Carla Chieffo, VMD, PhD, 1 Lawrence A. Frohman, MD, 2 Harry Quandt, BS, 1 Stefanie Decker, MS, 1 Mônica R. Gadelha, MD, PhD 3 1 Endo Pharmaceuticals Inc., Chadds Ford, PA, USA; 2 University of Illinois at Chicago, Chicago, IL, USA; 3 Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil This research was funded by Endo Pharmaceuticals Inc., Chadds Ford, PA, USA. The information concerns an investigational use of a drug that has not been approved by the US Food and Drug Administration Effectiveness and Safety of an Octreotide Hydrogel Implant in Patients With Acromegaly

Approximately 60% of patients with acromegaly achieve biochemical control with octreotide long-acting release (OLAR) 1 OLAR and lanreotide sustained release require monthly injections and are associated with large peak-to-trough changes in drug concentrations 2 Drug-release technologies that extend the dosing interval and reduce drug-concentration fluctuations could improve compliance, symptom management, and tolerability A subcutaneous octreotide hydrogel implant (OHI) has been developed that provides constant octreotide release for 6 months Background 1 Freda et al. J Clin Endocrinol Metab. 2005;90(8): ; 2 Astruc et al. J Clin Pharmacol. 2005;45(7):

Objective –To evaluate the effectiveness and safety of a subcutaneous 52-mg OHI for the treatment of acromegaly Study Design –Phase II, open-label, randomized study at a single Brazilian center First study to evaluate the effectiveness and safety of OHI –Acromegaly patients were randomized to receive one or two 52-mg hydrated OHI (60-mg octreotide acetate) Inserted subcutaneously in the upper arm on day 1 and removed at month 6 Visits were scheduled monthly through month 7 Objective and Study Design

InclusionExclusion Aged ≥18 y with a GH-secreting tumor ≥3 mm from the optic chiasm Demonstrated response to octreotide Serum GH concentration ≥1 ng/mL after OGTT Serum IGF-1 concentration ≥30% above upper limit of age-adjusted normal value Octreotide discontinuation due to poor tolerability or efficacy Previous radiotherapy or recent pituitary surgery <12 weeks before screening Dopamine agonist or investigational drug within 2 or 3 months of screening, respectively Liver disease, symptomatic cholelithiasis, signs/symptoms of coronary heart disease (≤3 mo of screening), heart failure, drug or alcohol abuse, hypersensitivity to octreotide, pregnancy GH=growth hormone; IGF-1=insulin-like growth factor–1; OGTT=oral glucose tolerance test Inclusion/Exclusion Criteria

Serum IGF-1 concentration assessed monthly using single blood samples (months 1–7) Serum GH concentration assessed monthly using –Single blood samples (months 1, 3, 5, 7) –5 serial blood samples drawn every 30 minutes for 2 hours (day 1/preinsertion and months 2 and 4) OGTT at screening and month 6 –GH concentration assessed 0, 30, 60, 90, and 120 minutes after OGTT Tumor size and quality of life (QoL) were assessed at screening and month 6 Safety –Adverse events (AEs), physical examination, vital signs, electrocardiograms, gallbladder ultrasound, hematology, clinical chemistry, thyroid profiles, and HgbA1c Assessments

11 patients met the screening criteria and were implanted All patients completed 6 months of treatment Baseline Patient Characteristics Characteristics 1-Implant Group (n=5) 2-Implant Group (n=6) All Patients (n=11) Age (mean [range]), y50.8 (39−78)43.8 (31−58)47.0 (31−78) Women, n (%)5 (100)2 (33)7 (64) Weight (mean ± SD), kg74.8± ± ±13.5 Past acromegaly therapy OLAR, n (%)5 (100)6 (100)11 (100) Other, n (%)*1 (20)1 (17)2 (18) *1 patient received bromocriptine and 1 patient received cabergoline ≥3 y before the study

Mean IGF-1 Concentration

Normalization of IGF-1 Normal age-adjusted range was achieved by 1 patient in the 1-implant group and 2 patients in the 2-implant group ≥40% decrease in patients who did not normalize IGF-1 Month 1Month 6 Patient Characteristics 1-Implant Group (n=5) 2-Implant Group (n=6) 1-Implant Group (n=5) 2-Implant Group (n=6) Normalized IGF-1, n (%)1 (20)2 (33)0 (0)2 (33) Did not normalize IGF-1, n (%)4 (80)4 (67)5 (100)4 (67) Mean ± SD decrease in IGF-1, %42±1650±2643±1642±23

Mean GH Concentration

Suppression of GH GH after OGTT at month 6 and mean on-treatment GH are shown 1-Implant Group (n=5) 2-Implant Group (n=6) GH concentration following OGTT at month 6, n (%) Patients with GH <1 ng/mL1 (20)3 (50) Patients with the following mean on-treatment GH concentrations, n (%) Mean GH <5 ng/mL Mean GH <2.5 ng/mL Mean GH <1 ng/mL 5 (100) 4 (80) 1 (20) 5 (83) 4 (67) 2 (33)

Tumor Size Reduced by 23% with 1 implant and 38% with 2 implants n=3 n=5

1.To what extent do you feel that the treatment you are receiving for acromegaly is effective? 2.To what extent are you satisfied with the current treatment regimen? 3.To what extent is your current treatment uncomfortable or painful? 4.To what extent is your current treatment regimen inconvenient or disruptive to work or other activities? Quality of Life

Patient ratings of effectiveness and satisfaction were high Patient ratings of discomfort/pain and disruption of daily activities were low Scale: 0=lowest, 10=highest

Safety AEs, n (%) 1-Implant Group (n=5) 2-Implant Group (n=6) Most frequent AEs Fatigue Diarrhea Hyperhidrosis Arthralgia Headache Paresthesia Peripheral edema Treatment-related AEs Diarrhea Abdominal pain Abdominal distension Alopecia Flatulence Loose stools Vomiting Implant site pain * *Mild insertion site pain the day of the implantation procedure; dipyrone was administered, and the pain resolved the next day

52-mg OHI provided consistent biochemical control over 6 months and reduced tumor size OHI was a safe and effective delivery system for treating patients with acromegaly High satisfaction and effectiveness ratings for the OHI Phase III studies of the OHI (84 mg) are ongoing Conclusions This research was funded by Endo Pharmaceuticals Inc., Chadds Ford, PA, USA The information concerns investigational use of a drug that has not been approved by the US Food and Drug Administration

Author Disclosures Carla Chieffo: employee of Endo Pharmaceuticals Inc. Lawrence A. Frohman: consultant to Endo Pharmaceuticals Inc. Harry Quandt: employee of Endo Pharmaceuticals Inc. Stefanie Decker: employee of Endo Pharmaceuticals Inc. Mônica R. Gadelha: nothing to disclose Presenter: Theodore Danoff, MD, PhD, Vice President of Clinical Development, Endocrinology/Urology, Endo Pharmaceuticals Inc.

At each monthly visit, suppression of –IGF-1 –GH (single GH and mean 2-h serial GH concentrations) After an OGTT at month 6, suppression of GH to <1.0 ng/mL Within patient, IGF-1 and GH concentration over the entire 6-month treatment period Reduction in tumor size QoL ratings of the treatment Endpoints