Deflazacort for the Treatment of Patients with DMD
Tim Cunniff, Pharm.D. EVP, Research & Development (R&D) June 27, 2016
1 Deflazacort U.S. Development & Registration Program: Studies and Timeline
2013 2014 2015 2016 2017
Expected Orphan IND Pre NDA File NDA Approval Drug Designation Fast Track Drug-Drug Pediatric Rare TQT Study Designation Interaction Study Disease Designation Post-approval Licensed: Two Phase 3 Efficacy Studies PK Study-DMD DMD Safety Extension Study (Children & Adolescents) Hepatic Study Phase 3b Study in Infants & Young Children BA/Suspension BE/Food Study Phase 3b Pulmonary Renal Study Study in Non-Ambulatory Calcort BE Study Patients DMD Expanded Access Program
Genetic Tox Monkey 9 month Tox Study Carcinogenicity Studies (6) (mice & rats) Black: Regulatory Rat 6 month Tox Study Red: Pre-Clinical Post-approval Blue: Clinical Rat Juvenile Tox Study Deflazacort NDA Review Timeline Marathon anticipates Priority NDA review (will be assigned by FDA at time of NDA filing)
2 NDAs: Tablets and Oral Suspension
Pre-NDA Meeting NDA Aug 2015 NDA assembly Submission FDA NDA review NDA PDUFA Date June 9, 2016 February 9, 2017
2015 2015 2015 2016 2016 2016 2016 2017 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1
NDA Potential Advisory BA study to Calcort Filing Committee Meeting August 8, 2016 December 2016
Q4 2015 Expanded Access Program (initiated) Pivotal Efficacy Study 1
EFFICACY AND SAFETY OF DEFLAZACORT VERSUS PREDNISONE AND PLACEBO IN THE TREATMENT OF DUCHENNE/BECKER MUSCULAR DYSTROPHY
4 Study Design Segment 1 (Week 0-12) Segment 2 (Week 13-52)
Deflazacort (1.2 mg/kg/d) Deflazacort (0.9 mg/kg/d) Prednisone (0.75 mg/kg/d)
Deflazacort (1.2 mg/kg/d) Placebo Deflazacort (0.9 mg/kg/d) Prednisone (0.75 mg/kg/d) Primary 1 to 7 end point days
Screen Baseline 6 12 24 36 52 Week
Data on file. MP-104-NM-001 Clinical Study Report. Marathon Pharmaceuticals; 2015. 5 Study Met Its Primary End Point and Demonstrated Deflazacort and Prednisone Significantly Improved Muscle Strength Versus Placebo
Change in average muscle strength from baseline to week 12 P=.0002 P=.0003 P=.0173 0.3 0.26 0.27 0.25 0.2 0.15 0.15 0.1 0.05 0 Change, ITT Population Change, -0.05 -0.1 -0.10 -0.15
LS Mean LS Mean Deflazacort Deflazacort Prednisone Placebo 0.9 mg/kg/d 1.2 mg/kg/d 0.75 mg/kg/d (n=50) (n=48) (n=46) (n=45)
ITT, intent-to-treat; LS, least squares. Data on file. MP-104-NM-001 Clinical Study Report. Marathon Pharmaceuticals; 2015. 6 Deflazacort Significantly Improved Muscle Strength From Week 12 to 52 vs Prednisone Change in average muscle strength from week 12 to 52
P=.0044
0.2 0.17 0.15
0.1
0.05 0.04
0
Change, ITT Population Change, -0.05
-0.1 -0.12
LS Mean LS Mean -0.15 Deflazacort Deflazacort Prednisone 0.9 mg/kg/d 1.2 mg/kg/d 0.75 mg/kg/d (n=41) (n=34) (n=37)
ITT, intent-to-treat; LS, least squares. Data on file. MP-104-NM-001 Clinical Study Report. Marathon Pharmaceuticals; 2015. 7 Deflazacort Significantly Improved Timed Motor Function Tests vs. Placebo at Week 12
Change in timed function tests, baseline to week 12; All comparisons P<.002 vs placebo
Deflazacort 0.9 mg/kg/d Deflazacort 1.2 mg/kg/d Prednisone 0.75 mg/kg/d Placebo 10.0 6.1 5.0 2.1 1.2 0.0 -1.5 -1.8 -2.5 -2.4 -5.0 -2.8 -3.0 -2.8 -6.3 Times -10.0
-15.0
-20.0 -19.5 Supine to Standing Climbing 4 Stairs Run/Walk 30 Feet
Data on file. MP-104-NM-001 Clinical Study Report. Marathon Pharmaceuticals; 2015 Improvements in Timed Function Tests were Maintained at Week 52 Change in timed function tests, baseline to week 52
Deflazacort 0.9 mg/kg/d Deflazacort 1.2 mg/kg/d Prednisone 0.75 mg/kg/d
0.0
-1.53 -1.54 -2.53 -2.45 -5.0 -2.83 -3.79 -4.44 -4.22
