Pasireotide
SOM230, Pasireotide diaspartate, Pasireotide pamoate, Pasireotide LAR, Multireceptor-targeted somatostatin analogue
Pasireotide is a second-generation somatostatin analogue with a deliberately broad receptor profile, binding four of the five somatostatin receptor subtypes with high affinity, and SSTR5 far more potently than octreotide does. That breadth is what allows it to work in Cushing's disease and in acromegaly resistant to first-generation analogues, and it is also why hyperglycaemia is its defining adverse effect.
Mechanism
Pasireotide binds human somatostatin receptors with reported pKi values of roughly 8.2 at SSTR1, 9.0 at SSTR2, 9.1 at SSTR3, below 7.0 at SSTR4 and 9.9 at SSTR5; exact values vary between published binding studies and should be read as approximate. The critical comparison is with octreotide, which is heavily SSTR2-dominant: pasireotide has roughly 40-fold greater SSTR5 affinity and substantially greater affinity at SSTR1 and SSTR3, while being somewhat weaker at SSTR2. Corticotroph adenomas in Cushing's disease express SSTR5 densely but relatively little SSTR2, and glucocorticoid excess further downregulates SSTR2. This is the accepted explanation for why first-generation analogues fail in Cushing's disease and pasireotide does not: it engages the receptor the tumour actually expresses, suppressing pro-opiomelanocortin transcription and adrenocorticotropic hormone secretion, with a consequent fall in adrenal cortisol output.
The same receptor breadth explains its principal liability. SSTR5 is the dominant somatostatin receptor on pancreatic beta cells and on the enteroendocrine cells that secrete glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Pasireotide therefore suppresses insulin secretion and blunts the incretin response far more than octreotide does, while sparing glucagon relatively, producing a distinctive incretin-deficient hyperglycaemia. Pasireotide has also been described as a functionally biased agonist at SSTR2, inducing less receptor internalisation and beta-arrestin recruitment than octreotide, which may reduce receptor desensitisation over time; this is a mechanistic observation from cell systems rather than a clinical finding. It is a cyclohexapeptide rather than a shortened somatostatin analogue, built from unnatural amino acids on a rigid ring, which gives it a 12-hour half-life against 1-3 minutes for the native hormone.
What the research shows
Pasireotide occupies a narrow but real niche. In Cushing's disease the phase 3 data are unambiguous about direction and equally unambiguous about magnitude: urinary free cortisol fell by roughly half by month 2, but only 14.6% and 26.3% of patients on the two doses normalised it at six months without a dose increase. In acromegaly, pasireotide LAR was formally superior to octreotide LAR in treatment-naive patients (31.3% versus 19.2%), and PAOLA showed it can rescue 15-20% of patients in whom first-generation analogues have already failed, against 0% on continued first-generation treatment. That resistant population is where the drug is most defensible clinically, because the alternatives are surgery, radiotherapy, a growth hormone receptor antagonist or dopamine agonists.
The negative side of the ledger is substantial and well documented. Hyperglycaemia is not an occasional adverse event but a predictable pharmacological consequence of SSTR5-mediated suppression of insulin and incretin secretion: hyperglycaemia-related adverse events affected 118 of 162 patients in the Cushing's trial, glucose-lowering medication was started in 74 of them, the head-to-head acromegaly trial recorded 57.3% versus 21.7% against octreotide, and in PAOLA around a quarter of patients developed diabetes. Mechanistic work has shown the hyperglycaemia is incretin-driven and responds preferentially to incretin-based glucose-lowering agents rather than to metformin monotherapy, which has shaped expert consensus on management. There is also an inherent tension in Cushing's disease: cortisol excess itself causes diabetes, so a drug that lowers cortisol while raising glucose produces a complicated net metabolic effect that varies between patients.
Evidence assessment
High-quality evidence
Pasireotide has approved labelling from the FDA and from European regulators including the MHRA for Cushing's disease and acromegaly, based on adequately powered randomised double-blind trials with biochemical primary endpoints: a 162-patient phase 3 study in Cushing's disease, a 358-patient double-blind head-to-head superiority trial against octreotide in acromegaly, and the 198-patient randomised PAOLA trial in analogue-resistant acromegaly. Evidence quality is high, though the response rates themselves are modest and the hyperglycaemia burden is substantial.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
A 12-month phase 3 study of pasireotide in Cushing's disease Preclinical only
The primary endpoint, urinary free cortisol at or below the upper limit of normal at month 6 without a dose increase, was met by 12 of 82 (14.6%) on the lower dose and 21 of 80 (26.3%) on the higher dose. Median urinary free cortisol fell by roughly 50% by month 2 and then remained stable. Normalisation was more frequent in patients with baseline levels not exceeding five times the upper limit of normal. Hyperglycaemia-related adverse events affected 118 of 162 patients and glucose-lowering medication was started in 74 of 162. This trial supported approval, but most patients did not normalise cortisol.
