IGF-1 Therapy and Muscle Function in Duchenne Muscular Dystrophy

Transcription

1 IGF-1 Therapy and Muscle Function in Duchenne Muscular Dystrophy Brenda Wong, MD On behalf of the DMD IGF-1 study group, Cincinnati Children s Hospital Medical Center

2 Type of clinical trial Pilot, interventional, phase II randomized, open label, controlled study

3 Hypothesis Primary hypothesis: IGF-1 therapy improves/preserves muscle function in patients with Duchenne Muscular Dystrophy

4 Hypothesis Secondary hypotheses: - IGF-1 therapy will be tolerated without significant side effects - IGF-1 therapy improves growth rate in DMD boys treated with glucocorticoids - IGF-1 therapy improves or preserves cardiopulmonary function

5 Background DMD - the most common and severe childhood MD; relentless progression to wheelchair dependence by age 12; and death from cardiopulmonary dysfunction in early 20s - no curative therapies - only available therapy - long term glucocorticoid therapy to slow progression of disease; but with side effects including growth failure, excessive weight gain, insulin resistance/carbohydrate intolerance, osteoporosis and pubertal delays

6 IGF-1 IGF-1 : - a growth factor - key mediator of anabolic pathways in muscle, stimulates whole body protein metabolism (Fryburg,1994) - role in muscle repair and regeneration - stimulates the proliferation and differentiation of skeletal muscle cells (Rosenthal 1995, Engert 1996, Rosenthal 1999) - FDA approved for the treatment of severe IGF deficiency

7 IGF-1 Scientific rationale for IGF-1 therapy in DMD: Preclinical studies: - Transgenic overexpression of IGF-1 in mdx mice : increased EDL and diaphragm muscle mass, increased force generation; reduced fibrosis and myonecrosis (Barton 2002; Shavlakadze 2004) - Subcutaneous infusion of IGF-1 in 129ReJ dy/ dy mice with laminin 211 deficiency and mdx mice increased muscle mass and force output (Lynch 2001, Gregorevic 2002)

8 IGF-1 Scientific rationale for IGF-1 therapy in glucocorticoid (GC) treated patients with DMD: Reduce some of the effects of GC therapy growth failure, insulin resistance and carbohydrate intolerance - clinical studies in GH-resistant and IGF-1 deficient children (Chernausek 2007) - FDA approved for severe primary IGF deficiency

9 IGF-1 (INCRELEX TM ) Mecasermin [rdna origin] injection Recombinant human insulin-like growth factor-1 Consists of 70 amino acids identical sequence to endogenous human IGF-1 Route of administration: subcutaneous injection

10 Research Plan Prospective, randomized, open label, controlled study 40 subjects will be recruited: - Group I (Control): standard GC - Group II (Intervention): IGF-1 and standard GC IGF-1 once daily sc in am with breakfast Duration of study: 6 months (3 study visits)

11 Research Plan Anticipated risks: Hypoglycemia: - risk is low with concurrent steroid therapy - to take IGF-1 with a meal - glucose monitoring with IGF-1 treatment - Injection site changes - lipohypertrophy: - to rotate injection sites Increased intracranial pressure Hypersensitivity reactions urticaria, hives, wheals

12 Research Plan Outcomes: Primary: change in muscle function of DMD patients on IGF-1 therapy vs controls measured by 6MWT Secondary motor outcomes : myometry, timed motor function tests, North Star ambulatory assessment Secondary growth outcome: growth measures (height, arm span, ulnar length, weight, BMI, DEXA body composition) Secondary cardiopulmonary outcomes: PFT, EKG, cardiac MRI/echocardiograms Safety outcomes: safety labs, clinical exams

13 Research Plan Who is eligible to participate in this study? Male Diagnosis of DMD Age 5 yr or older Ambulatory On glucocorticoid (prednisone or deflazacort) therapy for > 12 months

14 Research Plan Other Inclusion criteria: - Bone maturation (assessed by bone age x-ray): 11 yr - Informed consent - Willingness and ability to comply with all protocol requirements and procedures

15 Research Plan Exclusion criteria: - Current and prior treatment with GH or IGF-1 therapy - non ambulatory - Pubertal (based on clinical Tanner staging examination) - Congestive cardiac failure - History of intracranial hypertension - Daytime ventilatory dependence (non invasive/tracheostomy) - Concomitant therapy other therapies that affect muscle function need to have been started 3 months prior to enrollment - Patients enrolled in other clinical drug trials - Any physical or mental condition which may render the subject unable to complete the tasks of the study

16 DMD IGF-1 study 10 m run/fast walk 6 minute walk hallway

17 DMD IGF-1 study Climb 4 steps Myometry

18 DMD IGF-1 study: Clinical team Investigators: Dr M Rutter Dr J Collins Endocrine Neurology Dr P Backeljauw Dr B Wong Endocrine Neurology Dr M Taylor Cardiac MRI

19 Study coordinators: Paula Morehart and Ray Hu Neurology Samantha Blum Endocrine

20 Acknowledgements Funding sponsors: Charley s Fund Nash Avery Foundation Action Duchenne Tercica (Subsidiary of Ipsen) Familes and patients with DMD DMDConnect/PPMD