1. Joint BES/BBS Seminar Sequential vs initial combination therapy in a rare disease Presenter: Evan Davies 22nd November 2018

2. Disclosure/Disclaimer
The presenter is a permanent employee of Actelion Pharmaceuticals Ltd.
Views or opinions expressed here are those of the presenter, and should not be taken to reflect views or opinions of Actelion or the Janssen group of pharmaceutical companies.

3. Early planning for implementation
Considerations to cover
Disease area
Current treatment options
What is the decision problem?
How could a preference study help?
What are the key methods considerations?

4. PULMONARY ARTERIAL HYPERTENSION (PAH) IS A PROGRESSIVE AND FATAL DISEASE OF THE PULMONARY VASCULATURE1
In PAH, blood vessels gradually narrow, resulting in the obstruction of blood flow, and increasing the workload of the right ventricle1
These changes will result in right ventricular dysfunction and ultimately right-sided heart failure and death1
NORMAL
PAH
Vascular lesions occluding the vessel
Loss of the pulmonary vasculature
Right ventricular dilation and dysfunction
Adapted from Lai et al, 20141
Common symptoms include: shortness of breath, chest pain, fainting, dizziness, tiredness, swelling in stomach and ankles
References: Lai et al. Circ Res. 2014;115(1):

5. Reference: 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

6. CURRENT PAH TREATMENTS TARGET THREE PATHOLOGICAL PATHWAYS
NITRIC OXIDE PATHWAY
ENDOTHELIAL PATHWAY
ET-1
ETA
ETB
Pro-endothelin-1
ERAs
Ambrisentan
Bosentan
Macitentan
Dual ERA
Single ERA
PROSTACYCLIN PATHWAY
L-arginine
Arachidonic Acid
ENDOTHELIAL LAYER NO
Exogenous NO
PGI2
sGC stimulator
PDE-5 inhibitors
IP receptor
sGC
PDE-5
SMOOTH MUSCLE LAYER
cAMP
GTP cGMP GMP
Synthetic prostacyclin
PGI2 analogues
Non-prostanoid IP receptor agonist
PDE-5 inhibitors
Sildenafil
Tadalafil
sGC stimulator
Riociguat
PGI2 analogues
IP receptor agonists
Epoprostenol
Selexipag
Iloprost
Beraprost
Treprostinil
References: 1. Humbert et al. Circulation. 2014;130(24): Galie et al. Eur respir J. 2015;46(4):
Abbreviations: cAMP, cyclic adenosine monophosphate; ERA, endothelin receptor antagonist; ET, endothelin; (c)GMP, (cyclic) guanosine monophosphate; GTP, guanosine triphosphate; IP receptor, prostacyclin receptor; NO, nitric oxide; PDE-5, phosphodiesterase 5; PGI2, prostacyclin; sGC, soluble guanylate cyclase.

7. Treatment algorithm Treatment goal is to prevent disease progression
Reference: 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

8. Risk stratification for progression
Treatment goals can be categorised into different risk categories from low to intermediate to high risk.
Risk stratification is important as the number of low risk attributes can affect disease progression and therefore overall survival.
Here we are focusing for the time being on three criteria that can be assessed non-invasively – NYHA/WHO functional class (which describes severity of disease and can be thought of for now as the level of limitations experienced by a patient from no physical limitations in functional class I to severe limitations e.g., dyspnoea at rest in functional class IV), 6 minute walk distance (which is how many metres a patient can walk in 6 minutes), and NT- proBNP (a hormone produced in response to pressure changes in the heart which can be measured with a simple blood test)
Reference: 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

9. Transplant free survival according to number of non-invasive low-risk criteria achieved at first re-evaluation
Reference: Boucly et al Eur Resp J

10. Benefits vs risks consideration
Examples of treatment related risks
Drug related AEs
Headache
Diarrhea
Jaw pain
Nausea
Myalgia
Vomiting
Pain in extremity
Arthralgia
Liver toxicity
Examples of benefits
Functional Class
6MWD
NT-proBNP
Symptoms (e.g., dyspnoea, fainting, chest pain)

