunteers)
Title:
• A Single Center, Phase I, Double-Blind, Randomized, PlaceboControlled Study to Investigate the Safety, Tolerance and
Pharmacokinetic Profile of Single and Multiple Doses of R406 in Young
Healthy Male Subjects
Design:
• Single Dose:
5 sequentially rising doses (80, 250, 400, 500, and 600 mg)
5-6 R406 and 1-2 placebo subjects per group
• Multiple Dose:
3 sequentially rising doses (100, 200, and 300 mg bid) given for 7 days
6 R406 and 2 placebo subjects per group
127
R406 Phase I Clinical Study Details
ƒ Safety
• Adverse event profile
• Vital signs
• ECG (lead II & 12-lead)
• Clinical laboratory safety tests (chemistry, hematology, urinalysis)
ƒ Pharmacokinetics
• In multiple dose phase, subjects were administered a single dose on Days 1 and 7
and two doses per day on Days 2-6, to allow for optimal PK profiling
ƒ Pharmacodynamics
•
•
•
128
Activated Basophil Assay (FACS, CD63+ve), Fcε signaling
FACS analysis of peripheral blood
Platelet aggregation
R406 Phase I Results – Safety
ƒ Single Dose Phase
• All doses levels well tolerated, with the highest dose of 600 mg
associated with an increased frequency of postural dizziness
• No other significant findings, including vital signs, ECG, laboratory
testing (hematology,chemistry, urinalysis)
ƒ Multiple Dose Phase
• 100 and 200 mg bid
™ Well
tolerated; no significant findings including vital signs, ECG,
laboratory testing
• 300 mg bid
™ Several
adverse events of moderate severity, including increased
standing diastolic BP, a variety of mild GI-related symptoms, and
headache
™ Hematology
™ No
129
findings included ↓ Neutrophils
significant findings in chemistry, urinalysis, or ECG testing
Activated Basophil Assay: Biomarker for
R406 activity in patient’s blood
ƒ Demonstrate effects on the Fcε pathway, based on the commercially available
Basotest assay
ƒ Human peripheral blood basophils stimulated with anti-IgE ex vivo undergo
degranulation and express CD63 (gp53, LAMP-3) on the cell surface. CD63 is
readily detected by anti-CD63-FITC specific antibodies using flow cytometry.
Basophils are identified by positive staining with a PE labeled anti-IgE
antibody
ƒ Reference range is 15-60% activated (CD63+) basophils, however, some
subjects were low responders
130
Basophil Activation Assay demonstrates
activity of R406 in blood of normal volunteers
Single Dose Group Means
% Activated Basophils
60
Placebo
40
80 mg
250 mg
400 mg
20
500 mg
600 mg
0
0
4
8
12
16
Time Post-Dose (h)
131
20
24
PK/PD Correlation, Basophil Activation Assay
for R406 in normal volunteers
160
140
120
Observed
PD (%)
100
Predicted
80
60
40
20
0
1
10
100
1000
10000
Plasma Conc.of R940406 (ng/mL)
Parameter
Emax
EC50
Unit
Estimate
Standard Error
CV (%)
84.2
3.82
4.53
496
42.2
8.51
2.25
0.19
8.54
% Control
*
ng/mL
Gamma
* Parameters were obtain using a Sigmoidal
132
-Emax model, with 1/y weighting.
