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

4. Phase III Trial Design: Study 24380 o Double-Blind o Placebo-Controlled o N = 325 o Duration 36 weeks: o 12 Wks Induction o 24 Wks Maintenance (ARM A only) 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) Baseline12 Wks24 Wks36 Wks Randomized 3:1 Placebo DD GH 2 mg AD Placebo AD GH 4 mg DD GH 2 mg AD R ARM A = 244 ARM B = 81 Weeks 0 - 12Weeks 12-36 Open-label extension Study 25373 n = 92 n = 73 n = 93 n = randomized and received study drug

5. Endpoints & Eligibility: Study 24380 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 and WHR  0.95 Women: WC > 75.3 cm and WHR  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 VAT = Visceral Adipose Tissue on CT scan at L4-5 WC = Waist circumference WHR = Waist:Hip Ratio

6. Baseline Characteristics: Study 24380 Characteristic Placebo (n=79) 4 mg DD (n=243) p-value Age (yrs)*45 ± 0.845 ± 0.40.365 % Female11 (14)36 (15)0.846 CD4 (cells/mm 3 )*493 ± 32501 ± 180.814 BMI (kg/m 2 )*27.8 ± 0.527.2 ± 0.20.629 % Body Fat22 ± 122 ± 0.50.432 CT VAT (cm 2 )*135 ± 7136 ± 40.620 DXA Trunk Fat (kg)*12.3 ± 0.511.8 ± 0.30.346 DXA Limb SAT (kg)*6.1 ± 0.55.6 ± 0.20.289 Use of PI (n [%])50 (62)152 (62)>0.999 Use of NRTI (n [%])81 (100)228 (93)0.015 Use of NNRTI (n [%])37 (46)114 (47)0.898 * Mean ± SEM

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

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

9. VAT: Weeks 12 to 36VAT: Baseline to Week 36 Maintenance Therapy: Study 24380 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 All Patients (ITT) ‡ from baseline, p = 0.295 between groups Patients who lost VAT from Weeks 1 to 12 ‡ from baseline, p = 0.473 between groups GH-Placebo p = 0.027 ‡ - 7.9 cm 2 Mean Change (cm 2 ) - 15.7 cm 2 p < 0.001 ‡ GH-GH 2ADGH-Placebo p <0.001 ‡ p = 0.008 ‡ -10.0 cm 2 Mean Change (cm 2 ) -26.6 cm 2 GH-GH 2AD

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

11. Most Common Adverse Events (  10%)* Week 12, Study 24380 Adverse Event, n (%) Placebo (n=81) 4 mg DD (n=244) p-value Edema peripheral4 (5)113 (46)<0.001 Arthralgia14 (17)95 (39)<0.001 Pain in extremity3 (4)46 (19)<0.001 Headache3 (4)39 (16)0.004 Hypoesthesia034 (14)<0.001 Myalgia3 (4)34 (14)0.014 Blood glucose increased2 (3)33 (14)0.003 Paresthesia3 (4)25 (10)0.107 *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 (  10%), n (%) 4DD-PL-PL (n=93) 4DD-2AD-2AD (n=92) p-value Upper respiratory tract infection 15 (16)7 (8)0.110 4DD-PL-PL4DD-2AD-2AD Typical AEs, n (%)(n=93)(n=92)p-value Edema peripheral4 (4)6 (7)0.536 Arthralgia5 (5)8 (9)0.405 Pain in extremity5 (5)2 (2)0.444 Headache4 (4)5 (5)0.747 Hypoesthesia1 (1)5 (5)0.118 Myalgia2 (2) >0.999 Blood glucose increased3 (3)6 (6)0.330 Paresthesia4 (4) >0.999 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. 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 Summary & Conclusions: Study 24380

14. Thanks to all 24380 Study Subjects, Study Personnel, Advisors, and Investigators Acknowledgements 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

15. Back-up Slides

16. Mean baseline (cm 2 ) Placebor-hGH 4 mg DD Baseline VAT & SAT in both studies Study 24380 * Kotler et al., Letter, JAIDS, 2006 (in press) Placebo r-hGH 4 mg DD Study 22388 Mean baseline (cm 2 )

17. Mean change from baseline (cm 2 ) * * Placebor-hGH 4 mg DD Mean Change in VAT & SAT during 12- Week Induction Therapy in Both Studies Greater percent decrease in VAT than SAT on r-hGH Study 24380 * p < 0.001 compared to placebo, corrected data (Kotler et al., Letter, JAIDS, 2006, in press) * p < 0.001 compared to placebo Placebor-hGH 4 mg DD Study 22388 * * Mean change from baseline (cm 2 )

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

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

21. VAT: Weeks 12 to 36Percent change VAT: BL to Week 36 Maintenance Therapy, Study 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 All Patients (ITT): 24380 ‡ from baseline, p = 0.367 between groups Patients who lost VAT from Weeks 1 to 12 % Change ‡ from baseline, p = 0.911 between groups p < 0.001 ‡ p = 0.014 ‡ p = 0.018 ‡ p = 0.103 ‡ GH-GH 2AD GH-Placebo GH-GH 2ADGH-Placebo +3.1%-3.5% +0.8%-14.7%