Download GDC-0449: From Corn Lilies to a Cure

GDC-0449:
From Corn Lilies to a Cure
BCCNS Symposium
September 19.2009
Simon S. Yoo, MD
Assistant Professor of Dermatology, Otolaryngology, and
Surgery
Feinberg 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 Genetics
There 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 cycle
SHH 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 GLI
SMO when activated works with another protein called GLI1 (Gliomaassociated oncogene homolog 1 ) to cause increased cell proliferation
and decrease apoptosis or cell death.
Cyclopamine
Cyclopamine 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 BASALCELL CARCINOMA
DANIEL 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 GDC0449, 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
Results
GDC-0449 Activity in Patients with Locally Advanced Basal-Cell Carcinoma
Von Hoff D et al. N Engl J Med 2009;10.1056/NEJMoa0905360
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 3003000 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 GDC0449, 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