OR17-5 Efficacy and Safety of Oral Octreotide in Acromegaly: Results of a Multicenter Phase III Trial in 155 Patients

Program: Abstracts - Orals, Poster Preview Presentations, and Posters
Session: OR17-From Genetics to Clinical Trials in Pituitary Disease
Sunday, June 22, 2014: 11:30 AM-1:00 PM
Presentation Start Time: 12:30 PM
W192 (McCormick Place West Building)
S Melmed1, V Popovic-Brkic2, M Bidlingmaier3, M Mercado4, AJ van der Lely5, N R Biermasz6, M Bolanowski7, M Coculescu8, J Schopohl9, K Racz10, B Glaser11, M I Goth12, Y Greenman13, P J Trainer, MD FRCP14, E Mezosi15, I Shimon16, A Giustina17, D L Kleinberg18, S L Teichman19, R Mamluk20, A Haviv20 and C J Strasburger21
1Cedars-Sinai Med Center, Los Angeles, CA, 2Clinical Center of Serbia, Belgrade, Serbia, 3Klinikum der Univ Muenchen, Munich, Germany, 4Centro Médico ABC, Mexico City, Mexico, 5Erasmus Medical Center, Rotterdam, The Netherlands, 6Leiden University Medical Center, Leiden, 7Wroclaw University, Wroclaw, Poland, 8National Institute of Endo, Bucharest, Romania, 9University of Munich, Munich, Germany, 10Semmelweis University, Budapest, Hungary, 11Hadassah Medical Center, Jerusalem, Israel, 12Military Hospital, Budapest, Hungary, 13Sourasky Medical Center, Tel Aviv, Israel, 14Department of Endocrinology, Christie Hospital, Manchester, UK, 15University of Pecs,Pecs,Hungary, 16Rabin Medical Center, Petah-Tikva, Israel, 17University of Brescia, Brescia, Italy, 18NYU Langone Medical Center, New York, NY, 19San Francisco,CA, 20Chiasma, Jerusalem, Israel, 21Charite, Berlin, Germany
Background:Oral octreotide acetate (OOA), a novel formulation of octreotide, is biologically active, inhibiting pituitary growth hormone (GH) secretion in healthy volunteers. Accordingly, OOA was tested for acromegaly efficacy and safety in a phase III, global, multicenter, open-label, dose-titration, baseline-controlled study.

Methods:After screening, 155 subjects shown to be controlled (defined as IGF-I levels <1.3 ULN, and 2hr integrated GH <2.5 ng/mL, measured centrally), while on 3 months of injectable somatostatin receptor ligand (SRL), were enrolled. Following OOA pre-treatment baseline establishment and after 4 weeks from last SRL injection, subjects were switched to OOA. All entered a dose escalation phase, initially receiving OOA 40 mg/day, titrated as required to 60 mg/day, and up to 80 mg/day (divided into two separate daily doses), to normalize IGF-I levels. This was followed by a fixed dose phase for up to a total duration of 7 months of OOA treatment (core treatment period). Controlled patients were then offered an additional 6-month extension phase.

Results:Of 151 evaluable subjects that initiated OOA treatment and had at least one evaluation following first dose, 98 (65%) achieved the primary endpoint of hormonal control at their last assessment during the core treatment period, with IGF-I levels <1.3 ULN and mean 2 hr GH concentrations of <2.5 ng/mL. Following individual dose titration based on IGF-I levels, 61, 33, and 57 patients reached doses of 40, 60, and 80 mg, respectively. Of the 91 subjects who were controlled (IGF-I <1.3 ULN) at the end of dose escalation, 83 (91%) maintained this response at the end of the core treatment period. A total of 102 subjects completed the core treatment period, of whom 88 (86%) elected to continue treatment in the 6 month extension phase. Twenty-four subjects (15%) were considered treatment failures due to IGF-I level >1.3 ULN and terminated prior to the end of the core period. Seventeen subjects (11%) terminated for possible drug-related adverse events (AEs), consistent with known octreotide or disease-related AEs. Ten of the early terminations were due to GI symptoms (mostly mild to moderate nausea, diarrhea, or abdominal pain). Two deaths were reported: one of myocardial infarction in a patient with pancreatic carcinoma and obstructive jaundice, and another of suspected biliary obstruction and sepsis.

Conclusions: Oral octreotide acetate exhibits efficacy in controlling IGF-I and GH levels in acromegaly patients treated for at least 7 months, following a switch from injectable SRLs with a safety profile consistent with approved SRLs. OOA is a viable option for administration as oral acromegaly monotherapy.

Disclosure: SM: Principal Investigator, Pfizer, Inc., Ad Hoc Consultant, Genentech, Inc., Ad Hoc Consultant, Novartis Pharmaceuticals, Ad Hoc Consultant, Ipsen. VP: Coinvestigator, Roche Pharmaceuticals. MM: Speaker, Sanofi/Ipsen, Consultant, Sanofi/Ipsen, Speaker, Novartis Pharmaceuticals, Consultant, Novartis Pharmaceuticals. JS: Study Investigator, Chiasma, Study Investigator, Novartis Pharmaceuticals. PJT: Advisory Group Member, Roche Pharmaceuticals, Investigator, Chiasma, Advisory Group Member, unrelated to this study/product - unpaid ad hoc advisory board member. IS: Ad Hoc Consultant, Novartis Pharmaceuticals, Ad Hoc Consultant, Pfizer, Inc., Ad Hoc Consultant, Novo Nordisk, Ad Hoc Consultant, Neopharm. DLK: Advisory Group Member, Genentech, Inc.. SLT: Employee, chiasma. RM: Employee, Chiasma. AH: Employee, Chiasma Pharma. CJS: Advisory Group Member, Chiasma. Nothing to Disclose: MB, AV, NRB, MB, MC, KR, BG, MIG, YG, EM, AG

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Sources of Research Support: Chiasma