the story of velcade ™ a biotech love story
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The Story of VELCADE ™ A Biotech Love Story. The Life-Cycle of Intracellular Proteins. Synthesis. Amino Acids. Proteins. Degradation. Ubiquitin-Proteasome Pathway. Ub. Ub. Ub. Ub. Ub. Ub. ATP. ATP. Peptides. Ubiquitination Enzymes. 26S Proteasome Complex. - PowerPoint PPT PresentationTRANSCRIPT
The Story of VELCADE™
A Biotech Love Story
The Life-Cycle of Intracellular Proteins
ProteinsProteins Degradation
AminoAcidsAminoAcids
Synthesis
Ubiquitin-Proteasome Pathway
UbUb UbUbUbUbUbUb
UbUb
UbiquitinationEnzymes
ATPATPPeptidesPeptides
UbUb
26S ProteasomeComplex
ATPATP
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
Irwin Rose 1/3 of the prize
USA
Avram Hershko1/3 of the prize
Israel
Crystal structure of the 20S proteasome Central cavity built by two rings of beta subunits cut open along the sevenfolfd axis:
Ac-Leu-leu-norleucinal inhibitor bound to the N-terminal threonine of the beta subunity
NH2
OH3C
OHR
NH
HN
H3C
O
O
NH
H
O
O
N H
BOH
OH
O N H
H N
N H
O
H
OO
O
MG-132
Aldehyde Surrogates
General structure:N H
H N B
R1
OH
O
R2
POH
R BOHOH
BR
OHOH
H2 N
H3C O
HO
H
H
NH3
H3C O
HO
H
Proteasome Inhibitors:Mechanism of Inhibition
Boronic acids
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
– Weak mdr substrate
– Hypoxic cells are hypersensitive
H N B
N H
O
O
OHN
N
OH
Ki=0.6 nMKi=0.6 nM
How Proteasome Inhibition Works
Proteasome inhibitors block the proteasome, producing conflicting regulatory signals and
interfering with critical cellular functions
Normal Cells: less sensitive than cancer cells to
proapoptotic effects
Normal Cells: can recover
Cancer Cells: have difficulty processing overload
Cancer Cells: can 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™
ca. 4000 vials (February 1999)
PS-341 finished drug product (lyophilized)
Disease n Evaluation
Prostate 1 Radiographic(1x/wk x 4; 0.4 mg/m2)
Prostate 3/16 PSA reduction; (1x/wk x 4; 1.6 mg/m2) Radiographic
Renal 1 Radiographic(2x/wk x 2; 0.75 mg/m2)
Head & Neck 1 Radiographic (2x/wk x 2; 1.3 mg/m2)
Lung 1 Radiographic(2x/wk x 2; 1.56 mg/m2)
Melanoma (Lung Mets) 1 Radiographic(2x/wk x alt. wk; 1.0 mg/m2)
Antitumor Activity (Objective Measures)
Disease n Evaluation
Follicular NHL 1/2 Radiographic (2x/wk x 4; 1.38 mg/m2)
Mantle Cell NHL 1/3 Radiographic (2x/wk x 4; 1.38 mg/m2)
AML 1 Reduction in(2x/wk x 4; 1.25 mg/m2) circulating blasts
Multiple Myeloma 7/10 Bone Marrow & IgG(2x/wk x 4; 1.04 mg/m2)
Waldenstrom’s 1/1 Bone marrow; IgM (2x/wk x 4; 1.2 mg/m2)
Antitumor Activity (Objective Measures)
• 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).
PS-341 in Multiple Myeloma
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
Relapsed Disease•Transient Response to Therapy•Survival 1-3 years
Diagnosis•Survival 3-5* yrs•Survival <6mo without therapy
Refractory •Resistant to all therapy•Universally fatal •Survival 6-9 months
First-Line:• VAD or CVAD• MP•*Transplant
32,000 Newly Diagnosed per year (14K/yr US, 15K/yr EU, 3K Japan)
5-year Mortality, 75%, 10-year Mortality, 95-98%
Second Line:• VAD or CVAD• Dexamethasone • Transplant• Investigational Therapy
Refractory:• Supportive or palliative care• Investigational Therapy• Deaths 12,000/yr.
