Comprehensive Monograph on Linerixibat (GSK2330672): An Investigational IBAT Inhibitor for Cholestatic Pruritus in Primary Biliary Cholangitis

Executive Summary

Linerixibat, also known by its developmental code GSK2330672, is an investigational, orally administered, small-molecule drug designed as a selective and minimally absorbed inhibitor of the ileal bile acid transporter (IBAT).[1] Its primary therapeutic target is the treatment of moderate to severe cholestatic pruritus, a debilitating form of internal itching, in adult patients with the rare autoimmune liver disease Primary Biliary Cholangitis (PBC).[4] This indication addresses a significant unmet medical need, as pruritus affects up to 90% of individuals with PBC, severely degrading quality of life through sleep disruption, fatigue, and psychological distress, and is often inadequately managed by current therapeutic options.[4]

The mechanism of action of Linerixibat is localized to the terminal ileum, where it inhibits IBAT to interrupt the enterohepatic circulation of bile acids. This blockade increases the fecal excretion of bile acids, thereby reducing the systemic bile acid load that is believed to be a primary driver of cholestatic pruritus.[2]

Pivotal clinical evidence is derived from the Phase 3 GLISTEN trial (NCT04950127), in which Linerixibat successfully met its primary endpoint. The trial demonstrated a statistically significant, albeit modest, reduction in itch severity compared to placebo over a 24-week period.[5] Furthermore, the study achieved a key secondary endpoint, showing a significant improvement in itch-related sleep interference.[5]

The safety and tolerability profile of Linerixibat is consistent with its mechanism of action and is characterized predominantly by gastrointestinal adverse events. Diarrhea is the most common adverse event reported, generally described as mild in intensity, but it represents a critical factor influencing patient tolerability and treatment adherence.[1]

As of June 2025, Linerixibat is not approved for use in any country.[5] However, a New Drug Application (NDA) and a Marketing Authorisation Application (MAA) have been accepted for review by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), respectively.[5] The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target action date of March 24, 2026.[8] The central clinical proposition for Linerixibat involves balancing its proven, statistically significant symptomatic benefit against a predictable and highly prevalent, mechanism-based side effect profile.

Drug Profile and Chemical Characteristics

General Classification

Linerixibat is classified as a small molecule drug.[15] Chemically, it belongs to the class of organoheterocyclic compounds known as benzothiazepines, which are characterized by a benzene ring fused to a seven-membered thiazepine ring.[16] From a pharmacological standpoint, it is categorized as an Ileal Bile Acid Transport (IBAT) Inhibitor.[17]

Nomenclature and Identifiers

The compound is identified by the generic name Linerixibat.[8] Throughout its development, it has also been referred to by the codes GSK2330672, GSK-2330672, and GSK 672, as well as the synonyms Iinerixibat and linerixibatum.[15] Key database identifiers include DrugBank ID DB11729 and CAS Number 1345982-69-5.[15]

Chemical Structure and Formula

The molecular formula for Linerixibat is C28​H38​N2​O7​S.[15] Its formal IUPAC name is 3-methylamino]pentanedioic acid.[15]

Physicochemical Properties

The physicochemical properties of Linerixibat are fundamental to understanding its behavior in a biological system. These characteristics, summarized in Table 1, align with the drug's intended design as a gut-restricted agent with minimal systemic absorption. Properties such as a high hydrogen bond donor count (4), a high hydrogen bond acceptor count (9), and a large topological polar surface area (150 Ų) are generally unfavorable for passive diffusion across the intestinal epithelium according to established principles like Lipinski's Rule of Five, which the compound violates.[15] This is not a design flaw but rather a deliberate feature. To exert its effect locally on the IBAT in the terminal ileum while minimizing systemic exposure and potential off-target effects, the molecule was engineered to have poor membrane permeability. This design is corroborated by pharmacokinetic data demonstrating an exceptionally low oral bioavailability.[20]

Table 1: Key Chemical and Physical Properties of Linerixibat

Property	Value	Source(s)
Generic Name	Linerixibat	16
Developmental Code	GSK2330672	15
DrugBank ID	DB11729	15
CAS Number	1345982-69-5	15
Molecular Formula	C28​H38​N2​O7​S	15
Molecular Weight	546.68 g/mol	16
IUPAC Name	3-methylamino]pentanedioic acid	15
Water Solubility	0.00735 mg/mL (predicted)	16
pKa	Strongest Acidic: 2.02; Strongest Basic: 8.41 (predicted)	16
Polar Surface Area	142.03 Ų (predicted)	16
Rotatable Bond Count	13 (predicted)	16

