Matthieu Ruffin

Pasireotide Versus Octreotide in Acromegaly: A Head-to-Head Superiority Study

Context: Biochemical control reduces morbidity and increases life expectancy in patients with acromegaly. With current medical therapies, including the gold standard octreotide long-acting-release (LAR), many patients do not achieve biochemical control. Objective: Our objective was to demonstrate the superiority of pasireotide LAR over octreotide LAR in medically naive patients with acromegaly. Design and Setting: We conducted a prospective, randomized, double-blind study at 84 sites in 27 countries. Patients: A total of 358 patients with medically naive acromegaly (GH >5 μg/L or GH nadir ≥1 μg/L after an oral glucose tolerance test (OGTT) and IGF-1 above the upper limit of normal) were enrolled. Patients either had previous pituitary surgery but no medical treatment or were de novo with a visible pituitary adenoma on magnetic resonance imaging. Interventions: Patients received pasireotide LAR 40 mg/28 days (n = 176) or octreotide LAR 20 mg/28 days (n = 182) for 12 months. At months 3 and 7, titration to pasireotide LAR 60 mg or octreotide LAR 30 mg was permitted, but not mandatory, if GH ≥2.5μg/L and/or IGF-1 was above the upper limit of normal. Main Outcome Measure: The main outcome measure was the proportion of patients in each treatment arm with biochemical control (GH <2.5 μg/L and normal IGF-1) at month 12. Results: Biochemical control was achieved by significantly more pasireotide LAR patients than octreotide LAR patients (31.3% vs 19.2%; P = .007; 35.8% vs 20.9% when including patients with IGF-1 below the lower normal limit). In pasireotide LAR and octreotide LAR patients, respectively, 38.6% and 23.6% (P = .002) achieved normal IGF-1, and 48.3% and 51.6% achieved GH <2.5 μg/L. 31.0% of pasireotide LAR and 22.2% of octreotide LAR patients who did not achieve biochemical control did not receive the recommended dose increase. Hyperglycemia-related adverse events were more common with pasireotide LAR (57.3% vs 21.7%). Conclusions: Pasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option for acromegaly.

A first-in-man study to evaluate the safety, tolerability, and pharmacokinetics of pasireotide (SOM230), a multireceptor-targeted somatostatin analog, in healthy volunteers

Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for four of the five somatostatin receptor subtypes (sst1,2,3 and sst5), and potential clinical activity in several neuroendocrine and oncologic conditions, including acromegaly, Cushing’s disease, and neuroendocrine tumors (NET). This manuscript reports the first-in-man dose-escalation study of pasireotide, evaluating its safety, tolerability, and pharmacokinetics (PK) in healthy male volunteers. A single dose of pasireotide 1–1200 μg was administered subcutaneously in four to eight subjects per dose level, with two additional subjects per cohort administered placebo. PK and safety evaluations were carried out over 7 days post-dose. Growth hormone (GH) suppression was evaluated using a GH-releasing hormone stimulation test on Day –1 and Day 1 at 3–5 hours post-injection. Seventy-two subjects completed the study. Pasireotide was well tolerated with no serious adverse events observed at any dose. Transient elevations in blood glucose levels were observed 2–6 hours after administration of pasireotide at doses between 200 μg and 1200 μg, but this resolved without intervention by 23 hours post-dosing. The maximum tolerable dose was not established within the tested range. Pasireotide demonstrated a favorable PK profile with fast absorption (tmax: 0.25–0.5 hours), low clearance (CL/F: 8–13 L/hour), long effective elimination half-life (mean t½,β: 7–11 hours), and a proportional dose-exposure relationship. GH suppression of 79%–96% was observed at single pasireotide doses between 200 μg and 1200 μg. In conclusion, pasireotide demonstrated favorable safety, tolerability, and PK profiles, as well as promising activity in suppressing the release of GH. The efficacy and safety of pasireotide is currently being evaluated in patients with acromegaly, Cushing’s disease, NET, and various non-neuroendocrine disorders.

Safety, tolerability, and pharmacokinetics of a single dose of pasireotide long-acting release in healthy volunteers: a single-center Phase I study.

OBJECTIVE This study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PKs) of different doses of a long-acting release (LAR) formulation of pasireotide in healthy subjects. DESIGN Single-center, open-label, randomized Phase I study. METHODS Twelve healthy male subjects received a single s.c. dose of pasireotide 300 μg followed by a washout period of 7 days (or at least 5 days), before receiving an i.m. injection of pasireotide -LAR 40 mg (n=5) or 60 mg (n=7). Assessments included adverse events (AEs), PKs, and glucose, insulin, glucagon, and HbA1c levels. RESULTS Pasireotide LAR showed an extended-release profile over 1 month with two concentration peaks observed 1 and around 20 days after injection. The area under curve exposure of pasireotide LAR was dose proportional when the dose levels were compared, and the bioavailability of the LAR relative to the s.c. formulation was complete. Administration of pasireotide LAR resulted in an increase in fasting and postprandial glucose levels; however, an attenuation of the hyperglycemic effect was observed after 15 days. The most frequently reported AEs were mild-to-moderate diarrhea, abdominal pain, and flatulence. Only gastrointestinal AEs and injection site reactions were suspected to be drug related. CONCLUSIONS Pasireotide LAR was generally well tolerated with mostly mild AEs at doses up to 60 mg and showed a dose-proportional, extended-release profile in healthy subjects. Based on the favorable results of this study, further clinical development of pasireotide LAR is under way, which will give insight into the PKs, efficacy, and safety of pasireotide LAR in patient populations.

