Somatostatin receptors are expressed in many tissues, especially in neuroendocrine tumors where hormones are excessively secreted including adrenocorticotropic hormone (ACTH) in Cushing's disease. Due to its broad-binding profile to somatostatin receptors, pasireotide has the potential to treat diseases characterized by expression of those receptors in the target tissues.
studies have shown that corticotroph tumor cells from Cushing's disease patients display a high expression of hsst5 whereas the other receptor subtypes are either not expressed or are expressed at lower levels. Pasireotide binds and activates the hsst receptors of the corticotrophs in ACTH-producing adenomas resulting in inhibition of ACTH secretion. The high affinity of pasireotide for 4 of the 5 hssts, especially to hsst5 (see Table 1), provides the basis for pasireotide to be an effective treatment for Cushing's disease patients.
In a randomized double-blinded mechanism study conducted in healthy volunteers, the development of hyperglycemia with pasireotide administered as Signifor SC at doses of 600 and 900 mcg twice a day was related to significant decreases in insulin secretion as well as incretin hormones [ie, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)]. Pasireotide did not affect insulin sensitivity. In another randomized study conducted in healthy volunteers, the effects of pasireotide on blood glucose were investigated by comparison between administrations of Signifor SC 600 mcg twice a day alone and with co-administration of an anti-hyperglycemic drug (metformin, nateglinide, vildagliptin or liralgutide, respectively. Insulin was not studied) over a 7-day period. Incretin-based therapy (GLP-1 agonists and DDP-IV inhibitors) was most efficacious in treating pasireotide-associated hyperglycemia in healthy volunteers.
The effect of Signifor on the QT interval was assessed in 2 open-label, controlled, crossover dedicated QT studies. In both studies, an effect of pasireotide on the QTc interval was observed with the maximum placebo-subtracted mean change from baseline occurring at 2-hr post dose. In one of the studies investigating a 1950 mcg twice daily dose, the maximum mean placebo-subtracted QTcF change from baseline was 17.5 ms (90% CI: 15.53; 19.38). In the other study, investigating doses of 600 mcg twice daily and 1950 mcg twice daily, the maximum mean placebo-subtracted QTcI change from baseline was 13.19 ms (90% CI: 11.38; 15.01) and 16.12 ms (90% CI: 14.30; 17.95 ms), respectively. Both pasireotide doses decreased heart rate, with a maximal difference to placebo observed at 1 hr for pasireotide 600 mcg twice daily (-10.39 bpm), and at 0.5 hrs for pasireotide 1950 mcg twice daily (-14.91 bpm). No episodes of Torsade de pointes (transient or sustained) were observed.
Mechanism of Action:
Pasireotide is a novel cyclohexapeptide, injectable somatostatin analogue. Like natural peptide hormones, somatostatin-14 and somatostatin-28 [also known as somatotropin release inhibiting factor (SRIF)] and other somatostatin analogues, pasireotide exerts its pharmacological activity via binding to somatostatin receptors. Five (5) human somatostatin receptor subtypes are known: Hsst 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Somatostatin analogues bind to hsst receptors with different potencies (see Table 1). Pasireotide binds with high affinity to 4 of the 5 hssts.
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A phase III, multicenter, randomized study was conducted to evaluate the safety and efficacy of different dose levels of Signifor >12-month treatment period in Cushing's disease patients with persistent or recurrent disease or de novo
patients for whom surgery was not indicated or who refused surgery.
The study enrolled 162 patients with a baseline ultrafiltration capacity (UFC) >1.5 x upper limit of normal (ULN) who were randomized in a 1:1 ratio to receive a dose of either Signifor 0.6 mg SC twice daily or 0.9 mg SC twice daily. After 3 months of treatment, patients who had a mean 24-hr UFC ≤2 x ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3 mg twice daily. After the initial 6 months in the study, patients entered an additional 6-month open-label treatment period. If response was not achieved at month 6 or the response was not maintained during the open-label treatment period, dosage could be increased by 0.3 mg SC twice daily. The maximum dose administered to patients was 1.2 mg SC twice daily. The dose could be reduced by 0.3 mg twice daily decrements at any time during the study for intolerability.
The primary efficacy endpoint was the proportion of patients in each arm who achieved normalization of mean 24-hr UFC levels (UFC ≤ ULN) after 6 months of treatment and who did not have a dose increase (relative to randomized dose) during this period. Secondary endpoints included, among others, changes from baseline in: 24-hr UFC, plasma adrenocorticotrophic hormone (ACTH), serum cortisol levels, clinical signs and symptoms of Cushing's disease and health-related quality of life (HRQL) as measured by the Cushing QoL. All analyses were conducted based on the randomized dose groups.
Baseline demographics were well balanced between the 2 randomized dose groups and consistent with the epidemiology of the disease. The mean age of patients was approximately 40 years old with a predominance of female patients (77.8%). The majority of the patients had persistent or recurrent Cushing's disease (83.3%) and few patients (≤5%) in either treatment group had received previous pituitary irradiation.