-10.0 P=.0461
-15.0 P=.0012 Times -20.0
-25.0 -24.62
-30.0
Supine to Standing Climbing 4 Stairs Run/Walk 30 Feet
Note: Data on file. MP-104-NM-001 Clinical Study Report. Marathon Pharmaceuticals; 2015 Change in Average Muscle Strength at 12 weeks in Non- Ambulatory Patients (N= 45 of 196 in study) Post-Hoc Analysis
0.6
0.5 *
0.4
0.3
0.2
0.1
0.0 Change in Average Muscle Strength
-0.1 Deflazacort Deflazacort Prednisone Placebo 0.9 mg/kg/d 1.2 mg/kg/d 0.75 mg/kg/d
Change from baseline Difference vs placebo
* P=.04 vs placebo. Change in Average Muscle Strength from Baseline to 52 Weeks in Non-Ambulatory Patients Post-Hoc Analysis
0.5 *
0.4
0.3
0.2
0.1
0.0
-0.1 Change in Average Muscle Strength
-0.2 Deflazacort Deflazacort Prednisone 0.9 mg/kg/d 1.2 mg/kg/d 0.75 mg/kg/d
Change from baseline Difference vs prednisone
* P=.09 vs placebo. Deflazacort Improved Pulmonary Function in Non- Ambulatory Patients (post-hoc)
Percent of patients with improvement in FVC Percent of patients with improvement in MVV
Deflazacort 0.9 mg/kg Deflazacort 1.2 mg/kg Deflazacort 0.9 mg/kg Deflazacort 1.2 mg/kg Prednisone 0.75 mg/kg Placebo Prednisone 0.75 mg/kg Placebo 100 100 100 91 92 91 90 90 83 82 80 80 73 70 67 70 58 60 60
50 44 50 44 Patients, % Patients, 40 Patients, % Patients, 40 40 33 30 30 30
20 20
10 10
0 0 12 Weeks 52 Weeks 12 Weeks 52 Weeks Time From Baseline Time From Baseline
Note: FVC, forced vital capacity; MVV, maximum voluntary ventilation. Most Frequent Adverse Events
Pivotal Study 1
Deflazacort Deflazacort Prednisone Adverse Event Placebo 0.9 mg/kg/d 1.2 mg/kg/d 0.75 mg/kg/d (%) (n=50) (n=68) (n=65) (n=63) Cushingoid 60.3 69.2 77.8 12.0 Hirsutism 35.3 36.9 44.4 2.0 Weight Gain 27.9 32.3 34.9 6.0 Central Obesity 25.0 24.6 42.9 4.0
Increased Appetite 11.8 12.3 19.0 2.0
Abnormal Behavior 8.8 6.2 14.3 6.0
Aggression 4.4 3.1 7.9 2.0 Mood Swings 4.4 4.6 7.9 2.0 Cataract 4.4 1.5 1.6 0.0 Mean Weight Change Between Baseline and Week 52 Mean weight change baseline to week 52
P<.0001
P<.0001 10.00 8.45 8.00 5.60 6.00 5.05 4.00
ITT Population ITT 2.00 LSMean Change, kg, 0.00 Deflazacort Deflazacort Prednisone 0.9 mg/kg/d 1.2 mg/kg/d 0.75 mg/kg/d (n=41) (n=35) (n=37)
Deflazacort Deflazacort Prednisone 0.9 mg/kg/d 1.2 mg/kg/d 0.75 mg/kg/d (N=68) (N=65) (N=63) Patients discontinuing due to 1 (1.5%) 2 (3.1%) 4 (4.8%) weight-related TEAEs
Note: ITT, intent-to-treat; TEAE, treatment-emergent adverse event. Data on file. MP-104-NM-001 Clinical Study Report. Marathon Pharmaceuticals; 2015. Selected Non-Registrational Studies Supporting the Use of Deflazacort in Patients with DMD Deflazacort Delayed Loss of Ambulation Significantly Longer than Prednisone
Probability of ambulation by treatment regimen
CINRG1 DuchenneConnect2
Daily PRED (n=94) High-dose 2 days/week PRED (n=19) Deflazacort (n=370) Low-dose intermittent PRED (n=14) Daily deflazacort (n=80) Prednisone (n=263)
100 1.00
75 0.75
50 0.50 Ambulatory, % Ambulatory, Survival Probability Survival 25 0.25
0 0 6 8 10 12 14 16 18 20 0 5 10 15 20 Age, years Time to Wheelchair, years
LOA, loss of ambulation; PRED, prednisone or prednisolone. 1. Bello L et al. Neurology. 2015;85(12):1048-1055. 2. Wang RT et al. PLoS Curr. 2014;6. Eli Lilly Tadalafil Phase 3 Study in Patients with Duchenne (N=331) Change in 6MWD by Steroid Type in Placebo Arm N=116; 50 on deflazacort (0.7 mg/kg/d avg dose or 77% target) and 50 on prednisone/prednisolone (0.6 mg/kg/d avg dose or 80% target) Post Hoc Analysis Presented at MDA Clinical Conference March 2016 All Patients Excluding Patients Losing Ambulation
20 20
0 0
(20) (20)
(40) (40)
