Pasireotide (Signifor®, Signifor LAR®): A Comprehensive Monograph on a Multireceptor-Targeted Somatostatin Analog

Executive Summary and Introduction

Overview

Pasireotide is a second-generation, multireceptor-targeted somatostatin analog (SSA) representing a significant evolution in the medical management of certain endocrine disorders.[1] Developed initially by Novartis and now part of the portfolio of Recordati Rare Diseases, Pasireotide is a synthetic, long-acting cyclic hexapeptide engineered to mimic the inhibitory actions of the natural hormone somatostatin.[2] It is commercially available under two distinct brand names corresponding to its formulation and route of administration: Signifor®, a solution for subcutaneous (SC) injection, and Signifor LAR®, a long-acting release (LAR) formulation for intramuscular (IM) injection.[6]

Primary Indications

Pasireotide holds orphan drug status and is approved for two primary indications. It is used for the treatment of adult patients with Cushing's disease, a condition of chronic hypercortisolism, for whom pituitary surgery is not a viable option or has not been curative.[6] Additionally, the long-acting formulation, Signifor LAR®, is approved for the treatment of acromegaly, a disorder of excessive growth hormone (GH) secretion, in adult patients who have demonstrated an inadequate response to surgery or for whom surgery is not an option.[6]

Core Mechanism and Clinical Distinction

The defining characteristic of Pasireotide, and the foundation of its clinical utility and challenges, is its unique and broad somatostatin receptor (SSTR) binding profile. Unlike first-generation SSAs such as octreotide and lanreotide, which are highly selective for SSTR subtype 2 (SSTR2), Pasireotide exhibits high-affinity binding to four of the five SSTR subtypes: SSTR1, SSTR2, SSTR3, and most notably, SSTR5.[1] It possesses a binding affinity for SSTR5 that is approximately 40-fold greater than that of other SSAs.[6] This broad-spectrum activity, particularly its potent agonism at SSTR5, underpins its efficacy in Cushing's disease, as the underlying corticotroph adenomas predominantly express SSTR5, a receptor poorly targeted by first-generation agents.[12] However, this same pharmacological property is directly responsible for Pasireotide's most prominent and clinically significant adverse effect: hyperglycemia. The drug's potent inhibitory effect on insulin secretion, mediated via SSTRs on pancreatic islet cells, establishes a fundamental paradigm where its therapeutic benefit is mechanistically linked to its primary safety concern.[11]

Report Scope

This monograph provides an exhaustive and detailed analysis of Pasireotide. It synthesizes current knowledge on the drug's physicochemical characteristics, its complex pharmacodynamic and pharmacokinetic profiles, and the clinical evidence supporting its therapeutic applications. Furthermore, it presents a comprehensive safety profile, detailed administration guidelines, a summary of its regulatory and commercial history, and an overview of emerging investigational uses that are shaping its future role in medicine.

Physicochemical Properties and Formulations

Chemical Identity and Structure

Pasireotide is classified as a small molecule, synthetic peptide.[2] Structurally, it is a homodetic cyclic hexapeptide, meaning it is a cyclical peptide composed of six amino acid residues linked in a single ring.[3] Its design as a somatostatin analog allows it to mimic the physiological functions of the endogenous hormone.[3]

• Classification: Small Molecule, Somatostatin Analog, Cyclic Hexapeptide.[2]
• Chemical Name: cyclo((4R)-4-(2-aminoethylcarbamoyloxy)-L-prolyl-L-phenylglycyl-D-tryptophyl-L-lysyl-4-O-benzyl-L-tyrosyl-L-phenylalanyl-).[2]
• IUPAC Name: -1,4,7,10,13,16-hexazabicyclo[16.3.0]henicosan-20-yl] N-(2-aminoethyl)carbamate.[3]
• Identifiers:
• DrugBank ID: DB06663.[2]
• CAS Number: 396091-73-9 (free base).[3]
• Molecular Formula: C58​H66​N10​O9​.[3]
• Molecular Weight: 1047.2 g/mol.[3]
• InChIKey: VMZMNAABQBOLAK-DBILLSOUSA-N.[3]
• Synonyms: The drug is widely known in research and development literature by its investigational code, SOM230.[3]

Physical Properties

Pasireotide in its pure form presents as a white to off-white powder.[17] It is reported to be soluble in dimethyl sulfoxide (DMSO).[17] For long-term stability, storage at -20°C is recommended.[17]

Pharmaceutical Formulations and Salts

The development of two distinct pharmaceutical formulations for Pasireotide reflects a sophisticated strategy for managing chronic endocrine diseases. This approach provides an immediate-release option for initial therapy and dose optimization, and a long-acting option for maintenance therapy, prioritizing patient convenience and adherence.