Formulation and Presentation

Linerixibat is administered as an oral tablet.[3] Despite its low intrinsic water solubility, the drug is formulated as a zwitterionic, nonhygroscopic, crystalline salt. This form exhibits good aqueous solubility at physiological intestinal pH ($>$7 mg/mL at pH 7.4), a critical feature that facilitates its dissolution in the gastrointestinal lumen, making it available to interact with its target in the ileum.[19]

Pharmacology and Mechanism of Action

Primary Target: Ileal Bile Acid Transporter (IBAT/ASBT)

The primary molecular target of Linerixibat is the ileal sodium/bile acid cotransporter, a protein also known as the apical sodium-dependent bile acid transporter (ASBT or IBAT).[2] This transporter is encoded by the

SLC10A2 gene and is predominantly expressed on the apical membrane of epithelial cells in the terminal ileum.[16] Its physiological function is pivotal for the enterohepatic circulation, where it facilitates the active reabsorption of approximately 95% of bile acids from the intestinal lumen into the portal venous system for return to the liver.[1] Linerixibat is a highly potent, competitive, and reversible inhibitor of human IBAT, with a reported half-maximal inhibitory concentration (

IC50​) of 42 ± 3 nM.[18]

Pharmacodynamic Effects of IBAT Inhibition

By inhibiting IBAT, Linerixibat effectively interrupts the enterohepatic circulation of bile acids.[2] This action is localized to the gastrointestinal tract, as the drug is designed to be minimally absorbed.[3] The direct consequence of this inhibition is an increased flux of bile acids into the colon, leading to a substantial increase in their fecal excretion.[2] This diversion of bile acids away from reabsorption reduces the total bile acid pool that returns to the liver, consequently lowering the concentration of bile acids in the systemic circulation.[3] This reduction in systemic bile acids is the core therapeutic principle for alleviating cholestatic pruritus, a condition believed to be mediated by the accumulation of pruritogenic bile acids and other substances that activate itch-sensitive nerve endings in the skin.[4]

The broader pharmacology of IBAT inhibition also explains the drug's primary side effect. The increased delivery of bile acids to the colon stimulates gut motility and interacts with receptors such as TGR5, which can influence fluid secretion and transit time.[1] This same mechanism has been explored therapeutically for chronic constipation and was also the basis for Linerixibat's initial investigation for Type 2 Diabetes Mellitus, where bile acid signaling in the gut can influence incretin hormone secretion.[16] This context clarifies that diarrhea is not an off-target toxicity but rather an unavoidable, on-target consequence of the drug's intended mechanism of action.

Key Pharmacodynamic Biomarkers

The pharmacodynamic effects of Linerixibat can be monitored using specific biomarkers that reflect its engagement with the IBAT target and the subsequent physiological response.

Serum 7α-hydroxy-4-cholesten-3-one (C4)

The reduction in bile acids returning to the liver via the portal vein relieves the normal negative feedback inhibition on the enzyme cholesterol 7α-hydroxylase (CYP7A1), which is the rate-limiting step in the classical pathway of bile acid synthesis.[28] This leads to a compensatory upregulation of bile acid production from cholesterol. Serum C4, a metabolic intermediate in this pathway, serves as a validated and sensitive biomarker of this upregulation and, by extension, of IBAT inhibition and bile acid malabsorption.[1] Treatment with Linerixibat results in a rapid, dose-dependent increase in serum C4 levels, an effect that reaches saturation at a total daily dose of approximately 180 mg.[1]

This biomarker serves as a powerful tool for understanding both efficacy and tolerability. A clear causal chain has been established: Linerixibat dose leads to IBAT inhibition, which in turn causes both an increase in colonic bile acids and a compensatory rise in serum C4. The increased colonic bile acids directly cause diarrhea. Crucially, modeling studies have demonstrated that the magnitude of the C4 increase directly correlates with the probability of patient-reported diarrhea.[1] This transforms C4 from a simple marker of target engagement into a quantitative predictor of the primary adverse event. This relationship is fundamental to defining the therapeutic window for Linerixibat and underscores the central challenge of optimizing the dose to maximize pruritus relief while minimizing the burden of diarrhea.[1]

