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The Story of VELCADE ™ A Biotech Love Story. The Life-Cycle of Intracellular Proteins Proteins Degradation Amino Acids Amino Acids Synthesis.

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Presentation on theme: "The Story of VELCADE ™ A Biotech Love Story. The Life-Cycle of Intracellular Proteins Proteins Degradation Amino Acids Amino Acids Synthesis."— Presentation transcript:

1 The Story of VELCADE ™ A Biotech Love Story

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

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

4 Ubiquitin-Proteasome Pathway

5 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 Hershko 1/3 of the prize Israel

6 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

7 MG-132 Aldehyde Surrogates

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

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 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

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



15 Development of PS-341 > Bortezomib > VELCADE™

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

17 DiseasenEvaluation Prostate1Radiographic (1x/wk x 4; 0.4 mg/m 2 ) Prostate3/16PSA reduction; (1x/wk x 4; 1.6 mg/m 2 )Radiographic Renal1Radiographic (2x/wk x 2; 0.75 mg/m 2 ) Head & Neck1Radiographic (2x/wk x 2; 1.3 mg/m 2 ) Lung1Radiographic (2x/wk x 2; 1.56 mg/m 2 ) Melanoma (Lung Mets)1Radiographic (2x/wk x alt. wk; 1.0 mg/m 2 ) Antitumor Activity (Objective Measures)

18 DiseasenEvaluation Follicular NHL1/2Radiographic (2x/wk x 4; 1.38 mg/m 2 ) Mantle Cell NHL1/3Radiographic (2x/wk x 4; 1.38 mg/m 2 ) AML1Reduction in (2x/wk x 4; 1.25 mg/m 2 ) circulating blasts Multiple Myeloma7/10Bone Marrow & IgG (2x/wk x 4; 1.04 mg/m2) Waldenstrom’s1/1Bone marrow; IgM (2x/wk x 4; 1.2 mg/m 2 ) Antitumor Activity (Objective Measures)

19 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

20 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

21 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 Rate All patients relapse Unmet Medical Need PS-341 Focus Multiple Myeloma: 2000

22 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

23 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 Proportion Overall Survival and Time to Progression (N=202)

24 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!)

25 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)

26 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.

27 Patient Advocacy Patients and Families Academic Institutions Government Industry Collaborations!

28 So where do we go from here?

29 The Hedgehog Pathway in Cancer: Targeting the Cancer Environment and Prolonging Remissions to Make Cancer a Chronic Disease…

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

31 *Chen et al., 2002 G&D 16:2743

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

33 33 Source: PLANTS database, USDA Veratrum californicum primarily found in western United States Veratrum californicum is readily found in the wild Cyclopamine Sourcing

34 Cyclopamine: Starting Point for an Oral Hh Antagonist? 34 Poor pharmaceutical properties: Solubility (5  g/mL in pH 7) Chemical stability (low at pH 1.9) Sourcing of material Low potency

35 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

36 IPI-926: Potent and orally active Smo inhibitor from the natural product 36 cyclopamine IPI-926 ↑ Solubility ↑ Chemical stability ↑ Potency ↑ Selectivity ↑ Metabolic Stability

37 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

38 IPI-926 in Minimal Residual Disease (MRD)

39 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

40 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. Tumor size (mm 3 ) Days Vehicle IPI-926 E/P → Vehicle E/P → IPI-926 End E/P

41 Human IHh expressionMurine Gli-1 expression Pre-treated with E/P Travaglione AACR 2009 Chemotherapy Upregulates IHh Ligand and Signaling to Stromal Cells

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

43 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

44 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

45 Acknowledgements  W. MatsuiJohns Hopkins University  N. WatkinsJohns Hopkins University  R. VessellaUniversity of Washington  B. RuedaMGH  C. DierksUniversity of Freiburg  T. LinLSU  Ken Olive, Dave TuvesonCambridge University

46 The Infinity Team

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