Tadalafil Phase 3 Trial for Duchenne Muscular Dystrophy

Tadalafil Phase 3 Trial for Duchenne Muscular Dystrophy David A. Cox, Ph.D. Eli Lilly and Company PPMD Connect Conference 2015 June 19, 2015 Disclo...
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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”

Company Confidential © 2015 Eli Lilly and Company

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:

Company Confidential © 2015 Eli Lilly and Company

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.

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