Baseline characteristics were balanced between the 2 randomized dose groups, except for marked differences in the mean value of the baseline 24-hr UFC (1156 nmol/24 hrs for the 0.6 mg twice daily group and 781 nmol/24 hrs for the 0.9 mg twice daily group); normal range 30-145 nmol/24 hrs).
At month 6, normalization of mean UFC levels was observed in 14.6% (95% CI 7-22.3) and 26.3% (95% CI 16.6-35.9) of patients randomized to pasireotide 0.6 mg twice daily. and 0.9 mg twice daily, respectively. The study met the primary efficacy objective for the 0.9 mg twice daily group as the lower limit of the 95% CI is greater than the prespecified 15% boundary. The response in the 0.9-mg dose arm seemed to be higher for patients with lower mean UFC at baseline (see Table 2). The majority of responders (55.6%) at month 6 were also responders at month 12. The responder rate at month 12 was comparable to month 6 with 13.4% and 25% in the 0.6 mg twice daily and 0.9 mg twice daily, respectively.
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A supportive efficacy analysis was conducted in which patients were further classified into 3 response categories regardless of up-titration at month 3: Controlled (UFC ≤1 x ULN), partially controlled (UFC >1 x ULN but with a reduction in UFC ≥50% compared to baseline) or uncontrolled (all other patients). The controlled and partially controlled responder rates at month 6, constituted 34% and 41% (0.6 mg twice daily and 0.9 mg twice daily, respectively) of the randomized patients (see Table 3). Patients uncontrolled at both months 1 and 2 were likely (90%) to remain uncontrolled at months 6 and 12.
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In both dose groups, Signifor resulted in a rapid and robust decrease in the mean UFC after 1 month of treatment which was maintained over time (see figure). Dose decreases and increases appeared to have minimal effect on UFC response, though some patients experienced further reduction in UFC levels with dose up-titration.
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Robust decreases were also demonstrated by the overall percentage of change in the mean and median UFC levels at month 6 and 12 as compared to baseline values (see Table 4). Reductions in mean serum cortisol and plasma ACTH levels were also observed at each time point for each dose group.
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Clinically meaningful decreases in sitting systolic and diastolic blood pressure, body mass index (BMI), and total cholesterol were observed in both dose groups at month 6. Overall reductions in these parameters tended to be greater in patients that normalized UFC. Similar trends were observed at month 12, with the addition of serum triglycerides also decreasing at that time point. No clinically meaningful changes in bone mineral density were observed.
There were favorable shifts in all of the studied signs of Cushing's disease in both dose groups at month 6. Facial rubor improved in 36.7% (18/49) and 59.6% (28/47) of patients treated with 0.6 and 0.9 mg twice daily, respectively. More than a 3rd of patients in either treatment group also demonstrated improvement in supraclavicular fat pad and dorsal fat pad. Similar findings were recorded at the month 12 visit.
Baseline mean and median global Cushing QoL scores were similar for the 2 dose groups. At the month 3 visit, patients in both dose groups reported increases in scores, indicating improvement in the patient-reported HRQL. At month 6, median improvements from baseline were 13.2% and 30% in the 0.6 mg and 0.9 mg twice daily dose groups, respectively. At month 12, median improvements from baseline were 26% and 20.6% in the 0.6 mg and 0.9 mg twice daily dose groups, respectively.
In healthy volunteers, pasireotide demonstrates approximately linear pharmacokinetics (PK) for a wide dose range from 0.0025-1.5 mg. In Cushing's disease patients, pasireotide demonstrates linear dose-exposure relationship in a dose range from 0.3-1.2 mg.
In healthy volunteers, pasireotide is rapidly absorbed and peak plasma concentration (Cmax
) is reached within time-to-peak plasma concentration (Tmax
) 0.25-0.5 hr. Peak plasma concentration and area under the curve (AUC) are approximately dose-proportional following administration of single and multiple doses.
No studies have been conducted to evaluate the bioavailability of pasireotide in humans. Based on data of absolute bioavailability from preclinical studies in rats and monkeys, the absolute bioavailability of pasireotide SC is predicted to be complete in humans.
Food effect is unlikely to occur since Signifor is administered via parenteral route.
In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution (Vz
/F >100 L). Distribution between blood and plasma is concentration independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein-binding is moderate (88%) and independent of concentration.
Pasireotide has low passive permeability and is likely to be a substrate of P-gp, but the impact of P-gp on absorption, distribution, metabolism, excretion (ADME) of pasireotide is expected to be low. Pasireotide is not a substrate of breast cancer resistance protein (BCRP), organic cation transporter 1 (OCT1), nor organic anion-transporting polypeptides (OATP) 1B1, 1B3, or 2B1.
Pasireotide was shown to be highly metabolically stable in human liver and kidney microsomes. In healthy volunteers, pasireotide in its unchanged form is the predominant form found in plasma, urine and feces.
Pasireotide is eliminated mainly via hepatic clearance (biliary excretion) with a small contribution of the renal route. In a human ADME, study 55.9±6.63% of the radioactivity dose was recovered over the first 10 days post dosing, including 48.3±8.16% of the radioactivity in feces and 7.63±2.03% in urine.
