the story of velcade ™ a biotech love story

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