Developing a BRAF Kinase Inhibitor: A case study

Developing a BRAF Kinase Inhibitor: A case study

Developing a BRAF Kinase Inhibitor: A case study of Personalized Health Care Andreas Wallnoefer General Partner BioMed Partners Life Science VC Ltd. Basel, Switzerland Former Head Clinical Research & Exploratory Development, Senior Vice President Roche Pharma Research & Early Development (pRED) June 5th 2018 Objectives of the Session Identify opportunities and limitations to translate molecular disease mechanisms into the clinics. When and how can the concept of Personalized Healthcare be pursued in drug development Apply the steps of strategy development Outline and assess development strategy options for the BRAF kinase inhibitor, including: Selection of the targeted patient population Management of time, costs and risks

Establishment of competitive positioning Extract case specific and general learnings Agenda 08:30 08:40 08:40 08:55 Introducing by Adam Cohen Short introduction BRAF inhibitor case and clarification of the assignment 08:55 11:00 Group work on assignments 11:00 11:15 11:15 11:30 11:30 11:45 11:45 12:00 Presentation results 1st group Presentation results 2nd group Presentation results 3rd group Presentation results 4th group 12:00 12:30

Synthesis, what really happened and take home messages Paul Janssen Futurelab Leiden 3 Groups Group 1: Laurien, Josine, Sam, Bas, Remco Group 2: Koen, Hein, James, Anneke, Tom Group 3: Rudiger, Osne, Anouk, Charlotte Group 4: Imre, Vincent, Juul, Deepak It starts with the science and the understanding the molecular mechanisms of disease A clear Medical Need: Metastatic melanoma 200,000 patients diagnosed each year

Global incidence is on the rise at 35% per year Poor prognosis Fast disease progression (median PFS ~2 months) About 50% of patients survive 810 months Fewer than 10% survive >5 years Amongst most common fatal cancers in young adults Primary risk factor UV/sun Limited effective treatment options (chemotherapy, radiotherapy, immunotherapies) and high toxicity. New therapeutic opportunities and progress due to introduction of immunomodulators and targeted tumor fingerprinting Growth factor pathways in the heartland of cancer Common Cancer Mutations PP PIP PIP22 PP PP PIP PIP33 PP

PP PTEN PTEN p110a p110a p85 p85 Ras Ras PI3K PP PP AKT AKT B-Raf B-Raf PP PP TSC1

TSC1 TSC2 TSC2 PP MEK MEK PP ERK ERK PP Cyclin Cyclin D1 D1 PP Forkhead Forkhead Cell Cellcycle cycle progression progressionand

and proliferation proliferation p27 p27 FasL FasL Bad Bad Bcl-2 Bcl-2 Survival Survival mTOR mTOR PP Protein Protein synthesis synthesisand and

growth growth Mutations Analysis Jakob et al. Cancer 2011 Fitting Treatments to Patients Key steps to bringing new value for better, more predictable medicines 1. Understand heterogeneity of diseases 2. Discover and develop relevant biomarkers 3. Stratify patients with diagnostic tests 4. Build evidence for better benefit-risk ratio B-Raf mutations stimulate cell growth

PP PIP PIP22 PP PP PIP PIP33 PP PP PTEN PTEN p110a p110a p85 p85 Ras Ras PI3K PP

PP AKT AKT B-Raf B-Raf PP PP TSC1 TSC1 TSC2 TSC2 PP MEK MEK PP ERK ERK

PP Cyclin Cyclin D1 D1 Forkhead Forkhead Cell Cell cycle cycle progression progression and and proliferation proliferation p27 p27 PP FasL FasL Bad Bad

Bcl-2 Bcl-2 Survival Survival PP mTOR mTOR Protein Protein synthesis synthesis and and growth growth Zelboraf (Vemurafenib) inhibits mutant B-Raf signaling PP PIP PIP22 PP

PP PIP PIP33 PP PP PTEN PTEN p110a p110a p85 p85 Ras Ras PI3K PP PP AKT AKT B-Raf

B-Raf PP PP TSC1 TSC1 TSC2 TSC2 PP MEK MEK PP ERK ERK PP Cyclin Cyclin D1 D1 Forkhead

