The Story of VELCADE

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The Story of VELCADE A Biotech Love Story
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The Life-Cycle of Intracellular Proteins
Synthesis
Amino Acids
Proteins
Degradation
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Ubiquitin-Proteasome Pathway
Ub
Ub
Ub
Ub
Ub
Ub
ATP
ATP
Peptides
Ubiquitination Enzymes
26S Proteasome Complex
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Ubiquitin-Proteasome Pathway
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The Nobel Prize in Chemistry 2004"for the
discovery of ubiquitin-mediated protein
degradation
Avram Hershko 1/3 of the prize Israel
Aaron Ciechanover 1/3 of the prize Israel
Irwin Rose 1/3 of the prize USA
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Crystal structure of the 20S proteasome
Central cavity built by two rings of beta
subunits cut open along the sevenfolfd axis
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Aldehyde Surrogates
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Proteasome InhibitorsMechanism of Inhibition
Boronic acids
General structure
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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

Ki0.6 nM
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How Proteasome Inhibition Works
Normal Cells less sensitive than cancer cells to
proapoptotic effects
Normal Cells can recover
Proteasome inhibitors block the proteasome,
producing conflicting regulatory signals and
interfering with critical cellular functions
Cancer Cells have difficulty processing overload
Cancer Cells can lead to apoptosis
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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

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1998 VELCADE Clinical Development Begins

• June 8th NCI officially endorses package
• Unanimous vote
• July 24th IND submitted (56,515)
• gt3,000 pages (Matthew Smith, MD)
• October 7th first clinical trial (prostate) at
  MDACC
• Supported by a grant from CapCURE (Howard Soule)
• Chris Logothetis

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Millennium
LeukoSite
ProScript
MyoGenics
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Development of PS-341 gt Bortezomib gt VELCADE
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PS-341 finished drug product (lyophilized)
ca. 4000 vials (February 1999)
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Antitumor Activity (Objective Measures)

• 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)

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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) Waldenstroms 1/1 Bone marrow IgM
(2x/wk x 4 1.2 mg/m2)
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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).
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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

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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

• Relapsed Disease
• Transient Response to Therapy
• Survival 1-3 years

• Diagnosis
• Survival 3-5 yrs
• Survival lt6mo without therapy

• Refractory
• Resistant to all therapy
• Universally fatal
• Survival 6-9 months

• First-Line
• VAD or CVAD
• MP
• Transplant

• Second Line
• VAD or CVAD
• Dexamethasone
• Transplant
• Investigational Therapy

• Refractory
• Supportive or palliative care
• Investigational Therapy
• Deaths 12,000/yr.

50 - 75 Response Rate All patients relapse
Unmet Medical Need PS-341 Focus
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Previous Therapies
100

• Median lines of prior therapy 6 (range 2-15)
• 91 had progressed on last therapy before entry

90
80
70
60
50
40
30
20
10
0
SCT
Steroids
Alkylating
Anthracyc.
Thalidomide
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Overall Survival and Time to Progression (N202)
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Conclusions

• In 202 patients with relapsed and refractory
  multiple myeloma bortezomib achieved
• Documented CRs (4 Blade, 6 IF)
• Overall response rate (CRPRMR) 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!)

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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)

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• 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.

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Collaborations!
Patient Advocacy
Industry
Academic Institutions
Government
Patients and Families
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So where do we go from here?
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The Hedgehog Pathway in CancerTargeting the
Cancer Environmentand Prolonging Remissions to
Make Cancer a Chronic Disease
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The Hedgehog signaling pathway
Chen et al., 2002 GD 162743
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The Hedgehog signaling pathway
Chen et al., 2002 GD 162743
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The Hedgehog signaling pathway
Chen et al., 2002 GD 162743
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Cyclopamine Sourcing
Veratrum californicum primarily found in western
United States
Source PLANTS database, USDA
Veratrum californicum is readily found in the wild
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Cyclopamine Starting Point for an Oral Hh
Antagonist?
Sourcing of material
Poor pharmaceutical properties Solubility (5
mg/mL in pH 7) Chemical stability (low at pH 1.9)
Low potency
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Overview of Cyclopamine Sourcing
Biomass sourcing
Drying Milling
Extraction
Isolation
Cyclopamine isolation is efficient and scalable
Keeler RF. Phytochemistry. 19687303. Oatis Jr
JE, et al. Chemistry Central Journal. 2008212.
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IPI-926 Potent and orally active Smo inhibitor
from the natural product
cyclopamine
? Solubility ? Chemical stability ? Potency ?
Selectivity ? Metabolic Stability
IPI-926
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Malignant Activation of the Hedgehog Pathway in
Cancer
Ligand dependent
Ligand Independent
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IPI-926 in Minimal Residual Disease (MRD)
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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
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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.
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Chemotherapy Upregulates IHh Ligand and Signaling
to Stromal Cells
Pre-treated with E/P
Pre-treated with E/P
Travaglione AACR 2009
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Primary ovarian tumor xenografts

• Primary tumors passaged mouse-to-mouse
• Preserved serous histology throughout transplant
  generations

Growden and Rueda, SGO 2009
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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 MGH SGO 2009
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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
  studyRecommend Phase 2 starting dose
• Markers of response
• Response by RECIST criteria, PET, and disease
  specific tumor markers, tumor biopsies
• PD assay - skin biopsy

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Acknowledgements

• W. Matsui Johns Hopkins University
• N. Watkins Johns Hopkins University
• R. Vessella University of Washington
• B. Rueda MGH
• C. Dierks University of Freiburg
• T. Lin LSU
• Ken Olive, Dave Tuveson Cambridge University

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The Infinity Team