Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Recordati Rare Diseases, Immeuble Le Wilson, 70 avenue du Général de Gaulle, 92800, Puteaux, France
Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatostatin and analogues
ATC code: H01CB05
Pasireotide is a novel cyclohexapeptide, injectable somatostatin analogue. Like the 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 human somatostatin receptor subtypes are known: hsst1, 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 2). Pasireotide binds with high affinity to four of the five hssts.
Table 2. Binding affinities of somatostatin (SRIF-14), pasireotide, octreotide and lanreotide to the five human somatostatin receptor subtypes (hsst1-5):
| Compound | hsst1 | hsst2 | hsst3 | hsst4 | hsst5 |
|---|---|---|---|---|---|
| Somatostatin (SRIF-14) | 0.93±0.12 | 0.15±0.02 | 0.56±0.17 | 1.5±0.4 | 0.29±0.04 |
| Pasireotide | 9.3±0.1 | 1.0±0.1 | 1.5±0.3 | >1.000 | 0.16±0.01 |
| Octreotide | 280±80 | 0.38±0.08 | 7.1±1.4 | >1.000 | 6.3±1.0 |
| Lanreotide | 180±20 | 0.54±0.08 | 14±9 | 230±40 | 17±5 |
Results are the mean±SEM of IC50 values expressed as nmol/l.
Somatostatin receptors are expressed in many tissues, especially in neuroendocrine tumours in which hormones are excessively secreted, including ACTH in Cushing’s disease.
In vitro studies have shown that corticotroph tumour cells from Cushing’s disease patients display a high expression of hsst5, whereas the other receptor subtypes either are not expressed or are expressed at lower levels. Pasireotide binds and activates four of the five hssts, especially hsst5, in corticotrophs of ACTH-producing adenomas, resulting in inhibition of ACTH secretion.
A phase III, multicentre, randomised study was conducted to evaluate the safety and efficacy of different dose levels of Signifor over a twelve-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 UFC >1.5 x ULN who were randomised in a 1:1 ratio to receive a subcutaneous dose of either 0.6 mg or 0.9 mg Signifor twice daily. After three months of treatment, patients with a mean 24-hour UFC ≤2 x ULN and below or equal to their baseline value continued blinded treatment at the randomised 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 if the response was not maintained during the open-label treatment period, dosage could be increased by 0.3 mg twice daily. The dose could be reduced by decrements of 0.3 mg twice daily at any time during the study for reasons of intolerability.
The primary efficacy end-point was the proportion of patients in each arm who achieved normalisation of mean 24-hour UFC levels (UFC ≤ULN) after 6 months of treatment and who did not have a dose increase (relative to randomised dose) during this period. Secondary end-points included, among others, changes from baseline in: 24-hour UFC, plasma ACTH, serum cortisol levels, and clinical signs and symptoms of Cushing’s disease. All analyses were conducted based on the randomised dose groups.
Baseline demographics were well balanced between the two randomised dose groups and consistent with the epidemiology of the disease. The mean age of patients was approximately 40 years and the majority of patients (77.8%) were female. Most patients (83.3%) had persistent or recurrent Cushing’s disease and few (≤5%) in either treatment group had received previous pituitary irradiation.
Baseline characteristics were balanced between the two randomised dose groups, except for marked differences in the mean value of baseline 24-hour UFC (1156 nmol/24 h for the 0.6 mg twice daily group and 782 nmol/24 h for the 0.9 mg twice daily group; normal range 30-145 nmol/24 h).
At month 6, normalisation of mean UFC levels was observed in 14.6% (95% CI 7.0-22.3) and 26.3% (95% CI 16.6-35.9) of patients randomised to pasireotide 0.6 mg 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 pre-specified 15% boundary. The response in the 0.9 mg dose arm seemed to be higher for patients with lower mean UFC at baseline. The responder rate at month 12 was comparable to month 6, with 13.4% and 25.0% in the 0.6 mg and 0.9 mg twice-daily groups, respectively.
A supportive efficacy analysis was conducted in which patients were further classified into 3 response categories regardless of up-titration at month 3: Fully controlled (UFC ≤1.0 x ULN), partially controlled (UFC >1.0 x ULN but with a reduction in UFC ≥50% compared to baseline) or uncontrolled (reduction in UFC <50%). The total proportion of patients with either full or partial mean UFC control at month 6 was 34% and 41% of the randomised patients to the 0.6 mg and 0.9 mg dose, respectively. Patients uncontrolled at both month 1 and month 2 are likely (90%) to remain uncontrolled at months 6 and 12.
In both dose groups, Signifor resulted in a decrease in mean UFC after 1 month of treatment which was maintained over time.
Decreases were also demonstrated by the overall percentage of change in mean and median UFC levels at month 6 and 12 as compared to baseline values (see Table 3). Reductions in plasma ACTH levels were also observed at each time point for each dose group.