• Signifor® (Pasireotide diaspartate): This formulation is marketed as a diaspartate salt (CAS# 820232-50-6) and is designed for subcutaneous (SC) administration.[2] It is supplied as a clear, colorless, sterile solution in single-dose glass ampoules, intended for twice-daily injection.[7] The availability of multiple strengths—0.3 mg/mL, 0.6 mg/mL, and 0.9 mg/mL—facilitates precise dose titration based on individual patient response and tolerability.[8] This formulation is ideal for initiating treatment, as it allows clinicians to quickly adjust the dose to find the optimal balance between efficacy and adverse effects.
• Signifor LAR® (Pasireotide pamoate): This is a long-acting release (LAR) formulation engineered for once-monthly intramuscular (IM) injection.[6] The active ingredient is pasireotide pamoate (CAS# 396091-79-5).[19] It is supplied as a powder in a vial that requires reconstitution with a provided diluent prior to administration by a healthcare professional.[8] The LAR formulation utilizes biodegradable polymer microspheres, similar in design to octreotide LAR, to ensure a slow and extended release of the active drug over a 28-day period.[13] Available strengths include 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg per vial, providing a range of options for long-term maintenance therapy.[8] This formulation was deliberately designed to reduce the peak-to-trough fluctuations in plasma concentration seen with the SC formulation, which may help minimize certain acute side effects and significantly improves patient convenience, a critical factor for adherence in chronic conditions.[13]
• Other Salt Forms: For research and development purposes, other salt forms of Pasireotide have been synthesized, including pasireotide acetate and pasireotide ditrifluoroacetate, though these are not used in the commercially approved products.[18]

Pharmacodynamics and Mechanism of Action

Receptor Binding Profile: The Core of Pasireotide's Action

The pharmacological identity of Pasireotide is defined by its action as a multireceptor-targeted somatostatin analog.[12] It functions by binding to and activating somatostatin receptors (SSTRs), thereby mimicking the widespread inhibitory effects of endogenous somatostatin.[12]

Pasireotide's key therapeutic distinction lies in its broad receptor binding profile. It binds with high affinity to four of the five known human SSTR subtypes: SSTR1, SSTR2, SSTR3, and SSTR5, with only low affinity for SSTR4.[1] This profile contrasts sharply with that of first-generation SSAs like octreotide and lanreotide, which are highly preferential for SSTR2.[1]

The most critical aspect of this profile is Pasireotide's exceptionally high affinity for SSTR5. It binds to SSTR5 with an affinity that is approximately 40 times greater than that of octreotide.[6] It also demonstrates higher affinity for SSTR1 and SSTR3, while its affinity for SSTR2 is comparable to or slightly lower than that of octreotide.[2] Quantitative binding studies have reported pKi values (a measure of binding affinity, where higher values indicate stronger binding) of 8.2 for SSTR1, 9.0 for SSTR2, 9.1 for SSTR3, and a remarkable 9.9 for SSTR5, confirming its subnanomolar affinity for the SSTR5 subtype.[14] This unique multireceptor engagement, with a strong SSTR5 component, is the foundation for both its expanded therapeutic efficacy and its distinct side effect profile.

Table 1: Comparative Somatostatin Receptor (SSTR) Binding Profile

Compound	SSTR1 Affinity	SSTR2 Affinity	SSTR3 Affinity	SSTR4 Affinity	SSTR5 Affinity	Key Characteristic
Pasireotide	High (pKi 8.2)	High (pKi 9.0)	High (pKi 9.1)	Low (pKi <7.0)	Very High (pKi 9.9)	Multireceptor-targeted, SSTR5 dominant 2
Octreotide	Low	Very High	Low	Low	Moderate	SSTR2-preferential 1
Lanreotide	Low	High	Low	Low	Moderate	SSTR2-preferential 1
Somatostatin-14	High	High	High	Moderate	High	Natural ligand, binds all subtypes 21

Mechanism of Action in Endocrine Disorders

Pasireotide's therapeutic utility is a direct result of applying its unique receptor binding profile to diseases characterized by specific SSTR expression patterns on pathological tissues.

• Cushing's Disease: The primary therapeutic rationale for Pasireotide in Cushing's disease is rooted in the molecular biology of corticotroph adenomas. These ACTH-secreting pituitary tumors exhibit high levels of SSTR5 expression, while expression of SSTR2 is often low or absent.[12] This molecular signature renders first-generation, SSTR2-preferential SSAs largely ineffective. Pasireotide, with its potent SSTR5 agonism, directly targets the predominant receptor on these tumor cells. Upon binding, it activates inhibitory signaling pathways that potently suppress the synthesis and secretion of ACTH.[2] The subsequent reduction in circulating ACTH levels leads to decreased stimulation of the adrenal cortex, thereby lowering cortisol production and mitigating the systemic signs and symptoms of hypercortisolism.[2]
• Acromegaly: In acromegaly, the underlying pathology is a GH-secreting pituitary adenoma, or somatotropinoma.[16] These tumors typically express high levels of both SSTR2 and SSTR5.[13] Pasireotide's ability to potently engage both of these receptor subtypes provides a dual mechanism for inhibiting pathological GH secretion.[2] The suppression of GH, in turn, reduces hepatic production of IGF-1, the principal mediator of the somatic overgrowth and metabolic complications associated with acromegaly.[15] The superior efficacy of Pasireotide compared to octreotide in a significant subset of patients, particularly those inadequately controlled by first-generation SSAs, is attributed to this added SSTR5-mediated inhibitory pathway. It provides a means to control GH secretion in tumors that are either less responsive to SSTR2 agonism or have a high SSTR5 expression level.[13]

Mechanism of Hyperglycemia: The "Off-Target" On-Target Effect

The pharmacology of Pasireotide creates an intricate web of clinical effects, where a single molecular interaction drives both therapeutic benefit and the most significant adverse event. The high-affinity binding to SSTR5 is the central event that dictates the drug's clinical profile. While this property confers unique efficacy in SSTR5-expressing tumors, it also has profound metabolic consequences because pancreatic islet cells also express these receptors.

