Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Amryt Pharmaceuticals DAC, 45 Mespil Road, Dublin 4, Ireland
Pharmacotherapeutic group: Pituitary and hypothalamic hormones and analogues, somatostatin and analogues
ATC code: H01CB02
Octreotide is a synthetic octapeptide derivative of naturally occurring somatostatin with similar pharmacological effects, but with a considerably prolonged duration of action. It inhibits pathologically increased secretion of GH and of peptides and serotonin produced within the gastro-entero-pancreatic (GEP) endocrine system.
In animals, octreotide is a more potent inhibitor of GH, glucagon and insulin release than somatostatin is, with greater selectivity for GH and glucagon suppression.
In healthy subjects, octreotide has been shown to inhibit:
Unlike somatostatin, octreotide inhibits GH secretion preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (i.e. GH in patients with acromegaly).
In a single-dose study conducted in healthy volunteers, inhibition of GH was observed in all subjects receiving Mycapssa, as compared to their GH levels prior to Mycapssa.
In a study designed to assess the duration of Mycapssa-induced increased intestinal permeability, an increase in paracellular permeability was observed 2 hours after Mycapssa administration and returned to baseline by 5.5 hours after Mycapssa administration. Mycapssa-induced permeability is completely reversible within this timeframe.
The efficacy and safety of Mycapssa in patients with acromegaly were established in 3 phase 3 clinical studies: a 9-month, randomised, open-label, active-controlled study, preceded by a 6-month run-in phase (OOC-ACM-302); a 9-month, randomised, double-blind, placebo-controlled study (OOC-ACM-303); and a 7-month, open-label, baseline-controlled study (CH-ACM-01). All 3 studies were switch studies in patients with acromegaly who had responded to treatment with injectable somatostatin analogues. All 3 studies comprised optional open-label extension phases. In all 3 studies, the Mycapssa starting dose was 40 mg (20 mg in the morning and 20 mg in the evening). Dose increase of Mycapssa was allowed during dose titration to 60 mg (40 mg in the morning and 20 mg in the evening) and to a maximal dose of 80 mg daily (40 mg in the morning and 40 mg in the evening) until patients were deemed adequately controlled based on biochemical results and/or clinical judgement. Patients then maintained their target dose until end of treatment.
In the active-controlled study (OOC-ACM-302), 146 patients initiated Mycapssa run-in treatment within the routine dosing interval from their last somatostatin analogue injection. Mean baseline IGF-1 was 0.9 times the upper limit of normal (ULN). 116 patients (79.5%) completed the 6-month run-in phase; 30 patients (20.5%) discontinued. Most frequent reasons for discontinuation during the run-in phase were treatment failure (5.5%) and adverse events (9.6%; mostly mild to moderate gastrointestinal events).
Of the 146 patients enrolled, 92 patients (63.0%) completed the run-in phase and were biochemically controlled (defined as IGF-1 ≤1.3 times ULN and GH <2.5 ng/mL). These patients were randomised to either continue treatment with Mycapssa or revert to their previous treatment with injectable somatostatin analogues.
The primary efficacy endpoint of study OOC-ACM-302 was the proportion of patients who were biochemically controlled throughout the 9-month randomised controlled treatment (RCT) phase. A patient was considered biochemically controlled if the IGF-1 time-weighted average of all IGF-1 assessments during the RCT phase was < 1.3 times ULN.
90.9% of patients treated with Mycapssa versus 100% of patients treated with injectable somatostatin analogues were biochemically controlled throughout the RCT phase. The primary endpoint met the prespecified non-inferiority criterion of -20% (see Table 2).
Table 2. Primary endpoint results of study OOC-ACM-302:
| Mycapssa (N=55) | Injectable somatostatin analogues (N=37) | |
|---|---|---|
| Primary analysis | ||
| Biochemically controlled1, n (%) | 50 (90.9) | 37 (100) |
| Difference in adjusted proportions2 | -9.1 | |
| 95% CI | (-19.9, 0.5) | |
1 Defined as IGF-1 time-weighted average of all IGF-1 assessments during the RCT phase <1.3 times ULN
2 The adjusted difference and CI were obtained using the stratified M&N method
CI = confidence interval; IGF-1 = insulin-like growth factor 1; M&N = Miettinen & Nurminen; RCT = randomised controlled treatment; ULN = upper limit of normal
Table 3 includes data on active acromegaly symptoms reported during the run-in and RCT phases of OOC-ACM-302 study.