Forkhead Cell Cell cycle cycle progression progression and and proliferation proliferation p27 p27 PP FasL FasL Bad Bad Bcl-2 Bcl-2 Survival Survival PP

mTOR mTOR Protein Protein synthesis synthesis and and growth growth About 50% of BRAF V600 mutated patients respond to vemurafenib Before initiation of vemurafenib 15 weeks on vemurafenib Vemurafenib in metastatic melanoma patients Mutated BRAF vs non- mutated BRAF patients % progression-free survival 100 90 BRAF V600E Mutant

80 BRAF wild type 70 60 50 40 30 20 10 0 60 120 180 240 300 360 420

Time since first dose (days) 480 540 600 However Relapse occurs Case study Before initiation of vemurafenib 15 weeks on vemurafenib 23 weeks after therapy Escape from B-Raf inhibition may be through activating C-Raf PP PIP PIP22 PP PP

PIP PIP33 PP PP PTEN PTEN p110a p110a p85 p85 Ras Ras PI3K PP PP AKT AKT B-Raf B-Raf

C-Raf PP PP TSC1 TSC1 TSC2 TSC2 PP MEK MEK PP ERK ERK PP Cyclin Cyclin D1 D1 Forkhead

Forkhead Cell Cell cycle cycle progression progression and and proliferation proliferation p27 p27 PP FasL FasL Bad Bad Bcl-2 Bcl-2 Survival Survival mTOR

mTOR PP Protein Protein synthesis synthesis and and growth growth Increasing Evidence that Inhibition of the MAPK Pathway at Different Levels is Needed to Prevent Relapse and Tumor Progression Core Elements of Business Performance Strategy is about making choices Business Acumen Understand the competitive dynamics of the industry Strategic Clarity Define the set of choices to make to compete: Where and how to win and to differentiate from competitors Execution Excellence Mobilize resources effectively to deliver the choices When executives call everything strategy they create confusion and undermine their own credibility

Don Hambrick and James Frederickson "Are you sure you have a strategy? Academy Management Executive 2005, 19: 51-62 Competitive Landscape (at the time of development strategy decisions) BristolMyers Squibb (BMS), in partnership with Exelixis were ready to enter Phase I with their compound XL-281. This molecule targets wild-type BRAF and CRAF as well as mutant V600E. GlaxoSmithKlines compound, on the other hand, was highly selective for V600E, and has already entered phase I. GSK had communicated that, the company is genotyping patients for the trial.. AstraZeneca was developing an inhibitor of MEK, which lies directly downstream from BRAF and is an alternative target in the BRAF pathway. The agent was entering phase II for melanoma. Mid 2009, the combined Roche/Genentech portfolio pipeline contained 3 MEK inhibitor molecules: one from Roche, one from Genentech and one from Chugai. an internal task force evaluated, which one of the molecules would be the best the portfolio also included a PI3K inhibitor another promising combination option, originating from the Genentech labs in San Francisco. Questions to Address Strategy Defining what to do and what not to do 1. 2.

3. Focus 4. Economics Where will we focus? Where do we want to position How much to invest where and expected our product? returns? What are we looking for? What is our target profile? What are our resources? What are the key questions? Where do we want to be Does the added benefit justify adequate opportunistic? pricing? Differentiators 5. Operations How will we win, can we build on our current and / or How do we implement our strategy? our future strengths? What is Insourced/ outsourced ? What is Take outside-in and inside-out perspectives our internal core expertise ?

Staging How do we reach alignment in the company and the support of major What are our main decision points? How do we stakeholders, including Genentech and manage risks? Diagnostics What information do we need? When, where and how aggressive shall we implement? Situation 2009 Project is at a Critical Point Questions to consider for the development strategy How could vemurafenib become the first BRAF kinase inhibitor on the market? How could the benefit / risk ratio be best assessed and demonstrated? How could the safety concerns regarding cutaneous squamous cell carcinoma be addressed and best managed? To what extent and how long could placebo controlled studies be justified?