Average plasma concentration for R406 in normal
human volunteers when R406 was orally administrated
8000
R940406 plasma conc. (ng/mL)
7000
6000
5000
100 mg Day 7
200 mg Day 7
300 mg Day 7
4000
3000
2000
1000
0
144
154
164
174
184
Time (h)
133
Time shown in # of hours
194
204
214
R406 Phase I Results –
Human PK Comparison with Rat CIA
R406 Plasma concentration (ng/mL)
10000
200 mg (2.5 mg/kg) Human (Day 7)
10 mg/kg, Rat CIA model (Day 18)
30 mg/kg, Rat CIA model (Day 18)
1000
100
Efficacy in the Rat CIA
10
1
0
2
4
6
8
10
12
14
Time Post-Dose (h)
Time (hours)
16
18
Hind Paw
score
Hindclinical
Paw Clinical
Score
8
Vehicle
7
10 mg/kg b.i.d
6
30 mg/kg b.i.d
5
4
3
202
22
24
1
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18
Days Post Arthritis Onse t
134
Conclusions of R406/788 as an Oral RA
Treatment
ƒ R406/788 is a potent and selective inhibitor of Syk
ƒ R406/788 blocks FcγR signaling on mast cells and macrophages, and
BCR signaling
ƒ R406/788 is orally bioavailable in all species tested
ƒ Efficacy demonstrated in multiple autoimmune disease models reduction in multiple inflammation cytokines and tissue protection
ƒ Good safety profile in animal models
ƒ Clinical studies underway - promising pharmacodynamics in Phase I
ƒ May be useful for several disease indications (ITP, AML, MS, SLE)
135
Next Steps in RA for R406/788
ƒ Evaluate safety and PK in single and multiple dose / drug-drug
interaction studies (eg. Methotrexate)
ƒ Evaluate preliminary efficacy and safety in patients with
rheumatoid arthritis - 2H 2006
ƒ Identify additional clinical indications for R788 in autoimmune
diseases
ƒ Rigel to continue program through NDA
136
R406/788 in Several Disease Areas: leverage
molecule across multiple clinical opportunities
Target cells
MOA
Inhibition by R406
(EC50)
Allergy/Asthma
Mast cells
B cells
Disease area
Ig-FcγR/Syk
30-60 nM
Macrophages
Autoimmune diseases
(MS/SLE/ITP)
Inflammatory
diseases
Leukemic cells
Dendritic cells
137
Leukemia
FLT3L/FLT3R
10-80 nM
Autoimmune
diseases (MS)
R788 in ITP
ƒ Immune Thrombocytopenia Purpura (ITP): autoimmune
hematological disease characterized by destruction of platelets
™
™
™
Prevalence of approx. 200,000 in US
More women than men; half new cases in children
Current therapy inadequate -- steroids mainstay
• Platelet destruction mediated by IgG signaling
• R788 potent inhibitor of IgG signaling
• R788 shown to protect from thrombocytopenia in animal
models
138
R788 in ITP
R788…
ƒ Improves thrombocytopenia in ITP mouse model
ƒ Does not affect murine bleeding time
ƒ Does not affect platelet aggregation in humans in response to
collagen
ƒ Phase I studies nearly completed
139
R788 in Acute Mylelogenous Leukemia (AML)
ƒ Flt3-mutant AML
• Approximately 20-30%of AML is Flt3-mutant
• Flt3-mutant AML patients have poor prognosis
ƒ R788 also potently inhibits Flt3
ƒ R788 inhibits tumor growth of human Flt3 AML cells in mouse
xenografts
ƒ R788 extends survival in mouse model of leukemia
140
R788 in Flt3 AML
Survival
Percent survival
100
Vehicle
20mg/kg
40mg/kg
80mg/kg
75
>51% ILS
50
45% ILS
P<0.01
Dosing began day 14
post-implantation
25
Tumor Shrinkage
15
13% ILS
Vehicle
20mg/kg R788 bid
40mg/kg R788 bid
0
25
50
Day
75
100
Change inTumor
Volume (V/V 0)
0
10
%T/C = 35.1
5
0
%T/C = -0.4
0
5
10
15
Day
141
20
25
30
R788: Next Steps in
ITP/Flt3 AML/Autoimmune Diseases
ƒ Complete Phase I safety studies 1H 2006
ƒ Initiate clinical trials in 2H 2006
ƒ Obtain proof of concept clinical data late 2006
ƒ Animal model studies underway in other more chronic
autoimmune diseases (MS/SLE)
142
Rigel Pipeline Connections
R406/788
