Carla Chieffo, VMD, PhD,1 Lawrence A. Frohman, MD,2 Harry Quandt, BS,1 Stefanie Decker, MS,1 Mônica R. Gadelha, MD, PhD3

1Endo Pharmaceuticals Inc., Chadds Ford, PA, USA; 2University of Illinois at Chicago, Chicago, IL, USA; 3Federal 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 monthlyinjections and are associated with large peak-to-trough changes in drug concentrations2

• 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

1Freda et al. J Clin Endocrinol Metab. 2005;90(8):4465-4473; 2Astruc et al. J Clin Pharmacol. 2005;45(7):836-844

• 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

Inclusion Exclusion

• 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

Characteristics1-Implant Group

(n=5)2-Implant Group

(n=6)All Patients

(n=11)

Age (mean [range]), y 50.8 (39−78) 43.8 (31−58) 47.0 (31−78)

Women, n (%) 5 (100) 2 (33) 7 (64)

Weight (mean ± SD), kg 74.8±12.9 88.0±11.6 83.0±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 1 Month 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±16 50±26 43±16 42±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/mL 1 (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=3

n=5

n=5

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

5 4 4 2 3 4 3

3 3 3 4 3 1 1

Treatment-related AEs Diarrhea Abdominal pain Abdominal distension Alopecia Flatulence Loose stools Vomiting Implant site pain

4 1 0101 1 0

3 11 01 001*

*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