scholarly journals Safety and Efficacy of Switching Injected Peptide Long-Acting Somatostatin Receptor Ligands to Once Daily Oral Paltusotine: ACROBAT Edge Phase 2 Study

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A526-A527
Author(s):  
Monica R Gadelha ◽  
Murray B Gordon ◽  
Mirjana Doknic ◽  
Emese Mezősi ◽  
Miklós Tóth ◽  
...  
Keyword(s):  
Adverse Events ◽  
Treatment Period ◽  
Somatostatin Receptor ◽  
Study Drug ◽  
Receptor Ligands ◽  
Primary Analysis ◽  
Once Daily ◽  
Safety And Efficacy ◽  
Somatostatin Receptor Ligands ◽  
Long Acting

Abstract Patients with acromegaly not cured by surgery are often initially treated with injected peptide long-acting somatostatin receptor ligands (SRLs). Non-peptide small molecules can also activate the somatostatin receptor and do so with a high degree of precision for the target therapeutic receptor subtype. Paltusotine (formerly CRN00808) is a small molecule somatostatin type 2 (SST2) receptor agonist with high oral bioavailability (70%) and pharmacokinetic profile suitable for once daily dosing. In healthy volunteers, paltusotine has been shown to lower growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. We hypothesized that patients with acromegaly could switch from injected SRLs to once daily oral paltusotine while maintaining baseline IGF-1 levels. ACROBAT Edge (NCT03789656) was a single-arm study designed to evaluate the safety and efficacy of switching from injected SRLs to paltusotine in patients with acromegaly. The primary analysis population consisted of those who had not achieved normal IGF-1 levels despite stable therapy with long-acting octreotide or lanreotide. Eligible patients received their last injection of SRL 4 weeks prior to switching to once daily oral paltusotine monotherapy for a 13-week treatment period. The starting dose of 10 mg per day was uptitrated in 10 mg increments at specified study visits to a maximal dose of 40 mg per day based on protocol specified study drug toleration and IGF-1 criteria. The primary endpoint was change in IGF-1 from baseline to the completion of the 13-week treatment period. Statistical testing was based on non-parametric Wilcoxon Sign Rank test of whether the median change is different from zero. In addition, the rise in IGF-1 during a 4-week washout period was used to provide supportive evidence of efficacy. Twenty-five patients were enrolled in the primary analysis group, three patients discontinued from the study for non-study drug related reasons, two during the treatment period and one during the washout period after completing treatment. The primary endpoint was achieved as paltusotine treatment resulted in no significant change in IGF-1 levels at week 13 compared to baseline [change in IGF-1 =-0.034 (-0.107, 0.107), median (IQR), p>0.6]. Of the 23 patients who completed the dosing period, 20 (87%) achieved IGF-1 levels at the end of treatment that were within 20% of baseline or lower. Median IGF-1 values rose significantly after paltusotine washout (p<0.0001). The most common treatment-emergent adverse events (>10%) included: headache, arthralgia, fatigue, peripheral swelling, paresthesia and hyperhidrosis. There were no discontinuations due to adverse events and no treatment related serious adverse events. These results suggest that patients with acromegaly treated with injected SRLs can switch to oral paltusotine while maintaining IGF-1 and that paltusotine appeared to be well tolerated.

scholarly journals A Randomized Phase 2 Study of Long-Acting TransCon GH vs Daily GH in Childhood GH Deficiency

2017 ◽  
Vol 102 (5) ◽  
pp. 1673-1682 ◽  
Author(s):  
Pierre Chatelain ◽  
Oleg Malievskiy ◽  
Klaudziya Radziuk ◽  
Ganna Senatorova ◽  
Magdy O. Abdou ◽  
...  
Keyword(s):  
Adverse Events ◽  
Gh Deficiency ◽  
Area Under The Curve ◽  
Study Drug ◽  
Height Velocity ◽  
Controlled Study ◽  
Open Label ◽  
Safety And Efficacy ◽  
Treatment Naïve ◽  
Long Acting

