Download Cancer Drug Development in Industry

Cancer Drug Development
in Industry:
Outline of my Talk
• Targeted Therapy for Cancer
• Challenges and Costs
• Another Example: Hepatitis C
• Approval Times for New Cancer Drugs
• Combination is Key – What are the Costs?
• Future Directions
Outline of my Talk
• Targeted Therapy for Cancer
• Challenges and Costs
• Another Example: Hepatitis C
• Approval Times for New Cancer Drugs
• Combination is Key – What are the Costs?
• Future Directions
Cancer in Europe
• 30% of all Europeans will come down with cancer during their
lifes.
• 20% of all Europeans will die due to cancer.
• Cancer is the second most frequent cause of death in Europe.
• European Community (2013):
- Cancer Morbidity: 1,500,000 pts. per year
- Cancer Mortality:
700,000 pts. per year
Cancer Treatment: Paradigm Shift
Chemotherapy,
Radiotherapy, Surgery
Unspecific targets
Targeted therapy
Specific targets
Reduction of
tumour mass
Inhibition of
tumour growth
Survival
Do we know the optimal target?
Shc
Grb2
PI3-K
Sos-1
Ras
AKT
MEKK-1
Raf
MEK
mTOR
MKK-7
ERK
JNK
Apoptosis
Proliferation
Angiogenesis
Metastasis
Do we know the optimal target?
Shc
Grb2
PI3-K
Sos-1
Ras
AKT
MEKK-1
Raf
MEK
mTOR
MKK-7
ERK
JNK
Sos-1
PI3-K
Grb2
Shc
Raf
MEK
MEKK-1
JNK
MKK-7
ERK
AKT
Ras
Where is the target?
Sos-1
PI3-K
Grb2
Shc
Raf
MEK
MEKK-1
JNK
MKK-7
ERK
AKT
Ras
An Engineer’s Perspective…
EGF
EGFR
EGFR
Do we know the Optimal Target?
NO – plain and simple!
2001
Imatinib
2005/06
Sorafenib
Sunitinib
Dasatinib
2009
Everolimus
Pazopanib
2012
Axitinib
Pazopanib
Bosutinib
Ponatinib
Cabozantinib
Regorafenib
2014
Ceritinib
Ibrutinib
Idelalisib
32 small molecules
within 14 years!
2003/04
Erlotinib
Gefitinib
2007
Lapatinib
Nilotinib
Temsirolimus
2011
Crizotinib
Ruxolitinib
Vemurafenib
Vandetanib
2013
Afatinib
Dabrafenib
Trametinib
2015
Lenvatinib
Alectinib
Palbociclib
Panobinostat
Nindetanib
Outline of my Talk
• Targeted Therapy for Cancer
• Challenges and Costs
• Another Example: Hepatitis C
• Approval Times for New Cancer Drugs
• Combination is Key – What are the Costs?
• Future Directions
The Challenges for the Global Industry
• Of 4300 companies, 261 (6%) have registered a new cancer drug since 1950.
• Patent expirations 2010-2014: more than $113 Billion
• For every dollar lost, new revenues projected at 26 cents
• R&D Productivity in decline
- Discovery of new cancer drugs down 50% in past 5 years
• 200,000 industry jobs will be shed 2009 – 2015
• Average cost of a cancer drug to market: $1.1 billion
- But late stage failures make real cost $4.5-11.7 billion!
The Challenges for the Society (US)
1.
Annual cancer care costs in the US are projected to rise from $ 104 billion in 2006
to $ 175 Billion in 2020. Germany (2014): € 15 Billion
2.
The number of new cases of cancer will rise from 11.3 million in 2007 to 15.3
million in 2030. Germany (2014): 450,000 pts.
3.
The US spend for cancer drugs rose 400% from 1998-2008, largely driven by new
biological agents.
4.
Generic biologics will likely be costly.
5.
The cost of drugs given in doctor‘s office rose 276% from 1997-2004 while
insurance increase was 47%.
6.
A new cancer drug is ten times more likely to be prescribed for a patient in the US
as compared to Europe.
7.