What would be the position of IRBs and regulators? Should a broader group of melanoma patients be included? The recurrence of the disease and resistance to therapy was a concern. Which combination therapies should be envisaged and when should they be explored? How could the program be differentiated from competitors. When and at what intensity should other indications be pursued (thyroid or colorectal cancer)? Assignment

Prepare different strategic options to develop Vemurafenib to the market. Present the strategy , the outline of your plan options and your considerations. Take into account your internal environment and strengths and the external landscape (use inside out and outside in perspective). Assess your options for cost, time, and risks as well as for benefits for patients and for the company. Make recommendations and provide your rationale to the Futurelabs R&D Committee in 10 minutes. The scenarios should address the need to be first in class or best in class (or both) and to ensure best therapies for patients AND a sustainable strong market position for Roche / Genentech with Vemurafenib Follow the instructions in the briefing package, including the assumptions for trial recruitment. Use the IB as data source. Wrap up and Take home messages Andreas Wallnoefer What matters for R&D Productivity: People, science and focus on decision making Ringel M. et al. Nature Reviews (12) 2013: 901-902 Different ways to reach the destination . and to develop drugs The vehicle should be tailored to journey and

purpose Phase II Study: Open-label, 132 patients, progressing disease after IL-2 or chemo confirmed positive Phase I exploratory results Vemurafenib Phase III trial (BRIM III): Active Controlledstudy vs Dacarbazine (83 patients crossed over) NEW YORK TIMES SEPTEMBER 19, 2010 TARGET CANCER New Drugs Stir Debate on Rules of Clinical Trials Monica Almeida/The New York Times, left Two Cousins, Two Paths Thomas McLaughlin, left, was given a promising experimental drug to treat his lethal skin cancer in a medical trial; Brandon Ryan had to go without it. By AMY HARMON Published: September 18, 2010 Additional Clinical Benefit of Combined BRAF and MEK Inhibition: dabrafenib plus trametinib Chronology - What Ultimately Happened APPROVAL of MEK/ BRAF combination (GSK) trametinib /dabrafenib

(January 2014) BioMerieux Dx approved Flaherty et al 2012 Clinical MEKi /BRAFi combo 2015 Nov 2015 Roche FDA Vemurafenib + Cobimetinib 2014 Sept 2013 Roche initiation coBRIM Vemurafenib + Cobimetinib (MEKi) 2013 Vemurafenib APPROVAL Aug. 2011 Roche Dx approved APPROVAL of trametinib (Mekinist, GSK) Optimization of formulation to reach needed exposures Adaptive Resistance to RAF Inhibitors in Melanoma State of Science in 2018 becoming more complex

The number of effective treatment options has increased substantially. At the same time they have revealed multiple resistance mechanisms. 1. Re-setting of the ERK 1/2 pathway - 2. 3. ERK 1/2 rebound, RAS activation after BRAF inhibition, BRAF/CRAF heterodimer activation AKT activation after up-regulation of RTK De-regulation of metabolic processes Combinatorial trageting of ERK pathway and adaptive responses may increase the efficacy of current therapies - Need to identify biomarkers indicative of the adaptive processes Advent and synergies with immuno-oncology therapies such as checkpoint inhibitors Treatment of Systemic Metastatic Melanoma Disease (stage IV) - ESMO Clinical Practice Guidelines Annals of Oncology 26 (Supplement 5): v126v132, 2015

Patients with metastatic melanoma should have metastasis (preferably) or the primary tumour screened for detection of BRAFV600-mutation. Treatment options for the first- and second-line setting include anti-PD1 antibodies (pembrolizumab, nivolumab), an anti-CTLA4 antibody ipilimumab for all patients, and BRAF/MEK inhibitor combinations for patients with BRAF-mutant melanoma [II, B]. Take Home Messages Good understanding of disease mechanisms enhances successful translation into the clinics and rationale therapeutic regimens (e.g. combinations). Requires upfront investment in translational

research Cases of successful Personalized Healthcare approaches primarily in oncology. However, molecular mechanisms are for most diseases not (yet) understood. Companion diagnostic follows distinct approval process and needs to start early Investment in profiling and patient responder population, - even if it takes more time upfront - pays for success and speed of confirmatory program. Address key questions upfront Balance cost, risks and time and have clear decision points. Define benefits and be clear about differentiation options. Patients, physicians and payers are expecting that new medicines add relevant medical value in clinical practice. Filing does not yet mean reimbursement. Monitor competition. Define a clear strategy for differentiation and positioning.

Assess benefits of first in class and best in class strategies. Me too is mostly no go Dont become internally focused only. Keep critical outside in perspective. Success factors in R&D are good science, focus on decision making and competent people taking ownership

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