R112 / R343
Airway Mucosal inflammation
/ atopic diseases
Same target different cellular activities
Chronic Tissue inflammation /
destruction
Allergic Rhinitis/Asthma
Rheumatoid Arthritis/MS/SLE/ITP
• 1º mucosal mast cells
• Fcε - Syk kinase signaling
• Multiple inflammatory mediators
released
• B Cells/macrophages/T cells
• Fcγ - Syk kinase signaling
• Multiple inflammatory mediators
Same cells different cytokine target
R017 series
Chronic tissue rejection
Transplant rejection
• Bcells/Tcells - MLR
• Jak3 kinase/cytokine signals
• Specific immune cell proliferation
143
R763
Different growth factors and
cellular responses
Tumor Growth / progression
Leukemia/Lymphoma/Solid
tumor growth
• Inhibit Transit through:
• Specific phase of cell cycle
• Selective growth factor
responses
• Aurora kinase inhibitor
Organ Transplantation Overview
ƒ Approximately 90,000 organ transplants worldwide
ƒ 27,022 transplants in the U.S. in 2004 with 6% growth
ƒ First year survival rates are ~90% for the major organs
ƒ Chronic rejection rates are high (~50% at 5-10 years)
ƒ Conventional maintenance therapy consist of 3 drug combo:
>Calcineurin inhibitor (NeoralTM or PrografTM)
>Mycophenolate mofetil (CellceptTM)
>Corticosteroids
144
Transplantation Pharma Market
ƒ Current Global pharma sales approx. $4B
TM
> Cellcept (Roche)= $1.1B
TM
> Prograf (Fujisawa)= $1.1B
TM
> Neoral (Novartis)= $1.0B
ƒ Current drugs exhibit non-immune specific toxicities
ƒ Current Focus
> Reduce calcineurins (Neoral/Prograf) and steroid use
> Better balance between toxicity and immune suppression
ƒ Current Patient Needs
> Reduce toxicities (1º nephrotox, 2° hypertension, neurotox,
hyperlipidemia)
> Prevention of chronic rejection and vasculopathy
145
Pathogenesis and Treatments of Transplant Rejection
NK Cell
CD8+ T cells
5 IL15
5 IL7
Allograft
Progenitor
2
B7.1/B7.2
CD28
IL2
5
3
MHC
DC
IL2 5
T Cell Proliferation 4
IL4
TCR
1
5
T
CD40L
B
1 OKT3
B
B
2 CTLA4-Ig
3 CsA/FK506
4 MMF, azathioprine
5 Cytokine signaling inhibitors - Rapamycin
146
Alloantibody
Production
The IL-2 and IL-4 Pathway: Key Signals in immune
mediated rejection
IL-2
IL-4
γc
IL-2Rα
P
P
Y phosphorylation
P
S/T phosphorylation
JAK1
JAK3
γc
IL-4Rα
P
JAK1
JAK3
IL-2Rβ
P
IRS
P
P STAT3/5
Shc
P STAT6
Grb2
Accessory Pathways Sos
PI3K
STAT3/5
P
P
ERK
Akt
STAT3/5
P
Modulatory Pathways
P38, Erk, other kinases?
P
Nuclear Translocation
STAT3/5
P
P
STAT3/5
P
P
Gene Transcription
Janus Tyrosine Kinase 3
ƒ A cytoplasmic tyrosine kinase
ƒ Expression limited to T & B cells, natural killer (NK) cells,
mast cells, and macrophages
ƒ Activated by multiple cytokines, including IL-2, IL-4, IL-7,
IL-9, IL-15, and IL-21
ƒ Plays a critical role in lymphocyte development and function
ƒ Attractive target based on limited tissue distribution
148
Properties of Rigel Jak3 inhibitor - R017 series
ƒ Potent: <100nM in cell-based assays of T-cell, IL4, IL2 signaling and MLR
ƒ Selective against IFNγ and Epo signaling
ƒ Good selectivity against other off target assays
ƒ HERG ≥ 12µM
ƒ Ames negative
ƒ Soluble: > 20mg/ml in water
ƒ Good exposure and sustained levels in animal models
ƒ Good distribution to target tissues
ƒ Activity in the mouse DTH model
ƒ Well tolerated up to 80mg/kg/day in Lewis rat
149
Heterotopic Rat Heart Transplant Allograft
Model
ƒ Brown Norway (BN) male hearts are grafted onto the abdominal region of Lewis
(LW) male rats
ƒ Vascularized Model
ƒ Graft Heart Ischemia to Reperfusion about 30 min
ƒ BN to LEW rats MHC RI is mismatched, robust immune response
ƒ Average Rejection Day 7+/- 1 without treatment
