1. Cancer Drug Development in Industry:

2. 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

3. 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

4. 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: ,000 pts. per year

5. Cancer Treatment: Paradigm Shift
Chemotherapy,
Radiotherapy, Surgery
Targeted therapy
Unspecific targets
Specific targets
Reduction of
tumour mass
Inhibition of
tumour growth
Survival

6. Do we know the optimal target?
Proliferation
Metastasis
Angiogenesis
Apoptosis
Shc
Grb2
PI3-K
Sos-1
Ras
AKT
Raf
MEKK-1
MEK
mTOR
MKK-7
ERK
JNK

7. Do we know the optimal target?
Shc
Grb2
PI3-K
Sos-1
Ras
AKT
Raf
MEKK-1
MEK
mTOR
MKK-7
ERK
JNK

8. Sos-1
Ras
MEKK-1
MEK
Shc
PI3-K
Raf
MKK-7
Grb2
AKT
JNK
ERK

9. Where is the target? Sos-1 PI3-K Ras Grb2 Shc Raf MEK MEKK-1 JNK MKK-7
AKT
JNK
ERK

10. An Engineer’s Perspective…
EGF
EGFR

11. Do we know the Optimal Target?
NO – plain and simple!

12. 32 small molecules within 14 years!
2012
Axitinib
Pazopanib
Bosutinib
Ponatinib
Cabozantinib
Regorafenib
2005/06
Sorafenib
Sunitinib
Dasatinib
2014
Ceritinib
Ibrutinib
Idelalisib
2009
Everolimus
Pazopanib
2001
Imatinib
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

13. 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

14. The Challenges for the Global Industry
Of 4300 companies, 261 (6%) have registered a new cancer drug since 1950.
Patent expirations : 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 $ billion!

15. The Challenges for the Society (US)
Annual cancer care costs in the US are projected to rise from $ 104 billion in to $ 175 Billion in Germany (2014): € 15 Billion
The number of new cases of cancer will rise from 11.3 million in 2007 to million in Germany (2014): 450,000 pts.
The US spend for cancer drugs rose 400% from , largely driven by new biological agents.
Generic biologics will likely be costly.
The cost of drugs given in doctor‘s office rose 276% from while insurance increase was 47%.
A new cancer drug is ten times more likely to be prescribed for a patient in the US as compared to Europe.
The average US household budget for health care is the same as for food.

16. The Challenge for Germany
500
Cost
(Billion EURO)
Market Development
Cancer (15)
Dementia (50)
200
„NHS“
Diabetes (80)
2014
2035

17. 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
Nab-Paclitaxel
Tubulin
Pancreas
$ 80,000
Lenalidomide
IMID
Myeloma
Bortezomib
Proteasome
$ 60,000
Imatinib
acr-abl
CML
$ 70,000
Ofatumumab
CD-20
CLL
5-Fluorouracil TS
CRC
$ 300

18. The Cost-Effectiveness Plane

20. 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

21. Enter The Block Buster Hurricane Season
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 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

22. 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)

23. 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

24. 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

25. 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

26. Clinical And Approval Times By Therapeutic Class

27. Time For Development of Oncology Drugs

28. Crizotinib: Pathway from Compound Identification to FDA Approval
Crizotinib (XALKORI®): Targeting the ALK fusion gene, a direct driver of oncogenesis
Lead Com-pound
identified
Clinical testing begins
Discovery of EML4-ALK
fusion gene
First clinical responses
observed in ALK+ tumours
Phase 3 lung cancer trial initiated
ASCO plenary of expanded ALK+ cohort
NEJM publication of ALK+ cohort2
NDA, PMA Sub-
missions
XALKORI®, FISH test approvals
2005
2006
2007
2008
2009
2010
2011
Rapid Timeline from Compound Identification, Target Discovery and Clinical Results 28 28

29. 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
Ramucirumab
VEGF-R2
Gastric cancer; NSCLC
But the current emerging pharmaco-economic challenges are in earlier approvals and in combinations!

30. 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

31. Targeted Therapy: Combination Studies
Most striking example:
Malignant Melanoma

32. Metastatic Malignant Melanoma:
Immunotherapy
Targets:
DTIC:
Alkyting agent
Ipilimumab:
anti-CTLA-4
Nivolumab:
anti-PD-1
DTIC
Ipilimumab
Nivolumab
Ipi + Nivo
39.7
Median OS
(months) 6 12 18 24

33. Metastatic Malignant Melanoma:
TKIs
DTIC
Targets:
Vemurafenib:
B-raf
Dabrafenib:
B-raf/MEK1,2
Trametinib: MEK1,2
Vemurafenib
Dabrafenib
Trametinib
Dab + Tra
Not reached
Median OS
(months) 6 12 18 24

34. 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

35. 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

36. 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

37. 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
Explore utility of new cancer drugs in other indications and vice versa

38. 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!