The Story of VELCADE™
A Biotech Love Story
The Life-Cycle of Intracellular
Proteins
Synthesis
Proteins
Degradation
Amino
Acids
Ubiquitin-Proteasome Pathway
Ub
Ub Ub
Ub
Ub Ub
ATP
Ubiquitination
Enzymes
ATP
Peptides
26S Proteasome
Complex
Ubiquitin-Proteasome Pathway
The Nobel Prize in Chemistry 2004
"for the discovery of ubiquitin-mediated protein degradation”
Aaron Ciechanover
1/3 of the prize
Israel
Avram Hershko
1/3 of the prize
Israel
Irwin Rose
1/3 of the prize
USA
Crystal structure of the 20S proteasome
Central cavity built by two rings of beta subunits cut open along the sevenfolfd axis:
O
H 3C
N
H
O
H
N
N
H
O
H
O
NH2
H 3C
O
R
OH
Ac-Leu-leu-norleucinal inhibitor bound to the N-terminal threonine of the beta subunity
Aldehyde Surrogates
O
O
O
H
N
N
H
N
H
O
MG-132
N
H
B
OH
OH
H
O
Proteasome Inhibitors:
Mechanism of Inhibition
Boronic acids
R2
General structure:P
N
H
O
H2
N
H
OH
H
N
B
R1
NH 3
H
O
H
H 3C
H
O
R
B
OH
OH
R B OH
OH
H
O
O
H 3C
OH
PS-341: In Vitro Activity
• Cytotoxicity involves multiple mechanisms of action
– Stabilization of cell-cycle
regulatory proteins
– Inhibition of NF-B activation
– Anti-angiogenic
– Induction of apoptosis
– Override of bcl-2 resistance
O
N
N
N
H
H
N
O
– Weak mdr substrate
– Hypoxic cells are hypersensitive
Ki=0.6 nM
OH
B
OH
How Proteasome Inhibition Works
Normal Cells: less
Normal Cells:
sensitive than cancer cells to
proapoptotic effects
can recover
Proteasome inhibitors block the proteasome,
producing conflicting regulatory signals and
interfering with critical cellular functions
Cancer Cells: have
Cancer Cells: can
difficulty processing overload
lead to apoptosis
1995 to 1997 Preclinical Work in Cancer
• ProScript teams up with the NCI to test tumor cell lines
(CRADA)
– Ed Sausville
• Lewis lung carcinoma model in mice tested at Dana
Farber
– Beverly Teicher
• Multiple mouse models of cancer, including prostate,
colon
– Al Baldwin/Jim Cusack/Ken Anderson/ David McKonke
1998 VELCADE Clinical Development
Begins
• June 8th NCI officially endorses package
– Unanimous vote
• July 24th IND submitted (#56,515)
– >3,000 pages (Matthew Smith, MD)
• October 7th first clinical trial (prostate) at MDACC
– Supported by a grant from CapCURE (Howard Soule)
– Chris Logothetis
Development of
PS-341 > Bortezomib > VELCADE™
PS-341 finished drug product (lyophilized)
ca. 4000 vials (February 1999)
Antitumor Activity (Objective Measures)
Disease
n
Evaluation
Prostate
(1x/wk x 4; 0.4 mg/m2)
1
Radiographic
Prostate
(1x/wk x 4; 1.6 mg/m2)
3/16
Renal
(2x/wk x 2; 0.75 mg/m2)
1
Radiographic
Head & Neck
(2x/wk x 2; 1.3 mg/m2)
1
Radiographic
Lung
(2x/wk x 2; 1.56 mg/m2)
1
Radiographic
Melanoma (Lung Mets)
(2x/wk x alt. wk; 1.0 mg/m2)
1
Radiographic
PSA reduction;
Radiographic
Antitumor Activity (Objective Measures)
Disease
n
Evaluation
Follicular NHL
(2x/wk x 4; 1.38 mg/m2)
1/2
Radiographic
Mantle Cell NHL
(2x/wk x 4; 1.38 mg/m2)
1/3
Radiographic
AML
(2x/wk x 4; 1.25 mg/m2)
1
Multiple Myeloma
(2x/wk x 4; 1.04 mg/m2)
7/10
Bone Marrow & IgG
Waldenstrom’s
(2x/wk x 4; 1.2 mg/m2)
1/1
Bone marrow; IgM
Reduction in
circulating blasts
PS-341 in Multiple Myeloma
• Multiple myeloma demonstrates a strong dependency for
NF-B and NF-B-dependent genes as growth factors
and adhesion of plasma cells in the bone marrow (IL-6,
VEGF, VCAM-1)
