Challenges to Drug Development in

Academia

Charles L. Sawyers, M.D.Chair, Human Oncology and

Pathogenesis Program (HOPP)

Investigator, Howard Hughes Medical Institute

Memorial Sloan-Kettering Cancer Center; New York,

NY

Disclosure

I am a co-inventor of the drug MDV3100, now in a phase III clinicaltrial in prostate cancer, and I own stock in the company Medivation.

Two translational tales

1) Dasatinib (Sprycel) in chronic myeloid leukemia:

serendipitous marriage of a discovery in academia that reshaped a pharma-driven drug development program

2) MDV3100 in prostate cancer:

academia-based target validation and drug screening project that resulted in a biotech/pharma licensing deal for clinical development

The Ph Chromosome: t(9;22) Translocation

22

bcr

abl

Ph ( or 22q-)

bcr-abl

FUSION PROTEINWITH TYROSINEKINASE ACTIVITY

9 9 q+

Normal CML

Imatinib/STI571 (Gleevec) blocks BCR-ABL

Goldman JM, Melo JV. NEJM. 344:1084-1086

Blood counts of the first 6 patients who took 300 mg/day of Gleevec

WB

C x

10

3

100

10

1

0 30 60 90 120150

Days on Gleevec

Gleevec is not a cure:

Small numbers of CML cells are detected in patients who are in “remission.”

Patients can relapse while taking Gleevec.

Why?

WILD-TYPE T315I MUTANT (MODEL)

A mutation isolated from patients who relapse on Gleevec blocks drug binding to BCR-ABL

(Gorre et al Science, 2001)

E255K/V

BCR-ABL Kinase Domain Mutations Associated with Imatinib Resistance

M244V M351T

L248V

Y253H/F

E279K

F317L

E355G/D

F359C/V/D

H396R/PQ252H/R

S417Y

E459K

F486S

E450G

M388L G250E

D276G

T277A

L387F/M

V379I

A397P

P-loop Activation loop

E453G/K

T315I/

DF311L/I

V289AL298V

> 50 distinct mutations reported

Imatinib resistance mutations impairconformational flexibility of the ABL kinase

John Kuriyan, Bhushan Nagar (UC-Berkeley)

P loop

Direct contact with drug

hinge

Location of Mutations

Problem: Over 50 different mutations can cause resistance to Gleevec

Structural biology prediction: Mutations change the shape of BCR-ABL so that it favors the “open” conformation.

Solution: Drugs that target the “open” conformation should work in patients with Gleevec resistance.

How do we deal with resistance?

DasatinibGleevec

The SRC/ABL inhibitor dasatinib (BMS-354825) is active against all but one of the known mutations in BCR-ABL that

confer imatinib resistance

0

0.2

0.4

0.6

0.8

1

1.2

0 1 5 10 50 100

BCR/ABL/WT

M244V

G250E

Q252H

Q252R

Y253F

Y253H

E255K

E255V

T315I

F317L

M351T

E355G

F359V

H396R

F486S

Ba/F3nM BMS-354825

Nor

mal

ized

cel

l via

bili

ty

Shah et al Science, 2004

T315I

F317L

wt BCR-ABL

BCR-ABL genotype predicts clinical response to dasatinib

Talpaz ….Sawyers, NEJM, 2006

1) Imatinib has been frontline CML therapy

-75% of patients achieve complete cytogenetic response -20% relapse within 5 years, usually with mutant BCR-ABL

2) Dasatinib and nilotinib were initially approved as 2nd line therapy for imatinib-resistant CML (2006, 2007)

3) Upfront comparisons show than 2nd generation compounds are superior to imatinib

(Kantarjian et al NEJM 2010; Saglio et al NEJM 2010)

Chronic Myeloid Leukemia: 2010

Inhibition of androgen receptor (AR) signaling

AR

Androgen receptor

P

AR kinases

testosteronehormone

CoR vs Coactivators

ARAR

Pol II

ARE

NCoR/HDACCyto

plasm

nucleus

P P Transcription of AR target genes eg PSAActivation of TMPRSS/ERG fusion

LHRH agonists

Anti-androgens Bicalutamide* Flutamide*

*Both drugs are partial agonists/antagonists

Typical Response to Hormone Therapy

Time

Dis

ease

Bu

rden Hormone Therapy

Discontinue Antiandrogen

1) AR is overexpressed in castration resistant sublines of multiple prostate cancer xenograft models (and in patients)

2) Forced AR overexpression confers castration-resistance3) AR knockdown impairs castration-resistant growth4) AR antagonists act as agonists when AR levels are high

(Chen et al Nature Med, 2004)

Primary Mechanism of Resistance to Castration and/or Current Antiandrogens

AR is required to maintaincastrate resistance in vivo

Tum

or

volu

me

(mm

3 )

0

200

400

600

0 24 48 72

Vector

AR shRNA

**

**

Time (days)