Abstract Context: TransCon Growth Hormone (GH) (Ascendis Pharma) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency (GHD). Objective: To compare the pharmacokinetics, pharmacodynamics, safety, and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD. Design: Randomized, open-label, active-controlled study of three doses of weekly TransCon GH versus daily Genotropin (Pfizer). Setting: Thirty-eight centers in 14 European countries and Egypt. Patients: Prepubertal male and female treatment-naïve children with GHD (n = 53). Interventions: Subjects received one of three TransCon GH doses (0.14, 0.21, or 0.30 mg GH/kg/wk) or Genotropin 0.03 mg GH/kg/d for 26 weeks. Main Outcome Measures: GH and insulinlike growth factor-1 (IGF-1) levels, growth, adverse events, and immunogenicity. Results: Both GH maximum concentration and area under the curve were similar following TransCon GH or Genotropin administration at comparable doses. A dose response was observed, with IGF-1 standard deviation scores increasing into the normal range for all three TransCon GH doses. Annualized mean height velocity for the three TransCon GH doses ranged from 11.9 cm to 13.9 cm, which was not statistically different from 11.6 cm for Genotropin. Adverse events were mild to moderate, and most were unrelated to the study drug. Injection site tolerance was good. One TransCon GH subject developed a low-titer, nonneutralizing antibody response to GH. Conclusions: The results suggest that long-acting TransCon GH is comparable to daily Genotropin for GH (pharmacokinetics) and IGF-1 (pharmacodynamics) levels, safety, and efficacy and support advancement into phase 3 development.

Somatostatin receptor ligands induce TSH deficiency in thyrotropin-secreting pituitary adenoma

2021 ◽  
Vol 184 (1) ◽  
pp. 1-8
Author(s):  
Frédéric Illouz ◽  
Philippe Chanson ◽  
Emmanuel Sonnet ◽  
Thierry Brue ◽  
Amandine Ferriere ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Somatostatin Receptor ◽  
Receptor Ligands ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Somatostatin Receptor Ligands ◽  
Central Hyperthyroidism ◽  
Long Acting ◽  
Tsh Deficiency

Objective Somatostatin receptor ligands (SRL) are useful to control central hyperthyroidism in patients with thyrotropin-secreting pituitary adenoma (TSH pituitary adenoma). The aim of this study was to describe the frequency of thyrotropin deficiency (TSH deficiency) in patients with TSH pituitary adenoma treated by SRL. Design Retrospective study. Methods Patients with central hyperthyroidism due to TSH pituitary adenoma treated by short or long-acting SRL were retrospectively included. TSH deficiency was defined by a low FT4 associated with non-elevated TSH concentrations during SRL therapy. We analysed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency. Results Forty-six patients were included. SRL were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%) after a median time of 4 weeks (4–7) and for a median duration of 3 months (2.5–3). The TSH deficiency occurred after one to three injections of long-acting SRL used as first-line therapy in 6/7 cases. There were no differences in terms of clinical and hormonal features, size of adenomas or doses of SRL between patients with or without TSH deficiency. Conclusions SRL can induce TSH deficiency in patients with central hyperthyroidism due to TSH pituitary adenoma. Thyrotropic function should be assessed before the first three injections of SRL in order to track TSH deficiency and reduce the frequency of injections when control of thyrotoxicosis rather than tumour reduction is the aim of the treatment.

scholarly journals Disease and Treatment-Related Burden in Patients With Acromegaly Who Are Biochemically Controlled on Injectable Somatostatin Receptor Ligands

2021 ◽  
Vol 12 ◽  
Author(s):  
Maria Fleseriu ◽  
Mark Molitch ◽  
Alexander Dreval ◽  
Nienke R. Biermasz ◽  
Murray B. Gordon ◽  
...  
Keyword(s):  
Side Effects ◽  
Symptom Severity ◽  
Treatment Satisfaction ◽  
Daily Life ◽  
Somatostatin Receptor ◽  
Emotional Reaction ◽  
Receptor Ligands ◽  
Somatostatin Receptor Ligands ◽  
Index Of Severity ◽  
Long Acting

