A WEALTH OF COMPOUNDS IN DEVELOPMENT IN ONCO-IMMUNOLOGY: HOPE FOR PATIENTS BUT A CHALLENGE FOR COMMERCIAL SUCCESS

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PROF DR WALTER VAN DYCK VLERICK HEALTHCARE MANAGEMENT CENTRE

1 A WEALTH OF COMPOUNDS IN DEVELOPMENT IN ONCO-IMMUNOLOGY: HOPE FOR PATIENTS BUT A CHALLENGE FOR COMMERCIAL SUCCESS PROF DR WALTER VAN DYCK VLERICK HEALTHCARE MANAGEMENT CENTRE FACULTY OF PHARMACEUTICAL SCIENCES, KU LEUVEN LEUVEN, JANUARY, 2018

2 DISCLOSURE INFORMATION PROF DR WALTER VAN DYCK I have the following financial relationships to disclose (other than public research funding sources Vlerick ARF used for research on machine learning methods and their use in pharmaco-epidemiological and economics real world contexts): Unconditional grants received from Roche under a Research Chair, from MSD under a Prime Foundation Partnership, from AstraZeneca under Contract Research, all on pharmaceutical market access policy research ( ) Unconditional grant received from Medtronic under a Prime Foundation Partnership and in collaboration with KU Leuven on value-based healthcare and medical technology assessment (2017 ) Co-founding scholar (with Isabelle Huys and Steven Simoens) of the KU Leuven Personalized Medicine Strategies Fund at the Faculty of Pharmaceutical sciences established by MSD, Janssen-Cilag, BMS, AstraZeneca, and Roche in October 2017.

3 THE CANCER DRUG PIPELINE IS NOT ONLY DELIVERING, IT S ALSO MOVING INTO A DISRUPTIVE TREATMENT PARADIGM: IMMUNOTHERAPY Source: QuintilesIMS Institute (2017), Understanding the Dynamics of Drug Expenditure. Shares, Levels, Compositions and Drivers

4 IO IS CONSIDERED TO BE VALUABLE INNOVATION* Breakthrough appeal of the systemic nature of immunotherapy, following on to the now dominantly known targeted therapies Considered to be valuable innovation i.e. No existing treatment present In areas of true Unmet Need Hence to which patients should be given early access in early entry agreements Art 81 However, advances in cancer treatment should be seen as incremental, as opposed to the revolutionary spin often given to breakthrough treatments being able to cure *Findings of a July 2015 round table organized by the Belgian Parliament on Immunotherapies

5 THE CANCER IMMUNOTHERAPY MARKET > $13 BN IN 2023, WHICH SALES WILL BE DOMINATED BY ICI. DECISION RESOURCES GROUP IN JUNE 2015 The European Expert Group on Immuno-Oncology, 2014

6 CANCER IMMUNOTHERAPY OFFERS THE POSSIBILITY FOR LONG-TERM CONTROL OF CANCER Immune Checkpoint Inhibitors (ICI) are antibodies that re-establish the immune system s capacity to attack a tumor ICIs block pathways used by tumors to inhibit anti-tumor immunity Immunotherapy can train the immune system to remember cancer cells. This immunomemory may result in longer-lasting and potentially permanent protection against cancer recurrence. Clinical studies on long-term overall survival have shown that the beneficial responses to cancer immunotherapy treatment are durable that is, they can be maintained even after treatment is completed.

8 WHAT IS EXCITING ABOUT IMMUNOTHERAPIES? They may offer the potential for long-term quality survival to a number of patients for whom treatment options were previously very limited. Adapted from: Ribas et al (2012)

9 WHY THE ENTHUSIASM FOR IMMUNOTHERAPY?

10 WITH PD-1 IO IMMUNOTHERAPY A BETTER QOL IN SQUAMOUS NSCLC

11 TREND: IO IS NOWHERE NEAR ITS POTENTIAL CLINICAL AND COMMERCIAL PEAK Waves of new therapies and classes building upon each other, with combinations amplifying wave magnitudes: drug discovery is an evolutionary process (2015)