Hyperglycemia is the most frequent and clinically important adverse effect of Pasireotide therapy, and it is a direct, on-target consequence of its mechanism of action.[6] Pasireotide is more potent than even natural somatostatin at inhibiting the secretion of key metabolic hormones, particularly insulin.[2] This effect is mediated by the drug's high-affinity binding to SSTR2 and SSTR5 on pancreatic beta-cells, which strongly suppresses insulin release.[11] Compounding this effect, Pasireotide also inhibits the secretion of gut-derived incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are crucial for augmenting insulin secretion in response to a meal.[1] This dual blockade—reducing both basal and glucose-stimulated insulin secretion—is the primary driver of Pasireotide-induced hyperglycemia and the frequent development or worsening of diabetes mellitus. This creates a clinical scenario where the endocrinologist prescribing Pasireotide must simultaneously act as a diabetologist, proactively managing the predictable metabolic consequences of the therapy.

Other Pharmacodynamic Effects

• Antiproliferative and Proapoptotic Activity: Beyond its antisecretory effects on hormones, Pasireotide has demonstrated direct antiproliferative and proapoptotic activities in preclinical studies.[18] This suggests a potential to inhibit tumor growth and induce cell death, an effect that has been observed clinically with findings of tumor volume reduction in patients with both Cushing's disease and acromegaly.[27]
• Cardiac Electrophysiology: Pasireotide has demonstrable effects on cardiac function. Dedicated QT studies have confirmed that it can cause a dose-dependent prolongation of the QTc interval, with the maximal effect observed approximately 2 hours after administration.[9] It also induces bradycardia (slowing of the heart rate), with the maximal effect occurring 0.5 to 1 hour post-dose.[12] These effects necessitate careful cardiovascular monitoring in patients receiving the drug.

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Pasireotide varies significantly between its two formulations, which are designed for different clinical applications. A key finding across studies is a notable difference in drug clearance between healthy individuals and patients with Cushing's disease, a factor with direct implications for dosing and safety.

Absorption

• SC Formulation (Signifor®): Following subcutaneous injection, Pasireotide is rapidly absorbed into the systemic circulation. The time to reach maximum plasma concentration (Tmax) is short, occurring within 0.25 to 0.5 hours.[2] Both the peak concentration (Cmax) and the total drug exposure (Area Under the Curve, AUC) increase in a dose-proportional manner with both single and multiple doses, indicating predictable pharmacokinetics across the therapeutic dose range.[2]
• LAR Formulation (Signifor LAR®): The long-acting release formulation is engineered to provide sustained drug levels over a one-month dosing interval. After a single intramuscular injection, it exhibits a characteristic biphasic absorption profile. An initial peak in plasma concentration occurs on the first day, followed by a slow decline and a second, broader peak around day 20 post-injection.[13] The total bioavailability of the LAR formulation is complete relative to the SC formulation, and its exposure (AUC) is dose-proportional, ensuring predictable drug delivery with monthly administration.[13]

Distribution

Pasireotide is widely distributed throughout the body, as evidenced by a large apparent volume of distribution (Vz/F) exceeding 100 L.[2] Its binding to plasma proteins is moderate, at approximately 88%, and this binding is independent of drug concentration.[2] The drug is primarily located within the plasma compartment.[12]

Metabolism

Pasireotide is a metabolically stable peptide, and its metabolism in the body is minimal.[2] However, it has been identified as an inhibitor of the Cytochrome P450 3A4 (CYP3A4) enzyme system.[30] This property is clinically significant as it creates a high potential for drug-drug interactions. By inhibiting CYP3A4, one of the most important drug-metabolizing enzymes, Pasireotide can increase the plasma concentrations and potential toxicity of numerous co-administered medications that are substrates for this enzyme, such as certain statins (atorvastatin), benzodiazepines, and calcium channel blockers.[2] This necessitates a thorough medication review before initiating therapy.

Excretion

Pasireotide is eliminated from the body primarily through hepatic clearance, with biliary excretion being the main route (accounting for approximately 48% of elimination).[2] A minor portion of the drug is cleared via the renal route (approximately 7.63%).[2] The terminal elimination half-life for the immediate-release SC formulation is approximately 12 hours.[2]

Pharmacokinetics in Special Populations

• Patient vs. Healthy Volunteer Clearance: A critical pharmacokinetic finding is the difference in drug clearance between populations. Systemic clearance is approximately 7.6 L/h in healthy volunteers but is significantly lower, at approximately 3.8 L/h, in patients with Cushing's disease.[2] This 50% reduction in clearance means that for a given dose, patients with Cushing's disease will experience approximately double the drug exposure (steady-state concentration) compared to a healthy individual. This disease-specific alteration in drug handling underscores the need for careful, individualized dose titration in the patient population to balance the increased potential for both efficacy and toxicity.
• Hepatic Impairment: As the liver is the primary organ of elimination, hepatic impairment significantly alters Pasireotide's pharmacokinetics. In patients with moderate hepatic impairment (Child-Pugh B), drug exposure (AUC) is increased by 60% and clearance is reduced by 37% compared to individuals with normal liver function.[12] This necessitates specific, reduced starting and maximum doses for these patients.[8] Due to the potential for significant drug accumulation, Pasireotide use should be avoided in patients with severe hepatic impairment (Child-Pugh C).[8]
• Renal Impairment: While renal clearance is a minor pathway, caution is advised when using Pasireotide in patients with severe renal impairment, as increased exposure to the unbound (active) fraction of the drug may occur.[21]

