Santhera Pharmaceuticals Holding AG · SIX:SANN

Santhera Pharmaceuticals — Technical Presentation (October 2014)

35 slides from Santhera Pharmaceuticals's technical presentation, Oct 15, 2014

  1. Slide 1: PPMD Webinar: Efficacy of Catena/Raxone (Idebenone) on Respiratory Outcome in Duchenne

    PPMD Webinar for the patient community Efficacy of Catena®/Raxone® (Idebenone) on Respiratory Outcome in Duchenne 15 October 2014

  2. Slide 2: Disclaimer

    2 Disclaimer This presentation is not and under no circumstances to be construed as a solicitation, offer, or recommendation, to buy or sell securities issued by Santhera Pharmaceuticals Holding AG. Santhera Pharmaceuticals Holding AG makes no representation (either express or implied) that the info

  3. Slide 3: Speakers

    Speakers Gunnar M Buyse, MD PhD Child Neurology, University Hospitals Leuven & KU Leuven, Leuven, Belgium [email protected] Professor Dr. Buyse is child neurologist and full professor of medicine. He is the principal investigator of the Phase 2 and Phase 3 studies with idebenone in DMD. Thoma

  4. Slide 4: Agenda

    Agenda  The medical need: respiratory illness in DMD  Idebenone (Catena®/Raxone®) as a novel therapeutic approach for DMD • rationale, hypothesis • preclinical study (mdx mouse), phase 2 trial (DELPHI)  Phase 3 study (DELOS): efficacy & safety of Idebenone in DMD  Summary  Q&A Session 4

  5. Slide 5: Respiratory illness in DMD

    Respiratory illness in DMD  Progressive weakness of respiratory muscles leads to restrictive pulmonary disease followed by respiratory failure  Glucocorticosteroids delay onset/progression of respiratory dysfunction. • risks/side effect profile; not all respond (to same extent)  Respiratory illne

  6. Slide 6: PEF and FVC as markers of respiratory function decline in DMD

    PEF and FVC as markers of respiratory function decline in DMD  In DMD weakness of respiratory muscle Expiratory Flow leads to restrictive pulmonary syndrome PEF FVC  In the absence of bronchial obstruction PEF reflects expiratory muscle strength and inspiratory effort 1,2  In DMD PEF is considere

  7. Slide 7: Decline in respiratory function in DMD

    Decline in respiratory function in DMD Clinical data demonstrate early onset and progressive decline in respiratory function. Patients treated with steroids experience slower decline. *Henricson E. et al. (2013) Muscle Nerve 48: 55-67 7

  8. Slide 8: Idebenone as a novel therapeutic approach for DMD - mechanism

    Idebenone as a novel therapeutic approach for DMD - mechanism  2-(10-hydroxy-decyl)-5,6-dimethoxy-3-methyl-[1,4] benzoquinone (Idebenone)  Dual mode of action: reduces oxidative stress /inhibits lipid peroxidation, enhances mitochondrial respiratory chain function (electron transfer, ATP levels) 1

  9. Slide 9: Rationale for use of Idebenone in DMD

    Rationale for use of Idebenone in DMD dystrophin Abnl Ca2+  Oxid [Ca2+] i  [Ca2+] mit  deficiency handling Phosphoryl DMD: cascade of cellular Ox radicals  ATP pathology apoptosis generation production • mitochondrial dysfunction • reduced oxidative phosphorylation • impaired energy (ATP) produc

  10. Slide 10: Idebenone as a novel therapeutic approach - preclinical (animal)

    Idebenone as a novel therapeutic approach for DMD - preclinical (animal) strategy:  observer-blinded, placebo-controlled animal (mdx) trial  EARLY-initiated, VERY long-term therapy  most profound outcome assessment methods 10

  11. Slide 11: Idebenone as a novel therapeutic approach - phase 2 study (DELPHI)

    Idebenone as a novel therapeutic approach for DMD - phase 2 study  Phase 2 study (DELPHI): proof-of-concept, age 8-16 yrs PEF%p (DELPHI) indicated larger effect size for PEF%p (and FVC%p) in patients not treated with concomitant steroids Buyse GM et al: Neuromusc Disord. 2011;21:396-405 Buyse GM et

  12. Slide 12: Phase 3 DELOS trial - patients and treatment

    Phase 3 DELOS trial – patients and treatment Primary Objective: To assess the efficacy of Idebenone, compared to placebo, in improving or delaying the loss of respiratory function Method: Phase 3, multicenter international RCT (Europe, USA) Patients: Randomized treatment:  64 patients randomized an