12 THE CANCER IMMUNOTHERAPY OR IMMUNE CHECKPOINT INHIBITORS (ICI) INNOVATION RACE 1990s Late 1990s May 2014 Oct 2014 Dec 2014 Feb 2015 UC Berkeley: Allison Patent Estate anti CTLA-4 Kyoto University/ Prof Tasuku Hojo: anti-pd-1 Harvard & dana Farber: Freeman & Sharpe anti-pd-1 Dr Chen Mayo Clinic anti-pd-l1 Medarex MDX-010 Sublicensed from Gilead BMS + Ono Pharmaceuticals (2009) ipilimuab (Yervoy) Ind.: unresectable or metastatic melanoma, Pfizer (2008) tremelimuab Ind.: adv. melanoma, Discontinued 2008 AstraZeneca (2011) tremelimuab Ind.: adv. melanoma Roche/Genetech atezolizumab (Tecentriq) Ind.: FDA Breakthrough May 2014 Bladder Merck (Sep 2014) pembrolizumab (Keytruda) Remark: No binary Ind.: sep 2014 FDA Breakthrough response in PD-L1-neg. for EGFR-, ALK- following chemo tumours adv. Melanoma Oct 2014 NSCLC BMS + Ono Pharmaceuticals (Dec 2014) nivolumab (Opdivo) Ind.: FDA Breakthrough melanoma Roche/Genetech atezolizumab (Tecentriq) Ind.: FDA Breakthrough feb 2015 Lung NSCLC XXX anti-cd-19

13 A WEALTH OF NEW ANTIBODY DRUGS IN CLINICAL TRIALS Anti-PD-1 Nivolumab(Opdivo, BMS) Pembrolizumab(Keytruda, Merck) MEDI-0680 (AstraZeneca) PDR001 (Novartis) REGN2810 (Regeneron) BGB-A317 (BeiGene) Anti-PD-L1 Atezolimumab(Tecentriq, Roche) Durvalumab(Imfinzi, AstraZeneca) Avelumab(Bavencio, EMD Serono/Pfizer) MDX-1105 (BMS) 50 agents in clinical trials, 80 under development in China

14 HOWEVER COMPLEX BIOMARKER SIGNATURES FOR CANCER IMMUNOTHERAPIES ARE LIKELY TO EMERGE PD-L1 expression on the tumor alone is not a good enough biomarker Need biomarkers that help to identify patients who are most likely to respond to a given treatment, and least likely to experience side effects. Freeman, G. in Science Webinar, 16 Jan 2018

15 THE WAY FORWARD IN THE INNOVATION RACE: COMBINATION THERAPIES

16 THE FUTURE IS COMBINATION IMMUNOTHERAPY Hodi, SITC 2017

17 TREND: EXPECTED COMBINATIONS OF TARGETED AND IO- AGENTS IMPROVING OUTCOMES BUT COMPLICATING TRIAL & COMMERCIALIZATION STRATEGIES (2015)

18 THE PHARMACOECONOMICS OF COMBINATION THERAPIES Durkee et al. (2016) Journal of Clinical Oncology

19 CAR-T: TALKING ABOUT EXPENSIVE THERAPIES

BE PAYER VIEW: IO THERAPIES ACCOUNT FOR HALF OF THE PROSPECTIVE CANCER

budget of therapies on the market or in development (m ) 2 Immunotherapies

Targeted therapies (52%) 217 Ph2 3 targeted therapy Marketed targeted

21 BE PAYER VIEW: IO THERAPIES ACCOUNT FOR HALF OF THE PROSPECTIVE CANCER THERAPY BUDGET # of therapies on the market or in development Prospective budget of therapies on the market or in development (m ) 2 Immunotherapies (31%) 53 Immunotherapies (48%) Targeted therapies 69% 18 Targeted therapies (52%) 217 Ph2 3 targeted therapy Marketed targeted therapy Ph2 3 immunotherapy Marketed immunotherapy Source: Vlerick HMC and NIHDI analysis, Jan 2016

22 HOUSTON, WE DO HAVE A PROBLEM A SURGE IN BUDGET WILL BE NEEDED TO FUND A DELIVERING CANCER THERAPEUTIC PIPELINE Figure 19: (a) 2020 projection of innovative cancer therapies defined as targeted therapies and immunotherapies as part of the overall Belgian pharmaceutical specialties budget for oncology;