Table 2: Summary of Pharmacokinetic Parameters (SC vs. LAR Formulations)

Parameter	Signifor® (SC Formulation)	Signifor LAR® (IM Formulation)
Administration Route	Subcutaneous (SC)	Intramuscular (IM)
Tmax (Peak Time)	Rapid: 0.25–0.5 hours 2	Biphasic: Peaks at Day 1 and ~Day 20 13
Release Profile	Immediate release 2	Extended-release over 28 days 13
Cmax/AUC Proportionality	Dose-proportional 2	Dose-proportional 13
Volume of Distribution (Vd)	>100 L 12	>100 L 12
Plasma Protein Binding	88% 12	88% 12
Metabolism	Minimal; CYP3A4 inhibitor 2	Minimal; CYP3A4 inhibitor 2
Primary Excretion Route	Hepatic (biliary) 12	Hepatic (biliary) 12
Elimination Half-life	~12 hours 2	Not applicable (extended release)
Clearance (in Cushing's)	~3.8 L/h 2	~3.8 L/h 2

Clinical Efficacy and Therapeutic Applications

The clinical development program for Pasireotide has strategically established its role as a valuable therapy for specific patient populations with Cushing's disease and acromegaly, demonstrating efficacy where first-generation SSAs are insufficient or as a superior option in certain settings.

Cushing's Disease

Pasireotide is the first medical therapy approved to directly target the underlying pituitary pathology of Cushing's disease. Its efficacy has been established in a robust clinical trial program.

• Pivotal Trial (PASPORT-CUSHINGS, Phase III): This landmark study was the largest randomized Phase III trial conducted in patients with Cushing's disease.[32] The primary endpoint was the proportion of patients who achieved normalization of mean 24-hour urinary free cortisol (UFC) levels, a key biomarker of disease activity, after six months of treatment without requiring a dose increase.[12] The results demonstrated a clear dose-dependent effect. After six months, 26% of patients receiving the 0.9 mg twice-daily (BID) dose and 15% of patients on the 0.6 mg BID dose achieved UFC normalization.[33] A larger cohort of patients experienced a partial response, defined as at least a 50% reduction in UFC levels (41% in the 0.9 mg group and 34% in the 0.6 mg group).[33] The mean reduction in UFC across both dose groups was clinically significant at approximately 48%.[25] In addition to biochemical control, patients also showed improvements in clinical parameters, including decreases in blood pressure, body weight, body mass index (BMI), and waist circumference.[32]
• Long-Acting Formulation (Signifor LAR®): The efficacy of the once-monthly IM formulation was evaluated in a Phase III study (NCT01374906).[34] Data from this trial showed that approximately 41% of patients with Cushing's disease responded to treatment within seven months.[33] A subsequent 12-month extension study confirmed that the benefits of the LAR formulation were sustained over the long term.[36]
• Combination Therapy (Phase II, NCT01915303): Recognizing that monotherapy may not be sufficient for all patients, a Phase II study investigated a stepwise approach, adding the dopamine agonist cabergoline to Pasireotide in patients who did not achieve biochemical control.[37] The rationale for this combination is based on the co-expression of SSTR5 and dopamine D2 receptors on many corticotroph adenomas.[38] The study found that 50% of the total patient population achieved the primary endpoint of mUFC control. Notably, half of these responders achieved control with Pasireotide monotherapy, while the other half achieved it after the addition of cabergoline. This result validates the combination as an effective strategy to enhance biochemical control in a subset of patients with an incomplete response to Pasireotide alone.[38]

Acromegaly

In acromegaly, Pasireotide has been strategically positioned as a superior medical therapy for treatment-naive patients and as an essential rescue therapy for those inadequately controlled by first-generation SSAs.

• Head-to-Head vs. Octreotide in Medically Naive Patients (C2305, Phase III): This pivotal trial directly compared the efficacy of Pasireotide LAR (starting dose 40 mg) against the then-standard-of-care, octreotide LAR (starting dose 20 mg), in 358 medically naive patients with active acromegaly.[11] Pasireotide LAR demonstrated statistically significant superiority. At the 12-month primary endpoint, 31.3% of patients in the Pasireotide arm achieved biochemical control (defined as mean GH <2.5 µg/L and normal IGF-1 levels), compared to only 19.2% in the octreotide arm (p=0.007).[11] The superiority was primarily driven by a greater ability to normalize IGF-1 levels (38.6% for Pasireotide vs. 23.6% for octreotide, p=0.002).[11] Both treatments were effective at reducing tumor volume, with a mean reduction of approximately 40% in both groups.[11]
• Superiority in Inadequately Controlled Patients (PAOLA, Phase III): The PAOLA study provided definitive evidence for Pasireotide's role as a second-line therapy. The trial enrolled 198 patients with acromegaly who remained biochemically uncontrolled despite receiving maximal approved doses of first-generation SSAs (octreotide or lanreotide).[28] Patients were randomized to either continue their existing therapy (active control) or switch to Pasireotide LAR at a dose of 40 mg or 60 mg. The results were striking and practice-changing. After 24 weeks, 15.4% of patients on Pasireotide 40 mg and 20.0% on Pasireotide 60 mg achieved full biochemical control. In stark contrast, 0% of patients who continued on their first-generation SSA achieved control (p<0.001 for both Pasireotide arms vs. control).[28] This trial unequivocally established Pasireotide as an effective rescue therapy for a patient population with no other pituitary-directed medical options.
• Long-Term Efficacy: The long-term benefits of Pasireotide in acromegaly are well-documented. An extension of the PAOLA study demonstrated that Pasireotide provided a durable and consistent reduction in GH and IGF-1 levels for up to 5.8 years, accompanied by sustained improvements in acromegaly-related symptoms.[42] Another long-term follow-up study reported sustained clinical benefit and tolerability for over 11 years in patients, most of whom were resistant to first-generation SSAs.[43]