Table 3. Proportion of patients with active acromegaly symptoms in patients that enrolled to the randomised controlled treatment phase of study OOC-ACM-302:
| Run-in phase | RCT phase | |||
|---|---|---|---|---|
| Symptom | Baseline Run-in Injectable somatostatin analogues % (N=92) | End of Run-in Mycapssa % (N=92) | End of RCT Injectable somatostatin analogues % (N=37) | End of RCT Mycapssa % (N=55) |
| Joint pain | 71 | 62 | 70 | 60 |
| Swelling of extremities | 47 | 33 | 41 | 42 |
| Perspiration | 50 | 42 | 54 | 38 |
| Fatigue | 75 | 64 | 65 | 64 |
| Headache | 50 | 48 | 43 | 53 |
RCT = randomised controlled treatment
The placebo-controlled study OOC-ACM-303 enrolled 56 patients. Mean baseline IGF-1 was 0.8 times ULN. The primary efficacy endpoint was the somatostatin dose-adjusted proportion of patients who maintained their biochemical response, defined similarly to the inclusion criteria, as an IGF-1 level less than or equal to the ULN at the end of 9 months of treatment. 58.2% of patients treated with Mycapssa versus 19.4% of patients treated with placebo maintained their biochemical response (p=0.0079; see Table 4).
Table 4. Primary endpoint results of study OOC-ACM-303:
| Mycapssa (N=28) | Placebo (N=28) | |
|---|---|---|
| Maintained biochemical response1, adjusted proportions2 | 58.16 | 19.42 |
| Difference in adjusted proportions2 | 38.74 | |
| 95% CI | (10.68, 59.90) | |
| p-value | 0.0079 |
1 Defined as average IGF-1 ≤1 x ULN after 9 months of treatment. Early discontinuation was regarded as non-response.
2 Adjusted for treatment group, baseline SRL dose and baseline IGF-1 level
CI = confidence interval; IGF-1 = insulin-like growth factor 1; SRL = somatostatin receptor ligand; ULN = upper limit of normal
The baseline-controlled study CH-ACM-01 enrolled 151 patients. Mean baseline IGF-1 was 0.9 times ULN. The primary efficacy endpoint was the proportion of responders at the end of the 7-month core treatment phase. Response was defined similarly to the inclusion criteria, as IGF-1 levels less than 1.3 times ULN and GH levels less than 2.5 ng/mL. Overall, 64.9% of patients were responders at the end of the core treatment phase (see Table 5).
Table 5. Primary endpoint results of study CH-ACM-01:
| Mycapssa (N=151) | |
|---|---|
| Responders1, n (%) | 98 (64.9) |
| Exact 95% CI for %2 | (58.4, 74.2) |
1 Defined as IGF-1 <1.3 times ULN (adjusted for age and sex) and 2-hour integrated GH <2.5 ng/mL after 7 months of treatment (LOCF analysis)
2 Obtained using Clopper-Pearson (Exact) method
CI = confidence interval; GH = growth hormone; IGF-1 = insulin-like growth factor 1; LOCF = last observation carried forward; ULN = upper limit of normal
The individual symptom scores for swelling of extremities and joint pain showed a statistically significant improvement at the end of core treatment period, while treated with Mycapssa, compared to baseline, while treated with injectable somatostatin analogues (p=0.0165 and p=0.0382, respectively).
See section 4.2 for information on paediatric use.
Orally administered octreotide is absorbed in the intestines via the paracellular route. Transient permeability enhancer (TPE) excipients in the formulation facilitate the absorption of octreotide. In a clinical study it was shown that TPE excipients increase intestinal absorption via the paracellular route, using the lactulose to mannitol ratio test (see section 4.5). Increased permeability was shown to be transient and reversible (see section 5.1).
In healthy subjects, systemic exposure, as measured by AUC, of a single oral dose of Mycapssa (20 mg octreotide acetate) was 95% to 100% of that of a single dose of subcutaneous octreotide acetate (0.1 mg octreotide acetate), demonstrating comparable exposure. Peak octreotide levels (Cmax) were 22%-33% lower following oral administration compared to the subcutaneous route. Absorption time was longer after oral administration than after subcutaneous administration; peak concentrations were reached at a median of 1.67-2.5 hours after oral administration and after 0.5 hours after subcutaneous administration.