  13. Slide 13: DELOS Study Group

    DELOS Study Group Leuven, Belgium: GM Buyse (Study PI), N Goemans, M van den Hauwe Paris, France: T Voit, V Doppler, T Gidaro Essen, Germany: U Schara, S Lutz Leiden, the Netherlands: JGM Verschuuren, CSM Straathof Lecco, Italy: MGN D’Angelo, E Brighina, S Gandossini Wien, Austria: G. Bernert, F. Kn

  14. Slide 14: DELOS Study - Design & Dosing

    DELOS Study – Design & Dosing Visit 1 Visit 7 Screening Baseline Week 56 Safety & Efficacy Assessments Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Week 4 Week 13 Week 26 Week 39 Week 52 Test item: RAXONE ®/CATENA® (900 mg idebenone/day)  2 tablets (150 mg each one) x 3 times orally with meals  Matchin

  15. Slide 15: Patients well balanced for general demographics

    Patients well balanced for general demographics ITT Population Idebenone Placebo Total N 31 33 64 Age (years) Mean (SD) 13.5 (2.7) 15.0 (2.5) 14.3 (2.7) Race (N,%) White/Caucasian 29 (93.5%) 31 (93.9%) 60 (93.8%) Asian 1 (3.2%) 1 (1.6%) Hispanic 1 (3.0%) 1 (1.6%) Other 1 (3.2%) 1 (3.0%) 2 (3.1%) Wei

  16. Slide 16: Assessment of respiratory function in DELOS

    Assessment of respiratory function in DELOS Spirometer – At Hospital Visits ASMA-1™ - Hospital Visits & Weekly Home Test performed with physiotherapist  Peak Expiratory Flow (PEF)  Peak Expiratory Flow (PEF)  Forced Expiratory Volume (FEV1)  Forced Vital Capacity (FVC)  Peak Cough Flow (PCF) Pr

  17. Slide 17: Change in PEF%p (ITT) (hospital-based spirometry)

    Change in PEF%p (ITT) (hospital-based spirometry) p=0.22 -2.57 71% reduction in loss p<0.001 of PEF%p ® Idebenone -8.84 Placebo Difference 3.90 8.32 7.60 6.27 Average Difference 6.52 p-value 0.10 <0.001 0.02 0.03 p-value 0.01 17

  18. Slide 18: Progression in absolute PEF [L/min] (ITT)

    Progression in absolute PEF [L/min] (ITT) (hospital-based spirometry) ® Idebenone Placebo Difference 14.1 33.6 32.7 28.1 Average Difference 27.1 p-value 0.18 0.002 0.02 0.03 p-value 0.01 18

  19. Slide 19: Change in PEF%p (ITT) (by ASMA-device)

    Change in PEF%p (ITT) (by ASMA-device at hospital visit ± 3-week window) p=0.45 -1.77 80% reduction in loss p<0.001 of PEF%p ® Idebenone -9.01 Placebo Difference 2.68 4.97 3.98 7.24 Average Difference 4.72 p-value 0.15 0.04 0.15 0.03 p-value 0.03 19

  20. Slide 20: Change in FVC%p (ITT)

    Change in FVC%p (ITT) p<0.001 37% -5.67 reduction p<0.001 in loss ® Idebenone of FVC%p Placebo -8.95 Difference 3.27 4.72 4.97 3.27 Average Difference 4.06 p-value 0.02 0.002 0.02 0.08 p-value 0.005 20

  21. Slide 21: Progression in absolute FVC [L] (ITT)

    Progression in absolute FVC [L] (ITT) ® Idebenone Placebo Difference 0.09 0.16 0.16 0.13 Average Difference 0.14 p-value 0.04 0.003 0.005 0.05 p-value 0.003 21

  22. Slide 22: Change in FEV1%p (ITT)

    Change in FEV1%p (ITT) p=0.37 -2.40 78% reduction p<0.001 in loss of FEV1%p ® Idebenone -10.68 Placebo Difference 5.53 8.26 5.77 8.29 Average Difference 6.96 p-value 0.02 0.01 0.09 0.03 p-value 0.01 22

  23. Slide 23: Progression in absolute FEV1 [L] (ITT)

    Progression in absolute FEV1 [L] (ITT) ® Idebenone Placebo Difference 0.18 0.27 0.24 0.33 Average Difference 0.26 p-value 0.02 0.01 0.05 0.01 p-value 0.01 23

  24. Slide 24: Outcome of other endpoints

    Outcome of other endpoints (Change to Week 52) Idebenone Placebo Mean (SE) Baseline Change Baseline Change Difference p-value MEP %p 28.3 (2.2) -1.79 (1.32) 25.1 (2.1) -3.01 (1.23) 1.22 (1.82) n.s. MIP %p 43.5 (4.0) -7.17 (1.91) 38.5 (2.9) -5.28 (1.80) -1.89 (2.63) n.s. PCF [L/s] 4.1 (0.2) 0.14 (0.1

