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Long-term efficacy and safety of subcutaneous pasireotide in acromegaly: results from an open-ended, multicenter, Phase II extension study.

ABSTRACT: 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 ≤ 2.5 μg/L and normal IGF-1) or showed clinically relevant improvements during the core study. Thirty of the 60 patients who received pasireotide (200-900 μg 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 ≤ 2.5 μg/L by 12/26 at month 6. Nine patients received pasireotide for ≥24 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 (≥20%) 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; hyperglycemia-related events occurred in 14 patients. Twenty patients had fasting plasma glucose shifted to a higher category during the extension. However, last available glucose measurements were normal for 17 patients. Pasireotide has the potential to be an effective, long-term medical treatment for acromegaly, providing sustained biochemical control and significant reductions in tumor volume.

SUBMITTER: Petersenn S

PROVIDER: S-EPMC3942632 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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:Abstract Background Oral octreotide capsules (OOC) are a treatment option for patients with acromegaly in the United States. The MPOWERED trial (NCT02685709) showed that OOC were noninferior to injectable somatostatin receptor ligands (iSRLs; octreotide or lanreotide) in maintenance of biochemical control in patients previously responding to both treatments, as well as demonstrated improvements in patient-reported outcomes among patients receiving OOC. Objective Report long-term safety and efficacy outcomes with OOC from the open-label extension (OLE) of MPOWERED. Methods Patients were eligible for and could voluntarily enroll into the OLE if they had completed the 15-month core treatment phase of MPOWERED (6-month Run-in phase plus 9-month randomized controlled treatment [RCT] phase or, for OOC nonresponders during/at end of Run-in at participating sites, combination sub-study evaluating OOC in combination with cabergoline) and were adequately biochemically controlled per investigator assessment. Maintenance of response (definition: IGF-I <1.3×ULN; single timepoint) was assessed in each year of the OLE in patients responding at the start of that year. Additional analyses were performed on patients switching to OOC in the OLE from iSRLs in the core study. Results Sixty patients elected to enroll in the OLE (35 who received OOC and 19 who received iSRLs in the RCT phase, 6 from the combination sub-study). Median and maximal OOC exposure durations in the OLE were 2.2 and 3.5 years, respectively. A total of 94%, 90%, and 93% of patients receiving OOC monotherapy maintained biochemical response at the end of years 1, 2, and 3 of the OLE, respectively (using last observation carried forward imputation). Of patients switching from iSRLs to OOC during the OLE, 79% reported very good (47%) or excellent (32%) symptom control at the end of the OLE, compared with 47% (42% very good, 5% excellent) at the end of the RCT phase while receiving iSRLs. Patients switching from iSRLs also experienced significant improvements in the treatment convenience and treatment satisfaction domains (both P<0.05) of the Acromegaly Treatment Satisfaction Questionnaire. Median OOC compliance rate during the OLE was 99%. OOC safety during the OLE was consistent with that observed during the core study, with no new safety signals observed with long-term exposure. Conclusions The OLE of MPOWERED demonstrated a high percentage (≥90%) of patients maintaining biochemical response while receiving OOC monotherapy with a favorable long-term safety profile of OOC. Those who switched from iSRLs to OOC demonstrated improvements in symptom control, treatment convenience, and treatment satisfaction. Presentation: Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

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Long-term efficacy and safety of subcutaneous pasireotide in acromegaly: results from an open-ended, multicenter, Phase II extension study.

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