• PS-341 potently down-regulates these genes
• PS-341 is pro-apoptotic at 1-10 nM range in human MM
isolates with and without stromal
cell environment
T. Hideshima et al., Cancer Res. 61, 3071-3076 (2001).
2000, continued
• Oct 12th MMRF invites Dr. J to participate at their round
table with MM investigator “dream team”
• Oct 12th (Dr. J pulls a fast one!) MMRF president, Kathy
Giusti agrees to a closed door meeting with
investigators: Summit protocol is designed …
– Michael Kauffman, Dixie Essletine
Multiple Myeloma: 2000
32,000 Newly Diagnosed per year (14K/yr US, 15K/yr EU, 3K Japan)
5-year Mortality, 75%, 10-year Mortality, 95-98%
Diagnosis
•Survival 3-5* yrs
•Survival <6mo without therapy
First-Line:
• VAD or CVAD
• MP
•*Transplant
50 - 75% Response Rate
All patients relapse
Relapsed
Disease
•Transient Response
to Therapy
•Survival 1-3 years
Second Line:
• VAD or CVAD
• Dexamethasone
• Transplant
• Investigational Therapy
Refractory
•Resistant to all therapy
•Universally fatal
•Survival 6-9 months
Refractory:
• Supportive or palliative care
• Investigational Therapy
• Deaths 12,000/yr.
Unmet Medical Need
PS-341 Focus
Previous Therapies
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
• Median lines of prior
therapy = 6 (range 2-15)
• 91% had progressed on
last therapy before entry
Overall Survival and Time to Progression
(N=202)
1.0
0.9
Median Survival: 16 months
0.8
Proportion
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
6
Months
12
18
Conclusions
• In 202 patients with relapsed and refractory multiple
myeloma bortezomib achieved
–
–
–
–
–
Documented CRs (4% Blade, 6% IF+)
Overall response rate (CR+PR+MR) of 35%
Median duration of response (12 mo)
Overall survival (16 mo)
Improvement in other disease parameters observed in responding
patients, including hemoglobin and quality of life.
– Well-tolerated and manageable side effects
– VELCADE approved May 13, 2003 (Dr J is happy!)
Bortezomib: First Proteasome Inhibitor
Approved
• Full approval, in second line relapsed MM(Bort vs Dex)
2004
• Mantle cell lymphoma approval, 2006
• Front line approvals in combination with
Melphalan/prednisone, other regimens as well, 2008
• Re-treatment with Bortezomib leads to re-response to
treatment (~50% of patients)
Thank You:
Patients and Caregivers
Michael Kauffman
David Schenkein
Ken Anderson Paul Richardson
and the Myeloma Investigators
NCI, CapCure (PCF), MMRF, IMF
ProScript Inc. (Peter Elliott and Vito Palombella)
Millennium Pharmaceuticals Inc.
Collaborations!
Patient
Advocacy
Industry
Academic
Institutions
Government
Patients and
Families
So where do we go from here?
The Hedgehog Pathway in Cancer:
Targeting the Cancer Environment
and Prolonging Remissions to Make
Cancer a Chronic Disease…
The Hedgehog signaling pathway
*Chen et al., 2002 G&D 16:2743
The Hedgehog signaling pathway
*Chen et al., 2002 G&D 16:2743
The Hedgehog signaling pathway
Cyclopamine
*Chen et al., 2002 G&D 16:2743
Cyclopamine Sourcing
Veratrum californicum primarily found in
western United States
Source: PLANTS database, USDA
Veratrum californicum is readily found in the wild
33
Cyclopamine: Starting Point for an Oral Hh
Antagonist?
Sourcing of material
H HN
27
22
18
23
13
11
19
H
1
H
HO
3
17
5
6
O H
Poor pharmaceutical
properties:
Solubility
12
(5 mg/mL in pH 7)
H
Chemical stability
(low at pH 1.9)
Low potency
34
Overview of Cyclopamine Sourcing
Biomass
sourcing
• Veratrum californicum
• Primary collection sites: Idaho and Utah USFS agreement
Drying &
Milling
• Alkaloids Extraction
Extraction
Isolation
• Chromatography
• Crystallization
• Typical purity > 95%
Cyclopamine isolation is efficient and scalable
Keeler RF. Phytochemistry. 1968;7:303.