The average US household budget for health care is the same as for food.
The Challenge for Germany
500
Cost
(Billion
EURO)
200
2014
2035
Cost Of Approved Oncology Agents
Drug
Target
Indication
Cost/Year
Ipilimumab
CTLA-4
Melanoma
$ 120,000
Sipulleucel-T
Cell therapy
Prostate
$ 90,000
Bevacizumab
VEGF-A
Various
$ 90,000
Nab-Paclitaxel
Tubulin
Pancreas
$ 80,000
Lenalidomide
IMID
Myeloma
$ 90,000
Proteasome
Myeloma
$ 60,000
Imatinib
acr-abl
CML
$ 70,000
Ofatumumab
CD-20
CLL
$ 120,000
5-Fluorouracil
TS
CRC
$ 300
Bortezomib
The Cost-Effectiveness Plane
Outline of my Talk
• Targeted Therapy for Cancer
• Challenges and Costs
• Another Example: Hepatitis C
• Approval Times for New Cancer Drugs
• Combination is Key – What are the Costs?
• Future Directions
Hepatitis-C:
Enter The Block Buster Hurricane Season
•
Following acute infection, a chronic, often asymptomatic disease
•
Prevalence (US): 16,000 acute, 3.2 million chronic
•
Over 20-30 years chronic infection will lead to cirrhosis (5-20%) or liver
cancer (5%)
•
No vaccine available
•
Until recently, treatment included peg-IFN, ribavirin +/- telaprevir or
boceprevir
•
And then the pharmaco-economic barometer dropped
Targeted Therapy in Another Tribe:
The Pharmaco-Economic Impact
Sofosbuvir (Solvaldi®, Gilead)
•
MOA: NS5B polymerase inhibitor
•
FDA approved in 2013
•
Pivotal Trial: Dual IFN-free Regimen of Sosobuvir plus Ribavirin for 24 weeks resulted in cure for
100% of treatment-naive patients
•
Early 2014, the American Association for Study of Liver Diseases and the Infectious Diseases Society
of America Jointly endorsed sofosbuvir and ribavirin +/- peg-IFN for first-line treatment of Hepatitis-C
•
Cost: $ 84,000 ($ 1,000/pill), BUT:
•
Benefit: 14.5 QLYS (favorable cost-utility compared to managing end stage liver failure, transplant or
cancer)
Targeted Treatment in Another Tribe:
The Perfect Storm
• FDA approves combination of ledipasvir (NS5A inhibitor) and sofosbuvir (NS5B
inhibitor) as first treatment for Hepatitis-C not containing IFN or ribavirin
• Ledipasvir to be priced at $ 94K/12 weeks vs. the cost of Sofosobuvir at $ 84K
• However, the possibility of ledipasvir monotherapy for 8 weeks would lower
cost to $ 66K (applicable to 50% of patients)
• Licensing agreements quickly established to make drug available in developing
countries at a fraction of cost
• With possibility of cure, insurances approved wider screening to detect
asymptomatic patients, compounding cost projections
The Hepatitis-C Paradigm
Will Oncology be So “Lucky”?
Cancer is more complex than a viral disease:
•
Cancer is > 200 different diseases: many orphans in the family
•
Multiple pathways, targets and mutations involved
•
Treatment toxicities weigh into the cost-benefit and cost-utility calculations
•
No accepted surrogate markers for clinical benefit
•
Complex and confoundable clinical trial endpoints requiring large studies
•
Combinations will be key to progress
•
Combinations may also be as problematic as for hepatitis-C
Outline of my Talk
• Targeted Therapy for Cancer
• Challenges and Costs
• Another Example: Hepatitis C
• Approval Times for New Cancer Drugs
• Combination is Key – What are the Costs?
