GDC-0449: From Corn Lilies to a Cure

BCCNS SymposiumSeptember 19.2009

Simon S. Yoo, MDAssistant Professor of Dermatology, Otolaryngology, and

SurgeryFeinberg School of Medicine

Northwestern University

Corn Lilies & Cyclops

• 1950s – Idaho sheep ranchers noticed strange birth defects

• USDA – 11 years to discover the culprit

• During droughts the sheep moved to higher ground to eat

• Corn lilies

Cyclops• Corn lilies contained a

poison, later called Cyclopamine (for obvious reasons)

• When pregnant ewes ate the lilies their offspring would develop birth defects most notably the cyclops

• 25 years past without any true explanation

Hedgehogs

• 1970s Volhard and Wieschaus discovered 50 genes essential for fruit fly development (1995 Nobel Prize)

• One gene when mutated caused flies to grow a coat of spines on their underbellies

• Hedgehog gene

Sonic Hedgehog

• 1993 Harvard scientists discovered a corresponding gene in mammals

• Mutations caused everything from cyclops to single front tooth or slight deformity

• Sonic hedgehog (Sega)

Sega’s Sonic Hedgehog

Light bulb

• 1998 – Phil Beachy (JHU) remembered that there were strange lambs seen in Idaho in the 1950s

• He wondered whether Cyclopamine could be used to induce changes in the sonic hedgehog pathway

Segue to Genetics

• Genes exist in every cell• During development they conduct the

orchestra that tells a single cell formed by a sperm and an egg how to become a human being

• During cancer these same developmental genes can be activated and cause uncontrolled growth of certain cells

• Sonic hedgehog tells the body how to develop a normal face during development of embryos

• After development defects in these sonic hedgehog pathway can lead to cancer:

• Basal Cell Nevus Syndrome was linked to a defect in this pathway relatively recently

Genetics of BCCNS• 2 proteins on the cell surface• Patch1 and Smoothened• Normally Sonic Hedgehog is not around in adults except during

hair follicle growth in the skin• When it isn’t around the system stays quiet• However when there is a defect in Patch1 or Smoothened the

system acts like Sonic Hedgehog is actually around and causes a number of effects subsequently that lead to tumors

• Patch1 – tumor suppressor, Smoothened - proto-oncogene• BCCNS – heterozygote loss of Patch1• Sporadic BCC – both loss of Patch1 and activating Smoothened

BCCNS GeneticsThere are 3 players at play in the sonic hedgehog signaling pathway:PTCH (or patch), SMO (smoothened), and SHH (sonic hedgehog).After development SHH is usually quiet except during hair follicle growth in the skin.If SHH is around, it can attach to PTCH and activate SMO to cause a number of events in the cell that can lead to cancer.

SHH and the cell cycleSHH can act via PTCH and other mechanisms to keep cells moving through their cycle leading to uncontrolled cell growth – a hallmark of cancer.

SMO and GLISMO when activated works with another protein called GLI1 (Glioma-associated oncogene homolog 1 ) to cause increased cell proliferation and decrease apoptosis or cell death.

CyclopamineCyclopamine as well as GDC-0449 to inhibits SMO and therefore decrease cell proliferation and increase cell death.

Cyclopamine and GDC-0449

• Cyclopamine blocks hedgehog signaling by binding Smoothened

• GDC-0449 is a small-molecule compound that is a selective hedgehog pathway inhibitor with greater potency and more favorable pharmaceutical properties and Cyclopamine

GDC-0449

• Antitumor activity in mouse model of medulloblastoma and human cell models of colorectal and pancreatic cancer

INHIBITION OF THE HEDGEHOG PATHWAY IN ADVANCED BASAL-CELL CARCINOMADANIEL D. VON HOFF, M.D., PATRICIA M. LORUSSO, D.O., CHARLES M. RUDIN, M.D., PH.D., JOSINA C. REDDY, M.D., PH.D., ROBERT L. YAUCH, PH.D., RAOUL TIBES, M.D., GLEN J. WEISS, M.D., MITESH J. BORAD, M.D., CHRISTINE L. HANN, M.D., PH.D., JULIE R. BRAHMER, M.D., HOWARD M. MACKEY, PH.D., BERTRAM L. LUM, PHARM.D., WALTER C. DARBONNE, M.S., JAMES C. MARSTERS, JR., PH.D., FREDERIC J. DE SAUVAGE, PH.D., AND JENNIFER A. LOW, M.D., PH.D.

