Efficacy of Raxone® (idebenone) on respiratory outcomes in

2016 Connect Conference
Efficacy of Raxone® (idebenone) on respiratory outcomes in patients with DMD
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Agenda
§ Medical need for treatment of pulmonary function loss in DMD
§ Mitochondrial pathology in DMD and rationale for idebenone
§ Santhera’s development program with Raxone® (idebenone) in DMD § Efficacy findings of the Phase 3 DELOS trial in DMD patients not using concomitant steroids
Ø Efficacy on expiratory and inspiratory function
Ø Efficacy on bronchopulmonary complications
§ SIDEROS – a new trial for patients using concomitant steroids
§ Regulatory update
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Pipeline with Raxone® (idebenone) in three indications with high unmet medical need
Leber’s Hereditary Optic Neuropathy (LHON): Approved in EU
Duchenne Muscular Dystrophy (DMD):
EU: MAA filed;; US: NDA in preparation
Primary progressive MS (PPMS): Phase II study ongoing
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Medical need for effective treatment of
respiratory illness in DMD
§ Medical complications include ineffective cough, nocturnal hypoventilation, sleep disordered breathing, and ultimately daytime respiratory failure
Courtesy: Nathalie Goemans, University Hospitals Leuven, Belgium
Loss of respiratory function
Assisted ventilation
Nocturnal ventilation
§ With age DMD patients develop cardiac and respiratory complications which become life-­threatening
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Measures of pulmonary function loss in DMD
DMD patient
healthy individual
Figures (B) and (C) courtesy of Dr. Oscar H. Mayer, Division of Pulmonology, The Children's Hospital of Philadelphia, USA.
PEF: peak expiratory flow
FVC: forced vital capacity
FEV1: forced expiratory volume in 1 sec
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Progressive and parallel decline in PEF%p and FVC%p between from ~10 years of age 100
FVC (%p)
PEF (%p)
FVC%p
Mean (SEM) PFT Value
80
PEF%p
60
40
20
6
8
10
12
14
16
18
Age [years]
20
22
24
26
28
30
Source: CINRG Natural history data base
N= 334 patients; data is mean ±SEM
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Patients’ treatment preference to preserve pulmonary function
§
Patient-­centered benefit-­risk survey conducted by PPMD in a community engaged approach
§
Focus on treatment priorities for disease aspects not directly related to skeletal muscle function §
155 participants (85% patients/caregivers with DMD)
§
Treatment of pulmonary disease (cough, prevention of airway infections) was highly prioritized by patients/caregivers
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Urgent medical need for patients unable to
take glucocorticoid steroids
§
With increasing age, fewer patients tolerate glucocorticoid steroids (side effects)
§
~ 40% of patients 10 years and older are not using glucocorticoid steroids §
There is currently no treatment available for this group of DMD patients
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Mitochondrial impairment in DMD
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Idebenone -­ mechanism of action in DMD PPMD Conference │ June 2016
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Santhera’s extensive development program
with Raxone® (idebenone) in DMD
Phase 3
Phase 2
GC: glucocorticoid steroids;; PPM study: prospectively planned matching study
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Phase 3
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Phase 3 DELOS trial – patients and treatment
The Lancet 2015;; 385:1748-­57
Patients:
Randomized treatment: §
Age 10-­18 years
§
Raxone® (900 mg/d): N=31
§
No selection for mutational status
§
Placebo: N=33
§
Patients had to be off chronic steroids
§
Mean Age: 14.3 y
§
92% of patients were non-­ambulatory
§
Treatment duration: 12 months
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Raxone® slows the loss of expiratory function
Raxone® benefit
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Raxone® benefit
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Inspiratory function is also impaired in DMD
§
Reduced V’I, max (FVC) [maximum inspiratory flow velocity]
§
Reduced inspiratory flow reserve (IFR)
Inspiratory Flow Reserve De Bruin et al., 2001. Inspiratory low reserve in boys with DMD. Pediatric Pulmonology 31:451-­457
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Raxone® also preserves inspiratory function Maximum Inspiratory Flow: V’I,max (FVC)
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Inspiratory Flow Reserve (IFR, %)
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Fewer patients on Raxone® fell below critical thresholds for Peak Cough Flow (PCF) "When the PCF falls below 160 L/min, the cough is no longer effective enough to provide adequate mucociliary clearance“1,2,3
1. Gauld LM et al., Ped Pulmonol (2005), 39:457-­‐460
2. Bach JR et al., Chest (1997), 112:1024-­‐1028
3. Tzeng AC et al., Chest (2000), 118: 1390-­‐1396
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No. of Patients
PCF at BL: >160 L/min
Patients with PCF < 160L/min during 1y
Raxone®
Placebo
26
33
1 (3.8%)
6 (18.2%)
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Fewer patients on Raxone® experienced
bronchopulmonary disease (e.g. airway infections)
Subjects (%)
Events
Raxone®
Placebo
6 (19.4%)
7
17 (51.5%)
28
Placebo
Raxone®
Hazard Ratio* 0.28; p=0.0026
Duration of bronchopulmonary disease (d)
Total Days
82
222
Bronchopulmonary disease classified as treatment emergent adverse events: larynx, airways, alveoli (bronchitis, influenza, laryngitis, pneumonia, upper respiratory tract infection, viral infection, respiratory failure, cough, dyspnoea); *proportional means regression analysis
McDonald CM, et al. Neuromuscul Disord. 2016; doi: 10.1016/j.nmd.2016.05.008. [Epub ahead of print].
