Discovering Breakthrough Treatments for Human Disease. Discovering Breakthrough Treatments for Human Disease

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1 Patient Reported Outcomes in Oncology Trials Pablo Lapuerta, MD Executive Vice President and Chief Medical Officer Discovering Breakthrough Treatments for Human Disease Discovering Breakthrough Treatments for Human Disease 2015 Lexicon Pharmaceuticals, Inc. Slide 0

2 Patient Reported Outcomes: A Personal Story 2015 Lexicon Pharmaceuticals, Inc. Slide 1

3 A Personal Story A family member participated in a clinical trial of cetuximab With complete response of stage IV adenocarcinoma of the lung There was extensive improvement - Better mood - More energy - Increased optimism - Good overall survival There was no change in patient reported outcomes! 2015 Lexicon Pharmaceuticals, Inc. Slide 2

4 Cetuximab with Chemotherapy in Lung Cancer No significant difference in quality of life between the two treatment arms was reported by the two relevant studies. The quality of the evidence is high for overall survival and one-year survival rate, but low for most secondary outcomes. Yang ZY et al. Cochrane Database Syst Rev Nov 17;11:CD doi: / CD pub Lexicon Pharmaceuticals, Inc. Slide 3

5 Why are Quality of Life Benefits Not Detected? The most common approach to questionnaire development is to be as comprehensive as possible However, this introduces a lot of items that will not be relevant to many patients and may not respond to effective treatment Moreover, grading is often on abbreviated scales that only capture large changes - Moderate vs. severe A general tendency is to provide equal weighting to all questions, even though one or two domains may be the most important 2015 Lexicon Pharmaceuticals, Inc. Slide 4

6 Example: the FACT-L Questionnaire 2015 Lexicon Pharmaceuticals, Inc. Slide 5

7 Additional Questions: The FACT-L 2015 Lexicon Pharmaceuticals, Inc. Slide 6

8 Where Should we Focus? An important aspect of cancer treatment is emotional well-being - Although this is complicated by many issues unrelated to treatment, even temporary success in the fight against cancer is meaningful to patients Success may manifest itself in satisfaction measures or overall global assessments 2015 Lexicon Pharmaceuticals, Inc. Slide 7

9 Relevant Questions from the FACT-L 2015 Lexicon Pharmaceuticals, Inc. Slide 8

10 Key Lessons A comprehensive questionnaire may include a lot of information unrelated to the intervention in a clinical trial Understanding patient priorities (the most relevant domains) can help appreciate benefit Emotional well-being may be particularly important - Although more work is needed to understand specifically how it relates to the fight against cancer - Measures of patient satisfaction or global assessments of the clinical trial experience may be helpful 2015 Lexicon Pharmaceuticals, Inc. Slide 9

11 A Potential Option: Patient Interviews A comprehensive questionnaire aims to quantify quality of life - The patient becomes a number Semi-structured interviews are less quantitative in nature but may be more informative - Knowing patient priorities - Understanding how symptoms are connected to each other - Appreciating their view of benefit/risk - Developing a vision of clinically meaningful change Listen to the voice of the patient 2015 Lexicon Pharmaceuticals, Inc. Slide 10

12 Quality of Life as a Story Rather than a Statistic A typical approach in patient reported outcomes research is to apply an instrument and develop an overall score This approach has significant limitations - You might select the wrong instrument - You could rely too much on a p-value to make conclusions - It may be difficult to interpret clinically meaningful change - You may not learn about the relationships between symptoms 2015 Lexicon Pharmaceuticals, Inc. Slide 11

13 Quality of Life as a Story Consider conducting semi-structured interviews in your clinical trial - Let the patients tell their stories - Have an expert guide the discussion, ensuring that broad domains are addressed - Read the transcripts or watch the videos - Gain a better clinical understanding of the trial experience 2015 Lexicon Pharmaceuticals, Inc. Slide 12

14 Example: Development of Telotristat Etiprate Telotristat etiprate is an investigational agent being developed for the treatment of carcinoid syndrome Carcinoid syndrome is the result of excessive serotonin production by metastatic neuroendocrine tumors - Diarrhea, abdominal pain - Facial flushing - Destruction of heart valves - Fibrosis in the abdomen Telotristat etiprate is intended to treat carcinoid syndrome by reducing serotonin production within the cancer cell 2015 Lexicon Pharmaceuticals, Inc. Slide 13

