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IGF-I Therapy of Primary IGF Deficiency Efficacy and Safety Considerations

IGF-I Therapy of Primary IGF Deficiency Efficacy and Safety Considerations. Philippe F. Backeljauw, MD Professor of Pediatrics University of Cincinnati College of Medicine Cincinnati Children’s Hospital Medical Center.

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IGF-I Therapy of Primary IGF Deficiency Efficacy and Safety Considerations

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  1. IGF-I Therapy of Primary IGF DeficiencyEfficacy and Safety Considerations Philippe F. Backeljauw, MD Professor of Pediatrics University of Cincinnati College of Medicine Cincinnati Children’s Hospital Medical Center

  2. We can review data on efficacy and safety of IGF-I therapy for short stature from: • Long term IGF-I therapy trials for severe primary IGFD – published • Clinical trials for milder IGFD – ongoing • IGFD Registry – developed in 2005

  3. Normal pregnancy Wt 3420 g, Lt 47.5 cm Growth failure (- 6.5 SD) Frontal bossing, mid-face hypoplasia, micrognathia, ↑ truncal fat, acromicria Delayed bone maturation Hypoglycemia GH : 28.5 – 51.5 ng/mL IGF- I : 2.0 – 4.8 ng/mL (- 4.5 SD) IGFBP- 3 : 0.3 mg/L GHBP : undetectable Treated with IGF-I (120 mcg/kg bid) Case Presentation 1

  4. First Year Growth Response 14 12 10 8 6 4 2 0 13 12 11 10 9 8 7 6 5 4 3 2 1 n=61 p=0.0003 * First-year height velocities Pre-treatment height velocities * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Year One Height Velocity * * * * * * * * * * * Height Velocity (cm/yr) * * * * * * * * * -12 -11 -10 -9 -8 -7 -6 -5 -4 40 60 80 100 120 Year One Average Dose (mg per kg BID) Pre-treatment Height SD Score Long Term Treatment with IGF-I in Children with Severe Primary IGF-I Deficiency due to GHIS versus year-one dosage versus pre-treatment height

  5. Linear Growth N = 58 9 8 7 N = 48 N = 38 6 N = 23 N = 21 N = 20 N = 16 N = 13 5 Mean Height Velocity (cm/yr) 4 N = 58 3 2 1 0 Pretreatment Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 ± 95% Confidence Interval JCEM 2007; 92(3): 902-910

  6. Individual Treatment Responses* to IGF-I Therapy *All subjects treated for at least 4 years

  7. Adverse Event Profile (percent) JCEM 2007; 92(3): 902-910

  8. What about patients with less severe primary IGF-I deficiency? • “Less severe” is defined as - height < - 2 SDS - IGF-I < - 2 SDS - GH ≥ 7 ng/ml with stimulation testing

  9. 600 600 500 500 400 400 300 300 IGF-μg/L) 200 200 100 100 0 0 0 0 5 5 10 10 15 15 20 20 Age How common is less severe IGF-I deficiency? IGF-I Levels <-2 SD in ISS suggestive of primary IGF-I deficiency n=67 GHD; n= 187 Non-GHD; n= 205 2 1 0 IGF-I SDS IGF-I (μg/L) -1 -2 -3 54% <-2 SD -4 9 10 11 12 13 14 15 Age (yr) Age (yr) Leschek E et al. JCEM 2004 Ranke MB et al. Horm Res 2000

  10. Ongoing Studies in Less Severe Primary IGFD • Study MS 301 - parallel-group study - one year duration - twice-daily administration up to 120 mcg/kg - subjects randomized to weight-based dosing of IGF-I vs observation-only - primary endpoint is height velocity • Study MS 306: long-term extension of MS 301 • Study MS 308 - single-arm study – duration 20 months, with interim analysis - once-daily administration of IGF-I - doses titrated to IGF-I SDS of + 2, with maximum 200 mcg/kg once-a-day - primary endpoint is height velocity • Study MS 316 - combined use of GH and IGF-I vs GH alone – three year duration

  11. Case Presentation 2 • Normal pregnancy Delivery at 35 weeks Wt 2270 g, Lt 47.0 cm • Growth failure Micrognathia, high-pitched voice, no dysmorphisms, proportionate short stature (- 2.6 SDS), BMI = 10-25th %-ile • Mild delay bone maturation • Laboratory GH : 34.3 ng/mL • IGF- I : 29.7 ng/mL (- 2 to - 3 SD) • IGFBP- 3 : 0.8 mg/L (0.9 - 4.1) • rhIGF-I 120 mcg/kg sc bid .

  12. Growth of the IGFD Registry

  13. Case Presentation 3 Short stature (height = - 2.7 SD) IGF-I = 27.5 ng/ml (- 3 SD) IGFBP-3 = 1.5 mg/l (- 2.5 SD) BA delayed by ± 18 months GH peak = 107.6 ng/ml Poor response to GH therapy

  14. Final Thoughts… • The safety and efficacy of rhIGF-I has been evaluated for more than a decade in patients with severe Primary IGFD • Doses of 80-120 µg/kg BID by SC injection induced significant increases in height velocity, height velocity SDS, and height SDS - maintained with prolonged dosing • Hypoglycemia was present but manageable • rhIGF-I appears to be effective and safe as a replacement therapy in children with short stature due to severe Primary IGFD

  15. Final Thoughts… • The availability of rhIGF-I has been an important development for the management of patients with severe primary IGF-deficiency • It is likely that primary IGF-I deficiency, the less severe form, is more prevalent with short stature patients than initially believed • Controlled studies to evaluate the efficacy and safety of rhIGF-I are underway, and preliminary data are encouraging regarding treatment responsiveness • The safety profile, especially related to hypoglycemia, for the less severe IGFD patients, is reassuring • Ongoing evaluation into the safety and efficacy of IGF-I therapy is needed to bring rhIGF-I into the position of first line therapeutic agent in this population of patients with less severe primary IGF-I deficiency

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