Rewriting the Medical Textbooks:

Why Clinical Research Matters

Designing Clinical Research

14 September 2010

Susan Desmond-HellmannMD, MPHChancellor

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Agenda

• Challenges & Opportunities

• Lessons Learned

• Academia’s Role

• What’s Possible

Discoveries should reach the greatest number of patients and have the greatest good for society

Always be vigilant that innovation could be harmful as well

Discoveries should reach the greatest number of patients and have the greatest good for society

Always be vigilant that innovation could be harmful as well

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Bringing Discoveries to the Clinic

• My Perspective: Moving a discovery into clinical trials is a step in the journey, not the goal

• Goals: FDA approval, product commercialization

• #1 Challenge: Patient safety

– During clinical trials, as the number of patients exposed increases

– Proving long-term safety

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Developing First-in-Class TherapiesCase Studies

• Herceptin (trastuzumab)

• Avastin (bevacizumab)

Date Event

1985 HER2 gene cloned

1987Dr. Dennis Slamon and colleagues at UCLA publish in Science the link between HER2 overexpression with a more aggressive type of breast cancer in 25-30% of patients for the first time.

1990 Len Presta and Paul Carter of Genentech humanize an antibody directed at HER2.

1991 IND filed and Phase I trials initiated.

1993 Phase II trials initiated.

June 1995 Enrollment of Phase III pivotal combination trial begins.

Mar. 1997 Phase III trials completed.

May 1998Results from a Phase III clinical trial show that Herceptin in combination with chemotherapy slows the progression of cancer and increases tumor shrinkage. Submitted application for FDA approval.

Sept. 1998 Herceptin is approved by the FDA for treating women with HER2 positive metastatic breast cancer.

Dec. 2000Genentech, in collaboration with leading cancer cooperative groups announces the initiation of Phase III clinical trials evaluating Herceptin in the adjuvant setting for breast cancer.

Mar. 2001Data from a pivotal Phase III clinical trial is published in the New England Journal of Medicine (NEJM) that shows a 25% increase in survival rates for women with HER2+ metastatic breast cancer who receive Herceptin and chemotherapy over chemotherapy alone.

Dec. 2001 Received approval from the FDA to include information about the increase in survival rates for Herceptin patients in the product labeling.

Aug. 2002 Received FDA approval to include information about a breast cancer gene-detection FISH testing in the product label.

April 2005Data from two Phase III studies in HER2+ early-stage breast cancer showed that patients receiving Herceptin plus chemotherapy had a 52% reduction in the risk of disease recurrence compared to those patients who received chemotherapy alone.

Nov 2006 Herceptin is approved by the FDA for the adjuvant treatment of HER2+ breast cancer

…20 Years in the Making

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Trastuzumab: Scientific Background

• Nature 1981; 290:261-264. Shih, Padhy, Murray, Weinberg DNAs from multiple tumor lines can transform NIH3T3 cells on transfection

• Nature 1984; 312:513-516. Schechter, Stern, Vaidyanathan, Decker, Drebin, Greene and Weinberg

A series of rat neuro/glioblastomas all contain the same transforming gene (neu) which induces synthesis of a tumor antigen p185. Described homology between neu and erb-B oncogenes

• Cell 1985; 41:695-706. Drebin, Link, Stern, Weinberg, Greene Down-modulation of oncogene protein product p185 and reversion of the transformed phenotype by monoclonal antibodies to the neu gene product

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* Combined metastatic and adjuvant patients. Slamon et al. Science. 1987;235:177. Pauletti et al. J Clin Oncol. 2000;18:3651.

* Combined metastatic and adjuvant patients. Slamon et al. Science. 1987;235:177. Pauletti et al. J Clin Oncol. 2000;18:3651.

HER2 positive protein HER2 positive protein overexpressionoverexpression

IHC (using rabbit antibody)IHC (using rabbit antibody)

HER2 positive protein HER2 positive protein overexpressionoverexpression

IHC (using rabbit antibody)IHC (using rabbit antibody)

Scientific Rationale - Breast Cancer

HER2 geneHER2 geneamplificationamplification

FISHFISH

HER2 geneHER2 geneamplificationamplification

FISHFISH

Shortened Median Survival*

HER2 positive 3 years

HER2 normal 6-7 years

Trastuzumab

5 months

(22.7%)

100%

50%

25%

1250 52 mos

3500 108 mos

11000 349 mos

* Easy to miss a potentially active new therapy as target prevalence decreases

Actual Benefit (All Patients)

5 mos (22.7%)

2.5 mos (11.4%)

1.25 mos (5.7%)

First Line MBC (median survival ~ 22 months)

The Importance of a Predictive Biomarker

Expected Benefit Target Prevalence Required Sample Size

And Study Duration

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20.3 mo

25.4 mo (25% )

RR = 0.76p = .025

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USE OF CHEMOTHERAPY PLUS A MONOCLONAL ANTIBODY AGAINST HER2 FOR METASTATIC

BREAST CANCER THAT OVEREXPRESSES HER2Dennis J Slamon et al

 New Engl J Med 2001;344

DFS=85%

DFS=67%

Pe

rce

nta

ge (

%)