(60) (60) LS Mean Change in 6MWD (meters) in Change Mean LS 6MWD (meters) in Change Mean LS
(80) (80)
(100) (100) 0 12 24 36 48 0 12 24 36 48 Study Week Study Week Deflazacort Prednisone/prednisolone Deflazacort Prednisone/prednisolone
Deflazacort baseline mean 6MWD = 347 m Deflazacort baseline mean 6MWD = 349 m Prednisone baseline mean 6MWD = 328 m Prednisone baseline mean 6MWD = 332 m Study MP-104-CL-058: Relative Bioavailability of 21- Desacetyldeflazacort After Oral Administration of Marathon Proposed Commercial Deflazacort Tablets Compared ® toT Calcort (Deflazacort) Tablets in Healthy Volunteers
Marathon’s proposed commercial deflazacort tablets are bioequivalent to Calcort® deflazacort tablets MP-104-CL-058: Marathon’s Proposed Commercial Deflazacort Tablets Compared to Calcort® (Deflazacort) Tablets in Healthy Volunteers Mean plasma concentration-time curves of 21-desDFZ (semi-log scale) after single doses of Marathon’s proposed commercial deflazacort tablet formulation compared to Calcort®
1000
100 Marathon commercial tablets
] (ng/mL) Calcort tablets 10 desDFZ
- 1
0.1 Mean [21
0.01 0 2 4 6 8 10 12 14 16 Time (h)
Mean plasma concentrations of 21-desDFZ after oral administration of Marathon proposed commercial and Calcort® tablet DFZ formulations in healthy volunteers were similar. By 16 hours post-oral dose, only one subject had a measurable plasma concentration of 21-desDFZ.
19 MP-104-CL-025 PK Drug-Drug Interaction Study
Significant DDI Leading to Labeling Recommendation in Dosage & Administration:
Concomitant use of EMFLAZA with moderate or strong CYP3A4 or Pgp inhibitors will cause increased plasma concentrations of 21- desacetyldeflazacort (21-desDFZ), deflazacort’s active metabolite. Avoid concomitant use of moderate or strong CYP3A4 and Pgp inhibitors. If concomitant use of a moderate or strong CYP3A4 or Pgp inhibitors cannot be avoided, reduce the dose of EMFLAZA 3- fold to 0.3 mg/kg/day [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
20 Concomitant Administration of Deflazacort with Clarithromycin (strong inhibitor of CYP3A4)
Mean Plasma 21-desacetyl-DFZ Concentration Versus Time Plot with Treatments Overlaid for Cohort B (Linear Scale)
• Treatment C = Deflazacort alone • Treatment D = Deflazacort + Clarithromycin
21 Common CYP3A4 Inhibitors
• Weak inhibitors: cimetidine
• Moderate inhibitors: amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, conivaptan
• Strong inhibitors: Clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir
22 Marathon Deflazacort Research Initiatives
• Optimize and simplify deflazacort (DFZ) dosing regimens – Dose-exposure-response modeling – Clinical trial simulations
• Assess potential benefits of DFZ in young children (and infants) with DMD (Study MP-104-CL-060) – Early intervention – Tolerability, efficacy, dose and exposure-responses – Assess covariates and factors that may influence response to DFZ
• Quantify potential benefits of DFZ on pulmonary function in non-ambulatory patients with DMD (Study MP-104-CL-061)
23 New Study MP-104-CL-060 (4Q2016): Randomized, Double-Blind Study Evaluating the Efficacy and Safety of Three Dosing Regimens of Deflazacort vs. Placebo in Males Aged 3-36 Months Diagnosed with Duchenne
Segment I – 4 Arms for 26 Weeks
Segment II – Placebo subjects re-randomized to treatment after Week 26. All arms will continue for another 26 weeks New Study MP-104-CL-061 (4Q2016): Randomized, Double-Blind Study Evaluating the Efficacy and Safety of Two Dosing Regimens of Deflazacort vs Placebo on Pulmonary Function in Non-Ambulatory Boys with Duchenne
Screening Visit 1 Visit 2 Visit 3 Visit 4 Visit 5/ET Week -1 to Week -4 Baseline/Week 1 Week 13 Week 26 Week 39 Week 52