The clearance (CL/F) of pasireotide in healthy volunteers and Cushing's disease patients is approximately 6.7 L/hr and 3.8 L/hr, respectively.
Following multiple SC doses, pasireotide demonstrates linear and time-independent pharmacokinetics in the dose range of 0.05-0.6 mg once a day in healthy volunteers, and 0.3-1.2 mg twice a day in Cushing's disease patients. Based on the accumulation ratios of AUC, the calculated effective half-life (t½
) in healthy volunteers was approximately 12 hrs (on average between 10 and 13 hrs for 0.05, 0.2 and 0.6 mg everyday doses).
Special Populations: Elderly:
Age has been found to be a covariate in the population PK analysis of Cushing's disease patients. Decreased total body clearance and increased PK exposures have been seen with increasing age. In the studied age range 18-73 years, the AUC at steady state for 1 dosing interval of 12 hrs (AUCss
) is predicted to range from 86-110% of that of the typical patient of 41 years. This variation is moderate and considered of minor significance considering the wide age range in which the effect was observed.
Data on Cushing’s disease patients >65 years are limited but do not suggest any clinically significant differences in safety and efficacy in relation to younger patients.
No studies have been performed in pediatric patients.
Clinical studies have not been performed in patients with impaired renal function. However, renal clearance has a minor contribution to the elimination of pasireotide in humans. Renal function is not expected to significantly impact the circulating levels of pasireotide.
In a clinical study in subjects with impaired hepatic function (Child-Pugh A, B and C), subjects with moderate and severe hepatic impairment (Child-Pugh B and C) showed significantly higher exposures than subjects with normal hepatic function. Upon correction for covariate effect (age, BMI and albumin) AUCinf
was increased by 60% and 79%, Cmax
increased by 67% and 69%, and CL/F decreased by 37% and 44% respectively, in the moderate and severe hepatic impairment groups relative to the control group.
Population PK analyses of Signifor suggest that race and gender, do not influence PK parameters. Lean body weight, which subtracts the estimated weight of body fat from the total body weight, has been found to be a covariate in the population PK analysis of Cushing's disease patients. In the studied lean body weight range 33-83 kg, the AUCs
is predicted to range from 67-134% of that of the typical patient of 49 kg (the corresponding range of total body weight was 43-175 kg, with a median of 77.4 kg). This variation is considered as moderate and of minor clinical significance.
Toxicology: Nonclinical Safety Data:
Nonclinical safety studies included safety pharmacology, repeated-dose toxicity, genotoxicity and carcinogenic potential, toxicity to reproduction and development. Most findings seen in repeated toxicity studies were reversible and attributable to the pharmacology of pasireotide. Effects in nonclinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
In safety pharmacology studies, pasireotide had no adverse effects on respiratory or cardiovascular functions. Decreases in general and behavioral activity were observed in mice at the dose of 12 mg/kg, equivalent to approximately 32-fold of the maximum recommended therapeutic human dose (MHRD) based on surface area.
Pasireotide was not genotoxic in a battery of in vitro
assays (Ames mutation test in Salmonella and Escherichia coli
and mutation test in human peripheral lymphocytes). Pasireotide was not genotoxic in an in vivo
rat bone marrow nucleus test at doses up to 50 mg/kg, approximately 250-fold the MHRD based on surface area, mg/m2
Carcinogenicity studies conducted in rats and transgenic mice did not identify any carcinogenic potential.
In embryofetal development studies in rats and rabbits, pasireotide was not teratogenic at maternally toxic doses (respectively 10 and 5 mg/kg/day) leading to exposures (AUC0-24 hrs
), respectively 145- and 40-fold higher than the MHRD. At 10 mg/kg/day in rats, the frequency of early/total resorptions and malrotated limbs was increased. At 5 mg/kg/day in rabbits, increased abortions, reduced fetal weights and ensuing skeletal variations were observed. Reduced fetal weight and ensuing delayed ossification were seen at 1 mg/kg/day (6.5-fold MHRD). Pasireotide had no effects on labour and delivery in rats administered up to 10 mg/kg/day (52-fold higher than the MHRD based on surface area, mg/m2
). Available toxicological data in animals have shown excretion of pasireotide in milk. Retardation of physiological growth, attributed to growth hormone (GH) inhibition was observed at 2 mg/kg/day (10-fold higher than the MHRD based on surface area, mg/m2
) during a pre- and postnatal study in rats. After weaning, body weight gains in the rat pups exposed to pasireotide were comparable to controls, showing reversibility. Pasireotide did not affect fertility in male rats at doses up to 10 mg/kg/day (a dose 52-fold higher than the MHRD based on surface area, mg/m2
). In female rats, as expected from the pharmacology of pasireotide, fertility was decreased at daily doses of 0.1 mg/kg/day (0.6-fold the MHRD
based on surface area, mg/m2
) as shown by decreased numbers of corpora lutea and implantation sites. Abnormal cycles or acyclicity were observed at 1 mg/kg/day (5-fold higher than the MHRD based on surface area, mg/m2