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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!