Table 3: Key Efficacy Outcomes from Pivotal Phase III Trials

Trial Name	Indication	Patient Population	Intervention Arms	Primary Endpoint	Key Result (%)
PASPORT-CUSHINGS 32	Cushing's Disease	Surgery-ineligible or failed surgery	Pasireotide SC 0.6 mg BID vs. 0.9 mg BID	Proportion with normal UFC at 6 months	15% (0.6 mg) vs. 26% (0.9 mg)
C2305 11	Acromegaly	Medically naive	Pasireotide LAR 40 mg vs. Octreotide LAR 20 mg	Proportion with biochemical control at 12 months	31.3% vs. 19.2% (p=0.007)
PAOLA 28	Acromegaly	Inadequately controlled on 1st-gen SSAs	Pasireotide LAR 40 mg vs. 60 mg vs. Active Control	Proportion with biochemical control at 24 weeks	15.4% (40 mg) & 20.0% (60 mg) vs. 0% (p<0.001)

Safety, Tolerability, and Risk Management

The safety profile of Pasireotide is well-characterized and distinct from that of first-generation SSAs. While it shares some class effects, its unique pharmacology leads to a higher incidence and severity of certain adverse events, particularly hyperglycemia. This necessitates a proactive and comprehensive risk management strategy that begins before the first dose and continues throughout treatment.

Comprehensive Adverse Event Profile

• Most Common Adverse Events: The most frequently reported adverse events (AEs), occurring in 20% or more of patients in clinical trials, are hyperglycemia, new-onset or worsening diabetes mellitus, diarrhea, nausea, cholelithiasis (gallstones), headache, abdominal pain, fatigue, and injection site reactions (pain, erythema, swelling).[2]
• Other Common Adverse Events: A wide range of other common AEs have been reported, including elevations in liver enzymes (ALT, AST), increased hemoglobin A1c (HbA1c), hypertension, dizziness, vomiting, bradycardia, hypokalemia (low blood potassium), hair loss (alopecia), constipation, and decreased appetite.[9]

Table 4: Comparative Frequency of Key Adverse Events: Pasireotide vs. First-Generation SSAs (PAOLA Trial)

Adverse Event	Pasireotide LAR (40/60 mg) Incidence (%)	Active Control (Octreotide/Lanreotide) Incidence (%)
Hyperglycemia	31–33%	14%
Diabetes Mellitus (new onset/worsening)	21–26%	8%
Diarrhea	16–19%	5%
Cholelithiasis	26% (vs. 36% in C2305 comparator)¹	-
Nausea	-	-
Headache	-	-
Data sourced from PAOLA trial.28 ¹Cholelithiasis data from C2305 trial for context.44

In-depth Analysis of Key Risks

The clinical use of Pasireotide requires vigilant management of several key risks, each linked to its mechanism of action.

• Hyperglycemia and Diabetes Mellitus:
• Incidence and Severity: This is the most significant safety concern associated with Pasireotide. Pharmacovigilance data show that reports of "Metabolic and nutrition disorders" are far more frequent and severe for Pasireotide (17.5% of reports) compared to octreotide (4.6%) or lanreotide (4.5%).[16] The PAOLA trial confirmed this, with hyperglycemia occurring in over 30% of Pasireotide-treated patients versus 14% of controls, and new-onset diabetes in up to 26% versus 8%.[28] The risk is higher in patients with pre-existing diabetes or pre-diabetic conditions, and higher doses are associated with more severe events.[21]
• Risk Management: A rigorous glycemic management plan is mandatory. Before initiating therapy, baseline fasting plasma glucose (FPG) and HbA1c levels must be obtained.[9] Following initiation, blood glucose must be monitored weekly for the first 2-3 months, for 4-6 weeks after any dose increase, and periodically thereafter.[9] Patients with poorly controlled diabetes must have their antidiabetic regimen optimized before starting Pasireotide. Initiation or adjustment of antidiabetic medications is often required during treatment.[9] In rare cases of suspected diabetic ketoacidosis, Pasireotide must be discontinued immediately and the patient treated appropriately.[9]
• Cardiovascular Risks:
• Bradycardia and QTc Prolongation: Pasireotide can cause a clinically significant slowing of the heart rate (bradycardia) and prolong the QTc interval on an electrocardiogram (ECG), which is a risk factor for serious cardiac arrhythmias like Torsade de pointes.[9]
• Risk Management: Caution is essential in patients with pre-existing cardiac conditions (e.g., congestive heart failure, high-grade heart block) or risk factors for bradycardia.[9] A baseline ECG is required before starting treatment, with periodic monitoring during therapy advisable.[9] Electrolyte imbalances, particularly hypokalemia and hypomagnesemia, can exacerbate QTc prolongation and must be corrected before and monitored during treatment.[9]
• Hepatotoxicity:
• Incidence: Mild, transient elevations in liver aminotransferases (ALT, AST) are commonly observed.[9] While rare, cases of more significant liver injury, including concurrent elevations of ALT >3x the upper limit of normal (ULN) and bilirubin >2x ULN, have been reported.[21]
• Risk Management: A structured liver function monitoring schedule is required. Liver tests should be performed at baseline, again at weeks 1, 2, 4, 8, and 12 of treatment, and as clinically indicated thereafter.[9] Therapy should be discontinued if signs of clinically significant liver dysfunction develop or if enzyme elevations are sustained and significant (e.g., AST/ALT ≥5x ULN).[9]
• Cholelithiasis (Gallstones):
• Incidence: As with other SSAs, Pasireotide is associated with an increased risk of gallstone formation.[6] This can lead to complications such as cholecystitis (inflammation of the gallbladder) or cholangitis (inflammation of the bile ducts), which may require cholecystectomy.[9]
• Risk Management: A gallbladder ultrasound is recommended at baseline and then periodically at 6- to 12-month intervals during therapy.[9] If complications of cholelithiasis are suspected, Pasireotide should be discontinued and the patient treated appropriately.[9]
• Hypocortisolism and Pituitary Function:
• Mechanism: The potent suppression of ACTH in patients with Cushing's disease can sometimes be excessive, leading to hypocortisolism (abnormally low cortisol levels) and symptoms of adrenal insufficiency.[9] Furthermore, as an SSA, Pasireotide has the potential to inhibit other anterior pituitary hormones.[9]
• Risk Management: Patients should be monitored for signs and symptoms of adrenal insufficiency (e.g., weakness, fatigue, nausea, hypotension). Pituitary function, including thyroid (TSH/free T4) and gonadal axes, should be evaluated at baseline and periodically during treatment.[9] Temporary dose reduction or, in some cases, temporary glucocorticoid replacement therapy may be necessary to manage hypocortisolism.[9]