ƒ Pfizer compound CP-690,550 tested positive in murine model (DBA2 to C57/Bl6)75% survival at D28 (140 ng/ml blood level)
ƒ Most commonly used animal model in transplantation
ƒ Rapamycin, CsA, FK506 can completely sustain graft survival in rat allograft
model
150
R017 prolongs Heterotopic Heart Graft
Survival
100
% Grafts Survival
80
60
Vehicle (Allograft) (n=3) (BN
Vehicle (Isograft) (n=6) (LW LW)
R017 (Allograft) (20 mg/kg) b.i.d. (n=6) (BN
R017 (Allograft) (40 mg/kg) b.i.d (n=6) (BN
40
20
0
151
LW)
0
4
8
12
16
Time(Days)
20
24
28
LW)
LW)
Global effect of R017 on Grafted Hearts
152
LW
LW
BN
LW vehicle/untreated
BN
LW 40mg/kg R017
LW
LW
BN
LW vehicle/untreated
BN
LW 40mg/kg R017
Conclusions from Rat Heart Transplantation
Study with R017
ƒ Rats treated with R017 at 40 mg/kg maintain robust heart graft
function, prolongs graft survival for at least 28 days (6/6)
ƒ 20 mg/kg bid of R017 prolongs allograft function (5/6) for at
least 28 days
ƒ Dose Response of Efficacy with R017 at 40 mg/kg and 20
mg/kg: Gross appearance of grafts, heart graft contraction by
palpation, and ECG recordings
153
R017 series Jak3 inhibitor in
Transplantation: Status and 2006 plans
ƒ Lead molecule, R017, validated in animal model of cardiac
transplantation
ƒ Select clinical candidate, from R017 series, in 1H 2006
ƒ Complete IND enabling studies in 2H 2006
ƒ Initiate FIH studies / file IND in 1H 2007
154
Rigel Pipeline Connections
R406/788
R112 / R343
Airway Mucosal inflammation
/ atopic diseases
Same target different cellular activities
Chronic Tissue inflammation /
destruction
Allergic Rhinitis/Asthma
Rheumatoid Arthritis/MS/SLE/ITP
• 1º mucosal mast cells
• Fcε - Syk kinase signaling
• Multiple inflammatory mediators
released
• B Cells/macrophages/T cells
• Fcγ - Syk kinase signaling
• Multiple inflammatory mediators
Same cells different cytokine target
R017 series
Chronic tissue rejection
Transplant rejection
• Bcells/Tcells - MLR
• Jak3 kinase/cytokine signals
• Specific immune cell proliferation
155
R763
Different growth factors and
cellular responses
Tumor Growth / progression
Leukemia/Lymphoma/Solid
tumor growth
• Inhibit Transit through:
• Specific phase of cell cycle
• Selective growth factor
responses
• Aurora kinase inhibitor
Aurora A and B are Essential for Proper Chromosome
Segregation During Mitosis (cell division)
Prophase
Anaphase
Telophase
Metaphase
A - centrosomes
A - spindle pole
microtubules
B - centromere
A - polar microtubules
B - spindle midzone,
cell cortex at site
of cleavage furrow
Aurora A
Aurora B
Centrosome separation
and maturation
Spindle assembly
Kinetochore-microtubule
interactions
Spindle assembly checkpoint
Cytokinesis
Carmena and Earnshaw, Nat Rev Mol Cell Biol 2003. 4, 842-854.
156
A - midbody
B - midbody
Inhibition of Aurora A and B Causes Cell Death
And/or Endoreduplication
Apoptotic
nuclei
Cell death
No cell division
Endoreduplication
Mitotic cell
Aurora Kinase
Inhibitors
Absence of
cytokinesis
G2
S
157
M
G1
Enlarged
Nuclei
Biological Properties of Rigel’s Aurora Kinase
Inhibitor R763
ƒ
Potent antiproliferative effect across a broad panel of cell types
ƒ
Good selectivity over cell-based counter assays
ƒ
Phenotype consistent with inhibition of Aurora kinases:
-
Endoreduplication, i.e., exit from mitosis without cytokinesis and cell cycle arrest
Induces apoptosis
ƒ
No effect on quiescent primary hepatocytes
ƒ
Aurora B expression may correlate with R763 sensitivity in some tumors
ƒ
Inhibition of blood vessel formation (angiogenesis)
ƒ
70 gene “signature” identified as markers to discriminate R763 sensitive and
resistant Tumors: more focused patient selection possible