AC Paclitaxel

Years From Randomization

Data presented by Romond EH et al. at ASCO May 2005

AC Paclitaxel + Trastuzumab

DFS=87%

DFS=75%

2005: Trastuzumab results in the adjuvant setting

Disease-Free Survival (DFS) Joint Analysis Results (NSABP-B31 and NCCTG-9881)

Regimen # of Patients Events

AC Paclitaxel n=1679 261

AC Paclitaxel + Trastuzumab n=1672 134

HR=0.48, 2P=3x10-12

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Trastuzumab and Cardiotoxicity

• Most important safety issue for adjuvant tx

• Overall experience (Chien, NEJM 2006)

– ~1-4% cardiac failure

– ~ 10% decline in cardiac function

• Highest rates observed with concurrent anthracycline, adjuvant trials demonstrated higher than expected cardiac function decline following 4 cycles of AC

• Mutant mouse models suggest a pivotal role of erbB2 in the embryonic and prenatal heart

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“Clearly the results reported in this issue of the Journal are not evolutionary but revolutionary. The rational development of molecularly targeted therapies points the direction toward continued improvement in breast cancer therapy. Other targets and other agents will follow. However, trastuzumab and the two reports in this issue will completely alter our approach to the treatment of breast cancer.”

Gabriel N. Hortobagyi, M.D., NEJM, October 20, 2005

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Date Event

1989 Genentech scientist Napoleone Ferrara, M.D., identifies VEGF, a growth factor influencing the tumor angiogenesis process. Dr. Ferrara and his team at Genentech clone VEGF and publish in Science some of the first evidence that a specific angiogenic growth factor exist

1993 Dr. Ferrara and scientists at Genentech publish a study in Nature demonstrating that an anti-VEGF antibody can suppress angiogenesis and tumor growth in preclinical models.

1996 Genentech scientists humanize an anti-VEGF antibody.

1997 Investigational New Drug (IND) application submitted to the FDA and a Phase I trial of Avastin begins.

1998 Phase II trials of Avastin begin.

2000 Phase III trial of Avastin in first-line metastatic colorectal cancer (in combination with the IFL regimen) begins.

May 2003 Phase III pivotal trial of Avastin and the IFL chemotherapy regimen in first-line metastatic colorectal cancer exceeds primary endpoint of improving overall survival, and meets secondary endpoints of progression-free survival, response rate and duration of response. Trial demonstrated 34% reduction in the chance for death for patients with first-line metastatic colorectal cancer treated w/Avastin plus chemotherapy versus patients who received chemotherapy alone (NEJM 2004).

February 2004

FDA approves Avastin in combination w/intravenous 5-Fluorouracil-based chemotherapy as a 1st-line treatment for patients w/metastatic cancer of the colon or rectum, making Avastin first approved anti-angiogenesis treatment for cancer.

January 2005

Phase III trial demonstrates a 26% reduction in the risk of death, the primary endpoint, in patients with second-line metastatic colorectal cancer who received Avastin plus FOLFOX4 compared to FOLFOX4 alone (ASCO GI)

March 2005 Phase II/III trial showed that patients with first-line non-squamous, non-small cell lung cancer receiving Avastin plus Paclitaxel and Carboplatin had a 30% improvement in overall survival, compared to patients who received chemotherapy alone (ASCO May 2005)

April 2005 Phase III trial showed that patients with first-line metastatic breast cancer receiving Avastin plus Paclitaxel doubled the duration of surviving without cancer progression compared to Paclitaxel alone, which is equivalent to a 50% reduction in the risk of cancer progression, and a 49% improvement in the secondary endpoint of overall survival, which is the equivalent of a 33% reduction in the risk of death (ASCO May 2005)

October 2006

FDA Approves Avastin in to be used in combination with carboplatin and paclitaxel chemotherapy for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC), the most common type of lung cancer.

…16 Years in the Making

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1600

1200

800

400

00 7 14 21

Tum

or V

olum

e (m

m3 )

Time (days)

ControlControl mAb (200μg)Bevacizumab (10 μg)Bevacizumab (50μg)Bevacizumab (100μg)Bevacizumab (200μg)

Regulation by Vascular Endothelial Growth Factor of Human Colon Cancer Tumorigenesis in a Mouse Model of Experimental Liver Metastasis. Warren et al, J Clin Invest, Vol 95, 1995, pp 1789-1797.

Avastin Pre-Clinical Activity

• Neutralizing humanized anti-VEGF monoclonal antibody (derived from mouse mAb A4.6.1)

• Broad activity in pre-clinical models

VEGF mAb Control mAb

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Phase IIRefractory

Single Agent

Endpoints:• Time-to-progression• Response Rate• Survival

Phase I Program

Phase IIMetastatic withChemotherapy

Considerations in Trial Design

• Avastin Phase II Development Concept

Prostate Cancer

Breast Cancer

Renal Cell Carcinoma

Non-Small Cell Lung Cancer

Colorectal Cancer

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Hurwitz et al, New England Journal of Medicine, Vol. 350, June 3, 2004, pp 2335-2342.

