1 / 46

The Story of VELCADE ™ A Biotech Love Story

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.

kapono
Download Presentation

The Story of VELCADE ™ A Biotech Love Story

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. The Story of VELCADE™A Biotech Love Story

  2. The Life-Cycle of Intracellular Proteins Synthesis Amino Acids Proteins Degradation

  3. Ubiquitin-Proteasome Pathway Ub Ub Ub Ub Ub Ub ATP ATP Peptides Ubiquitination Enzymes 26S Proteasome Complex

  4. Ubiquitin-Proteasome Pathway

  5. 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

  6. Ac-Leu-leu-norleucinal inhibitor bound to the N-terminal threonine of the beta subunity Crystal structure of the 20S proteasome Central cavity built by two rings of beta subunits cut open along the sevenfolfd axis:

  7. MG-132 AldehydeSurrogates

  8. Proteasome Inhibitors:Mechanism of Inhibition Boronic acids General structure:

  9. 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 Ki=0.6 nM

  10. 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

  11. 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

  12. 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

  13. Millennium LeukoSite ProScript MyoGenics

  14. Development of PS-341 > Bortezomib > VELCADE™

  15. PS-341 finished drug product (lyophilized) ca. 4000 vials (February 1999)

  16. 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)

  17. 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)

  18. 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).

  19. 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

  20. 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% • Refractory • Resistant to all therapy • Universally fatal • Survival 6-9 months • Diagnosis • Survival 3-5* yrs • Survival <6mo without therapy • Relapsed Disease • Transient Response to Therapy • Survival 1-3 years • 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

  21. Previous Therapies 100% 90% • Median lines of prior therapy = 6 (range 2-15) • 91% had progressed on last therapy before entry 80% 70% 60% 50% 40% 30% 20% 10% 0% SCT Steroids Alkylating Anthracyc. Thalidomide

  22. 1.0 Median Survival: 16 months 0.9 0.8 0.7 0.6 0.5 Proportion 0.4 0.3 0.2 0.1 0 0 6 12 18 Months Overall Survival and Time to Progression (N=202)

  23. 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!)

  24. Bortezomib: First Proteasome Inhibitor Approved • Full approval, in second line relapsed MM(BortvsDex) 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)

  25. 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.

  26. Collaborations! Patient Advocacy Industry Academic Institutions Government Patients and Families

  27. So where do we go from here?

  28. The Hedgehog Pathway in Cancer:Targeting the Cancer Environmentand Prolonging Remissions to Make Cancer a Chronic Disease…

  29. The Hedgehog signaling pathway *Chen et al., 2002 G&D 16:2743

  30. The Hedgehog signaling pathway *Chen et al., 2002 G&D 16:2743

  31. Cyclopamine The Hedgehog signaling pathway *Chen et al., 2002 G&D 16:2743

  32. 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 • Poor pharmaceutical properties: • Solubility • (5 mg/mL in pH 7) • Chemical stability • (low at pH 1.9) Low potency

  34. Veratrum californicum • Primary collection sites: Idaho and Utah - USFS agreement • Alkaloids Extraction • Chromatography • Crystallization • Typical purity > 95% Overview of Cyclopamine Sourcing Biomass sourcing Drying & Milling Extraction Isolation 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 cyclopamine ↑ Solubility ↑ Chemical stability ↑ Potency ↑ Selectivity ↑ Metabolic Stability IPI-926

  36. Malignant Activation of the Hedgehog Pathway in Cancer Ligand dependent Ligand Independent Target tumor cell Target tumor cell Target microenvironment Target residual disease Ptc mutant tumors Solid Tumors Desmoplastic tumors Heme Malignancies ? Maintenance after debulking Improve PFS Inhibit oncogenic signaling Tumor cell apoptosis Decrease fibrosis Improve drug delivery Improve survival Elimination of progenitor Potential cure Inhibit autologous signaling SCLC, OvCa, NSCLC Advanced BCC, Medulloblastoma Pancreatic cancer CML, CLL, ALL, AML, MM ?

  37. IPI-926 in Minimal Residual Disease (MRD)

  38. 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

  39. IPI-926 delays LX22 tumor recurrence following chemotherapy Vehicle IPI-926 E/P → Vehicle E/P → IPI-926 Tumor size (mm3) 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.

  40. Chemotherapy UpregulatesIHh Ligand and Signaling to Stromal Cells Human IHh expression Murine Gli-1 expression Pre-treated with E/P Pre-treated with E/P Travaglione AACR 2009

  41. Primary ovarian tumor xenografts • Primary tumors passaged mouse-to-mouse • Preserved serous histology throughout transplant generations Growden and Rueda, SGO 2009

  42. 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

  43. 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

  44. 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

  45. The Infinity Team

More Related