Drug-Drug Interactions

Pasireotide's potential for significant drug-drug interactions (DDIs) adds another layer of complexity to its management.

• QTc-Prolonging Drugs: Co-administration with other drugs known to prolong the QTc interval is a major concern due to the additive risk of life-threatening arrhythmias. Numerous drugs, including certain antiarrhythmics, antipsychotics, and antibiotics (e.g., azithromycin), fall into this category. Such combinations should be avoided or used only with extreme caution and frequent ECG monitoring.[2]
• Bradycardia-Inducing Drugs: The bradycardic effect of Pasireotide can be potentiated by concomitant use of other drugs that slow the heart rate, such as beta-blockers, certain calcium channel blockers, and digoxin. Dose adjustments of these agents may be necessary.[2]
• CYP3A4 Substrates: As a moderate inhibitor of CYP3A4, Pasireotide can increase the plasma concentrations of drugs metabolized by this pathway. This requires careful review of a patient's medication list for potential interactions with drugs like atorvastatin, axitinib, and many others.[2]
• Antidiabetic Agents: Pasireotide's inherent hyperglycemic effect can counteract the efficacy of antidiabetic medications. Dose increases of insulin or oral hypoglycemic agents are frequently required to maintain glycemic control.[2]

Contraindications and Use in Pregnancy

• Contraindications: Pasireotide is contraindicated in patients with a known hypersensitivity to the drug or any of its components. It is also contraindicated in patients with severe hepatic impairment (Child-Pugh Class C).[21]
• Pregnancy and Lactation: There are limited data on the use of Pasireotide in pregnant women. Animal studies have indicated a potential risk for developmental delay. A notable consideration is that effective treatment of acromegaly can restore fertility in premenopausal women, making counseling on contraception important. The decision to use Pasireotide during pregnancy or lactation must be based on a careful assessment of the potential benefits versus risks.[6]

Dosage, Administration, and Clinical Monitoring

The dosing and administration of Pasireotide are highly specific to the indication and formulation being used. A comprehensive monitoring plan is essential for all patients to manage the drug's potent effects and potential toxicities.

Dosage Regimens

The following table summarizes the recommended dosing regimens for Pasireotide.

Table 5: Dosing and Administration Summary for Signifor® and Signifor LAR®

Indication	Formulation	Initial Dose	Titration / Maximum Dose	Administration Route	Key Considerations
Cushing's Disease	Signifor® (SC)	0.6 mg or 0.9 mg BID 8	Titrate based on UFC and tolerability. Max dose is 0.9 mg BID. 8	Subcutaneous	Response assessed at 2 months. Dose reduction in 0.3 mg decrements. 21
Cushing's Disease	Signifor LAR® (IM)	10 mg q4w 8	After 4 months, may increase up to 40 mg q4w based on UFC and tolerability. 8	Intramuscular	Administered by a healthcare professional. 22
Acromegaly	Signifor LAR® (IM)	40 mg q4w 8	After 3 months, may increase to 60 mg q4w if GH/IGF-1 not controlled and dose is tolerated. 8	Intramuscular	Dose reduction in 20 mg decrements for AEs. 8

Dosage in Hepatic Impairment

Given its primary hepatic clearance, dose adjustments are required for patients with moderate hepatic impairment (Child-Pugh Class B).

• Cushing's Disease:
• Signifor® SC: The recommended initial dose is 0.3 mg BID, with a maximum dose of 0.6 mg BID.[8]
• Signifor LAR® IM: The recommended initial dose is 10 mg every 4 weeks, with a maximum dose of 20 mg every 4 weeks.[8]
• Acromegaly:
• Signifor LAR® IM: The recommended initial dose is 20 mg every 4 weeks, with a maximum recommended dose of 40 mg every 4 weeks.[8]

Pasireotide should be avoided in patients with severe hepatic impairment (Child-Pugh Class C).8

Administration Instructions

Proper administration technique is crucial for ensuring efficacy and minimizing local reactions.