HR = 0.66 P=<0.001

First Phase III Clinical Validation and First Demonstration of Survival of the Long-pursued 'Anti-angiogenic' Hypothesis (ASCO 2003):

• Avastin first-line metastatic colorectal cancer Phase III 2107 trial results: The median duration of survival (indicated by the dotted lines) was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo.

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Pro

bab

ilit

y

Survival (in months)

Data presented by Sandler AB et al. at ASCO May 2005*Eligible patients.

Avastin Phase III Advanced Non-Squamous Non-Small Cell Lung Cancer Study (ECOG 4599)

• Survival Results -- Carboplatin/

Paclitaxel Alone

(n=431*)

-- Carboplatin/

Paclitaxel + Avastin

(n=424*)

12-Months 43.7% 51.9%

24-Months 16.9% 22.1%

Overall Survival 30% increase

Median Survival 10.2 months 12.5 months

Hazard Ratio 0.77 (0.65, 0.93)

P-value p=0.0007

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Avastin Phase III Non-Squamous Non-Small Cell Lung Cancer Study: Safety Data

Advanced Non-Squamous Non-Small Cell Lung Cancer Patients

Grade 3/4/5 Safety Data Avastin +Carboplatin/Paclitaxel (n=420)

Carboplatin/PaclitaxelAlone (n=427) P-value

Hematologic Toxicity

Neutrophils 24% 16.4% 0.006

Platelets 1.4% 0% 0.01

Hgb 0% 0.7% 0.25

GCP Fevers 3.3%* 1.9%* 0.20

Non-Hematologic Toxicity G3/4 (%) G5 (%) G3/4 (%) G5 (%)

Hemorrhage

CNS 0.9 0.2 -- --

Epistaxis 0.7 -- 0.2 --

Hemoptysis 0.4 1.2 0.2 --

GI 0.7 0.4 0.2 0.2

Other 0.2 -- -- --

Thrombosis 3.8 -- 3.0 --

CVA 0.9 -- 0.5 --

Cardiac Ischemia 0.5 -- 0.2 --

HTN 5.9 -- 0.7 --

Data presented by Sandler, AB et al at ASCO May 2005*Includes one death on each arm due to neutropenic fever

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0.0

0.2

0.4

0.6

0.8

1.0

Months

PFS

Pro

bab

ility

0 6 12 18 24 30

Avastin for Breast Cancer (E2100 results)

HR = 0.51 (0.43-0.62)

Log Rank Test p<0.0001

Avastin + Taxol 11.4 monthsTaxol Alone 6.11 months

484 events reported

Progression Free Survival

Data presented by Miller KD et al. at SABCS Dec 200519

Avastin Phase III First-line Metastatic Breast Cancer Study: Safety Data

First-line Metastatic Breast Cancer Patients

NCI-CTC Grade 3 and 4Avastin + Taxol

n=350Taxol Alone

n=332

Avastin Toxicities Grade 3 Grade 4 Grade 3 Grade 4

Hypertension* 15% <1% 2% 0

Thromboembolic 2% 0 2% 2%

Bleeding** 1% <1% 0 0

Proteinuria*** 1% 1% 0 0

Other Toxicities Grade 3 Grade 4 Grade 3 Grade 4

Neuropathy 22% 1% 17% 1%

Fatigue^ 8% <1% 4% <1%

Neutropenia NR 4% NR 3%

LVEF <1% 0 0 0

Data presented by Miller KD et al. at SA BCS Dec 2005*p<0.0001; **p=0.02; ***p= 0.002 ^p=0.05

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Avastin Summary and Open Questions

• Anti-angiogenesis can slow tumor growth and extend survival

• Differential patient benefit by tumor type but no biomarker yet available

• Key Questions– Duration of therapy

– Best dose

– Long term safety

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How Can We Improve Our Ability to

Translate Discoveries into Benefits?

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Reverse Translation

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Improved Translation

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More Effective Clinical Trials

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Translational Research in Academia

• Universities: stimulate curiosity and create knowledge

• Companies: develop and commercialize products

• Academia’s value added: the scholarly pursuit of technical excellence

• Translational programs emerging at UCSF:

– Clinical and Translational Sciences Institute (CTSI)

– Quantitative Biology Institute (QB3)

– Bioengineering and Therapeutic Sciences (BTS)

What I’ve Learned

• Always ask: does this approach offer the highest likelihood of (and fastest route to) relieving human suffering?

• Ensure that you learn something from:

– Each and every trial carried out (the answer may be yes or no, but the tragedy is when the answer is “maybe”)

– Every patient who enters any of your trials – both short- and long-term

• Ask: what can you do to make the approach as simple and as inexpensive as possible?

– Therapy should be scalable and accessible

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UCSF should contribute to change

• Prevention

– Moving from a disease-based to a health-based approach

– Will require new approaches (more reliable surrogate markers ,biomarkers) to advance more quickly

• Healthcare reform

– Can we utilize electronic health record instead of case report forms?

– What will be the impact of cost containment on the pace of innovation?

– Why can’t Medical Innovations drive down cost?

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What’s Possible

Turning biomedical discoveries into products that benefit patients

Thank you!

Questions?

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