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Patients on Raxone® used less antibiotics for the treatment of bronchopulmonary disease
Placebo
Subjects (%)
Events
Raxone®
Placebo
7 (22.6%)
8
13 (39.4%)
17
Raxone®
Hazard Ratio* 0.52; p=0.1330
Duration of antibiotic use (d)
Total Days
65
105
*proportional means regression analysis
McDonald CM, et al. Neuromuscul Disord. 2016; doi: 10.1016/j.nmd.2016.05.008. [Epub ahead of print].
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Summary of DELOS outcome § The Phase 3 trial met its primary endpoint
§ Supportive evidence for efficacy from secondary endpoints
§ Demonstrated a consistent treatment effect for idebenone (Raxone®) on expiratory and inspiratory function
§ Provides supportive evidence for efficacy in clinically relevant responder analyses (e.g. peak cough flow, FVC)
§ Demonstrates clinically relevant impact of bronchopulmonary disease and antibiotic use
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SIDEROS – a new trial with Raxone® in patients with DMD using concomitant glucocorticoids (GCs)
Phase 3
Phase 2
GC: glucocorticoid steroids;; PPM study: prospectively planned matching study
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Phase 3
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Steroid use delays the onset but not the rate of pulmonary function decline
100
current
Current GC users
naive/previous
Naïve/previous GC users
Mean FVC (% of predicted) (SE)
80
60
40
20
6
8
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12
14
16
18
Age [years]
20
22
24
26
28
30
Source: CINRG Natural history data base N= 334 patients; data is mean ±SEM
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The SIDEROS trial
Objective: To assess the efficacy of idebenone (Raxone®) compared to placebo, in slowing the loss of respiratory function in patients with DMD receiving glucocorticoids (GCs)
For more information: see poster
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SIDEROS – Lead Investigators
§ Study PI and Lead Investigator Europe: Dr. G Buyse (Leuven, Belgium)
§ Lead Investigator North America: Dr. OH Mayer (CHOP, Philadelphia)
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SIDEROS – status update
§ SIDEROS will be conducted in ~50 study sites in the US and Europe § Currently selected study locations in the US (sites are not yet recruiting):
§ For updates on study sites please consult: Clinicaltrials.gov
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Regulatory update
Europe:
§
§
§
Marketing Authorization Application USA:
§
A proposal has been submitted to the (MAA) with the EMA filed
FDA for an Accelerated Approval MAA is validated and the review process based on the DELPHI and DELOS has started.
programs using the SIDEROS trial as a confirmatory trial A decision by the CHMP is currently being expected in 1Q 2017
§
Awaiting FDA feedback
The intended indication is for patients in whom respiratory function has started to decline and who are currently not taking glucocorticoids. The indication would include patients who previously were treated with glucocorticoids or in whom glucocorticoid treatment is not desired, not tolerated or is contraindicated.
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Raxone® in the treatment of DMD
§
There is a sizeable proportion of patients who cannot tolerate glucocorticoids at the time when pulmonary function loss becomes evident
§
There is an urgent unmet medical need to slow down the decline of pulmonary function in these patients
§
Available data demonstrate that the investigational drug Raxone® slows the loss of pulmonary function in patients not using glucocorticoids §
Initial application for regulatory approvals for use in this patient group
§
Raxone® was tested in patients without restriction to specific mutational or disease status (i.e. non-­ambulant)
§
Raxone® is an oral medication (2 tablets, 3 times/day)
§
New study (SIDEROS) to investigate the efficacy of Raxone® on pulmonary function outcomes in patients using concomitant glucocorticoids
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