Imatinib pre-clinical and clinical development Stephen Oh, M.D,
Ph.D. Markey Program October 30, 2014
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Overview Historical narrative of imatinib development Paper
discussion Imatinib as a paradigm for other targeted therapies
(e.g. JAK2 inhibitors)
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Inhibiting the kinase activity of BCR/ABL wont work because:
ATP binding pocket of ABL is well conserved among many TKs Besides,
inhibition of BCR/ABL will also inhibit c- ABL, giving unknown
toxicity What we need is drug to block cancer-specific
pathways!
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518 protein kinases Goal: selective inhibitor of BCR-ABL
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Designing a BCR-ABL inhibitor How do you screen or design a
drug? What preclinical tests do you want? What animal studies do
you want? Who are the first patients to try drug? What are
endpoints? What to compare to? What is ultimate goal?
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~$800 million Discovery starts Year 8 (start Clinical) Year
15
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1. Cancer cell physiology 1960 = Nowell & Hungerford
Philadelphia chromosome observed, short chr. 22 1973 = banding
technique enables Rowley to identify Ph chr. = t(9;22) 1982 = ABL
involved on chr. 9, 1984 = BCR gene on chr. 22 1990 mouse models
validate BCR-ABL is necessary and sufficient for CML
development
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1985 1990
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2. Molecular target: Kinases 1980 Ciba-Giegy (Novartis) shut
down cancer research 1983 re-opened under Alex Matter Prior work on
interferon convinced him that nature could produce compounds to
kill cancer. Interest in pursuing kinase inhibitors solidified in
1985 Staurosporin inhibits PKC. PKC activity
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Kinases at Ciba-Giegy (Novartis) 1985 hired Nick Lydon to head
kinase program under Matter. 1988 Staurosporin derivatives against
PKC, but in search of a disease to target kinases. PDGF-R
identified as potential kinase with cancer and cardiology uses, so
began search for inhibitor. Lydon has connection with kinase group
at DFCI in Boston.
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Kinases at DFCI Lydon meets Brian Druker in 1988 on visit to
DFCI where he is post-doc fellow. Druker convinced BCR-ABL could be
targeted after seeing inhibition of EGFR results in Science 1988.
Approaches Lydon about BCR-ABL but CG is hesitant to pursue because
small number of CML patients, agrees to include ABL in kinase
screening panel. 1990-1993 DFCI sever ties with CG in favor of
Sandoz for kinase work. Druker has no contact with Matter,
Lydon.
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3. Lead identification/drug screening 2 main Questions after
identifying targets: 1. What compounds to test in system? 2. What
is your screening system? Empiric = NCI uses 60 cancer cell lines.
Screens 10,000 chemicals/yr from library in proliferation assay,
500 drugs pass and 5 novel agents recently identified. Rational
synthesis = CG/Novartis approach.
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1990 chemist Jurg Zimmermann and biologist Elizabeth Buchdunger
at CG. Goal: Rational synthesis to design drug that binds ATP
pocket in kinase domain (PDGF-R main target). 3. Lead
identification/drug screening
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Rational synthesis = Staurosporin derivatives: 1988 inhibit PKC
(s), 1990 EGF-R (s), Abl (non-selective) Screen compounds using in
vitro kinase phosphorylation assay against PKC, PKA, EGF-R, PDGF-R,
Alb, Src, Lyn, Fgr. Follow-up with in vitro antiproliferative assay
using kinase-transformed cell lines. 1990 Zimmermann use PAP
derivatives to screen for PKC inhibition. 1992 PDGF-R (ns- gets Abl
also) = LEAD COMPOUND ID! 3. Lead identification/drug
screening
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Phenylamino-pyrimidine (PAP) Until PAP used hundreds of
compounds screened but: lack Abl selectivity, poor drug likeness
PAP structure has good Drug likeness: absorb oral, nontoxic, not
destroyed in liver, stable in stomach, not excreted too fast.
StaurosporinPAP
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1985 1990 1992
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4. Lead (CGP57148) Optimization August 26, 1992 first batch of
drug. Buchdunger using in vitro kinase assay in early 1993 inhibits
Abl, and PDGF-R. Spring 1993 CG started to contact physicians for
CML interest NO INTEREST.