Effect of hepatic impairment on the pharmacokinetics of pasireotide (SOM230): results from a multicenter phase I study.

Pasireotide is a novel, multireceptor‐targeted somatostatin analogue with high affinity for sst1,2,3 and sst5 under clinical evaluation in tumors of neuroendocrine origin, including Cushings disease, acromegaly, and neuroendocrine tumors. In this phase I, open‐label, multicenter study, the pharmacokinetics and safety of a single subcutaneous (SC) injection of pasireotide 600 μg were evaluated in adults with normal hepatic function (n = 15) and mild (n = 6), moderate (n = 7), or severe hepatic impairment (n = 6). Following a single dose of pasireotide SC 600 μg, there were no significant differences in the plasma exposure of pasireotide between participants with normal hepatic function or mild hepatic impairment. Subjects with moderate and severe hepatic impairment showed an increase in AUC∞ by 56% and 42%, respectively; this increase was 60% and 79% respectively, after adjusting for differences in age, BMI, and baseline serum albumin level between treatment groups. The incidence and severity of adverse events were similar across cohorts, with no clinically relevant differences in type or frequency of adverse events between cohorts. In conclusion, a single dose of pasireotide SC 600 μg was well tolerated in subjects with hepatic impairment. Drug exposure in subjects with mild hepatic impairment was similar to that seen in healthy volunteers, whereas subjects with moderate and severe hepatic impairment experienced higher exposure to pasireotide. Adjustment of the pasireotide dose may be required for patients with moderate and severe hepatic impairment.

Erratum to: Long-term efficacy and safety of subcutaneous pasireotide in acromegaly: Results from an open-ended, multicenter, Phase II extension study (Pituitary DOI: 10.1007/s11102-013-0478-0)

Pasireotide has a broader somatostatin receptor binding profile than other somatostatin analogues. A 16-week, Phase II trial showed that pasireotide may be an effective treatment for acromegaly. An extension to this trial assessed the long-term efficacy and safety of pasireotide. This study was an open-label, single-arm, open-ended extension study (primary efficacy and safety evaluated at month 6). Patients could enter the extension if they achieved biochemical control (GH B 2.5 lg/L and normal IGF-1) or showed clinically relevant improvements during the core study. Thirty of the 60 patients who received pasireotide (200–900 lg bid) in the core study entered the extension. At extension month 6, of the 26 evaluable patients, six were biochemically controlled, of whom five had achieved control during the core study. Normal IGF-1 was achieved by 13/26 patients and GH B 2.5 lg/L by 12/26 at month 6. Nine patients received pasireotide for C24 months in the extension; three who were biochemically controlled at month 24 had achieved control during the core study. Of 29 patients with MRI data, nine had significant (C20 %) tumor volume reduction during the core study; an additional eight had significant reduction during the extension. The most common adverse events were transient gastrointestinal disturbances; Clinical Trials Registration Number: NCT00171730. Electronic supplementary material The online version of this article (doi:10.1007/s11102-013-0478-0) contains supplementary material, which is available to authorized users. S. Petersenn (&) ENDOC Center for Endocrine Tumors, Altonaer Str. 59, 20357 Hamburg, Germany e-mail: stephan.petersenn@endoc-med.de A. J. Farrall Brain Research Imaging Centre, Western General Hospital, University of Edinburgh, Edinburgh, UK C. Block Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Antwerp, Belgium S. Melmed Division of Endocrinology and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA J. Schopohl Medizinische Klinik und Poliklinik IV, Campus Innenstadt, University of Munich, Munich, Germany P. Caron Service d’Endocrinologie, Maladies Métaboliques et Nutrition, Centre Hospitalier Universitaire Larrey, Toulouse, France R. Cuneo Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, Australia D. Kleinberg Neuroendocrine Unit, New York University School of Medicine, New York, NY, USA A. Colao Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Naples, Italy M. Ruffin G. Hughes Novartis Pharma AG, Basel, Switzerland K. Hermosillo Reséndiz K. Hu Novartis Pharmaceuticals, East Hanover, NJ, USA A. Barkan Pituitary and Neuroendocrine Center, University of Michigan, Ann Arbor, MI, USA 123 Pituitary (2014) 17:132–140 DOI 10.1007/s11102-013-0478-0

Treatment with pasireotide LAR normalizes prolactin levels in patients with acromegaly and hyperprolactinemia: randomized, double-blind, 12-month, phase III study

A Colao,1 P Freda,2 F Gu,3 K Hermosillo Resendiz,4 M Ruffin,5 Y Chen,4 M Bronstein6 1Dipartimento di Medicina Clinica e Chirurgia, Universita Federico II di Napoli, Naples, Italy; 2Department of Medicine, Columbia University College of Physicians & Surgeons, New York, New York, USA; 3Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, China; 4Novartis Pharmaceuticals Corporation, Florham Park, New Jersey, USA; 5Clinical Development, Oncology Business Unit, Novartis Pharma AG, Basel, Switzerland; 6Neuroendocrine Unit, Division of Endocrinology and Metabolism, University of Sao Paulo Medical School, Sao Paulo, Brazil