• Signifor® SC: This formulation is intended for self-injection by the patient after receiving proper training from a healthcare professional.[7] The solution should be visually inspected for particulate matter or discoloration before use. The injection should be administered subcutaneously into the top of the thigh or the abdomen, avoiding the navel area. To prevent local irritation, injection sites should be rotated, and the same site should not be used for two consecutive injections. Inflamed or irritated skin should be avoided.[7] If a dose is missed, the patient should skip it and take the next dose at the regularly scheduled time; doses should not be doubled.[7]
• Signifor LAR® IM: This formulation must be administered by a trained healthcare professional.[10] It requires reconstitution immediately prior to injection and must never be administered intravenously. The injection is given deep into the gluteal muscle, alternating between the right and left sides for subsequent injections.[10]

Comprehensive Monitoring Plan

A structured monitoring plan is a cornerstone of safe and effective Pasireotide therapy.

• Baseline Assessments (Prior to Initiation): Before a patient receives their first dose, a comprehensive baseline evaluation must be performed, including [9]:
• Glycemic Status: Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c).
• Hepatic Function: Liver function tests (ALT, AST, bilirubin).
• Cardiac Status: A 12-lead electrocardiogram (ECG) to assess baseline QTc interval.
• Electrolytes: Serum potassium and magnesium levels.
• Biliary System: A gallbladder ultrasound to screen for pre-existing gallstones.
• Ongoing Monitoring during Treatment:
• Glycemic Control: Self-monitoring of blood glucose should be performed weekly for the first 2-3 months and for 2-4 weeks following any dose increase, then periodically as clinically appropriate.[9]
• Hepatic Function: Liver function tests should be repeated at weeks 1, 2, 4, 8, and 12, and then periodically as indicated.[9]
• Cardiac Function: Periodic ECGs to monitor the QTc interval and periodic checks of serum potassium and magnesium are advisable, especially in high-risk patients or those on concomitant medications.[9]
• Biliary Health: A follow-up gallbladder ultrasound should be performed at 6- to 12-month intervals.[9]
• Pituitary Function: Clinicians should monitor for signs of other pituitary hormone deficiencies (e.g., hypothyroidism, hypogonadism, adrenal insufficiency) before and during treatment.[9]

Regulatory and Commercial History

Development and Commercialization

Pasireotide was developed by the Swiss pharmaceutical company Novartis as a next-generation somatostatin analog.[6] It represented a strategic effort to build upon the success of their blockbuster first-generation SSA, Sandostatin® (octreotide), with a novel agent possessing a broader receptor profile and potential for expanded efficacy.[4]

In a significant move reflecting common strategic portfolio optimization in the pharmaceutical industry, the worldwide rights to Pasireotide (both Signifor® and Signifor LAR®), along with the investigational oral agent osilodrostat, were acquired by the Italian company Recordati Rare Diseases in July 2019.[4] The transaction involved an upfront payment of $390 million, with additional payments contingent on future milestones and royalties.[4] This divestment was part of a broader streamlining effort by Novartis, allowing them to offload a niche, high-maintenance product that had not met initial blockbuster sales expectations. For Recordati, a company with a dedicated focus on rare diseases, the acquisition was a "historical milestone," providing them with an established endocrine franchise that fit perfectly within their specialized commercial model.[4] Under the agreement, Novartis continues to supply the products to Recordati during a transitional period.[5]

U.S. Food and Drug Administration (FDA) History

• Orphan Designation: The FDA granted Pasireotide orphan drug designation for the treatment of Cushing's disease on July 24, 2009, acknowledging the unmet need in this rare condition.[46]
• Signifor® (SC): Following a positive recommendation from its advisory committee, the FDA approved Signifor® injection for adult patients with Cushing's disease on December 14, 2012.[6] This marked a significant advancement, as it was the first medication approved in the United States to directly target the underlying pituitary mechanism of the disease.[32]
• Signifor LAR® (IM): The long-acting formulation was first approved by the FDA on December 15, 2014, for the treatment of acromegaly.[6] Subsequently, on June 29, 2018, the indication for Signifor LAR® was expanded to include the treatment of patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.[46]

European Medicines Agency (EMA) History

• Orphan Designation: The EMA's Committee for Orphan Medicinal Products (COMP) granted Pasireotide orphan designation for the treatment of Cushing's disease on October 8, 2009.[49]
• Signifor® (SC): The EMA issued a positive opinion in January 2012, leading to a full marketing authorization from the European Commission for the treatment of Cushing's disease on April 24, 2012.[6]
• Signifor LAR® (IM): The long-acting formulation received EMA approval for the treatment of acromegaly in September 2014.[6] It was later also approved for Cushing's disease.[11]
• Market Exclusivity: As per orphan drug regulations, Pasireotide benefited from a 10-year period of market exclusivity. This exclusivity period for the Cushing's disease indication concluded in April 2022.[49]

Future Directions and Investigational Uses

The development trajectory of Pasireotide has evolved from broad oncologic exploration to a more focused strategy targeting highly specific, mechanistically-driven rare disease niches. This reflects a mature understanding of the drug's unique pharmacological profile, aiming to leverage its strengths in contexts where the benefit-risk balance is most favorable.

