1. 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)
September 12th 2017

2. 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

3. Agenda
08:30 – 08:40
08:40 – 08:55
08:55 – 10:15
10:15 – 10:30
10:30 – 11:30
11:30 – 11:45
11:45 – 12:00
12:00 – 12:30 
Introducing by Adam Cohen
Short introduction BRAF inhibitor case and clarification of the assignment
Group work on assignments
Coffee and tea break
Group work on assignments (cont’d)
Presentation results 1st group
Presentation results 2nd group
Synthesis, what really happened and take home messages

4. It starts with the science and the understanding the molecular mechanisms
of disease

5. A clear Medical Need: Metastatic melanoma
20,000 patients diagnosed each year
Global incidence is on the rise at 3–5% per year
Poor prognosis
Fast disease progression (median PFS ~2 months)
About 50% of patients survive 8–10 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

6. Cell cycle progression and proliferation Protein synthesis and growth
Growth factor pathways in the heartland of cancer
Common Cancer Mutations
FasL
Ras
ERK
B-Raf
MEK
Cell cycle progression and proliferation
Cyclin D1
p85
p110a
PIP2 P
PIP3
PTEN
Bad
p27
Bcl-2
Survival
mTOR
Protein synthesis and growth
PI3K
AKT
Forkhead
TSC1
TSC2

7. Mutations Analysis
Jakob et al. Cancer 2011

8. Fitting Treatments to Patients Key steps to bringing new value for better, more predictable medicines
Understand heterogeneity of diseases
Discover and develop relevant biomarkers
Stratify patients with diagnostic tests
Build evidence for better benefit-risk ratio

9. Cell cycle progression and proliferation Protein synthesis and growth
B-Raf mutations stimulate cell growth
FasL
ERK P
B-Raf
MEK
Cell cycle progression and proliferation
Cyclin D1
p85
p110a
PIP2
PIP3
PTEN
Bad
p27
Bcl-2
Survival
mTOR
Protein synthesis and growth
PI3K
Forkhead
AKT
TSC1
TSC2
Ras

10. Cell cycle progression and proliferation Protein synthesis and growth
Zelboraf® (Vemurafenib) inhibits mutant B-Raf signaling
FasL
ERK P
B-Raf
MEK
Cell cycle progression and proliferation
Cyclin D1
p85
p110a
PIP2
PIP3
PTEN
Bad
p27
Bcl-2
Survival
mTOR
Protein synthesis and growth
PI3K
Forkhead
AKT
TSC1
TSC2
Ras

11. Before initiation of vemurafenib
About 50% of BRAF V600 mutated patients respond to vemurafenib…
Before initiation of vemurafenib
15 weeks on vemurafenib

12. Time since first dose (days)
Vemurafenib in metastatic melanoma patients Mutated BRAF vs non- mutated BRAF patients
% progression-free survival
Time since first dose (days)
100 90 80 70 60 50 40 30 20 10
120
180
240
300
360
420
480
540
600
BRAF V600E Mutant
BRAF wild type

14. Before initiation of vemurafenib
…However Relapse occurs Case study
Before initiation of vemurafenib
15 weeks on vemurafenib
23 weeks after therapy

15. Cell cycle progression and proliferation Protein synthesis and growth
Escape from B-Raf inhibition may be through activating C-Raf
B-Raf P
FasL
ERK
MEK
Cell cycle progression and proliferation
Cyclin D1
p85
p110a
PIP2
PIP3
PTEN
Bad
p27
Bcl-2
Survival
mTOR
Protein synthesis and growth
PI3K
Forkhead
AKT
TSC1
TSC2
Ras
C-Raf

16. Increasing Evidence that Inhibition of the MAPK Pathway at Different Levels is Needed to Prevent Relapse and Tumor Progression

17. 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

18. Competitive Landscape (at the time of development strategy decisions)
Bristol–Myers 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.
GlaxoSmithKline’s 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.

19. Questions to Address – Strategy Defining what to do and what not to do
Focus
Where will we focus? Where do we want to position our product?
What are we looking for? What is our target profile?
What are the key questions? Where do we want to be opportunistic?
Differentiators
How will we win, can we build on our current and / or our future strengths?
Take “outside-in” and “inside-out” perspectives
Staging
What are our main decision points? How do we manage risks?
What information do we need?
When, where and how aggressive shall we implement?
Economics
How much to invest where and expected returns?
What are our resources?
Does the added benefit justify adequate pricing?
Operations
How do we implement our strategy?
What is Insourced/ outsourced ? What is our internal core expertise ?
How do we reach alignment in the company and the support of major stakeholders, including Genentech and Diagnostics

20. 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)?

21. 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 Futurelab’s 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.

22. Wrap up and Take home messages Andreas Wallnoefer

23. What matters for R&D Productivity: People, science and focus on decision making
Ringel M. et al. Nature Reviews (12) 2013:

24. The vehicle should be tailored to journey and purpose
Different ways to reach the destination .… and to develop drugs
The vehicle should be tailored to journey and purpose

25. Phase II Study: Open-label, 132 patients, progressing disease after IL-2 or chemo confirmed positive Phase I exploratory results

26. Vemurafenib Phase III trial (BRIM III):
Active Controlledstudy vs Dacarbazine (83 patients crossed over)

28. Additional Clinical Benefit of Combined BRAF and MEK Inhibition: dabrafenib plus trametinib

29. Chronology - What Ultimately Happened

30. Treatment of Systemic Metastatic Melanoma Disease (stage IV) - ESMO Clinical Practice Guidelines Annals of Oncology 26 (Supplement 5): v126–v132, 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].

31. 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
Don’t 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