• Consent • PFTs (FVC • PFTs (FVC • PFTs (FVC • PFTs (FVC • PFTs (FVC • Inc/Excl primary) primary) primary) primary) primary) • Medical History • Echo • ULF • ULF • ULF • Echo • Labs • ULF • C-SSRS • C-SSRS • C-SSRS • ULF • Vitals • PE • Labs, Vitals, • Labs, Vitals, • Labs, Vitals, • PE • ECG AEs AEs AEs • ECG • C-SSRS • C-SSRS • Labs, Vitals, • Labs, Vitals, AEs AEs Treatment Arm A: 30mg/Daily n=20
Randomization Treatment Arm B: 48 or 54mg/Daily n=20
Treatment Arm C: Placebo n=20
52 Weeks Deflazacort EAP
26 EAP: Differences from Typical Clinical Trial
§ Use of an investigational drug or biologic to treat a patient with a serious disease or condition who does not have comparable or satisfactory alternative therapies to treat the disease or condition § Intent is clearly treatment § Contrast with investigational drug in a clinical trial where the primary intent is research
27 EAP: Enrollment *patients enrolled as of 24-Jun-2016 *N=151
160
140
120
100
80
60
40
20
0 1-Jan-16 5-Feb-16 11-Mar-16 15-Apr-16 20-May-16 24-Jun-16
• Enrollment directly corresponds with site activation • We continue to enroll ~ 15 patients/week ACCESS DMD has 26 centers open for participation across the U.S Physician Institution City, State Status
Sumit Verma, MD Emory/Children’s Atlanta, Georgia Open, patients enrolled Healthcare of Atlanta Perry Shieh, MD UCLA Los Angeles, California Open, patients enrolled
Elena Bravver, MD Carolinas Healthcare Charlotte, North Carolina Open, patients enrolled System Susan Apkon, MD Seattle Children’s Hospital Seattle, Washington Open, patients enrolled
Farida Abid, MD Baylor College of Medicine Houston, Texas Open, patients enrolled
Saunder Bernes, MD Phoenix Children’s Hospital Phoenix, Arizona Open, patients enrolled
Jeffrey Statland, MD University of Kansas Kansas City, Kansas Open, patients enrolled Medical Center Vikki Stefans, MD UAMS College of Medicine Little Rock, Arkansas Open, patients enrolled
Randal Richardson, MD Gillette Children’s St. Paul, Minnesota Open, patients enrolled
Addie Hunnicutt, MD Greenville Health System Greenville, South Carolina Open, patients enrolled
Basil Darras, MD Boston Children’s Boston, Massachusetts Open, patients enrolled
L. Matthew Frank Children’s Specialty Group Norfolk, Virginia Open, patients enrolled
Tulio Bertorini, MD Wesley Neurology Clinic Memphis, Tennessee Open, patients enrolled ACCESS DMD has 26 centers open for participation across the U.S Physician Institution City, State Status
Jonathan McKinnon, MD Las Vegas Clinic Las Vegas, Nevada Open, patients enrolled
Peter Heydemann, MD Rush University Medical Chicago, Illinois Open, patients enrolled Center Erika Finanger, MD Shriner’s Hospital Portland Portland, Oregon Open, patients enrolled
Matthew Wicklund, MD Penn State Hershey Hershey, Pennsylvania Open, patients enrolled Medical Center Hoda Abdel-Hamid, MD UPMC Pittsburgh, Pennsylvania Open, patients enrolled
Kathryn Wagner, MD Kennedy Krieger Baltimore, Maryland Open, patients enrolled
Steven DeRoos, MD Helen Devos Children’s Grand Rapids, Michigan Open, patients enrolled Hospital
Craig McDonald, MD UC Davis Sacramento, California Open
William Burnette, MD Vanderbilt University Nashville, Tennessee Open
Warren Marks, MD Cook Children’s Medical Fort Worth, Texas Open Center Mathula Thangarajh, MD Children’s National Medical Washington, District of Open Center Columbia Katherine Mathews, MD University of Iowa Iowa City, Iowa Open
Joanne Janas Children’s Hospital Aurora, Colorado Open Colorado ACCESS DMD has several centers that are working on getting opened… Physician Institution City, State Status