OVER THE COMING 5 YEARS ONLY 24% OF PROJECTED CANCER THERAPEUTIC INNOVATION CAN BE FUNDED BY MECHANISTIC PRICE REDUCTIONS Figure 21: 2020 projection of funding released through expected mechanistic

23 OVER THE COMING 5 YEARS ONLY 24% OF PROJECTED CANCER THERAPEUTIC INNOVATION CAN BE FUNDED BY MECHANISTIC PRICE REDUCTIONS Figure 21: 2020 projection of funding released through expected mechanistic price cuts in Belgium and the expected sales from novel targeted therapies and immunotherapies. The total price reductions over these 5 years can fund 24% of the projected therapeutic innovation. (Source: Vlerick HMC Analysis)

24 OUR MOST RECENT ANALYSIS OF CTG DECISIONS PERIOD : BUDGET IMPACT AND THERAPEUTIC INNOVATION DRIVE DECISION MAKING NOT THE ICER BI and disease category are significant factors considered in decision making SMR or clinical evidence plays a role for positive and negative decisions Therapeutic differentiation (ASMR) plays a role but is probably illdefined Class 1 P(neg)>p(pos) if BI > 3 mio P(neg)>p(pos) if ICER> 31K/QALY P(Art81) raises with population DALY P(Art81) raises with BI Orphan P(pos) decreases with increasing BI P(pos) raises with population DALY P(Art81) raises with BI

25 DEFINING ADDED THERAPEUTIC VALUE IN AN INDICATION ATV Transversal or non-siloed budgeting ATV = NMB(i,j) = i * Q j - Cost j, HC system Added Therapeutic Value Net Monetary Benefit Willingness To Pay Added value vs comparator i = indication j = medicine Unmet Medical Need On market Under RWE investigation Competitive comparative effectiveness

26 Benefits NEGOTIATIONS SHOULD BE DRIVEN BY ATV, BI AND PERFORMANCE-BASED MARKET ENTRY AGREEMENTS ATV > EF yes uncertain no BI high low MEA Financial AIV EF MEA Negotiate Added Innovative Value Efficiency Frontier Managed Entry Agreement MEA Total cost MEA Outcome based EF price

27 GIVEN CURRENT DEMONSTRATED EFFECTIVENESS, COMPANIES SHOULD BE PREPARED TO NEGOTIATE PAY-FOR-PERFORMANCE SCHEMES Level of Real Outcome based on Innovation Level of Regulated Competition

PFP IS FEASIBLE IF A RWE INFRASTRUCTURE CAN BE SET UP AND A BIOMARKER SIGNATURE FOR RESPONSE IS DEFINED Comparison of modeled survival estimates with available ipilimumab data Estimated survival

28 PFP IS FEASIBLE IF A RWE INFRASTRUCTURE CAN BE SET UP AND A BIOMARKER SIGNATURE FOR RESPONSE IS DEFINED Comparison of modeled survival estimates with available ipilimumab data Estimated survival curves for ipilimumab using three-part curve fit Ipilimumab Modelled Pooled ipilimumab trial data (n: 1861) Prieto protocol 1n = 56 Larkin J1, Hatswell AJ2, Nathan P3, Lebmeier M4, Lee D. (2015) The Predicted Impact of Ipilimumab Usage on Survival in Previously Treated Advanced or Metastatic Melanoma in the UK. PLoS One. 10(12):e doi: /journal.pone

29 ADVANCED ANALYTICAL TECHNIQUES LIKE MACHINE LEARNING TO UNDERSTAND THE COMPLEX BIOMARKER SIGNATURE USING RWE: A PREREQUISITE FOR PFP CONTRACTS? Geldof, T, Huys, I, Van Damme, N. & W. Van Dyck, (2018) unpublished WIP, not to be cited

30 PLAY THE INCREASINGLY COMPETITION- AND VALUE- BASED MARKET ACCESS-BASED SYSTEM TO EVENTUALLY LEAD THE IO R&D RACE Move in early in areas of high unmet need Understand complex biomarker signature Build a portfolio to expand into other indications

31 THINK OCCAM'S RAZOR

32 THANK YOU!

Cancer Immunotherapy Survey

CHAPTER 8: Cancer Immunotherapy Survey All (N=100) Please classify your organization. Academic lab or center Small biopharmaceutical company Top 20 Pharma Mid-size pharma Diagnostics company Other (please