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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 H3C N H O H N N H O H O NH2 H3C O R OH Ac-Leu-leu-norleucinal inhibitor bound to the N-terminal threonine of the beta subunity Aldehyde Surrogates O O H N N H O MG-132 N H OH B OH O N H H O Proteasome Inhibitors: Mechanism of Inhibition Boronic acids R2 General structure:P H2 N H N H O R1 NH3 H O H H3C O R R B OH OH H O O H3C OH B OH H N B OH OH H 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