158
R763 in Leukemia Models
Effects of R763 on Tumor Growth in Leukemia
cell line (MV411) Mouse Xenograft Model
Schedule
Monitor Tumor growth, body weight, and
clinical observations
24
days
Day 0
Day 28
Day 70+
Animals remaining
12.5 mg/kg n=1
20 mg/kg n=5
Cell injection
into NOD SCID mice
(Subcutaneous)
Start treatment
Mean tumor
volume=333mm3
160
Stop treatment
Total treatment duration
= 4 cycles of 3 on/4 off
Effects of R763 on Tumor Growth in Leukemia
cell line (MV411) Mouse Xenograft Model
2500
1500
Percent Survival
2000
Tumor Volume (mm3)
100
R763 Vehicle
Cytarabine Vehicle
Cytarabine, 100mg/kg
R763, 7.5 mg/kg
R763, 10 mg/kg
R763, 12.5 mg/kg
R763, 20 mg/kg
1000
75
50
25
500
0
0
0
2
Treatment Phase
161
4
6
8
10
12
14
16
18
20
22
24
26
28
0
10
20
30
40
50
Study Day
Treatment Phase
Days on Study
30
R763 Dose Level
%ILS
Tumor Growth % partial %complete Apparent net tumor
Delay (days) regression regression
cell kill (logs)
7.5 mg/kg
100
19.7
0
0
-0.4
10 mg/kg
143
27.4
67
0
0
12.5 mg/kg
172
32.3
92
0
0.3
20 mg/kg
223
42.8
83
17
0.9
60
70
Status of Rigel Aurora Kinase & R763 program
ƒ From HTS hit, to filing of the R763 IND: 28 months
ƒ Partnership with Serono established October 2005, to develop R763 for
the treatment of cancer
ƒ Rigel will potentially receive up to $160 million in payments, including:
• Upfront payment of $25 million in cash and equity
• Milestone payments of $135 million
• Royalties on sales
ƒ Rigel to file an IND for R763 - December 2005
ƒ Serono will initiate clinical trials in 2006
ƒ Serono will develop and commercialize R763 and follow-up compounds
162
Rigel Pipeline Connections
R406/788
R112 / R343
Airway Mucosal inflammation
/ atopic diseases
Same target different cellular activities
Chronic Tissue inflammation /
destruction
Allergic Rhinitis/Asthma
Rheumatoid Arthritis/MS/SLE/ITP
• 1º mucosal mast cells
• Fcε - Syk kinase signaling
• Multiple inflammatory mediators
released
• B Cells/macrophages/T cells
• Fcγ - Syk kinase signaling
• Multiple inflammatory mediators
Same cells different cytokine target
R017 series
Chronic tissue rejection
Transplant rejection
• Bcells/Tcells - MLR
• Jak3 kinase/cytokine signals
• Specific immune cell proliferation
163
R763
Different growth factors and
cellular responses
Tumor Growth / progression
Leukemia/Lymphoma/Solid
tumor growth
• Inhibit Transit through:
• Specific phase of cell cycle
• Selective growth factor
responses
• Aurora kinase inhibitor
Rigel Product Pipeline
December 2005
CLINICAL STAGE
PHASE I
PHASE II
R112
inhaled Syk kinase
inhibitor for Allergic Rhinitis
R406/788 oral Syk kinase
inhibitor for Rheumatoid Arthritis
R763
oral/IV Aurora kinase
inhibitor for Oncology
PRE-CLINICAL IND-ENABLING PROGRAMS
2006
IND YEAR
PROGRAM
2007
ƒ R017 series Oral JAK3
Inhibitor for Transplant
Rejection
ƒ R343 Inhaled Syk Kinase
Inhibitor for Asthma
(with Pfizer)
ƒ 2nd Indication for
R406/788
(MS/SLE/ITP/AML)
ƒ Oral Axl Kinase Inhibitor
for Oncology and
Endometriosis
DISCOVERY
(ongoing lead molecule optimization)
ƒ Virology - Hepatitis C (NS2 cysteine protease inhibitor; IRES inhibitor)
ƒ Immunology/Inflammation - (TRAF-6 ligase inhibitor; PAK2 kinase inhibitor)
ƒ Oncology - (PRK-1 kinase inhibitor)
164
ƒ Metabolism - (Adiponectin mimetics)
PHASE III
Validation of Rigel Drug Discovery Approach
Through Large Pharma Partnerships
Asthma/COPD (2005)
Immune Diseases (1999)
Oncology (1998)
Angiogenesis (2001)
Immune Diseases (1999)
Ligase Target in Oncology (2002)
Ligase Targets in Oncology (2004)
Aurora Kinase Inhibitors in Oncology
(2005)
165
Questions and Answers
Rigel
NASDAQ:RIGL