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Safety and tolerability of pasireotide long-acting release in acromegaly-results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study.

ABSTRACT: Pasireotide long-acting release is a somatostatin analog that is indicated for treatment of patients with acromegaly. This analysis documents the safety of pasireotide long-acting release in patients with acromegaly enrolled in the ACCESS trial (ClinicalTrials.gov identifier: NCT01995734).ACCESS is an open-label, multicenter, single-arm, expanded-treatment protocol designed to provide patients access to pasireotide long-acting release pending regulatory approval. Patients received pasireotide long-acting release 40?mg administered intramuscularly every 28 days. The primary outcome was the proportion of patients having a treatment-emergent grade ?3 or serious adverse event. Efficacy data were not collected.Forty-four adult patients with active acromegaly were enrolled in the study for an average of 37.6 weeks (range, 4-70 weeks). Twenty-five grade ?3 treatment-emergent adverse events were reported in 11 patients (25.0?%), 3 of whom (27.3?%) experienced grade ?3 hyperglycemia. In patients treated with pasireotide long-acting release for ?3 months (n?=?42), mean glycated hemoglobin and fasting plasma glucose levels increased significantly from 5.9?% and 100.4?mg/dL at baseline to 6.8?% and 135.9?mg/dL at 3 months, respectively. Ten patients (22.7?%) were treated with pasireotide long-acting release for ?15 months, after which mean glycated hemoglobin and fasting plasma glucose levels were 6.3?% and 123?mg/dL, respectively. Twenty-one patients (48?%) initiated antidiabetic medication.Grade ?3 adverse events (primary outcome) were reported in 25.0?% of acromegaly patients treated with pasireotide long-acting release in a clinical setting. Hyperglycemia-related adverse events were reported in 45.5?% of patients, but were typically manageable, supporting the role of pasireotide long-acting release as a safe treatment option for acromegaly patients.

SUBMITTER: Fleseriu M

PROVIDER: S-EPMC5225222 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Safety and tolerability of pasireotide long-acting release in acromegaly-results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study.

Fleseriu Maria M Rusch Elisha E Geer Eliza B EB

Endocrine 20161128 1

<h4>Purpose</h4>Pasireotide long-acting release is a somatostatin analog that is indicated for treatment of patients with acromegaly. This analysis documents the safety of pasireotide long-acting release in patients with acromegaly enrolled in the ACCESS trial (ClinicalTrials.gov identifier: NCT01995734).<h4>Methods</h4>ACCESS is an open-label, multicenter, single-arm, expanded-treatment protocol designed to provide patients access to pasireotide long-acting release pending regulatory approval. ...[more]

PMID: 27896545

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Project description:Abstract Background: In a 24-week, Phase 3 study (PAOLA), long-acting pasireotide demonstrated superior efficacy (GH <2.5 µg/L and IGF-1 <ULN) over continued treatment with long-acting octreotide/lanreotide in pts with uncontrolled acromegaly (Gadelha MR, et al. Lancet Diabetes Endocrinol. 2014;2:875-884). An earlier (3 months) switch to long-acting pasireotide and the current criteria for biochemical control, i.e. GH <1 μg/L and IGF-1 <ULN, are considered in the present phase 3b study. This study (clinicaltrials.gov: NCT02354508) evaluated the efficacy (GH <1 μg/L and IGF-1 <ULN) and safety of long‑acting pasireotide in pts with uncontrolled acromegaly despite ≥3 months of treatment with maximal approved doses of first-generation SSAs. Methods: Adults with uncontrolled acromegaly (mean GH [mGH] ≥1 µg/L and IGF-1 >1.3xULN) despite ≥3 months of treatment with maximal approved doses of long-acting octreotide/lanreotide received open-label long-acting pasireotide 40 mg/28 days. Pasireotide dose could be up titrated to 60 mg/28 days after week 12 if the biochemical control was not achieved or down titrated to 20 mg/28 days or 10 mg/28 days for tolerability. Primary endpoint: proportion of pts with mGH <1 μg/L and IGF-1 <ULN at week 36 overall and by screening mGH (1.0-2.5 μg/L and >2.5 μg/L). Results: 123 pts received long-acting pasireotide: median age, 43.0 years (range, 22-76); female, 50.4%; baseline median (range) mGH, 5.4 µg/L (1.2-195.5) and IGF-1, 2.3xULN (1.4-7.9); prediabetic/diabetic at baseline, n=112 (91.1%). The median duration of exposure to pasireotide was 36.0 weeks (median dose intensity, 53.3 mg/month). Overall, 18 pts (14.6% [95%CI, 8.9-22.1]) achieved biochemical control at week 36 (primary endpoint); 12 (42.9% [95%CI, 24.5-62.8]) and 6 pts (6.4% [95%CI, 2.4-13.4]) by screening mGH levels of 1.0 to 2.5 µg/L (n=28) and >2.5 µg/L (n=94), respectively. At week 36, 23 (18.7%), 16 (57.1%) and 7 pts (7.4%) had GH <1 µg/L; and 38 (30.9%), 14 (50.0%) and 24 pts (25.5%) had IGF-1 <ULN overall and by screening mGH levels of 1.0 to 2.5 µg/L and >2.5 µg/L, respectively. The median percentage decreases in mGH and standardized IGF-1 from baseline to week 36 were 56.8% and 42.8%. The most common AEs (>15%) regardless of study drug relationship were hyperglycemia (43.1%), diabetes mellitus (22.0%), and diarrhea (15.4%). Hyperglycemia-related AEs suspected to be drug related occurred in 81 pts (66%) overall and 4 of 11 pts (36.4%) who were nondiabetic at baseline. A total of 10 pts (8.1%) discontinued treatment either because of AEs (n=4; 3.3%) or unsatisfactory therapeutic effect (n=3; 2.4%), or consent withdrawal (n=3; 2.4%). Conclusions: In pts with uncontrolled acromegaly, switching to long-acting pasireotide after ≥3 months of treatment with first-generation SSAs provided biochemical control (mGH <1.0 μg/L and IGF-1 <ULN) in 15% of all pts and 43% of pts with lower screening mGH (1.0-2.5 µg/L).