Table 3. Percentage change in mean and median UFC levels per randomised dose group at month 6 and month 12 compared to baseline values:
| Pasireotide 0.6 mg twice daily % change (n) | Pasireotide 0.9 mg twice daily % change (n) | ||
|---|---|---|---|
| Mean change in UFC (% from baseline) | Month 6 | -27.5* (52) | -48.4(51) |
| Month 12 | -41.3 (37) | -54.5 (35) | |
| Median change in UFC (% from baseline) | Month 6 | -47.9 (52) | -47.9 (51) |
| Month 12 | -67.6 (37) | -62.4 (35) |
* Includes one patient with significant outlying results who had a percent change from baseline of +542.2%.
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 were observed in patients with full and partial mean UFC control but tended to be greater in patients with normalised UFC. Similar trends were observed at month 12.
The European Medicines Agency has waived the obligation to submit the results of studies with Signifor in all subsets of the paediatric population in pituitary-dependant Cushing’s disease, overproduction of pituitary ACTH and pituitary dependant hyperadrenocorticism (see section 4.2 for information on paediatric use).
In healthy volunteers, pasireotide is rapidly absorbed and peak plasma concentration is reached within 0.25-0.5 h. Cmax and 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.
In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution (Vz/F >100 litres). Distribution between blood cells 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.
Based on in vitro data pasireotide appears to be a substrate of efflux transporter P-gp (P-glycoprotein). Based on in vitro data pasireotide is not a substrate of the efflux transporter BCRP (breast cancer resistance protein) nor of the influx transporters OCT1 (organic cation transporter 1), OATP (organic anion-transporting polypeptide) 1B1, 1B3 or 2B1. At therapeutic dose levels pasireotide is also not an inhibitor of UGT1A1, OATP, 1B1 or 1B3, P-gp, BCRP, MRP2 and BSEP.
Pasireotide is metabolically highly stable and in vitro data show that pasireotide is not a substrate, inhibitor or inducer of any major enzymes of CYP450. In healthy volunteers, pasireotide is predominantly found in unchanged form in plasma, urine and faeces.
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 radioactive dose was recovered over the first 10 days after administration, including 48.3±8.16% of the radioactivity in faeces and 7.63±2.03% in urine.
Pasireotide demonstrates low clearance (CL/F ~7.6 litres/h for healthy volunteers and ~3.8 litres/h for Cushing’s disease patients). Based on the accumulation ratios of AUC, the calculated effective half-life (t1/2,eff) in healthy volunteers was approximately 12 hours.
In Cushing’s disease patients, pasireotide demonstrates linear and time-independent pharmacokinetics in the dose range of 0.3 mg to 1.2 mg twice a day. Population pharmacokinetic analysis suggests that based on Cmax and AUC, 90% of steady state in Cushing’s disease patients is reached after approximately 1.5 and 15 days, respectively.
No studies have been performed in paediatric patients.
Renal clearance has a minor contribution to the elimination of pasireotide in humans. In a clinical study with single subcutaneous dose administration of 900 μg pasireotide in subjects with impaired renal function, renal impairment of mild, moderate or severe degree, or end stage renal disease (ESRD) did not have a significant impact on total pasireotide plasma exposure. The unbound plasma pasireotide exposure (AUCinf,u) was increased in subjects with renal impairment (mild: 33%; moderate: 25%, severe: 99%, ESRD: 143%) compared to control subjects.
In a clinical study in subjects with impaired hepatic function (Child-Pugh A, B and C), statistically significant differences were found in subjects with moderate and severe hepatic impairment (Child-Pugh B and C). In subjects with moderate and severe hepatic impairment, AUC inf was increased 60% and 79%, Cmax was increased 67% and 69%, and CL/F was decreased 37% and 44%, respectively.
Age has been found to be a covariate in the population pharmacokinetic analysis of Cushing’s disease patients. Decreased total body clearance and increased pharmacokinetic exposures have been seen with increasing age. In the studied age range 18-73 years, the area under the curve at steady state for one dosing interval of 12 hours (AUCss) is predicted to range from 86% to 111% 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 older than 65 years are limited but do not suggest any clinically significant differences in safety and efficacy in relation to younger patients.
Population pharmacokinetic analyses of Signifor suggest that race and gender do not influence pharmacokinetic parameters.
Body weight has been found to be a covariate in the population pharmacokinetic analysis of Cushing’s disease patients. For a range of 60-100 kg the reduction in AUC ss with increasing weight is predicted to be approximately 27%, which is considered moderate and of minor clinical significance.
Non-clinical safety data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, 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 non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Pasireotide was not genotoxic in in vitro and in vivo assays.
Carcinogenicity studies conducted in rats and transgenic mice did not identify any carcinogenic potential.
Pasireotide did not affect fertility in male rats but, as expected from the pharmacology of pasireotide, females presented abnormal cycles or acyclicity, and decreased numbers of corpora lutea and implantation sites. Embryo toxicity was seen in rats and rabbits at doses that caused maternal toxicity but no teratogenic potential was detected. In the pre- and postnatal study in rats, pasireotide had no effects on labour and delivery, but caused slight retardation in the development of pinna detachment and reduced body weight of the offspring.
Available toxicological data in animals have shown excretion of pasireotide in milk.
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