Ongoing Clinical Trials for New Indications

Current research is actively exploring Pasireotide's potential in new therapeutic areas where its potent inhibitory effects on hormone secretion could be repurposed.

• Post-Bariatric Hypoglycemia (PBH):
• Trial: The PASIPHY study (NCT05928390) is a pivotal Phase II, multicenter, randomized, placebo-controlled, dose-finding trial evaluating the efficacy and safety of subcutaneous Pasireotide in patients with PBH.[51]
• Rationale: PBH is a debilitating complication of bariatric surgery characterized by excessive and dysregulated post-meal insulin secretion, leading to severe hypoglycemia. The potent insulin-suppressive effect of Pasireotide, which is its primary liability in other indications, becomes the primary therapeutic mechanism in this context. The trial aims to determine if Pasireotide can control this pathological insulin release and normalize post-prandial glucose levels.[52]
• Design: The study is actively recruiting and employs a rigorous design. Participants are randomized to one of three doses of SC Pasireotide (50 µg, 100 µg, or 200 µg) or placebo, administered three times daily before meals. The trial includes a 12-week blinded treatment phase to assess the primary endpoint, followed by an optional 36-week open-label extension phase where all participants can receive active treatment.[51]
• Rare Sarcomas:
• Trial: The PAMSARC study (NCT06456359) is an academic-sponsored, non-commercial Phase II clinical trial investigating Pasireotide LAR as a maintenance therapy in adolescents and young adults with Synovial Sarcoma (SyS) and Desmoplastic Small Round Cell Tumor (DSRCT).[56]
• Rationale: This is a biomarker-driven study. It leverages Pasireotide's multireceptor profile by enrolling only patients whose tumors have been confirmed to express SSTR2, SSTR3, and/or SSTR5. The hypothesis is that for these rare, aggressive, fusion-gene driven sarcomas, Pasireotide may be able to stabilize disease and prolong progression-free and overall survival after patients have completed initial intensive chemotherapy.[56]
• Design: The trial will administer Pasireotide LAR (40 mg or 60 mg, depending on body surface area) monthly as a maintenance therapy and assess efficacy against historical controls.[56]

Further Research in Approved Indications

Research in the approved indications of Cushing's disease and acromegaly continues to focus on long-term outcomes and treatment optimization.

• Long-Term Data: Several rollover and extension studies are ongoing, gathering crucial data on the durability of efficacy and the long-term safety profile of Pasireotide. Some patients have now been treated for over a decade, providing invaluable insights into the chronic management of these diseases.[42]
• Combination Therapies: Studies continue to explore the utility of combining Pasireotide with other agents, such as cabergoline in Cushing's disease, to create a multimodality medical approach that can improve biochemical control in patients who do not fully respond to monotherapy.[37]

Discontinued and Other Investigational Areas

In its earlier stages of development, Pasireotide was investigated for a much broader range of conditions. These included various neuroendocrine tumors (e.g., carcinoid, pancreatic), malignant melanoma, prostate cancer, and meningioma. However, development for many of these indications has since been discontinued, likely due to a combination of insufficient efficacy and the challenging safety profile, particularly the management of hyperglycemia.[45]

Conclusion

Pasireotide (Signifor®, Signifor LAR®) represents a significant and distinct therapeutic agent in the armamentarium for managing rare endocrine disorders. As a second-generation, multireceptor-targeted somatostatin analog, its pharmacology is fundamentally different from that of its predecessors, octreotide and lanreotide. This distinction is the source of both its unique clinical advantages and its considerable management challenges.

The core of Pasireotide's identity is its high-affinity binding to four SSTR subtypes, most notably SSTR5. This property has allowed it to become the first effective pituitary-directed medical therapy for Cushing's disease, a condition where SSTR5 is the predominant receptor on corticotroph adenomas. In acromegaly, its ability to target both SSTR2 and SSTR5 has established its superiority over first-generation SSAs in treatment-naive patients and, critically, has positioned it as an indispensable rescue therapy for patients whose disease is inadequately controlled by standard care. These applications exemplify a successful translation of molecular biology into targeted, personalized medicine for pituitary disorders.

However, this therapeutic efficacy is inextricably linked to a demanding safety profile. The same receptor interactions that suppress pathological hormone secretion also potently inhibit insulin and incretin release, leading to a high incidence of hyperglycemia and diabetes mellitus. This primary on-target side effect, along with risks of QTc prolongation, bradycardia, hepatotoxicity, and cholelithiasis, mandates a rigorous and proactive multi-system monitoring program. The clinical use of Pasireotide is therefore not merely a prescription, but a commitment to a comprehensive surveillance strategy, transforming the management of the patient.

The drug's commercial and developmental trajectory reflects this complex profile. Its acquisition by Recordati Rare Diseases from Novartis underscores its value as a specialized tool for a focused patient population rather than a broad-market blockbuster. Ongoing research has pivoted away from general oncology towards highly specific, mechanistically-driven indications like post-bariatric hypoglycemia—where its primary side effect becomes the therapeutic effect—and biomarker-selected rare sarcomas.

In conclusion, Pasireotide is a powerful but high-maintenance therapy. Its successful application requires a nuanced understanding of its dual-edged pharmacology, careful patient selection, and a dedicated, multidisciplinary approach to managing its predictable metabolic and systemic effects. It stands as a testament to the progress in targeted endocrine therapy and serves as a key option for patients with difficult-to-treat Cushing's disease and acromegaly.

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