After single-dose administration of Mycapssa, the systemic exposure of octreotide in healthy subjects increased dose-proportionally for doses between 3 and 40 mg. In patients with acromegaly, there was a dose-related increase in mean plasma octreotide concentrations after chronic administration of Mycapssa 40 mg (20 mg twice daily), 60 mg (40 mg morning/20 mg evening), and 80 mg (40 mg twice daily).
In healthy volunteer studies, administration of Mycapssa 20 mg with food led to an approximate 90% decrease in the extent of absorption. Full size high fat meals provided 1 hour prior or 2 hours post dose significantly decreased the absorption of Mycapssa (see section 4.2).
In all phase 3 studies Mycapssa capsules were taken at least 1 hour prior or at least 2 hours after eating any food.
After subcutaneous injection, the volume of distribution is 0.27 L/kg, and the total body clearance 160 mL/min. Plasma protein binding amounts to 65%. The amount of octreotide bound to blood cells is negligible.
The elimination half-life after subcutaneous administration is 100 minutes. Most of the peptide is eliminated via the faeces, while approximately 32% is excreted unchanged into the urine.
Half-life after single oral administration of Mycapssa was similar to the subcutaneous route (2.66 hours and 2.27 hours respectively).
In patients with acromegaly, elimination after chronic dosing was slightly slower than that seen in healthy volunteers, with mean apparent half-life values at steady state ranging from 3.2–4.5 hours across doses (20 mg, 40 mg, 60 mg, and 80 mg). Elimination is complete approximately 48 hours after the last dose in patients who have achieved steady-state plasma levels.
Exposure in subjects with severe renal impairment (estimated glomerular filtration rate [eGFR] 15–29 mL/min/1.73 m²) was not substantially different from that of matched healthy controls. Subjects with end-stage renal disease (ESRD) requiring dialysis had higher mean plasma concentrations than those with severe renal impairment with higher mean values for peak plasma concentration, exposure (AUC), and half-life, consistent with an effect of renal impairment on octreotide exposure (see section 4.2).
The elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease.
Pharmacokinetics of octreotide after administration of 10 mg or 20 mg Mycapssa in subjects with stable cirrhosis and portal hypertension (Child Pugh A or B) were comparable to the pharmacokinetics in healthy volunteers (see section 4.2). No dose adjustment is necessary in patients with Child Pugh A or B.
Acute and repeated dose toxicology, genotoxicity, carcinogenicity and reproductive toxicology studies of octreotide acetate in animals revealed no specific safety concerns for humans.
Reproduction studies of octreotide acetate in animals revealed no evidence of teratogenic, embryo/foetal or other reproduction effects due to octreotide at parental doses of up to 1 mg/kg/day. Some retardation of the physiological growth was noted in the offspring of rats which was transient and attributable to GH inhibition brought about by excessive pharmacodynamic activity (see section 4.6).
No specific studies were conducted in juvenile rats. In the pre- and post-natal developmental studies, reduced growth and maturation was observed in the first filial generation (F1) offspring of dams given octreotide during the entire pregnancy and lactation period. Delayed descent of the testes was observed for male F1 offspring, but fertility of the affected F1 male pups remained normal. Thus, the above mentioned observations were transient and considered to be the consequence of GH inhibition.
In rats receiving octreotide acetate at daily subcutaneous doses up to 1.25 mg/kg body weight, fibrosarcomas were observed, predominantly in a number of male animals, at the subcutaneous injection site after 52, 104 and 113/116 weeks. Local tumours also occurred in the control rats, however development of these tumours was attributed to disordered fibroplasia produced by sustained irritant effects at the injection sites, enhanced by the acidic lactic acid/mannitol vehicle. This non-specific tissue reaction appeared to be particular to rats. Neoplastic lesions were not observed either in mice receiving daily subcutaneous injections of octreotide at doses up to 2 mg/kg for 98 weeks, or in dogs treated with daily subcutaneous doses of octreotide for 52 weeks, or in cynomolgus monkeys treated orally with 20 mg/day octreotide (as octreotide capsules) for 9 months.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