Oatis Jr JE, et al. Chemistry Central Journal. 2008;2:12.
35
IPI-926: Potent and orally active Smo
inhibitor from the natural product
H
O
cyclopamine
NH
H
H
H
HO
H
↑ Solubility
↑ Chemical stability
↑ Potency
↑ Selectivity
↑ Metabolic Stability
H
O
Cl
N H
HH
H
O
H3C S N
H
O
H
H
H
IPI-926
36
Malignant Activation of the Hedgehog
Pathway in Cancer
Ligand dependent
Ligand Independent
Target
tumor cell
Target
tumor cell
Ptc mutant
tumors
?
Inhibit oncogenic
signaling
Tumor cell apoptosis
Advanced BCC,
Medulloblastoma
Inhibit autologous
signaling
?
Target
microenvironment
Target
residual disease
Desmoplastic
tumors
Solid
Tumors
Heme
Malignancies
Decrease fibrosis
Improve drug delivery
Improve survival
Maintenance after
debulking
Improve PFS
Elimination of
progenitor
Potential cure
Pancreatic
cancer
SCLC, OvCa,
NSCLC
CML, CLL,
ALL, AML, MM
IPI-926 in Minimal Residual
Disease (MRD)
Small cell lung cancer LX22 primary
xenograft model
• LX22: Chemo naïve, patient-derived primary tumor
established subcutaneously and maintained in mice
• Sensitive to etoposide/carboplatin
Primary xenograft model
IPI-926 delays LX22 tumor recurrence
following chemotherapy
Tumor size (mm3)
Vehicle
IPI-926
E/P → Vehicle
E/P → IPI-926
End E/P
Days
LX-22 – Primary small cell lung cancer xenograft model treated with Etoposide/carboplatin.
IPI-926 is initiated 24 hours after the last dose of chemotherapy.
Chemotherapy Upregulates IHh Ligand and
Signaling to Stromal Cells
Human IHh expression
12
7.5
5
2.5
0
Naïve
Vehicle
IPI-926
Pre-treated with E/P
Fold change mGli-1
Fold change hIHH
10
Murine Gli-1 expression
9
6
3
0
Naïve
Vehicle
IPI-926
Pre-treated with E/P
Travaglione AACR 2009
Primary ovarian tumor xenografts
• Primary tumors passaged
mouse-to-mouse
• Preserved serous histology
throughout transplant
generations
Growden and Rueda, SGO 2009
IPI-926 Delays Regrowth of Ovarian Cancer
Following Carbo/Taxol Treatment
120
Carbo/Taxol
Carbo/Taxol/926
Relative tumor volume (%)
100
80
Last C/T dose
60
40
Last 926 dose
20
0
D1
D4
D9
D12
D16
D19
D23
D26
D30
D33
D37
D40
D44
D47
D51
Day (post treatment)
Carboplatin 50 mg/kg IP, Paclitaxel 15 mg/kg IP q 7d;
IPI-926 40 mg/kg PO, QOD ;
Growden, Rueda MGH
SGO 2009
A Phase 1 study of IPI-926 in patients with
advanced and/or metastatic solid tumor
malignancies
• Clinical sites
– Glenn Weiss, MD – TGEN
– Charlie Rudin, MD – Johns Hopkins
– Antonio Jimeno, MD – Univ. Colorado
• Trial design
– Accelerated phase followed by standard dose escalation
• Objectives
– Safety, pharmacokinetics, PD, and dose-ranging study
Recommend Phase 2 starting dose
• Markers of response
– Response by RECIST criteria, PET, and disease specific tumor
markers, tumor biopsies
– PD assay - skin biopsy
Acknowledgements
W. Matsui
N. Watkins
R. Vessella
B. Rueda
C. Dierks
T. Lin
Ken Olive, Dave Tuveson
Johns Hopkins University
Johns Hopkins University
University of Washington
MGH
University of Freiburg
LSU
Cambridge University
The Infinity Team
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The Story of Velcade - ADAMS Academy Fellowship