Download Imatinib pre-clinical and clinical development

Imatinib pre-clinical and
clinical development
Stephen Oh, M.D, Ph.D.
Markey Program
October 30, 2014
Overview
• Historical narrative of imatinib development
• Paper discussion
• Imatinib as a paradigm for other targeted
therapies (e.g. JAK2 inhibitors)
Inhibiting the kinase activity of BCR/ABL
“won’t work” because:
• ATP binding pocket of ABL is well conserved
among many TKs
• Besides, inhibition of BCR/ABL will also inhibit cABL, giving unknown toxicity
• What we need is drug to block cancer-specific
pathways!
Goal: selective inhibitor of BCR-ABL
• 518 protein kinases
Designing a BCR-ABL inhibitor
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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?
~$800 million
Discovery starts
Year 8
(start Clinical)
Year 15
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
1985
1990
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
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.
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.
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.
3. Lead identification/drug screening
• 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
• 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!
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.
Staurosporin
PAP
1985
1990
1992
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.
1985
1990
1992
1994-5
1994-5
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.
Nature Medicine, 1996
Fig. 4 In vivo antitumor activity of CGP 57148
Fig. 5 Colony-forming assays
1985
Typical 8yr
1990
1992
1994-95
1994-95
1995-97
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.
1985
1990
1992
1994-95
1994-95
Year 8
(start Clinical)
1995-97
1998-2000
(Imatinib = 3yrs.)
1999-2001
2000
Year 15
Apply 2/27/01approved 5/10/01
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
At 300 mg or higher,
53/54 (98%) with CHR
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.
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, multiinstitutional – applicable to “community” doctors.
• Endpoints usually survival or symptom control.
• 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
FDA approval
May 2001 based
on Phase II data
• 1106 patients randomized
• Complete hematologic response: 95% vs 56%
• Major cytogenetic response: 85% vs 22%
• Complete cytogenetic response: 74% vs 9%
Drug discovery cost analysis
6 yrs
DiMasi et al, J Health Econ. 2003 Mar;22(2):151-85.
Discovery to phase I = 4.3 years
12 year process
Phase I to FDA approval = 7.5 years Imatinib = 10 years
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!
Imatinib costs
• Interferon about $1,700-3,300/month
• Initial cost ~ $2,200/mo
INCOME
COST
< 43,000$/yr
free
43-100,000$/yr
20% of income
>100,000$/yr
Full price
• Price has more than tripled since initial approval ~$100k/yr
• Revenue for imatinib in 2012 ~$4.7 billion
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
Generic Gleevec
Imatinib as a paradigm for targeted therapies in
hematologic malignancies
BCR-ABL negative MPNs
Activation of JAK-STAT signaling in MPNs
JAK2 V617F
JAK inhibitors approved/in development for MPNs
JAK inhibitor
JAK2 IC50
JAK selectivity
Non-JAK targets
Clinical trials
Ruxolitinib
FDA approved
4.5 nM
JAK1 0.6x
JAK3 72x
TYK2 4x
Fedratinib
Phase III completed
3 nM
JAK1 35x
JAK3 332x
TYK2 135x
FLT3
RET
MF
PV
ET
Momelotinib
Phase III ongoing
18 nM
JAK1 0.6x
JAK3 8.6x
TYK2 Unk
JNK1
CDK2
MF
Pacritinib
Phase III
22 nM
JAK1 58x
JAK3 24x
TYK2 Unk
FLT3
MF
CEP-701
Phase II
1 nM
JAK1 Unk
JAK3 3x
TYK2 Unk
FLT3
TrkA
MF
PV
ET
LY2784544
Phase I/II
~60 nM
(JAK2 V617Fselective)
JAK1 Unk
JAK3 15x
TYK2 Unk
Unknown
MF
PV
ET
MF
PV
ET
JAK inhibitors approved/in development for MPNs
JAK inhibitor
JAK2 IC50
JAK selectivity
Non-JAK targets
Clinical trials
Ruxolitinib
FDA approved
4.5 nM
JAK1 0.6x
JAK3 72x
TYK2 4x
Fedratinib
Phase III completed
3 nM
JAK1 35x
JAK3 332x
TYK2 135x
FLT3
RET
MF
PV
ET
Momelotinib
Phase III ongoing
18 nM
JAK1 0.6x
JAK3 8.6x
TYK2 Unk
JNK1
CDK2
MF
Pacritinib
Phase III
22 nM
JAK1 58x
JAK3 24x
TYK2 Unk
FLT3
MF
CEP-701
Phase II
1 nM
JAK1 Unk
JAK3 3x
TYK2 Unk
FLT3
TrkA
MF
PV
ET
LY2784544
Phase I/II
~60 nM
(JAK2 V617Fselective)
JAK1 Unk
JAK3 15x
TYK2 Unk
Unknown
MF
PV
ET
MF
PV
ET
COMFORT-I
COMFORT-I
Gleevec redux?
Not so fast…
• No improvement in anemia
• No improvement in marrow
fibrosis
• Modest (at best) improvement in
JAK2 V617F allele burden
Can these inhibitors selectively
target and eradicate the
“malignant clone”?