Fibroblast Growth Factor 19 (FGF19)

FGF19 is an endocrine hormone produced by enterocytes in the ileum in response to bile acid uptake. It travels to the liver and acts as a potent suppressor of CYP7A1, thus downregulating bile acid synthesis. By blocking bile acid uptake, IBAT inhibitors like Linerixibat reduce the stimulus for FGF19 production. A meta-analysis of studies on IBAT inhibitors confirmed that this drug class causes a significant decrease in circulating FGF19 levels.[30]

Comprehensive Pharmacokinetic Profile (ADME)

The pharmacokinetic profile of Linerixibat has been definitively characterized in a dedicated human absorption, distribution, metabolism, and excretion (ADME) study (NCT03992014).[31] This study employed an intravenous radiolabeled microtracer dose of

[14C]-Linerixibat administered concurrently with an unlabeled oral dose, allowing for precise determination of its systemic disposition.[20]

Absorption

Linerixibat was designed for minimal gastrointestinal absorption, a feature confirmed by the ADME study. The absolute oral bioavailability is exceedingly low, measured at just 0.05%.[20] This minimal systemic exposure is a key safety feature, ensuring the drug's action is primarily localized to the gut. The low bioavailability is driven by a very small fraction of the oral dose being absorbed (fraction absorbed,

fa​ = 0.167%), with a secondary contribution from high first-pass hepatic extraction of the small amount that is absorbed.[20]

The drug exhibits "flip-flop" kinetics, a phenomenon where the rate of absorption is slower than the rate of elimination. This is evident from the observed half-life, which is much longer after oral administration (6-7 hours) compared to the very short half-life following intravenous administration (0.8 hours).[20]

Distribution

For the small fraction of Linerixibat that reaches systemic circulation, distribution into tissues is limited. The volume of distribution (Vd​) following intravenous administration is low at 16.3 L, indicating that the drug is largely confined to the plasma and extracellular fluids.[20]

Metabolism

A key finding from the human ADME study was that Linerixibat is minimally metabolized in vivo. Following intravenous administration, the vast majority of the drug recovered from both biliary/fecal and renal routes (over 90-97%) was in the form of the unchanged parent compound.[20]

This in vivo result stands in stark contrast to in vitro predictions. Preclinical studies using human liver microsomes strongly suggested that Linerixibat would be rapidly cleared via metabolism mediated by the cytochrome P450 3A4 (CYP3A4) enzyme. The in vitro model was quantitatively accurate in predicting the rate of hepatic clearance to within 1.5-fold of the observed value. However, it completely misidentified the mechanism of clearance. The human study unequivocally demonstrated that clearance occurs not through metabolism but via rapid biliary excretion of the unchanged drug.[20] This in vitro-in vivo disconnect is a significant finding, highlighting a limitation of preclinical models and underscoring the importance of active transport mechanisms in hepatic clearance for certain compounds. It also explains the lack of significant metabolites and reduces the likelihood of metabolism-based drug-drug interactions.

Excretion

The route of excretion for Linerixibat is almost entirely dependent on the route of administration.

• Oral Administration: Following an oral dose, elimination occurs almost exclusively via the feces. Over 99% of the administered radioactivity was recovered in feces, consisting overwhelmingly of unabsorbed, unchanged drug. Consequently, urinary excretion of an oral dose is negligible ($<$0.04% of the dose).[20]
• Intravenous Administration: The small amount of drug that is absorbed is cleared from the body efficiently and rapidly, with a high systemic clearance of 61.9 L/h. This clearance is partitioned between two primary routes: approximately 80% is eliminated via biliary/fecal excretion, and the remaining 20% is eliminated via renal excretion. In both pathways, the drug is excreted almost entirely as unchanged Linerixibat.[20]

The key pharmacokinetic parameters are summarized in Table 2.