September 2, 2009

Genentech Bio-Oncology

Phase I Multicenter Trial of GDC-0449, evaluating efficacy and safety

for advanced BCC

Introduction• Basal Cell Carcinoma (BCC) is the most common skin

malignancy, usually effectively treated w/surgery– Small subset has aggressive, invasive disease– If further surgery not possible, no other approved

therapy or standard of care• Metastatic BCC (mBCC) is quite rare (<0.1%)– Survival ranges from 8-14 mos to 5+ years (10%)– Metastatic sites: lymph nodes, lung, bone, liver,

soft tissue– No approved or standard of care therapy exists for

mBCC

Phase 1 Trial

• Open-label, multicenter, 2 stage phase 1 trial• Evaluating safety and tolerability of GDC-0449• 33 patients enrolled with metastatic or locally

advanced basal-cell carcinoma• 17 patients received 150 mg/day• 15 patients received 270 mg/day• 1 patient received 540 mg/day

Eligibility

• >18 yo• Histologically confirmed locally advanced or

metastatic BCC considered to be refractory to surgical or radiotherapy

• Negative pregnancy test• GDC-0449 was not started until >3 weeks after

last therapy of surgery

• 18/33 - Metastatic disease• 15/33 – Locally advanced disease• Of those that responded most noticed a

difference at 2 months

Exclusion

• Major organ dysfunction• A long QT interval on ECG (or any medication

known to prolong QT)• (e.g. Paxil, Effexor, Zomig, Prozac, Propulsid)• Active infection requiring IV antibiotics• Pregnancy• Inability to swallow drugs

Von Hoff D et al. N Engl J Med 2009;10.1056/NEJMoa0905360

GDC-0449 Activity in Patients with Locally Advanced Basal-Cell Carcinoma

Results

Results

• 18/33 - objective response (imaging, physical exam or both)– 2/18 complete response– 16/18 partial response

• 11/33 – stable disease• 4/33 – progressive disease• 9.8 months – average treatment time

Results 2

• 18 Metastatic tumors – 50% responded• 15 Locally advanced tumors – 60% responded

Side Effects

• 4/33 – Fatigue• 2/33 – Electrolyte imbalance (hyponatremia)• 1/33 – Muscle spasm• 1/33 – Heart palpitations (atrial fibrillation)

Relative Success

• Because of the relatively low side effects and the relative improvement of the BCCs Genentech has begun a phase II trial

FDA and Drugs

• Pre-clinical: test-tube and animal experiments• Phase 0: subtherapeutic or microdosing studies

done to rank drugs in order to decide which ones should be studied further

• Phase I: 20-50 subjects studied to assess safety, tolerability, and dose-ranging (usually healthy volunteers unless patients have terminal disease or lack other treatment options)

• Phase II – 20-300 subjects to assess how well the drug works as well as to continue Phase I safety assessments (if new drugs fail they fail here)

• Phase III – randomized controlled trials of 300-3000 subjects aimed at being the definitive assessment of how effective the drug is compared to current “gold standard” therapies

• Phase IV – post-marketing safety surveillance (e.g. Vioxx)

Genentech Bio-oncology

Phase II Multicenter Trial of GDC-0449, evaluating efficacy and safety

for advanced BCC

Inclusion Criteria

• >18 yo• Histologically confirmed disease considered

inoperable or medically contraindicated to surgery (as determined by Mohs, ENT, or Plastic Surgeon)– (multifocal superficial BCC is not considered

inoperable)

• Medical contraindications to surgery include:– BCC recurrence in same location after 2 or more

surgical procedures– Anticipated substantial morbidity/deformity from

surgery as determined the surgeon– Radiotherapy must have been tried in the past

unless contraindicated (BCCNS are exempt)

• Metastatic disease – histological confirmation of distant BCC

• Generally good health

Exclusion Criteria

• Pregnant/Lactating– Women who are of child-bearing potential must use 2 forms

of birth control• No other experimental drug within past 4 weeks• No exposure to hedgehog signaling inhibitors

previously• No history of other malignancies within past 3 years• No concurrent therapy (chemotherapy, radiation,

photodynamic)• Life expectancy >12 weeks

Study Protocol• Screening – CT scan, biopsies, ECG, blood work, urine analysis,

photographs• Patients seen every 4 weeks• Visits will continue until subject experience toxicity or

withdraws from study• Medication is dosed every day• Photographs taken every other visit• Blood drawn every visit• Target lesions are re-biopsied at week 24• Previously non-resectable tumors may be resected if approved

Acknowledgements

• Murad Alam, MD – Northwestern University• Brenda Bartlett, MD – Northwestern

University• Ivor Caro, MD – Genentech• David Kouba, MD, PhD – Henry Ford Hospital