11. What is the decision problem?
And how can a patient preference study help
Decision problem is related to:
Different treatments and strategies
Relative benefits and risks associated with different treatments and strategies
A patient preference study can help to inform us on the risks patients are willing to accept to obtain benefits

12. Audience for preference research in PAH
Preference for Treatment strategies – initial vs sequential combination
Medical community - How do clinicians make decisions?
Doctors use their medical expertise to treat an individual patient – they will know what to do when they see the patient
Knowing about patient preference could support personalized treatment strategies, for example:
a young patient who is caring for a child might be more likely to accept a higher risk to gain a longer progression free survival
an older patient might wish to have managed the symptoms of the disease with less side effects, while not putting as much importance on extended progression free survival
Patients - will this study help patients?
Information about treatment preferences could help patients and patient organisations become more aware of the potential treatment options and relative preferences of other patients in their situation
HTA bodies/payers - Can this study support decision making?
This study could help to inform HTA bodies or payers of what preference weights are assigned to different treatment attributes

13. Methods considerations
Stated preference methods can be used to quantify preferences in health economics, health technology assessment, benefit-risk analysis, and health services research.
The objective of stated-preference studies is to acquire information about:
trade-off preferences among treatment outcomes,
prioritization of clinical decision criteria,
likely uptake or adherence to health care products and acceptability of healthcare services or policies
In the case of the proposed study we would aim to assess patient preferences related to treatment outcomes related to different treatment strategies, treatment safety and tolerability associated with treatment strategies, and other potential factors that affect patient well being

14. Methods considerations cont.
Identification of a descriptive system
Attributes and Levels
Attributes for decision criteria need to be identified
These could incorporate elements of benefits and risks presented above, but a lot of additional work needs to be accomplished based not only on known clinical data but also review of the literature
Attribute levels need to be identified
Should encompass full range over which patients are likely to have well-defined preferences
Should encompass the relevant range of clinical and non-clinical attributes
Interviews with clinical experts and patients can be conducted to ensure attribute and level appropriateness

15. Methods considerations cont.
Method of assessment
Among the available techniques, best-worst scaling (BWS) and discrete choice experiments (DCE) provide the richest information regarding trade-offs individuals are willing to make among the topics of interest in the proposed study
Example from: Flynn, T.N., J.J. Louviere, T.J. Peters, and J. Coast, Estimating preferences for a dermatology consultation using Best-Worst Scaling: comparison of various methods of analysis. BMC Med Res Methodol, : p. 76.
Example from: Ryan M, Bate A, Eastmond CJ, Ludbrook A Use of discreet choice experiments to elicit preferences. Qual Health Care. 10 suppl 1:i55–i60

16. Methods considerations cont.
PAH is a rare disease so recruitment could be difficult
Which methods are feasible is also dependent on the number of patients available
A DCE design can be used if there are approximately patients available to take part
Alternatively, a BWS design can be used with fewer patients, so would be used if patients are available to take part

17. Next steps Move to project implementation
Research and develop draft attributes and levels
Determine most appropriate method for assessing preferences

18. Thank you.

19. Back up slides

20. Estimated proportion of patients who are free of any M/M event up to 3 years in the SERAPHIN trial1
Monotherapy
PDE-5 inhibitor
Combination therapy
ERA+ PDE-5 inhibitor
Patients without an event
(Kaplan-Meier estimate)
Time from treatment start (years)
100% 0%
80%
60%
40%
20% 2 3 1

21. Patients without an Event (%)
Estimated proportion of patients who are free of any M/M event up to 3 years in the Griphon trial
100 80 60 40 20
Patients without an Event (%)
Time (years) 2 3 1
PLACEBO+SoC
UPTRAVI®+SoC
Time to first confirmed M/M event up to EOT+7 days1
HR 0.60 (99% CI; 0.46, 0.78; p<0.001)
UPTRAVI® + SoC (n=574)
Placebo + SoC (n=582)

22. Transplant free survival according to number of non invasive low risk criteria at first re-evaluation
Low risk criteria analysed:
WHO/NYHA Functional class 1-2
6MWD >440m
- BNP <50 ng/l or NT-proBNP <300 ng/ml
Reference: Boucly et al Eur Resp J