Project description:Introduction: The efficacy and safety of subcutaneous (sc) pasireotide have been evaluated in a Phase III trial. Here, we report safety and efficacy results from a multinational, expanded-access study of pasireotide sc in patients with Cushing's disease (CD) in a real-world setting (clinicaltrials.gov, identifier: NCT01582061). Methods: Adults with active CD previously untreated with pasireotide were enrolled; pasireotide sc was initiated at 600 μg twice daily (bid; EU countries) or 900 μg bid (non-EU countries; 600 μg bid in patients with impaired glucose metabolism). Pasireotide dose could be adjusted in 300 μg increments/decrements to a maximum of 900 μg bid or minimum of 300 μg bid for sustained urinary free cortisol (UFC) normalization/tolerability issues. Primary objective: document the safety of pasireotide sc in patients with CD. Key secondary objectives: assess the proportion of patients with mean UFC (mUFC) not exceeding the upper limit of normal (ULN) and changes from baseline in clinical signs/symptoms and quality of life (QoL) to weeks 12, 24, and 48. Results: One hundred and four patients received pasireotide: female, n = 84 (80.8%); median duration of pasireotide exposure, 25.1 weeks; median (range) baseline mUFC, 321.2 nmol/24 h (142-10,920; 2.3 × ULN [1.0-79.2]). Forty (38.5%) patients completed the study. The most common reasons for premature discontinuation of pasireotide were unsatisfactory therapeutic effect (n = 26, 25.0%) and adverse events (AEs; n = 20, 19.2%). Drug-related grade 3/4 AEs or drug-related serious AEs (primary endpoint) were documented in 42 (40.4%) patients, most commonly diabetes mellitus (n = 12, 11.5%) and hyperglycemia (n = 8, 7.7%). All patients experienced ≥1 AE and most (n = 102; 98.1%) reported ≥1 drug-related AE; six (5.8%) patients discontinued treatment because of hyperglycemia-related AEs. At weeks 12, 24, and 48, respectively, 36/66 (54.5%), 22/46 (47.8%), and 9/21 (42.9%) evaluable patients had normalized mUFC levels. Clinical signs/symptoms and QoL were also improved. Conclusions: In an international, real-world, clinical-practice setting, pasireotide sc was generally well-tolerated (no new safety signals were identified), effectively reduced UFC (normalization in ~50% of evaluable patients) and improved clinical signs and QoL in patients with CD. While hyperglycemia-related AEs were common, consistent with previous studies, most were manageable, with <6% of patients discontinuing treatment because of these events.