Nancy Kuntz, MD Lurie Children’s Hospital Chicago, Illinois Pending
Kenneth Silver, MD Shriner’s Hospital Chicago Chicago, Illinois Pending
Erin Neil, MD University of Michigan Ann Arbor, Michigan Pending
Marcia Felker, MD Riley Hospital Indiana Indianapolis, Indiana Pending University Chamindra Konersman, Rady Children’s Hospital San Diego, California Pending MD Kara Godwin UF Health Shands Gainesville, Florida Pending Children’s Hospital Huiyuan Jiang, MD Children’s Hospital of Detroit, Michigan Pending Michigan Joaquin Wong, MD Children’s Hospital of New New Orleans, Louisiana Pending Orleans John-Michael Li, MD Northwestern Medicine Chicago, Illinois Pending
Robert Cranston, MD Carle Foundation Hospital Champaign, Illinois Pending
Diana Castro, MD UT Southwestern Medical Dallas, Texas Pending Center Dallas Ratna Bhavaraju-Sanka, UT San Antonio San Antonio, Texas Pending MD ACCESS DMD has several centers that are working on getting opened… Physician Institution City, State Status
Erica Simpson, MD Houston Methodist Houston, Texas Pending
Rebecca Scharf, MD University of Virginia Charlottesville, Virginia Pending
Chafic Karam, MD Oregon Health and Science Portland, Oregon Pending University Leslie Morrison, MD University of New Mexico Albuquerque, New Mexico Pending
Melanie Sanborn, MD Shriner’s Hospital Spokane Spokane, Washington Pending
Alyson Hommel, MD Wake Forest Baptist Health Winston Salem, North Pending Carolina Tom Crawford, MD Johns Hopkins Baltimore, Maryland Pending
Sharon Kim, MD Children’s Hospital Orange Orange County, California Pending County Jean Teasley, MD Virginia Commonwealth Richmond, Virginia Pending University EAP: How to Participate
Visit www.accessdmd.com to see if your doctor is listed as a participating physician
If You See Your Doctor/Hospital Listed… • Talk to your doctor to see if you are eligible to participate • Sign informed consent form • No required visits What To Do if Your Doctor/Hospital is not Listed… • Talk to your doctor about the EAP and ask that they sign up to participate (note this process can take up to several months) • Talk to a hospital/clinic near you that is already participating to see if they would be willing to partner with your doctor EAP: FAQ
• How quickly can I receive drug? • You need to respond to phone call from pharmacy to arrange delivery and you need to be present to sign for package (can be as quickly as 24 hours after you are enrolled) • What visits are required? • No visits, follow standard of care • Can I participate in other clinical studies while taking deflazacort from the EAP? • You may still be eligible for other studies (talk to your doctor for more information) Acknowledgements
• Pivotal Efficacy Study 1 Investigators & Contributors: – R.C. Griggs, MD, J.P. Miller, C.R. Greenberg, MD, D.L. Fehlings, MD, A. Pestronk, MD, J.R. Mendell, MD, R.T. Moxley, MD, W. King, P.T., J.T. Kissel, MD, V. Cwik, MD, M. Vanasse, MD, J. Florence, DPT, S. Pandya, DPT, M. Brooke, MD, G. Fenichel, MD, J.P. Bouchard, MD, J. Robison, MD • Marathon Bioscience Center, Chicago: – Clinical Affairs: Brian Beers, Elaine Kernbauer – Regulatory Affairs: Jenny Swalec, Matt Lee – Research: Steve Wanaski • Marathon Pharmaceuticals, Northbrook IL: – CMC: Jane Stachura – Medical Affairs: James Meyer – Quality Assurance: Karen Conway – Regulatory Affairs: Jill Charbonneau, Pam Larsen, Annette Truong • Marathon Pharmaceuticals, Regional Medical Team: – Panna Patel (Chicago), Pete Sazani (Boston), Joy Sherick (Atlanta), Charles Slusher (Sacramento), Charles Tyler (Houston),
Marathon R&D staff in attendance (8/17)
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