Table 2: Summary of Key Pharmacokinetic Parameters of Linerixibat

Parameter	Value	Source
Absolute Oral Bioavailability	0.05%	20
Half-life (Oral, apparent)	6–7 hours	20
Half-life (Intravenous)	0.8 hours	20
Systemic Clearance (CL)	61.9 L/h	20
Volume of Distribution (Vd​)	16.3 L	20
Primary Route of Elimination (Oral Dose)	Feces ($>$99% as unchanged drug)	20
Elimination Routes (IV Dose)	~80% Biliary/Fecal, ~20% Renal (both as unchanged drug)	20

Clinical Development Program and Efficacy Analysis

The clinical development of Linerixibat has focused primarily on its use for cholestatic pruritus in PBC, although it was also investigated in earlier phases for Type 2 Diabetes Mellitus and Primary Sclerosing Cholangitis (PSC).[2]

Phase 2b GLIMMER Trial (NCT02966834)

The GLIMMER study was a critical dose-ranging trial designed to evaluate the efficacy and tolerability of Linerixibat in 147 PBC patients with cholestatic pruritus.[33] This randomized, double-blind, placebo-controlled study tested once-daily (QD) doses of 20 mg, 90 mg, and 180 mg, and twice-daily (BID) doses of 40 mg and 90 mg against a placebo control.[33]

The primary endpoint, defined as the mean change from baseline in the mean worst daily itch (MWDI) score at Week 16, was not met in the primary intent-to-treat analysis. While all Linerixibat groups showed numerical improvements in itch scores that were greater than placebo, the differences did not achieve statistical significance.[3]

Despite the primary endpoint miss, this trial was instrumental in shaping the future development of the drug. A post-hoc analysis using a more robust endpoint—the change in monthly itch score, which was planned for the Phase 3 program—revealed statistically significant improvements versus placebo for the 180 mg QD (p=0.0424), 40 mg BID (p=0.0105), and 90 mg BID (p=0.0370) dose groups (Table 3).[3] Furthermore, a significant dose-dependent reduction in itch was observed in the per-protocol population.[34] The 40 mg BID dose emerged as a promising candidate, showing a strong efficacy signal in the post-hoc analysis while having a more manageable tolerability profile compared to higher doses, where the incidence of diarrhea increased.[34] This data-driven analysis provided the rationale and confidence to advance the 40 mg BID dose into the pivotal Phase 3 GLISTEN trial, a strategic decision that was ultimately validated by the positive results of that study.[35]

Table 3: Dose-Response Efficacy from the Phase 2b GLIMMER Trial (Post-Hoc Analysis)

Dose Group	N	Mean Change from Baseline in Monthly Itch Score (vs. Placebo)	P-value
Placebo	36	-	-
Linerixibat 180 mg QD	27	Significant Improvement	0.0424
Linerixibat 40 mg BID	23	Significant Improvement	0.0105
Linerixibat 90 mg BID	22	Significant Improvement	0.0370
Data derived from post-hoc analysis of the GLIMMER trial.3

Pivotal Phase 3 GLISTEN Trial (NCT04950127)

The GLISTEN trial was the global, confirmatory study for Linerixibat. This double-blind, randomized, placebo-controlled trial enrolled 238 PBC patients with moderate-to-severe pruritus, who were randomized on a 1:1 basis to receive either Linerixibat 40 mg BID or a placebo for 24 weeks.[5] The study design permitted patients to continue stable doses of background anti-itch therapies.[5]

Efficacy Results

The trial successfully met its primary endpoint, demonstrating that Linerixibat produced a statistically significant improvement in itch severity over 24 weeks compared to placebo. The key efficacy findings are summarized in Table 4. The least squares (LS) mean difference in the change from baseline in the monthly worst itch numerical rating scale (WI-NRS) score was -0.72 (95% CI: -1.15, -0.28), with a p-value of 0.001.[10]

Key secondary endpoints were also met. The onset of action was rapid, with a significant improvement in itch observed as early as Week 2 (p<0.001), and this effect was sustained throughout the 24-week treatment period.[10] Treatment with Linerixibat also led to a significant improvement in itch-related sleep interference, a critical aspect of quality of life for these patients (

p=0.024).[10]

While the results are unequivocally positive from a statistical standpoint, a deeper analysis reveals a more nuanced clinical picture. The absolute mean benefit of -0.72 on a 10-point scale, while statistically robust, is modest. Furthermore, the placebo response was substantial, with 43% of patients in the placebo group achieving a clinically meaningful response (defined as a ≥3-point reduction in WI-NRS).[10] This suggests that while Linerixibat provides a real and significant benefit beyond the placebo effect, it may not be a transformative therapy for all patients. Its clinical value lies in its ability to provide an additional therapeutic option for a severe and debilitating symptom in a population with very few effective treatments.[4]