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1985 1990 1992 1994-5
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5. Drug candidate selection/production August 1993 Druker
leaving DFCI for OHSU (no longer committed to Sandoz) contacts
Lydon at CG for update on inhibitors. Druker is convinced Abl
inhibitors will work. Gets 4 drugs from CG to test on BCR-ABL using
protein, cell and animal experiments. Feb. 1994 presents results to
CG = 90% inhibition of BCR-ABL in vitro and picks CGP57148 as best
drug to pursue for CML.
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Nature Medicine, 1996
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Fig. 4 In vivo antitumor activity of CGP 57148
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Fig. 5 Colony-forming assays
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1985 1990 1992 1994-95 1995-97 Typical 8yr
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Animal safety/toxicology 1995 rodent studies no problems with
IP delivery. March 1996 Ciba-Geigy and Sandoz merge to become
Novartis and new management take over. 1996 dog study problem.
Clots develop at IV catheter site entrance. Phase I planning slowed
at Novartis. Nov. 1996 rats develop liver toxicity and all
human/animal trial planning stopped. 1997 Druker convinces Novartis
to continue with STI571 and drug is made orally bioavailable. Rats
and dogs absorb oral formulation. Monkeys only got liver toxicity
at hi doses. Decided to proceed to human studies with same
formulation, despite rat/dog toxicity.
Cancer clinical trials - Phase I Phase I = What is the
tolerable dose of new drug for phase II studies? Typically not
tumor specific, 10-30 patients Patients with advanced disease,
resistant to standard therapy, and good organ function Dose
escalation, looking for acute toxicity. 3-6 patients at each dose
DLT = 33%, Rx. 3 more patients at same dose. STOP if toxicity, go
up if not DLT > 33%, STOP Use highest dose with DLT < 33% for
phase II
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At 300 mg or higher, 53/54 (98%) with CHR
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STI571 Phase I Novartis now has to mass produce for anticipated
demand this has never happened for a drug so early. Plans to scale
production from 50 kg in 9/99 to 23 tons in 2001.
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Cancer clinical trials - Phase II/III Phase II = Does drug have
activity against specific tumor? Tumor specific study. Pick
patients that are active (good performance status) and minimal
prior chemotherapy. Phase III = Compare efficacy of new drug to
standard of care in order to help physicians make treatment
decisions. Randomized, broad eligibility better, multi-
institutional applicable to community doctors. Endpoints usually
survival or symptom control.
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532 chronic phase IFN failures 400 mg imatinib daily Complete
hematologic response: 95% Major cytogenetic response: 60% Median 18
month f/u, 89% still in chronic phase, 95% alive 2% d/c due to
adverse events, no treatment-related deaths
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FDA approval May 2001 based on Phase II data
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1106 patients randomized Complete hematologic response: 95% vs
56% Major cytogenetic response: 85% vs 22% Complete cytogenetic
response: 74% vs 9%
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Drug discovery cost analysis 6 yrs Discovery to phase I = 4.3
years Phase I to FDA approval = 7.5 years 12 year process Imatinib
= 10 years DiMasi et al, J Health Econ. 2003 Mar;22(2):151-85.
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Drug discovery cost analysis DiMasi et al, J Health Econ. 2003
Mar;22(2):151-85. Methods in this analysis have been criticized
other estimates range widely: $55 million to $2 billion!
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Imatinib costs Interferon about $1,700-3,300/month Initial cost
~ $2,200/mo Price has more than tripled since initial approval
~$100k/yr Revenue for imatinib in 2012 ~$4.7 billion INCOMECOST
< 43,000$/yrfree 43-100,000$/yr20% of income >100,000$/yrFull
price
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Generic Gleevec Initial patent application filed in 1993 Did
not claim any specific salts or mention imatinib mesylate Patent
application filed in 1998 specifically mentioned beta crystalline
form of imatinib mesylate After lengthy delay, application in India
rejected in 2006 ruling that imatinib mesylate was already known
prior to development of Gleevec Appealed to Indian supreme court
rejected April 2013 Gleevec to go off patent in US July 2015
Generic Gleevec to become available in US Feb 2016
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Generic Gleevec
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Imatinib as a paradigm for targeted therapies in hematologic
malignancies
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BCR-ABL negative MPNs
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Activation of JAK-STAT signaling in MPNs
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JAK2 V617F
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JAK inhibitors approved/in development for MPNs
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COMFORT-I
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Gleevec redux? No improvement in anemia No improvement in
marrow fibrosis Modest (at best) improvement in JAK2 V617F allele
burden Not so fast Can these inhibitors selectively target and
eradicate the malignant clone?