Medical treatment for acromegaly commonly involves receiving intramuscular or deep subcutaneous injections of somatostatin receptor ligands (SRLs) in most patients. In addition to side effects of treatment, acromegaly patients often still experience disease symptoms even when therapy is successful in controlling GH and IGF-1 levels. Symptoms and side effects can negatively impact patients’ health-related quality of life. In this study, we examine the disease- and treatment-related burden associated with SRL injections as reported through the use of the Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ ©) and clinician-reported symptom severity through the Acromegaly Index of Severity (AIS). Patients included in this analysis were enrolled in a randomized phase 3 study, were biochemically-controlled (an IGF-1 < 1.3 × the upper limit of normal [ULN] and average GH < 2.5 ng/ml) and receiving SRL injections for ≥6 months with a stable dose of either long-acting octreotide or lanreotide monotherapy for ≥4 months. The sample (N = 91) was 65% female, 91% Caucasian, with a mean [standard deviation (SD)] age of 53 (1) years. Two-thirds of patients reported that they still experience acromegaly symptoms; 82% of these said they experience symptoms all of the time. Three-fourths experienced gastrointestinal (GI) side effects after injections, and 77% experienced treatment-related injection site reactions (ISRs). Patients commonly reported that these interfered with their daily life, leisure, and work activities. Those with higher symptom severity, as measured by the AIS, scored significantly worse on several Acro-TSQ domains: Symptom Interference, GI Interference, Treatment Satisfaction, and Emotional Reaction. Despite being biochemically controlled with injectable SRLs, most patients reported experiencing acromegaly symptoms that interfere with daily life, leisure, and work. GI side effects and ISRs were also common. This study highlights the significant disease burden that still persists for patients with acromegaly that have achieved biochemical control with the use of injectable SRLs.

COMPARATIVE EFFICACY OF MEDICAL TREATMENT FOR ACROMEGALY: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS OF INTEGRATED RANDOMIZED TRIALS AND OBSERVATIONAL STUDIES

2020 ◽  
Vol 26 (4) ◽  
pp. 454-462 ◽  
Author(s):  
Nidan Qiao ◽  
Min He ◽  
Ming Shen ◽  
Qilin Zhang ◽  
Zhaoyun Zhang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Observational Studies ◽  
Randomized Trials ◽  
Meta Analysis ◽  
Somatostatin Receptor ◽  
Credible Interval ◽  
Receptor Ligands ◽  
Somatostatin Receptor Ligands ◽  
The Mean ◽  
Long Acting

Objective: Comprehensive evidence comparing different medications for acromegaly is scarce. The aim of this study was to perform a network meta-analysis based on evidence from both randomized trials and observational studies of medical treatments for acromegaly. Methods: Electronic databases were searched for both observational studies and randomized trials that enrolled acromegaly patients treated with medications of interest. Simulated trials were generated by a machine learning algorithm and then synthesized with Bayesian random-effects network meta-analyses. The main outcome was the rate of insulin-like growth factor 1 (IGF-1) control after medical treatment. Results: We included 90 studies (100 arms, 4,523 patients) before matching. After matching, 28 simulated trials were generated. Balance of matched arms was checked by spatial distance and correlation matrix. Cotreatment with somatostatin receptor ligands and pegvisomant was the most effective treatment compared with other treatments. In unselected patients, pegvisomant was better than octreotide long-acting release (logOR, 0.85; 95% credible interval [CrI], 0.05 to 1.65) or lanreotide (logOR, 1.09, 95% CrI, 0.05 to 2.14), and the mean absolute IGF-1 control rate ranged from 40 to 60%. In partially responsive patients, cotreatment with somatostatin receptor ligands and pegvisomant was similar to pegvisomant monotherapy, ranking as the most two effective treatments, and the mean absolute IGF-1 control rate was over 60%. Conclusion: Our analysis suggested that the combination of data from observational studies and randomized trials in network meta-analysis was feasible. The findings of this network meta-analysis provided robust evidence supporting the current guidelines in treatment strategy for acromegaly. Abbreviations: CrI = credible interval; DA = dopamine agonist; GH = growth hormone; IGF-1 = insulin-like growth factor 1; ITT = intention-to-treat; LAN = lanreotide; LAN-ATG = lanreotide autogel; OCT = octreotide; OCT-LAR = octreotide long acting repeatable; OR = odds ratio; PEG = pegvisomant; PP = per-protocol; SRL = somatostatin receptor ligand

scholarly journals Biliary adverse events in acromegaly during somatostatin receptor ligands: predictors of onset and response to ursodeoxycholic acid treatment

