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Carl Grunfeld, MD, PhD Professor of Medicine, UCSF Chief, Metabolism and Endocrine Sections, VAMC

Recombinant human Growth Hormone (r-hGH) to treat HIV-associated Adipose Redistribution Syndrome (HARS): 12-Week Induction and 24-Week Maintenance Therapy. Carl Grunfeld, MD, PhD Professor of Medicine, UCSF Chief, Metabolism and Endocrine Sections, VAMC Veterans Affairs Medical Center

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Carl Grunfeld, MD, PhD Professor of Medicine, UCSF Chief, Metabolism and Endocrine Sections, VAMC

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  1. Recombinant human Growth Hormone (r-hGH) to treat HIV-associated Adipose Redistribution Syndrome (HARS): 12-Week Induction and 24-Week Maintenance Therapy Carl Grunfeld, MD, PhD Professor of Medicine, UCSF Chief, Metabolism and Endocrine Sections, VAMC Veterans Affairs Medical Center San Francisco, CA Melanie Thompson, Stephen Brown, Gary Richmond, Daniel Lee, Norma Muurahainen, Donald P. Kotler and the Study 24380 Investigators Group

  2. Background: HARS • Increased Visceral Adipose Tissue (VAT) often accompanied by subcutaneous lipoatrophy • Both have metabolic consequences • Characterized by abdominal fat accumulation (truncal fat, primarily VAT); may occur with subcutaneous fat depletion • Patients may also exhibit: • Dyslipidemia, insulin resistance, glucose intolerance • Excess dorsocervical fat (“buffalo hump”) • Poor quality of life, particularly psychological distress

  3. HARS Healthy VAT More VAT SAT* Less SAT* Visceral Adipose Tissue on Abdominal Cross-sectional CT Scan (L4-L5 Level) *Subcutaneous Adipose Tissue (SAT)

  4. Phase III Trial Design: Study 24380 n = randomized and received study drug Baseline 12 Wks 24 Wks 36 Wks n = 92 • Double-Blind • Placebo-Controlled • N = 325 • Duration 36 weeks: • 12 Wks Induction • 24 Wks Maintenance • (ARM A only) ARM A= 244 GH 2 mg AD GH 2 mg AD R GH 4 mg DD Placebo AD Placebo AD Open-label extension Study 25373 Randomized 3:1 n = 93 ARM B = 81 Placebo AD GH 4 mg DD Placebo DD n = 73 Weeks 0 - 12 Weeks 12-36 PRE-SPECIFIED EFFICACY ENDPOINTS: INDUCTION PHASE: Reduction of VAT at Week 12 (GH 4 mg DD vs Placebo DD) MAINTENANCE PHASE: During Weeks 12 to 36, less than 50% of pts on GH 2 mg AD regain >50% of VAT that they lost during the induction phase (baseline to Week 12)

  5. Induction and Maintenance Therapy Endpoints (EP): Primary EP: VAT at Week 12 Key Secondary EP: Trunk fat on DXA Fasting lipid profile Maintain reduced VAT Eligibility Criteria Documented HIV infection Receiving antiretroviral therapy Excess VAT by anthropometric criteria Men: WC > 88.2 cm andWHR 0.95 Women: WC > 75.3 cm andWHR  0.90 Not diabetic or receiving medications for diabetes Lipid-lowering agents permitted Glucose tolerance criteria Fasting glucose < 110 mg/dL 2-hr glucose < 140 mg/dL after 75 g oral glucose load Endpoints & Eligibility: Study 24380 VAT = Visceral Adipose Tissue on CT scan at L4-5 WC = Waist circumference WHR = Waist:Hip Ratio

  6. Baseline Characteristics: Study 24380 *Mean ± SEM

  7. % Change from baseline * % change from baseline * 5% loss * * Placebo r-hGH 4 mg DD Placebo r-hGH 4 mg DD Primary and Secondary Endpoints,Baseline to Week 12: Study 24380 VAT & SAT (CT scan) Trunk Fat & Limb Fat (DXA scan) *p < 0.001 for r-hGH vs. Placebo Decrease in VAT > SAT on r-hGH Decrease in Trunk Fat > Limb Fat on r-hGH

  8. % Change from baseline ‡ * * Placebo r-hGH 4 mg DD Cholesterol Profiles, Baseline to Week 12: Study 24380 Non-HDL & LDL Cholesterol HDL Cholesterol p = 0.018 for Non-HDL C p = 0.031 for HDL-C * Mean Change from baseline (mg/dL) Placebo r-hGH 4 mg DD *p < 0.001 for change from BL ‡p < 0.05 for change from BL

  9. Maintenance Therapy: Study 24380 VAT: Weeks 12 to 36 VAT: Baseline to Week 36 All Patients (ITT) • Major efficacy EP for maintenance was met: Less than 50% on r-hGH maintenance regained more than 50% of VAT lost during induction • Endpoint: Failure Rate = % who re-gained > 50% of VAT lost during induction • Placebo FAILED; 53.7% regained more than 50% of VAT lost • r-hGH 2 mg AD SUCCEEDED; 40.3% regained more than 50% of VAT lost GH-Placebo GH-GH 2AD - 7.9 cm2 - 15.7 cm2 Mean Change (cm2) p = 0.027‡ p < 0.001‡ ‡from baseline, p = 0.295 between groups Patients who lost VAT from Weeks 1 to 12 GH-Placebo GH-GH 2AD -10.0 cm2 -26.6 cm2 Mean Change (cm2) p = 0.008‡ p <0.001‡ ‡from baseline, p = 0.473 between groups

  10. 24380 Safety: CD4, Fasting Glucose, IGF-I, Insulin AUC in those receiving r-hGH induction-maintenance (Baseline-Week 36) Mean CD4 counts (cells/L) Mean fasting glucose (mg/dL) Mean IGF-I (ng/mL) Mean Insulin AUC (IU/mL-minute) *p < 0.001 * *

  11. Most Common Adverse Events (10%)*Week 12, Study 24380 *Overall, ~95% of events were only mild to moderate in severity. All serious adverse events were unlikely related, except for 1 possibly related SAE (migraine).