Table 4: Summary of Efficacy Endpoints from the Phase 3 GLISTEN Trial

Endpoint	Linerixibat (n=119)	Placebo (n=119)	LS Mean Difference (95% CI)	P-value
Change from Baseline in Monthly WI-NRS over 24 Weeks (Primary)	-	-	-0.72 (-1.15, -0.28)	0.001
Change from Baseline in WI-NRS at Week 2	-	-	-0.71 (-1.07, -0.34)	<0.001
Change from Baseline in Monthly Sleep Interference NRS over 24 Weeks	-	-	-0.53 (-0.98, -0.07)	0.024
Proportion of Patients with ≥3-point WI-NRS Reduction at Week 24	56%	43%	13% (0%, 27%)	0.043 (nominal)
Data compiled from multiple sources reporting GLISTEN trial results.10

Safety and Tolerability Profile

Overview

The safety profile of Linerixibat is well-characterized across its clinical development program and is dominated by on-target, mechanism-based gastrointestinal adverse events (AEs) stemming from the increased concentration of bile acids in the colon.[5]

Common Adverse Events

• Diarrhea: This is the most frequently reported AE. In the GLIMMER dose-ranging study, the incidence of diarrhea was dose-dependent, affecting up to 64% of patients in some treatment arms.[33] In the pivotal GLISTEN trial, diarrhea was reported in 61% of patients receiving Linerixibat.[13] The severity was described as "mostly mild".[10] However, it is a significant factor in tolerability, leading to treatment discontinuation in 4% of patients in the Linerixibat arm of GLISTEN, compared to less than 1% in the placebo arm.[10]
• Abdominal Pain: This AE is also commonly reported and is consistent with the physiological effects of increased colonic bile acids.[3]

Long-Term Safety

A global, open-label, long-term safety and tolerability study (LLSAT, NCT04167358) is currently ongoing to evaluate the safety of chronic Linerixibat administration in patients who have completed previous clinical trials.[38] The findings from this study will be essential for fully characterizing the long-term safety profile of the drug.

Contraindications and Precautions

As an investigational drug, Linerixibat does not have formal contraindications. However, the exclusion criteria used in its pivotal clinical trials provide a strong indication of populations where its use may be contraindicated or require significant caution. These include:

• Pre-existing Gastrointestinal Conditions: Patients with current clinically significant diarrhea or active inflammatory ileal diseases, such as Crohn's disease, were excluded.[36]
• Severe Hepatic Impairment: Patients with evidence of hepatic decompensation (e.g., variceal bleeding, ascites, encephalopathy) or with significantly elevated liver enzymes (ALT >5-6x ULN) or bilirubin (>2x ULN) were excluded.[36] A dedicated Phase 1 study (NCT05393076) has been conducted to assess pharmacokinetics in patients with moderate hepatic impairment.[29]
• Severe Renal Impairment: Patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73m² were excluded from trials.[36]

Drug-Drug Interactions

Given that Linerixibat is intended for use in PBC patients who are often on multiple medications, the potential for drug-drug interactions is a key consideration.

• Obeticholic Acid (OCA): OCA is a second-line therapy for PBC that can itself cause or worsen pruritus. A dedicated drug-drug interaction study (NCT05133830) was conducted in healthy volunteers to assess the pharmacokinetic effects of co-administering Linerixibat and OCA.[29] The results from this study will be critical for guiding the concomitant use of these therapies in clinical practice.
• Other Medications: Clinical trial protocols required a washout period for several medications that could either interact pharmacodynamically or confound the assessment of pruritus. These included bile acid sequestrants (e.g., cholestyramine), rifampicin, opioid antagonists (e.g., naltrexone), and selective serotonin reuptake inhibitors (SSRIs).[36]

