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

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.

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?

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):115-30.

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

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):2189-208. 2. Galie et al. Eur respir J. 2015;46(4):903-75. 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.

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

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

Transplant free survival according to number of non-invasive low-risk criteria achieved at first re-evaluation Reference: Boucly et al. 2017. Eur Resp J

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)

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

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

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

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

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, 2008. 8: p. 76. Example from: Ryan M, Bate A, Eastmond CJ, Ludbrook A. 2001. Use of discreet choice experiments to elicit preferences. Qual Health Care. 10 suppl 1:i55–i60

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 150-200 patients available to take part Alternatively, a BWS design can be used with fewer patients, so would be used if 75-150 patients are available to take part

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

Thank you.

Back up slides

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

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)

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. 2017. Eur Resp J