15 Telotristat Etiprate Phase 2 Results: Reduction in Bowel Movement Frequency Kulke et al. Endocr Relat Cancer Oct;21(5): Lexicon Pharmaceuticals, Inc. Slide 14

16 Telotristat Etiprate Phase 2 Patient Interviews 11 patients interviewed Gastrointestinal symptoms affected their everyday lives - Sleep -Fatigue - Function Ability to socialize, travel, or participate in usual activities or hobbies Improvements reported for several symptoms - Diarrhea (n=9) - Abdominal pain (n=5) - Abdominal cramping (n=4) - Facial flushing (n=4) -Gas (n=3) There was no worsening of symptoms Kulke et al Lexicon Pharmaceuticals, Inc. Slide 15

17 Telotristat Etiprate Phase 2 Individual Response # Bowel Movements Flushing Episodes Day -4 Day -3 Day -2 Day -1 Day 1 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 12 Day 13 Day 14 Day 15 Day 17 Day 18 Day 19 Day 20 Day 21 Day 22 Day 23 Day 24 Day 25 Day 26 Day 27 Day 28 Baseline Drug Initiation Drug Discontinued Drug Reinstated Lapuerta et al. Clinical Investigation 2015;5(5): Lexicon Pharmaceuticals, Inc. Slide 16

18 Individual Patient Interview #1 Extensive detail provided - Pleased with the initial response - Concerned about temporary interruption of therapy - Relieved to resume drug She provided a perspective on several important themes - Clinically meaningful change - Overall magnitude of potential response - Impact of symptom relief on other domains 2015 Lexicon Pharmaceuticals, Inc. Slide 17

19 Telotristat Etiprate Phase 2: Individual Response #2 10 Mean Number of BM Baseline WEEK RUN-IN Dose (mg tid) Adequate Relief No No No No Yes 2015 Lexicon Pharmaceuticals, Inc. Slide 18

20 Individual Patient Interview #2 Improvement in several symptoms - Gastrointestinal symptoms - Night sweats - Emotional well-being He provided a perspective on several themes - Social function - How a reduction in bowel movement frequency may relate to absorption of food and medication 2015 Lexicon Pharmaceuticals, Inc. Slide 19

Telotristat Etiprate Phase 3 Program: TELESTAR Stable-dose

mg TID + SSA Telotristat etiprate 250mg TID + SSA

SSA 3 to 4 week Run-In *1 week blinded titration period

Enrollment Criteria: Carcinoid Syndrome with > 4 Bowel

21 Telotristat Etiprate Phase 3 Program: TELESTAR Stable-dose somatostatin analog (SSA) R 1:1:1 Telotristat etiprate 500 mg TID + SSA Telotristat etiprate 250mg TID + SSA Telotristat etiprate 500mg TID + SSA (n=~120) Placebo TID + SSA 3 to 4 week Run-In *1 week blinded titration period 12-week treatment period* 36-week extension* (Open-label) Enrollment Criteria: Carcinoid Syndrome with > 4 Bowel movements/day Patient Interviews 2015 Lexicon Pharmaceuticals, Inc. Slide 20

22 Relevance of Interviews to Clinical Development Selection of patient reported outcomes for phase 3 - Question on sleep - Global assessments Planning additional interviews in phase 3 - Understanding unmet need - Providing perspective on primary endpoint - Directing focus to specific items of EORTC questionnaire - Supporting vision of clinically meaningful change Appreciating benefit/risk 2015 Lexicon Pharmaceuticals, Inc. Slide 21

23 Limitations of the Interview Approach Sample size is small Statistical interpretation may be limited Publication opportunities are unclear Unlikely to make a direct contribution to drug labeling 2015 Lexicon Pharmaceuticals, Inc. Slide 22

24 Conclusions Quality of life should be a story and not just a statistic - A more profound understanding can come from a detailed examination of different items and individual cases Focus on specific domains most likely to respond to therapy Consider global assessment of therapy Consider semi-structured interviews Listen to the voice of the patient 2015 Lexicon Pharmaceuticals, Inc. Slide 23

Clinical Development in the Treatment of Carcinoid Syndrome. Pablo Lapuerta, MD Executive Vice President and Chief Medical Officer

Clinical Development in the Treatment of Carcinoid Syndrome Pablo Lapuerta, MD Executive Vice President and Chief Medical Officer Carcinoid Syndrome Heart Pulmonic and tricuspid valve thickening Stenosis