Pituitary ◽  
2020 ◽  
Author(s):  
N. Prencipe ◽  
C. Bona ◽  
D. Cuboni ◽  
M. Parasiliti-Caprino ◽  
A. M. Berton ◽  
...  
Keyword(s):  
Adverse Events ◽  
Ursodeoxycholic Acid ◽  
Somatostatin Receptor ◽  
Stone Disease ◽  
Receptor Ligands ◽  
First Line ◽  
Metabolic Markers ◽  
Somatostatin Receptor Ligands ◽  
Igf I

Abstract Purpose Somatostatin receptor ligands (SRL) are the first-line medical treatment for acromegaly. Gallbladder alterations are one of most important SRL side effect, but according to some authors growth hormone hypersecretion itself is a risk factor for gallstones. This single center, longitudinal retrospective study evaluated the incidence and the predictors of biliary adverse events (BAE) in acromegaly during SRL therapy and their response to ursodeoxycholic acid (UDCA). Methods 91 acromegaly patients with indication to SRL were enrolled. Evaluations of acromegaly activity (GH, IGF-I, IGF-I/ULN) and metabolic profile were collected before starting treatment, yearly during follow-up and at BAE onset. In patients developing BAE we searched for predictors of UDCA effectiveness. Results 61.5% of patients developed BAE (58.9% cholelithiasis; 41.1% only sludge). IGF-I and IGF-I/ULN proved to be positive predictor of BAE, which occur about 5 years after SRL starting. None of metabolic markers proved to be associated with BAE. Only five patients (5.5%) underwent cholecystectomy for symptomatic cholelithiasis. 71% of patients started UDCA treatment, achieving regression of BAE in 60% of cases (88% in patients developing only sludge and 30% in patients affected by cholelithiasis, p < 0.001). BMI and obesity were negative predictors of UDCA efficacy. In 50% of the subjects BAE resolved after 36 months of therapy with a lower rate if cholelithiasis was present. Conclusion Biliary stone disease is a frequent SRL adverse event, although it is often symptomless. Ultrasound follow-up mainly in the first 5 years of therapy, early UDCA starting and proper lifestyle represent a valid strategy in their detection and management.

scholarly journals Presurgical somatostatin receptor ligands treatment does not affect tumor consistency in GH-secreting pituitary macroadenomas

2020 ◽  
Author(s):  
Marta Araujo-Castro ◽  
Héctor Pian ◽  
Ignacio Ruz-Caracuel ◽  
Alberto Acitores Cancela ◽  
Eider Pascual-Corrales ◽  
...  
Keyword(s):  
Remission Rate ◽  
Statistical Significance ◽  
Somatostatin Receptor ◽  
Treated Group ◽  
Receptor Ligands ◽  
Somatostatin Receptor Ligands ◽  
High Doses ◽  
Long Acting ◽  
Tumor Consistency ◽  
Pituitary Macroadenomas

Purpose: To evaluate whether pre-surgical treatment using long-acting somatostatin receptor ligands (SRL) may change pituitary tumor consistency and improve surgical outcome in GH-secreting pituitary macroadenomas. Methods: Retrospective study of 40 patients with GH-secreting pituitary macroadenomas operated for the first time by endoscopic transsphenoidal approach. Tumor consistency was evaluated intraoperatively and then correlated with histopathological fibrosis parameters and surgical outcomes. Surgical remission was reported based on the 2010 criteria. Results: The mean tumor size of GH-secreting macroadenomas was of 16.9±8.2mm and 25 were invasive pituitary adenomas (PAs). Presurgical treatment with long-acting SRL was performed in 17 patients (11 lanreotide, 6 octreotide). The cure rate was higher in those patients pre-treated with monthly doses ≥30mg of octreotide or ≥90mg of lanreotide than in those treated with lower doses or untreated (8/11 vs 11/29, P=0.049). However, although the proportion of soft tumors increased as higher doses of SRL were considered in the pre-treated group, no statistical significance was reached, even when the highest approved monthly doses were used (6/6 vs 23/34, P=0.102). Moreover, we found that the remission rate was similar between fibrous and soft tumors (P=0.873) and also of surgical complications (P=0.859), despite of the higher prevalence of Knosp>2 (P=0.035) and very large PA (P=0.025) in fibrous tumors than in soft tumors. Conclusions: Although presurgical treatment with high doses of SRL was associated with a 2.2-fold greater chance of surgical remission, this benefit was not related with changes in tumor consistency induced by the presurgical treatment.

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