  12. Most Common AEs and Typical AEs*Weeks 12-36; Study 24380 *Overall, ~95% of events were mild to moderate in severity. All serious adverse events unrelated or unlikely related, except 1 possibly related SAE (basal cell skin carcinoma).

  13. Summary & Conclusions: Study 24380 Induction Therapy (r-hGH 4 mg/day, Weeks 1-12) • Significant reduction in VAT on r-hGH 4mg/day versus Placebo • Reduction in trunk fat • Improvement in cholesterol profile Maintenance Therapy (r-hGH 2 mg alt day) • Fewer than 50% of patients on r-hGH regain >50% of VAT lost during induction therapy • Improvement in cholesterol profile Safety Profile of r-hGH: as anticipated • AEs mostly mild to moderate • Greater loss of VAT and trunk fat - than of abdominal SAT and limb fat • Transient increases in glucose, HbA1c, and insulin AUC

  14. Gary Blick, Norwalk, CT Cynthia Brinson, Austin, TX Stephen Brown, West Hollywood, CA Calvin Cohen, Boston, MA Daniel Coulston, Spokane, WA Eric Daar, Los Angeles, CA George Drusano, Albany, NY Michael Dube, Indianapolis, IN Jeffrey Fessel, San Francisco, CA Marshall Glesby, New York, NY Carl Grunfeld, San Francisco, CA Keith Henry, Minneapolis, MN Donald Kotler, New York, NY Daniel Lee, San Diego, CA Ken Lichtenstein, Denver, CO Ardis Moe, Los Angeles, CA Anne Morris, Springfield, MA Julio Montaner, Vancouver, BC Richard Pollard, Sacramento, CA Bruce Rashbaum, Washington, DC Gary Richmond, Miami, FL Michael Saag, Birmingham, AL Steve Santiago, Miami, FL Morris Schambelan, San Francisco, CA Mike Somero, Palm Springs, CA Corklin Steinhart, Miami, FL Alan Tenorio, Chicago, IL Melanie Thompson, Atlanta, GA Vilma Vega, Sarasota, FL Christine Wanke, Boston, MA David Wheeler, Annandale, VA Michael Wohlfeiler, North Miami Beach, FL Antonio Urbina, New York, NY Acknowledgements Thanks to all 24380 Study Subjects, Study Personnel, Advisors, and Investigators

  15. Back-up Slides

  16. Baseline VAT & SAT in both studies Study 22388 Study 24380 Mean baseline (cm2) Mean baseline (cm2) r-hGH 4 mg DD Placebo Placebo r-hGH 4 mg DD *Kotler et al., Letter, JAIDS, 2006 (in press)

  17. Study 22388 Mean change from baseline (cm2) * * Placebo r-hGH 4 mg DD Mean Change in VAT & SAT during 12-Week Induction Therapy in Both Studies Study 24380 Mean change from baseline (cm2) * * Placebo r-hGH 4 mg DD *p < 0.001 compared to placebo, corrected data (Kotler et al., Letter, JAIDS, 2006, in press) *p < 0.001 compared to placebo Greater percent decrease in VAT than SAT on r-hGH

  18. HbA1c and HIV-1 RNA levels, Baseline to Week 36: Study 24380 Mean HbA1c (%) Proportions of patients with HIV-1-RNA 400 copies/mL

  19. Mean Change in Non-HDL and LDLCholesterol, BL to Week 36: Study 24380 All Patients Dyslipidemic at Baseline† Mean Change from baseline (mg/dL) Mean Change from baseline (mg/dL) ‡ * * GH-Placebo GH-GH 2 mg AD GH-Placebo GH-GH 2 mg AD †Non-HDL-C 130 mg/dL LDL-C 100 mg/dL No significant differences - GH-GH 2 mg AD and GH-Placebo maintenance groups ‡p < 0.05 for change from BL *p < 0.001 for change from BL

  20. * * Mean Change from baseline (mg/dL) GH-Placebo GH-GH 2 mg DD Mean Change in HDL Cholesterol, Baseline to Week 36: Study 24380 All Patients (ITT) Dyslipidemic at Baseline† * * Mean Change from baseline (mg/dL) GH-Placebo GH-GH 2 mg DD †HDL-C <40 mg/dL No significant differences - GH-GH 2 mg AD and GH-Placebo maintenance groups *p < 0.001 for change from BL

  21. p = 0.014‡ p < 0.001‡ Maintenance Therapy, Study 24380 VAT: Weeks 12 to 36 Percent change VAT: BL to Week 36 All Patients (ITT): 24380 • Major endpoint for Maintenance was met: No more than 50% of pts regained more than 50% of the VAT lost during induction therapy • Pre-specified Endpoint: Failure Rate = Percentage of patients who (during Wks 12-36) regained > 50% of VAT lost during r-hGH induction therapy • Placebo FAILED; 53.7% regained more than 50% of VAT lost • r-hGH dosed 2 mg AD SUCCEEDED; 40.3% regained more than 50% of VAT lost GH-Placebo GH-GH 2AD +3.1% -3.5% % Change p = 0.103‡ p = 0.018‡ ‡from baseline, p = 0.367 between groups Patients who lost VAT from Weeks 1 to 12 GH-Placebo GH-GH 2AD +0.8% -14.7% % Change ‡from baseline, p = 0.911 between groups

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