Mario Maldonado

A 12-Month Phase 3 Study of Pasireotide in Cushing's Disease

BACKGROUND Cushings disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5. METHODS In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushings disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 μg (82 patients) or 900 μg (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 μg twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12. RESULTS Twelve of the 82 patients in the 600-μg group and 21 of the 80 patients in the 900-μg group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushings disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients. CONCLUSIONS The significant decrease in cortisol levels in patients with Cushings disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.).

LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing's disease: results from a multicenter, proof-of-concept study.

INTRODUCTION The clinical features and increased mortality associated with Cushings syndrome result from a chronic excess of circulating cortisol. As LCI699 potently inhibits 11β-hydroxylase, which catalyzes the final step of cortisol synthesis, it is a potential new treatment for Cushings disease, the most common cause of endogenous Cushings syndrome. METHODS Adult patients with moderate-to-severe Cushings disease (urinary free cortisol [UFC] levels >1.5 × ULN [upper limit of normal]) received oral LCI699 for 10 weeks in this proof-of-concept study. LCI699 was initiated at 4 mg/d in two equal doses; the dose was escalated every 14 days to 10, 20, 40, and 100 mg/d until UFC normalized, whereupon the dose was maintained until treatment ended (day 70). The primary endpoint was UFC ≤ ULN or a ≥50% decrease from baseline at day 70. RESULTS Twelve patients were enrolled and completed the study. Baseline UFC ranged over 1.6-17.0 × ULN. All 12 patients achieved UFC ≤ULN or a ≥50% decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. After treatment discontinuation (day 84), UFC was >ULN in 10 patients with available measurements. Mean 11-deoxycortisol, 11-deoxycorticosterone, and adrenocorticotropic hormone levels increased during treatment and declined after discontinuation. Mean systolic and diastolic blood pressure decreased from baseline by 10.0 and 6.0 mmHg, respectively. LCI699 was generally well tolerated; most adverse events (AEs) were mild or moderate. The most common AEs included fatigue (7/12), nausea (5/12), and headache (3/12). No serious drug-related AEs were reported. CONCLUSIONS LCI699 was efficacious and well tolerated in patients with Cushings disease enrolled in this proof-of-concept study.

High variability in baseline urinary free cortisol values in patients with Cushing's disease

Twenty‐four‐hour urinary free cortisol (UFC) sampling is commonly used to evaluate Cushings syndrome. Because there are few data on UFC variability in patients with active Cushings disease, we analysed baseline UFC in a large patient cohort with moderate‐to‐severe Cushings disease and assessed whether variability correlates with hypercortisolism severity. These data will help clinicians establish the minimum number of UFC samples required to obtain reliable data.

Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing's disease: results from a Phase III study

Signs and symptoms of Cushings disease are associated with high burden of illness. In this analysis, we evaluated the effect of pasireotide treatment on signs and symptoms in patients with Cushings disease.

Factors associated with insulin discontinuation in subjects with ketosis-prone diabetes but preserved β-cell function

Aim  To evaluate factors predictive of insulin discontinuation in subjects with ketosis‐prone Type 2 diabetes.

Fenofibrate Is Effective in Treating Hypertriglyceridemia Associated with HIV Lipodystrophy

Objective:To determine the effectiveness of fenofibrate in treating hypertriglyceridemia associated with highly active antiretroviral therapy–associated HIV lipodystrophy syndrome (HLS). Methods:The authors recruited from their HIV metabolic clinic 55 adult patients with anthropomorphic changes consistent with HLS together with hypertriglyceridemia. The patients had no prior history of taking lipid-lowering medications and were free of liver and renal disease. They were on various highly active antiretroviral therapy regimens, and these regimens were not altered during the course of the study. Fenofibrate was started at 54 mg a day and the dose increased every 2 weeks to a maximum of 162 mg/day. Fasting lipid concentrations were measured at baseline and 6 months after the intervention. Results:At baseline, the fasting plasma concentrations of total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol were 259 ± 11, 886 ± 172, and 35.7 ± 2.3 (mean ± SEM) mg/dL, respectively. After 6 months of fenofibrate treatment, the fasting plasma concentrations were as follows: total cholesterol, 243 ± 13; triglycerides, 552 ± 104, and HDL cholesterol, 35.7 ± 1.8 mg/dL. The decrease in fasting plasma triglyceride concentration was statistically significant (P < 0.05). Fenofibrate was well tolerated, and no subjects dropped out of the study. Conclusion:Fenofibrate is an effective, well-tolerated treatment for hypertriglyceridemia associated with HLS.

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.

An open-label dose-escalation study of once-daily and twice-daily pasireotide in healthy volunteers: safety, tolerability, and effects on glucose, insulin, and glucagon levels.