0

50

100

150

200

0 24 48 72

Vector

AR shRNA

*

**

**

LAPC4/CR LNCaP/CR

5’ LTR 3’ LTRGFPCMVTerm.AR RNAiU6

AR shRNA GFPLentivirus vector

Growth of castrate resistant xenografts in castrate male mice

1) AR is overexpressed in castration resistant sublines of multiple prostate cancer xenograft models (and in patients)

2) Forced AR overexpression confers castration-resistance3) AR knockdown impairs castration-resistant growth4) AR antagonists act as agonists when AR levels are high

(Chen et al Nature Med, 2004)

Primary Mechanism of Resistance to Castration and/or Current Antiandrogens

Second generation anti-androgens must:

• be effective in cells expressing high levels of androgen receptor

AND• overcome the problem of antagonist/agonist conversion

Design tools: - Crystal structure

- Homology modeling

- Binding affinity

NC

F3C N N

O

S

OH

RU 59063

High AR binding affinity(Ka = 20 nM for human AR)But with agonistic activity

Samedy Ouk, Michael Jung (UCLA Department of Chemistry)

Cell-based screen for compounds with greater antagonism and no agonism (“pure antagonists”)

Binding affinity to AR

Antagonist Activity

NF3C

NC

N

O

S

R1

R2

R

H-bond interaction

Hydrophobicinteraction

Rigidity

Hydrophobicinteractions with AR Jung et al, J Med Chem, 2010

Bic RD162 MDV3100Ve

h

Bic RD162 MDV3100Ve

h

RD162 and MDV3100 do not display agonism in AR overexpressing cells

Bic RD162 MDV3100Ve

h

Bic RD162 MDV3100Ve

h

…and have more potent antagonist activity

PSATMPRSS2

Tran et al, Science 2009

Immunodeficient SCID castrate male mice. Tumor volume was measured in 3 dimensions.

Tran et al, Science 2009

bicalutamide

RD162 (and MDV3100) are superior to bicalutamide in the castrate-resistant LNCaP-AR xenograft model

Androgen receptor activation and mechanism of antiandrogen action

Revised from Lancet Oncol. 2009 Oct;10(10):981-91.

Androgen (R1881)

BicalutamideMDV3100

R1881

42284

R1881+Bicalutamide

31832

R1881+MDV

1793

R1881 (androgen)

MDV

Overlap among AR binding peaks in response to antagonists (determined by AR ChIP-Seq)

peaks found by MACS, p-value <10-5

42284

Bicalutamide

18075

451

Ling Cai

A Phase 1-2 Multicenter First-in-Man Trial of MDV3100 in Castrate Resistant Prostate Cancer

1. Dose escalation, 3 patients per cohort, beginning at 30 mg/d to 600 mg/d

2. After safety was established at 60 mg/d, cohorts were expanded to 24 patients (12 chemo-naïve, 12 chemo failure)

3. First patient dosed in July, 2007

4. 140 men enrolled at 5 centers

(MSKCC, OHSU, U Wash, DFCI, MDACC)

Scher et al Lancet, 2010

Waterfall Plot of Best Percent PSA Change from Baseline

Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75)

62% (40/65)

>50% Decline

51% (38/75)

>50% Decline

Radiographic Changes in Soft Tissue (N=59) and in Bone (N=109)

Chemotherapy-Naïve Patients (N=65)

Post-Chemotherapy Patients (N=75)

Soft Tissue* (Best Response)

Partial Response

Stable Disease

N=25

36% (9/25)

44% (11/25)

N=34

12% (4/34)

53% (18/34)

Bone Scan (Week 12)

Stable Disease

N=41

63% (26/41)

N=68

51% (35/68)

*59 patients with evaluable soft tissue disease as defined by PCWG2 consensusJ Clin Oncol 2008.

Time to PSA Progression For Pre-and Post-Chemotherapy Treated Patients

Pre (Not reached)

Post (186 days)

Summary

1. Castration resistant prostate cancer remains dependent on androgen receptor (AR) function.

2. Pure AR antagonists like MDV3100 can overcome clinical resistance to partial antagonists (bicalutamide).

3. MDV3100 likely induces an AR conformation that precludes DNA binding.

4. MDV3100 development has progressed to a phase III registration trial in castration resistant, chemotherapy resistant prostate cancer

Mercedes Gorre Neil Shah John Nicoll

BMS clinical trialMoshe TalpazArt DecillisClaude NicaiseEric Bleickardt

Bhushan NagarJohn Kuriyan (UC Berkeley)Frank Lee (BMS)

Collaborators

Chris TranMike Burgess

Ron Paquette Liz Haddad

CML/Abl Inhibitor Project

Charlie Chen Derek Welsbie Chris TranJohn Wongvipat

Michael Jung(Chemistry)

Samedy Ouk(Chemistry)

Nicola Clegg

David Hung Medivation

Prostate Cancer/Antiandrogen Project