• Future Directions
Clinical And Approval Times By Therapeutic Class
Time For Development of Oncology Drugs
Crizotinib: Pathway from Compound Identification to FDA
Approval
Crizotinib (XALKORI®):
Targeting the ALK fusion gene, a direct driver of oncogenesis
Lead Com-pound Clinical
testing
identified
begins
2005
2006
Discovery of EML4-First clinical responses Phase 3 lung
cancer trial
observed in ALK+
ALK
initiated
tumours
fusion gene
2007
2008
2009
ASCO
plenary of
expanded
ALK+
cohort
XALKORI®,
NEJM
NDA, PMA SubFISH test
publication ofmissions
2
approvals
ALK+ cohort
2010
Rapid Timeline from Compound Identification, Target Discovery and Clinical Results
2011
Oncology NDAs in 2014
Drug
Target
Indication
Pembrolizumab
PD-1
Melanoma
Idelalisib
PI3K
CLL
Belinostat
HDAC
PTCL
Ceritinib
ALK
NSCLC
Siltuximab
IL-6
Castleman‘s disease
VEGF-R2
Gastric cancer; NSCLC
Ramucirumab
But the current emerging pharmaco-economic challenges are in earlier approvals
and in combinations!
Outline of my Talk
• Targeted Therapy for Cancer
• Challenges and Costs
• Another Example: Hepatitis C
• Approval Times for New Cancer Drugs
• Combination is Key – What are the Costs?
• Future Directions
Targeted Therapy: Combination Studies
Most striking example:
Malignant Melanoma
Metastatic Malignant Melanoma:
Immunotherapy
Targets:
DTIC:
Alkyting agent
Ipilimumab:
anti-CTLA-4
Nivolumab:
anti-PD-1
DTIC
Ipilimumab
Nivolumab
Ipi + Nivo
39.7
0
6
12
18
24
Median
OS
(months)
Metastatic Malignant Melanoma:
TKIs
DTIC
Targets:
Vemurafenib:
B-raf
Dabrafenib:
B-raf/MEK1,2
Trametinib:
MEK1,2
Vemurafenib
Dabrafenib
Trametinib
Not reached
Dab + Tra
0
6
12
18
24
Median
OS
(months)
Targeted Therapy in Melanoma
Breaking the Cost Barrier with Combinations
•
Trametinib (GSK):
MEK Inhibitor approved in 2013 (V600E-positive melanoma)
•
Dabrafenib (GSK):
BRAF Inhibitor approved in 2013 (V600E-positive melanoma)
•
Trametinib and Dabrafenib launched as monotherapy below the cost of vemurafenib at
$ 8500/$ 7985 per month versus $ 9400/month
•
In early 2014, FDA approved the agents as the first two to be found safe and effective
in combination
•
But, at a cost of $ 17,115/month
Outline of my Talk
• Targeted Therapy for Cancer
• Challenges and Costs
• Another Example: Hepatitis C
• Approval Times for New Cancer Drugs
• Combination is Key – What are the Costs?
• Future Directions
Making Early Drug Development More Efficient to
Control Research Risks and Costs
• More predictable (and reproducible) non-clinical models
• Use of validated biomarkers for staged risk management
- Proof of Mechanism (PoM) (target hit)
- Proof of Principle (PoP) (effect on disease, e.g., cell death markers)
- Proof of Concept (PoC) (clinical effect)
• Use of PK/PD to choose schedule early
- Moderate normal tissue toxicities
- Maximise pathway inhibition
- Maintain dose intensity
- Abrogate development of resistance
• Earlier investigation of combinations
• Inclusion of patients with earlier stages of disease
Making Late Stage Drug Development More Efficient to Control
Research Risks and Costs
• Risk sharing between companies
• Use of predictive biomarkers for patient selection
- Smaller, more focused phase 3 trials
- Potential need to screen many patients
- Decrease late stage failures
• NCI Innovative Clinical Trial Designs
- Identify biomarker signatures predicting response
- Graduate drug/biomarker pairs to smaller, more focused phase 3 trials
- Decrease late stage failures
• Explore utility of new cancer drugs in other indications and vice versa
Executive Summary
• We still do not know the optimal target for cancer treatment.
• Status: Approval time 7 years, costs $ 1.1 billion, success rate
< 20%.
• Combination is key – but might be “financially toxic”.
• Making cancer drug development more efficient is still a
challenge.
• Do not forget: In cancer care cost matters!