50 - 75% Response RateAll patients relapse
Unmet Medical Need
PS-341 Focus
Multiple Myeloma: 2000
• Median lines of prior therapy = 6 (range 2-15)
• 91% had progressed on last therapy before entry
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Steroids
Alkylating
Anthracyc.
Thalidomide
SCT
Previous Therapies
Median Survival: 16 months
1.0
0.9
0.8
0.7
0.6
0.5
0.4
181260
0.3
0.2
0.1
0
Months
Pro
port
ion
Overall Survival and Time to Progression (N=202)
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 CaregiversPatients and CaregiversMichael KauffmanDavid Schenkein
Ken Anderson Paul Richardson and the Myeloma Investigators
NCI, CapCure (PCF), MMRF, IMF
ProScript Inc. (Peter Elliott and Vito Palombella)Millennium Pharmaceuticals Inc.
Patient Advocacy
Patients andFamilies
Academic Institutions
Government
Industry
Collaborations!
So where do we go from here?
The Hedgehog Pathway in Cancer:
Targeting the Cancer Environmentand Prolonging Remissions to Make
Cancer a Chronic Disease…
*Chen et al., 2002 G&D 16:2743
The Hedgehog signaling pathway
The Hedgehog signaling pathway
*Chen et al., 2002 G&D 16:2743
Cyclopamine
The Hedgehog signaling pathway
*Chen et al., 2002 G&D 16:2743
33
Source: PLANTS database, USDA
Veratrum californicum primarily found in western United States
Veratrum californicum is readily found in the wild
Cyclopamine Sourcing
Cyclopamine: Starting Point for an Oral Hh Antagonist?
HO
O
HN
H
H
H
H H
3
1
1112
13
56
1917
2223
2718
34
Poor pharmaceutical properties:
Solubility
(5 g/mL in pH 7)
Chemical stability
(low at pH 1.9)
Sourcing of material
Low potency
35
Extraction
Isolation
• Veratrum californicum• Primary collection sites: Idaho and Utah -
USFS agreement
• Alkaloids Extraction
• Chromatography• Crystallization• Typical purity > 95%
Drying & Milling
Biomass sourcing
Keeler RF. Phytochemistry. 1968;7:303.Oatis Jr JE, et al. Chemistry Central Journal. 2008;2:12.
Cyclopamine isolation is efficient and scalable
Overview of Cyclopamine Sourcing
IPI-926: Potent and orally active Smo inhibitor from the natural product
36
HO
O NH
H
H
H
H H
H H
O NH
H
H
HNH
S
O
O
H3C
HH
Cl
cyclopamine
IPI-926
↑ Solubility↑ Chemical stability↑ Potency↑ Selectivity↑ Metabolic Stability
Ligand Independent Ligand dependent
Target residual disease
Maintenance after debulking
Improve PFS
Solid Tumors
SCLC, OvCa, NSCLC
Elimination of progenitor
Potential cure
Heme Malignancies
CML, CLL, ALL, AML, MM
Target microenvironment
Decrease fibrosis Improve drug delivery
Improve survival
Desmoplastic tumors
Pancreatic cancer
Target tumor cell
?
Inhibit autologous signaling
?
Target tumor cell
Inhibit oncogenic signaling
Tumor cell apoptosis
Advanced BCC, Medulloblastoma
Ptc mutant tumors
Malignant Activation of the Hedgehog Pathway in Cancer
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
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.
Tum
or s
ize
(mm
3 )
Days
VehicleIPI-926E/P → VehicleE/P → IPI-926
End E/P
0
2.5
5
7.5
10
Naïve Vehicle IPI-926
Fol
d ch
ange
hIH
H
Human IHh expression
0
3
6
9
12
Naïve Vehicle IPI-926Fol
d ch
ange
mG
li-1
Murine Gli-1 expression
Pre-treated with E/P Pre-treated with E/P
Travaglione AACR 2009
Chemotherapy Upregulates IHh Ligand and Signaling to Stromal Cells
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
Carboplatin 50 mg/kg IP, Paclitaxel 15 mg/kg IP q 7d; IPI-926 40 mg/kg PO, QOD ;
Growden, Rueda MGHSGO 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 Johns Hopkins UniversityN. Watkins Johns Hopkins UniversityR. Vessella University of WashingtonB. Rueda MGHC. Dierks University of FreiburgT. Lin LSUKen Olive, Dave Tuveson Cambridge University
The Infinity Team