Regulatory Status and Market Landscape

Global Regulatory Filings

Linerixibat is currently under review by major global health authorities. In June 2025, the U.S. FDA accepted the New Drug Application (NDA) for review, assigning a PDUFA target action date of March 24, 2026.[8] Concurrently, the European Medicines Agency (EMA) accepted the Marketing Authorisation Application (MAA) for review.[5] The drug has been granted Orphan Drug Designation in both the United States (for treatment of PBC) and the European Union (for treatment of cholestatic pruritus in PBC), recognizing the rarity of the condition and the unmet need.[5]

Expanded Access

Pending regulatory approval, expanded access or compassionate use programs have been made available to provide Linerixibat to eligible patients with moderate to severe cholestatic pruritus associated with PBC who have exhausted other treatment options and are unable to participate in clinical trials.[4]

Market Landscape and Competitive Context

The therapeutic landscape for PBC is undergoing a significant transformation, which will directly impact the potential positioning of Linerixibat. For many years, treatment for PBC-associated pruritus relied on off-label use of agents like cholestyramine, rifampin, and naltrexone, all of which have limitations in efficacy and tolerability.[4]

The IBAT inhibitor class is already established in other cholestatic liver diseases, with maralixibat and odevixibat approved for pediatric indications.[23] However, the most significant challenge to Linerixibat's market entry comes from a different class of drugs. In mid-2024, two new oral peroxisome proliferator-activated receptor (PPAR) agonists, seladelpar and elafibranor, received FDA approval for the treatment of PBC.[4] These drugs are disease-modifying, improving the biochemical markers of PBC, and critically, they have also demonstrated significant anti-pruritic effects.[6]

This development fundamentally alters the treatment paradigm. Previously, Linerixibat was positioned to address a symptom that was not effectively managed by the standard-of-care disease-modifying therapy (ursodeoxycholic acid).[4] Now, clinicians have the option to switch patients to a new disease-modifying agent that can treat both the underlying disease and the associated pruritus. This creates a scenario where a physician may prefer a single new agent over adding a second, symptom-focused drug like Linerixibat, especially one with a notable incidence of diarrhea. Consequently, Linerixibat's potential market may be narrowed to a niche population, such as patients with refractory pruritus who are stable on older therapies or those who cannot tolerate or do not respond to the new PPAR agonists.[4]

Synthesis and Expert Recommendations

Integrated Benefit-Risk Assessment

Linerixibat offers a targeted, mechanistically driven therapy for cholestatic pruritus in PBC. The clinical benefit is a statistically significant, rapid, and sustained, though modest, improvement in itch and associated sleep disturbance for a patient population with a high unmet need. The primary risk is the high incidence of on-target diarrhea. While generally mild, this side effect poses a considerable tolerability burden that may limit real-world treatment adherence and uptake. The overall benefit-risk balance appears to be positive for a well-defined patient population: those with debilitating pruritus who have failed or cannot tolerate other options and are adequately counseled on the potential for gastrointestinal side effects.

Future Research and Clinical Considerations

• Long-Term Data: The publication of complete results from the LLSAT long-term safety study (NCT04167358) is essential to confirm the safety and tolerability of chronic Linerixibat administration and to assess the durability of its anti-pruritic effect.
• Diarrhea Management: Upon potential approval, the development of clinical guidance for managing the predictable diarrhea will be crucial. This may include strategies related to dose timing, dietary modifications, or the potential use of anti-diarrheal agents. The established relationship between serum C4 levels and diarrhea also suggests a future potential for biomarker-guided dosing or patient selection to optimize the therapeutic window.[1]
• Quality of Life Outcomes: A detailed analysis of patient-reported outcomes from the clinical trials, such as the PBC-40 questionnaire data, will be important to translate the numerical reduction in itch scores into a more holistic understanding of the drug's impact on patients' overall well-being.[9]

Concluding Remarks on Therapeutic Potential

Linerixibat represents a scientifically rational and clinically validated approach to managing one of the most burdensome symptoms of Primary Biliary Cholangitis. Its positive Phase 3 results confirm its efficacy in a field with few proven options. However, its therapeutic utility is constrained by the narrow window between symptomatic relief and gastrointestinal intolerance. Furthermore, the recent approval of new disease-modifying therapies for PBC that also effectively treat pruritus will likely position Linerixibat as a specialized, niche therapy for patients with refractory itch. If approved, Linerixibat will not be a transformative agent for the management of PBC as a whole, but it will serve as a valuable and important tool for the symptomatic management of a difficult and historically underserved patient population.

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