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Bezlotoxumab (Zinplava) for Prevention of Recurrent Clostridium difficile Infection The FDA has approved the fully human monoclonal antibody bezlotoxumab (Zinplava – Merck) for use with antibacterial drug treatment to reduce recurrence of Clostridium difficile... Nusinersen (Spinraza) for Spinal Muscular Atrophy The FDA has approved nusinersen (Spinraza – Biogen) for treatment of spinal muscular atrophy (SMA), a hereditary neurodegenerative disease that occurs in about one in every 10,000... Exablate Neuro for Essential Tremor The FDA has approved use of Exablate Neuro (Insightec) for unilateral thalamotomy to treat medication-refractory essential tremor in patients ≥22 years old. Exablate Neuro uses... Obeticholic Acid (Ocaliva) for Primary Biliary Cholangitis Obeticholic acid (Ocaliva – Intercept), a farnesoid X receptor agonist, has been approved by the FDA for treatment of primary biliary cholangitis; it is indicated for use in combination... Triferic for Iron Replacement The FDA has approved ferric pyrophosphate citrate solution (Triferic – Rockwell Medical) to maintain hemoglobin concentrations in adults with hemodialysis-dependent chronic kidney... Inhibitors and Inducers of CYP Enzymes and P-glycoprotein (online only) View the Inhibitors and Inducers of CYP Enzymes and P-Glycoprotein table
The Medical Letter ® on Drugs and Therapeutics Volume 59 ISSUE ISSUE No 1433 1517 Volume 56 March 27, 2017 IN THIS ISSUE Bezlotoxumab (Zinplava) for Prevention of Recurrent Clostridium Difficile Infection p 49 Nusinersen (Spinraza) for Spinal Muscular Atrophy p 51 Exablate Neuro for Essential Tremor p 52 Obeticholic Acid (Ocaliva) for Primary Biliary Cholangitis p 54 Triferic for Iron Replacement p 55 Inhibitors and Inducers of CYP Enzymes and P-glycoprotein .online only Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Volume 59 March 27, 2017 Take CME Exams ISSUE ISSUE No 1433 1517 Volume 56 ▶ ALSO IN THIS ISSUE Nusinersen (Spinraza) for Spinal Muscular Atrophy p 50 Exablate Neuro for Essential Tremor p 52 Obeticholic Acid (Ocaliva) for Primary Biliary Cholangitis p 53 Triferic for Iron Replacement p 55 Inhibitors and Inducers of CYP Enzymes and P-Glycoprotein .online only Bezlotoxumab (Zinplava) for Prevention of Recurrent Clostridium difficile Infection The FDA has approved the fully human monoclonal antibody bezlotoxumab (Zinplava – Merck) for use with antibacterial drug treatment to reduce recurrence of Clostridium difficile infection (CDI) in adults with CDI at high risk for recurrence It is the first drug to be approved for this indication Pronunciation Key Bezlotoxumab: bez’’ loe tox’ ue mab Zinplava: zin plah’ va CDI — CDI is the most common infectious cause of healthcare-associated diarrhea in adults The incidence and severity of CDI have increased in recent years with the emergence of an epidemic hypervirulent strain (NAP1/B1/027).1 The recurrence rate after an initial episode of CDI is typically 20-25% Patients who develop one recurrent episode have up to a 35% chance of having another one, and patients with at least three CDI episodes have up to a 65% chance of additional recurrences.2 STANDARD TREATMENT — Oral metronidazole (Flagyl, and generics) and oral vancomycin (Vancocin, and generics) have been the drugs of choice for treatment of an initial episode of CDI for several years Recent data suggest that oral vancomycin is more effective than oral metronidazole in preventing death in patients with CDI.3 Fidaxomicin (Dificid) appears to be at least as effective as oral vancomycin for first-line treatment of CDI with fewer recurrences in patients not infected with the hypervirulent strain.4,5 Fecal microbiota transplantation (FMT) is an investigational therapy that has been highly effective in treating CDI and preventing recurrences It is generally used only in patients with severe, refractory CDI or in those who have had multiple recurrences More data from randomized, controlled trials are needed and its long-term safety is unknown.6 One randomized, openlabel trial found that oral vancomycin followed by FMT was not more effective than tapered oral vancomycin alone in reducing recurrent CDI.7 MECHANISM OF ACTION — Pathogenic strains of C difficile can express two exotoxins, A and/or B These toxins damage the epithelial cells of the gut wall, resulting in an increase in gut wall permeability and induction of an acute inflammatory response.8 Toxin B is more virulent than toxin A Bezlotoxumab binds to and neutralizes C difficile toxin B It does not bind to toxin A Table Pharmacology Formulation 1000 mg/40 mL vial Route IV infusion Metabolism Protein catabolism Half-life 19 days CLINICAL STUDIES — Approval of bezlotoxumab was based on the results of two randomized, doubleblind, placebo-controlled trials (MODIFY I and II) in 1554 adults with a positive stool test for toxigenic C difficile.9 MODIFY I included some patients who were treated with actoxumab, a drug that neutralizes toxin A, and both trials included groups that were treated with actoxumab in combination with bezlotoxumab Actoxumab alone was not effective, and the drug did not provide any additional benefit when used with bezlotoxumab A majority (77%) of the patients in the trials had one or more risk factor for CDI recurrence; these included: age ≥65 years, >1 previous CDI episode, immunosuppression, clinically severe CDI at study entry, infection with a hypervirulent strain, use of other antibacterial drugs during or after standard CDI 49 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ® therapy, and renal impairment A single infusion of bezlotoxumab 10 mg/kg or placebo was administered to patients receiving 10-14 days of treatment with metronidazole, vancomycin, or fidaxomicin A clinical cure of the initial episode of CDI occurred in