Tadalafil Phase 3 Trial for Duchenne Muscular Dystrophy David A. Cox, Ph.D. Eli Lilly and Company
PPMD Connect Conference 2015 June 19, 2015
Disclosure and Disclaimer • Full-time employee with Eli Lilly and Company, manufacturer of tadalafil • Tadalafil is currently approved only for the treatment of adults with erectile dysfunction (ED), pulmonary arterial hypertension (PAH), and signs and symptoms of benign prostatic hyperplasia (BPH) • This presentation is intended only for the purpose of scientific information exchange
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Tadalafil • Phosphodiesterase Type 5 (PDE5) Inhibitor • Approved indications • Erectile dysfunction (Cialis®) • Benign prostatic hyperplasia (Cialis®) • Pulmonary arterial hypertension (Adcirca®)
• Investigational drug for DMD – not approved for use in pediatric population
Company Confidential © 2015 Eli Lilly and Company
Phosphodiesterase Type 5 Inhibitor (PDE5i) Mechanism Nitric Oxide Synthase (NOS)
“ON Nitric SWITCH” Oxide
cGMPdependent protein kinase
Reduction in Ca2+
Guanylate cyclase
cGMP
PDE5 5'GMP
PDE5 inhibitors amplify the NO-cGMP pathway, leading to vasodilation and increased blood flow to affected tissues
“OFF SWITCH”
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VASODILATION calcium channel
Blood Flow Regulation in Muscle Sympathetic nerves
Exercising muscle
Resting muscle
NO NE
nNOS
NE
!cGMP
O2
vessels dilates
vessels constrict
NO = nitric oxide NOS = nitric oxide synthase Company Confidential © 2015 Eli Lilly and Company
Dystrophin and Nitric Oxide Synthase in Healthy Muscle Basal Lamina
α
Laminin-α2 Dystroglycan
α ε γ β δSspn γ β δ hin p o r t Dys
F-actin
β
Nitric Oxide Synthase (NOS) • specific form in muscle • generates nitric oxide • relaxes blood vessels • ↑ blood flow and oxygen • normally attached to dystrophin
sarcolemma
α-Dystrobrevin Syntrophins
nNOS
1995-1996
Dysferlin
Dystrophin-glycoprotein complex (DGC)
nNOS, neuronal nitric oxide synthase
Company Confidential © 2015 Eli Lilly and Company
Dysfunctional Muscle Blood Flow in DMD Sympathetic nerves
DMD
Exercising muscle
Resting muscle
NO nNOS
NE
NE
↓cGMP
↓O2
vessel dilation inhibited
vessels constrict
“functional muscle ischemia” = cell damage/necrosis Company Confidential © 2015 Eli Lilly and Company
Effect of Tadalafil on Muscle Ischemia in Muscular Dystrophy Sci Transl Med. 2012 Nov 28;4(162):162ra155:
Whether these effects on muscle blood flow regulation and ischemia have any clinical relevance related to slowing disease progression in DMD is unknown
Neurology. 2014 Jun 10;82(23):2085-91:
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Background of Program • August/September of 2012 – Lilly first contacted by members of DMD research and advocacy community regarding interest in collaborating on a Phase 3 registration study of tadalafil for DMD Q4 2012 Q1 2013 Q2 2013
Conceptual development preIND FDA meeting Protocol development/approval IND prepared/filed Site identification/selection
Q3 2013 Country regulatory approvals
EC/IRB approvals
US and OUS investigator training meetings
September 2013: Enrollment Began January 2015: Enrollment Completed (331 patients) Company Confidential © 2015 Eli Lilly and Company
Tadalafil DMD Phase 3: Original Study Design Double-Blind 48 weeks
Open-Label Extension 48 weeks
Tadalafil 0.6 mg/kg Screening/ Randomization
Tadalafil 0.3 mg/kg
Key inclusion criteria: • Males with DMD
Placebo
Tadalafil 0.3 or 0.6 mg/kg
(not mutation-specific)
• • • •
Age 7 to 14 years LVEF ≥50% Ambulatory On stable steroid rx
0 4
12
24
36
Study Visits (Week)
48
0 4
12
24
36
48
Study Visits (Week)
Primary Objective: Test the hypothesis that once daily oral tadalafil for 48 weeks compared with placebo lessens the decline in ambulatory ability in boys with DMD. LVEF, left ventricular ejection fraction
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Study Site Locations Patients enrolled at 63 sites in 15 countries North America
Europe/West Asia
Additional study locations: Puerto Rico, Argentina Company Confidential © 2015 Eli Lilly and Company
East Asia
Study Endpoint Measures PRIMARY
• 6-Minute Walk Distance (6MWD) • North Star Ambulatory Assessment (NSAA)
SECONDARY
• Timed-function tests (time and grading) • 10 meter walk/run • Rise from supine • Stair climbing/descending • PODCI (QoL)
EXPLORATORY
• PUL Scale (Performance of the Upper Limb) • Pulmonary function tests Company Confidential © 2015 Eli Lilly and Company
Substudies (Exploratory) Cardiac MRI (US sites) • cardiac function as measured by ventricular circumferential wall strain, left ventricular ejection fraction, and ventricular volumes
Lower-limb MRI/MRS (ImagingDMD sites - US) • progression of leg skeletal muscle pathophysiology (T2) and fat infiltration as measured by MRI and MRS
Muscle Blood Flow (Cedars-Sinai/Dr. Ron Victor) • skeletal muscle blood flow in response to exercise - brachial artery ultrasound (brachial artery blood flow) and near-infrared spectroscopy (muscle oxygenation). MRS, magnetic resonance spectroscopy
Tadalafil DMD Phase 3: Amended Study Design OLE Period 2 48 weeks
OLE Period 1 48 weeks
Double Blind 48 weeks TADALAFIL 0.6 mg/kg Screening
TADALAFIL
TADALAFIL 0.3 mg/kg
TADALAFIL
PLACEBO V1
V2 V3 V4 W0 W4 W12 .
V5 W24
V6 W36
V7 W48
V8 W60
V9 W72
V10 W84
PHONE OR OFFICE VISITS
V11 W96
V12 W108 PHONE VISIT
V13 W120
V14 W132
V15… W144
PHONE VISIT
• Amended protocol provides for continued access of tadalafil at least through end of double-blind period and availability of primary efficacy analyses • If trial meets primary endpoint then continued access will continue through at least Week 144 • Amendment also provides for collecting longer term safety follow-up, as well as information on ambulation and upper-extremity function through 3 years
Study Status and Future Milestones • Enrollment began September 2013 and completed January 2015 • 331 boys randomized • Completion of double-blind phase anticipated by end of 2015 • Initial results expected first half of 2016 www.clinicaltrials.gov; NCT01865084 Company Confidential © 2015 Eli Lilly and Company
Special Thanks To… • The boys and their families who gave (and continue to give) of their time to participate in the trial, • The site investigators and staff that made timely completion of enrollment possible, • DuchenneConnect and TREAT-NMD for recruitment assistance, and • The physiotherapist training team for their expertise and dedication in site evaluator training and support: Lindsay Alfano, Kristy Rose Cocayne, Michelle Eagle, Julaine Florence, Meredith James, Linda Lowes, Anna Mayhew, Elena Mazzone, and Leslie Nelson.