Pasireotide is a multireceptor-targeted somatostatin analogue that has high affinity for 4 of the 5 somatostatin receptor subtypes (sst1,2,3 and sst5) and has therapeutic potential in conditions with tumors of neuroendocrine origin, such as Cushing disease, acromegaly, and neuroendocrine tumors. This phase 1, open-label, dose-escalation study assessed the overall safety and tolerability of once-daily and twice-daily pasireotide and its effects on glucose, insulin, and glucagon levels in healthy volunteers. Eleven cohorts (n = 6 for each) received subcutaneous pasireotide 150, 300, 600, 900, 1200, or 1500 &mgr;g once daily, or 150, 300, 450, 600, or 750 &mgr;g twice daily, for 8 days. Pasireotide was generally well tolerated at all doses; adverse events were predominantly mild-to-moderate gastrointestinal disorders. All participants experienced fasting and postprandial plasma glucose elevations after all doses of pasireotide; increases in blood glucose level seemed to be dose dependent. Hyperglycemia was associated with a marked suppression of insulin secretion and a mild inhibition of glucagon secretion. In conclusion, pasireotide showed good overall tolerability at doses up to 1500 &mgr;g once daily and 750 &mgr;g twice daily for 8 days. Both fasting and postprandial hyperglycemia occurred after all doses of pasireotide, which was related to the suppression of insulin secretion.

A−β− Subtype of Ketosis-Prone Diabetes Is Not Predominantly a Monogenic Diabetic Syndrome

OBJECTIVE Ketosis-prone diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the A−β− subgroup of KPD, characterized by complete insulin dependence, absent β-cell functional reserve, lack of islet cell autoantibodies, and strong family history of type 2 diabetes, represents a monogenic form of diabetes. RESEARCH DESIGN AND METHODS Over 8 years, 37 patients with an A−β− phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes, including hepatocyte nuclear factor 4A (HNF4A), glucokinase (GCK), HNF1A, pancreas duodenal homeobox 1 (PDX1), HNF1B, neurogenic differentiation 1 (NEUROD1), and PAX4, were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated ethnically matched control subjects, consisting of 84 African American, 96 Caucasian, and 95 Hispanic subjects. RESULTS The majority (70%) of the A−β− KPD patients had no significant causal polymorphisms in either the proximal promoter or coding regions of the seven genes. The combination of six potentially significant low-frequency, heterozygous sequence variants in HNF-1α (A174V or G574S), PDX1 (putative 5′–untranslated region CCAAT box, P33T, or P239Q), or PAX4 (R133W) were found in 27% (10/37) of patients, with one additional patient revealing two variants, PDX1 P33T and PAX4 R133W. The A174V variant has not been previously reported. CONCLUSIONS Despite its well-circumscribed, robust, and distinctive phenotype of severe, nonautoimmune-mediated β-cell dysfunction, A−β− KPD is most likely not a predominantly monogenic diabetic syndrome. Several A−β− KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.

Improved outcomes in indigent patients with ketosis-prone diabetes: effect of a dedicated diabetes treatment unit.

OBJECTIVE To investigate whether a specialized intervention program could improve diabetes-related health outcomes in indigent patients with type 1 diabetes who were prone to occurrence of diabetic ketoacidosis (DKA). METHODS Patients with type 1 diabetes mellitus admitted because of DKA during a 24-month period were invited to receive outpatient care in a diabetes treatment unit (DTU). We compared DKA-related readmission rates, change in hemoglobin A1c (HbA1c) values, and diabetes-related medical costs in patients who participated in the DTU program (+DTU) and in those who did not (-DTU). RESULTS During the study period, 115 patients underwent assessment. Of this overall group, 57 patients (49.6%) consented to participate in the DTU program, and 58 (50.4%) did not. After the follow-up period (median duration, 657 days), the following significant improvements were observed in the +DTU group (in comparison with the -DTU group): lower frequency of readmission for DKA (16% versus 43%; P = 0.001), lower number of readmissions for DKA per patient (0.22 +/- 0.6 versus 1.17 +/- 2.2 [mean +/- standard deviation]; P = 0.003), lower HbA1c level (10.4 +/- 2.3% versus 13.5 +/- 2.3%; P<0.0001), and lower cost of diabetes-related medical care (3,427.20 US dollars +/- 6,275.60 versus 10,119.10 US dollars +/- 19,688.10; P = 0.01). Multivariate analysis revealed that participation in the DTU program was the only factor associated with a significantly decreased risk of DKA-related readmission. CONCLUSION Low-cost intervention by a dedicated outpatient DTU resulted in significant decreases in DKA-associated readmissions, in HbA1c values, and in costs of diabetes care in a multiethnic, indigent, ketosis-prone patient population.