  25. Slide 25: Pre-specified Responder Analyses

    Pre-specified Responder Analyses Fewer patients in Idebenone group deteriorate in Respiratory Function Tests Patients not Worsening in Respiratory Function Test n (%) Parameter Idebenone Placebo p-value1 PEF %p 14, (45.2%) 8, (24.2%) 0.0806 PEF [L/min] 18, (58.1%) 9, (27.3%) 0.0134 FVC %p 7, (22.6%)

  26. Slide 26: Treatment effect on PEF%p not influenced by previous glucocorticoid steroid use

    Treatment effect on PEF%p not influenced by previous glucocorticoid steroid use Change from Baseline to Idebenone Placebo Diff. Week 52 Previous Glucocorticoid -1.22 -7.95 6.73 Users Glucocorticoid -3.75 -9.95 6.19 Naive Patients ® Idebenone All patients -2.57 -8.84 6.27 Placebo 26

  27. Slide 27: Respiratory Function Outcome, Subgroups by age

    Respiratory Function Outcome, Subgroups by age Baseline Change Week 52 Difference Assessment Subgroup Treatment mean (SD) mean (95%CI) mean (95%CI) Idebenone (N=19) 54.7 (9.7) -1.71 (-7.48, 4.06) 7.29 ≤ 14 y (-1.77, 16.35) Placebo (N=13) 59.1 (12.3) -9.00 (-15.94, -2.06) PEF %p Idebenone (N=12) 51.5

  28. Slide 28: Fewer patients on Idebenone fell below the critical 1L-threshold for FVC

    Additional clinical observations Am J Respir Crit Care Med Vol 164. pp 2191–2194, 2001 Fewer patients on Idebenone fell below the critical 1L-threshold for FVC No. of Patients Idebenone Placebo BL FVC: > 1L but < 1.5 L 6 9 Patients with FVC < 1L during 1y 1 5 Analysis population: ITT population The

  29. Slide 29: Fewer patients on Idebenone fell below the 160 L/min threshold for PCF

    Additional clinical observations PCF below 160 L/min: cough Fewer patients on Idebenone fell below the no longer effective enough to critical 160 L/min-threshold for PCF provide adequate mucociliary clearance 1,2,3 No. of Patients Idebenone Placebo PCF at BL: >160 L/min 26 33 Patients with 1 6 PCF <

  30. Slide 30: Less Respiratory Tract Infection-related AEs in Idebenone group

    Additional clinical observations: Less Respiratory Tract Infection-related AEs in Idebenone group Adverse Events (Patients) Idebenone Placebo p-value1 Respiratory Tract Infections 20 (14) 44 (23) 0.076 Upper Respiratory Tract 15 (11) 34 (20) 0.051 Nasopharyngitis 12 (8) 11 (9) Upper Respiratory Trac

  31. Slide 31: Kaplan-Meier Analysis: Upper Respiratory Tract Infection

    Additional clinical observations: Kaplan-Meier Analysis: Upper Respiratory Tract Infection Cox Proportional Hazards Model ® Idebenone hazard ratio = 0.41 (95%CI: 0.19-0.91) Placebo p = 0.027 ITT Population Study Day: on-treatment period from Baseline 31

  32. Slide 32: Safety - Serious Adverse Events

    Safety - Serious Adverse Events There were no deaths in the study Events (Patients) Idebenone Placebo Total (acute) Respiratory failure 2 2 Dehydration 1 1 Femur fracture 1 1 Nasopharyngitis 1 1 Pneumonia 3 (2) 3 (2) Pulmonary microemboli 1 1 Pyrexia 1 1 Sleep apnoea syndrome 1 1 Tendinous contractu

  33. Slide 33: Safety - Adverse Events

    Safety - Adverse Events Adverse event rates were comparable for Idebenone and placebo AEs with incidence larger than Idebenone Placebo Total 10% of Total patients Serious Adverse Events 2 (2, 6.3%) 13 (5, 14.7%) 15 (7, 10.6%) Adverse Events 153 (30, 93.8%) 177 (32, 94.1%) 330 (62, 93.4%) Most Common

  34. Slide 34: Summary

    Summary  First completed and only positive phase 3 trial in DMD  Statistically significant and clinically relevant outcomes of primary and secondary endpoints demonstrate that Idebenone reduced the loss of respiratory function in 10-18 year old DMD patients not using concomitant glucocorticosteroi

  35. Slide 35: Thank you

    Thank you  We would like to thank the boys who participated in the DELPHI and DELOS studies and their families for their support  We thank PPMD for inviting us to this webinar 35

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