Project description:PurposeCushing's disease (CD) and acromegaly are characterized by excessive hormone secretion resulting in comorbidities such as impaired glucose metabolism, diabetes and hypertension. Pasireotide is a new-generation, multireceptor-targeted somatostatin receptor ligand approved for CD (subcutaneous [SC] injection formulation) and acromegaly (long-acting release [LAR] formulation). In clinical studies of pasireotide, hyperglycemia-related adverse events (AEs) were frequently observed. This review highlights differences in reported rates of hyperglycemia in pasireotide trials and discusses risk factors for and management of pasireotide-associated hyperglycemia.MethodsClinical trials evaluating pasireotide in patients with CD or acromegaly were reviewed.ResultsThe frequency of hyperglycemia-related AEs was lower in patients with acromegaly treated with pasireotide LAR (57.3-67.0 %) than in patients with CD treated with pasireotide SC (68.4-73.0 %). Fewer patients with acromegaly treated with pasireotide LAR discontinued therapy because of hyperglycemia-related AEs (Colao et al. in J Clin Endocrinol Metab 99(3):791-799, 2014, 3.4 %; Gadelha et al. in Lancet Diabetes Endocrinol 2(11):875-884, 2014, 4.0 %) than did patients with CD treated with pasireotide SC (Boscaro et al. in Pituitary 17(4):320-326, 2014, 5.3 %; Colao et al. in N Engl J Med 366(10):914-924, 2012, 6.0 %). Hyperglycemia-related AEs occurred in 40.0 % of patients with acromegaly treated with pasireotide SC, and 10.0 % discontinued treatment because of hyperglycemia. Ongoing studies evaluating pasireotide LAR in patients with CD and management of pasireotide-induced hyperglycemia in patients with CD or acromegaly (ClinicalTrials.gov identifiers NCT01374906 and NCT02060383, respectively) will address these key safety issues.ConclusionsDisease pathophysiology, drug formulation, and physician experience potentially influence the differences in reported rates of pasireotide-induced hyperglycemia in CD and acromegaly. Hyperglycemic effects associated with pasireotide have a predictable pattern, can be managed with antidiabetic agents, and are reversible upon discontinuation.

Project description:ContextBiochemical 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.ObjectiveOur objective was to demonstrate the superiority of pasireotide LAR over octreotide LAR in medically naive patients with acromegaly.Design and settingWe conducted a prospective, randomized, double-blind study at 84 sites in 27 countries.PatientsA 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.InterventionsPatients 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 measureThe 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.ResultsBiochemical 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%).ConclusionsPasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option for acromegaly.

Project description:Introduction: Acromegaly is a rare, serious endocrine disorder characterized by excess growth hormone (GH) secretion by a pituitary adenoma and overproduction of insulin-like growth factor I (IGF-I). Transsphenoidal surgery is the treatment of choice, although many patients require additional interventions. First-generation somatostatin analogs (SSAs) are the current standard of medical therapy; however, not all patients achieve control of GH and IGF-I. Outcomes from a Phase IIIb open-label study of patients with uncontrolled acromegaly on first-generation SSAs switching to pasireotide are reported. Methods: Adults with uncontrolled acromegaly (mean GH [mGH] ≥1 μg/L from a five-point profile over 2 h, and IGF-I >1.3× upper limit of normal [ULN]) despite ≥3 months' treatment with maximal approved doses of long-acting octreotide/lanreotide received open-label long-acting pasireotide 40 mg/28 days. Pasireotide dose could be increased (maximum: 60 mg/28 days) after week 12 if biochemical control was not achieved, or decreased (minimum: 10 mg/28 days) for tolerability. Patients who completed 36 weeks' treatment could continue receiving pasireotide during an extension (weeks 36-72) when concomitant medication for acromegaly was permitted. Primary endpoint was proportion of patients with mGH <1 μg/L and IGF-I <ULN at week 36. Biochemical control was also assessed during the extension. Safety was assessed throughout. Results: One hundred and twenty-three patients were enrolled and received pasireotide; 88 patients continued into the extension. Overall, 18 [14.6% (95% CI: 8.9-22.1)] patients achieved mGH <1 μg/L and IGF-I <ULN at week 36; biochemical control was achieved in 42.9% with screening mGH 1.0-2.5 μg/L and 6.4% with screening mGH >2.5 μg/L. For patients who entered the extension, 14.8% (95% CI: 8.1-23.9), 12.5% (95% CI: 6.4-21.3), 14.8% (95% CI: 8.1-23.9) and 11.4% (95% CI: 5.6-19.9) had mGH <1 μg/L and IGF-I <ULN at weeks 36, 48, 60, and 72, respectively. During the overall study period, most frequent investigator-reported drug-related adverse events were hyperglycemia (41.5%), diabetes mellitus (23.6%), and diarrhea (11.4%). Conclusions: Switching to long-acting pasireotide provided biochemical control in some patients, which was sustained with continued treatment. Long-term safety and tolerability of long-acting pasireotide was consistent with the known safety profile. These data support long-acting pasireotide for some patients with acromegaly who are uncontrolled on first generation SSAs. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT02354508.

Dataset Information

Safety and tolerability of pasireotide long-acting release in acromegaly-results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study.

Publications

Safety and tolerability of pasireotide long-acting release in acromegaly-results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study.

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