Transcript Danoff_Eff_saf_QoL_AACE_11_Presentation__final

Effectiveness and Safety of an
Octreotide Hydrogel Implant in
Patients With Acromegaly
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
Background
• 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 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
1Freda
et al. J Clin Endocrinol Metab. 2005;90(8):4465-4473; 2Astruc et al. J Clin Pharmacol. 2005;45(7):836-844
Objective and Study Design
• 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
Inclusion/Exclusion Criteria
Inclusion
Exclusion
• Aged ≥18 y with a GH-secreting tumor
≥3 mm from the optic chiasm
• Octreotide discontinuation due to poor
tolerability or efficacy
• Demonstrated response to octreotide
• Previous radiotherapy or recent pituitary
surgery <12 weeks before screening
• Serum GH concentration ≥1 ng/mL
after OGTT
• Serum IGF-1 concentration ≥30% above
upper limit of age-adjusted normal value
• 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
Assessments
• 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
Baseline Patient Characteristics
• 11 patients met the screening criteria and were implanted
• All patients completed 6 months of treatment
1-Implant Group
(n=5)
2-Implant Group
(n=6)
All Patients
(n=11)
50.8 (39−78)
43.8 (31−58)
47.0 (31−78)
5 (100)
2 (33)
7 (64)
74.8±12.9
88.0±11.6
83.0±13.5
OLAR, n (%)
5 (100)
6 (100)
11 (100)
Other, n (%)*
1 (20)
1 (17)
2 (18)
Characteristics
Age (mean [range]), y
Women, n (%)
Weight (mean ± SD), kg
Past acromegaly therapy
*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)
42±16
50±26
43±16
42±23
Mean ± SD decrease in IGF-1, %
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
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
0
1
0
1
1
0
3
1
1
0
1
0
0
1*
AEs, n (%)
*Mild insertion site pain the day of the implantation procedure; dipyrone was administered, and the pain resolved the next day
Conclusions
• 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
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.
Endpoints
• 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