Pasireotide versus octreotide in acromegaly: a head-to-head superiority study Preclinical only
Biochemical control (growth hormone below 2.5 micrograms/l with a normal IGF-1) at month 12 was achieved by 31.3% on pasireotide versus 19.2% on octreotide (P=0.007). Normal IGF-1 alone was reached by 38.6% versus 23.6% (P=0.002), while GH below 2.5 micrograms/l was similar (48.3% versus 51.6%). Superiority was demonstrated, but both control figures are low, roughly a quarter to a third of patients who missed control had not received the recommended dose increase, and hyperglycaemia-related adverse events were far more common with pasireotide (57.3% versus 21.7%).
Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial Preclinical only
At 24 weeks, 10 patients (15%) on pasireotide 40 mg and 13 (20%) on 60 mg achieved biochemical control, compared with none in the active control group (absolute differences 15.4% and 20.0%, P=0.0006 and P<0.0001). The zero-percent control arm is the striking result and confirms this is a genuinely resistant population. The cost was metabolic: hyperglycaemia in 33% and 31% versus 14%, and diabetes in 21% and 26% versus 8%.
Safety
Hyperglycaemia is the defining risk and the reason the drug requires structured monitoring. It occurs in the majority of treated patients, can appear within the first weeks, and ranges from modest glucose elevation to frank new-onset diabetes and, rarely, ketoacidosis. The mechanism, suppression of insulin and of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide through SSTR5, is why incretin-based therapies and dipeptidyl peptidase-4 inhibitors are generally more effective against it than metformin alone. Baseline glycated haemoglobin and fasting glucose, and regular monitoring thereafter, are specified in the labelling.
The remainder of the profile is the somatostatin analogue class effect: diarrhoea, nausea, abdominal pain, cholelithiasis and biliary sludge, and injection-site reactions. QT interval prolongation has been observed and warrants electrocardiographic attention in patients with cardiac risk factors or on other QT-prolonging drugs. Elevated liver enzymes occur; bradycardia is reported. In Cushing's disease, over-suppression can produce hypocortisolism requiring dose reduction or glucocorticoid cover. Pasireotide is a hospital-specialist medicine and is entirely unsuitable for unsupervised use, given that a majority of users will develop a measurable glycaemic disturbance that needs active management.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Licensed by the MHRA for the treatment of adult patients with Cushing's disease for whom surgery is not an option or has failed, and for acromegaly in patients inadequately controlled by surgery or by a first-generation somatostatin analogue. Prescription-only, specialist-initiated in endocrinology, with baseline and ongoing glycaemic monitoring required by the labelling. |
| United States | The subcutaneous formulation was approved by the FDA in December 2012 for Cushing's disease in adults for whom pituitary surgery is not an option or has not been curative. The long-acting intramuscular formulation was approved in 2014 for acromegaly and in 2018 for Cushing's disease. Prescription-only, with glucose monitoring specified in the labelling. |
| WADA (sport) | Not prohibited on the current Prohibited List. Pasireotide suppresses growth hormone and adrenocorticotropic hormone secretion rather than stimulating them. Note that this is the opposite pharmacology to the S2.4 corticotrophin-releasing factors, which are banned. The List is revised annually. |
Questions
Corticotroph adenomas express somatostatin receptor subtype 5 densely but subtype 2 only sparsely, and the high cortisol levels of Cushing's disease further downregulate subtype 2. Octreotide is essentially an SSTR2 drug, so it has almost nothing to bind. Pasireotide has roughly forty times greater affinity for SSTR5, which is the receptor the tumour actually presents, so it can suppress adrenocorticotropic hormone output where first-generation analogues cannot.
Not really, though it is manageable. It is a direct consequence of the same SSTR5 activity that makes the drug work, because SSTR5 mediates suppression of insulin and of the incretin hormones. Rates in the trials were high: 118 of 162 patients in the Cushing's disease study had a hyperglycaemia-related adverse event, and 57.3% did in the head-to-head acromegaly trial against 21.7% on octreotide. Expert consensus favours incretin-based glucose-lowering treatment rather than metformin first, because the defect is incretin deficiency rather than insulin resistance.
Modest proportions, and this should not be overstated. In the pivotal Cushing's disease trial, 14.6% and 26.3% of patients on the two doses normalised urinary free cortisol at six months. In treatment-naive acromegaly, 31.3% achieved full biochemical control against 19.2% on octreotide. In analogue-resistant acromegaly, 15-20% achieved control against 0% on continued first-generation treatment. The drug is superior to its comparators but is far from uniformly effective.
No. It is not on the current WADA Prohibited List. It suppresses growth hormone and adrenocorticotropic hormone secretion, the opposite of the substances banned under S2.2 and S2.4, and has no plausible performance-enhancing application.