about 80% of patients treated with bezlotoxumab or placebo in the two trials The CDI recurrence rate (new episode following initial clinical cure within 12 weeks after infusion of bezlotoxumab or placebo) in patients who started CDI antibacterial therapy before or within one day after receiving a study infusion was significantly lower with bezlotoxumab than with placebo (22% vs 33% in MODIFY I and 19% vs 33% in MODIFY II) The incidence of sustained cure through 12 weeks after infusion was significantly higher with bezlotoxumab than with placebo in MODIFY II (67% vs 52%), but not in MODIFY I (60% vs 55%) The efficacy of bezlotoxumab was not affected by the choice of antibacterial therapy A post-hoc analysis of European inpatients enrolled in the trials found that the rate of CDI-associated hospital readmissions within 30 days following discharge was lower in those treated with bezlotoxumab than in those who received placebo (4.5% vs 13.3%).10 ADVERSE EFFECTS — Nausea, pyrexia, and headache were the most common adverse effects of bezlotoxumab reported within weeks of infusion and more often than with placebo Infusion-related reactions reported in 1-3% of patients treated with bezlotoxumab included nausea, fatigue, pyrexia, dizziness, dyspnea, headache, and hypertension In patients with a history of congestive heart failure, use of bezlotoxumab was associated with higher rates of heart failure (12.7% vs 4.8% with placebo) and death (19.5% vs 12.5% with placebo) Overall rates of death among patients treated with bezlotoxumab or placebo were similar (7.1% and 7.5%) PREGNANCY — Bezlotoxumab has not been studied in pregnant women or animals IMMUNOGENICITY — None of the patients who received bezlotoxumab in the clinical trials tested positive for anti-drug antibodies after completing treatment DOSAGE, ADMINISTRATION AND COST — Zinplava is available in 40-mL single-dose vials containing 1000 mg of bezlotoxumab Prior to administration, the solution must be diluted in 0.9% sodium chloride or 5% dextrose to a final concentration of 1-10 mg/mL Bezlotoxumab must be administered during antibacterial treatment of CDI The recommended dosage is 10 mg/kg IV infused once over 60 minutes The cost for one vial is $3800.11 50 Vol 59 (1517) March 27, 2017 CONCLUSION — A single IV infusion of bezlotoxumab (Zinplava) in combination with standard antibacterial therapy significantly reduced post-treatment recurrence of Clostridium difficile infection (CDI) Use of bezlotoxumab in patients with a history of heart failure may increase the risk of heart failure and death ■ I See et al NAP1 strain type predicts outcomes from Clostridium difficile infection Clin Infect Dis 2014; 58:1394 DN Gerding et al Treatment of clostridium difficile infection Clin Infect Dis 2008; 46 Suppl :S32 VW Stevens et al Comparative effectiveness of vancomycin and metronidazole for the prevention of recurrence and death in patients with Clostridium difficile infection JAMA Intern Med 2017 Feb (epub) Fidaxomicin (Dificid) for Clostridium difficile infection Med Lett Drugs Ther 2011; 53:73 SD Goldenberg et al The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven NHS secondary care hospitals in England: a series of local service evaluations Eur J Clin Microbiol Infect Dis 2016; 35:251 K Rao and N Safdar Fecal microbiota transplantation for the treatment of Clostridium difficile infection J Hosp Med 2016; 11:56 SS Hota et al Oral vancomycin followed by fecal transplantation versus tapering oral vancomycin treatment for recurrent Clostridium difficile infection: an open-label, randomized, controlled trial Clin Infect Dis 2017; 64:265 Z Yang et al Mechanisms of protection against Clostridium difficile infection by the monoclonal antitoxin antibodies actoxumab and bezlotoxumab Infect Immun 2015; 83:822 MH Wilcox et al Bezlotoxumab for prevention of recurrent Clostridium difficile infection N Engl J Med 2017; 376:305 10 V Prabhu et al Bezlotoxumab decreases CDI recurrence and is associated with a reduction in 30-day readmissions: European analysis Presented at European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Amsterdam, The Netherland, April 9-12, 2016 Abstract P1340 11 Approximate WAC WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly March 5, 2017 Reprinted with permission by First Databank, Inc All rights reserved ©2017 www.fdbhealth.com/policies/drugpricing-policy ▶ Nusinersen (Spinraza) for Spinal Muscular Atrophy The FDA has approved nusinersen (Spinraza – Biogen) for treatment of spinal muscular atrophy (SMA), a hereditary neurodegenerative disease that occurs in about one in every 10,000 births.1 It is the first drug to be approved in the US for this indication Pronunciation Key Nusinersen: nue” si ner’ sen Spinraza: spin rah' zah SPINAL MUSCULAR ATROPHY — SMA is an autosomal recessive neuromuscular disorder in which degeneration of alpha motor neurons in the anterior horn cells of the spinal cord leads to muscle weakness and atrophy Most cases are caused by a homozygous The Medical Letter ® deletion or mutation in the 5q13 survival of motor neuron (SMN1) gene, which leads to SMN protein deficiency Mutations in a similar gene, SMN2, are correlated with a milder SMA phenotype.2 SMA is classified based on the age of symptom onset and motor function achieved Infants with type SMA (age of onset 0-6 months) are unable to sit unassisted; without respiratory support, they often die by years of age Children with type SMA (age of onset 18 months) initially have the ability to walk, but eventually require assistance with mobility Patients with type SMA (age of onset >21 years) are ambulatory with only mild weakness.3 Before approval of nusinersen, management of SMA consisted of supportive measures to address the respiratory, nutritional, and orthopedic/muscular complications of the disease MECHANISM OF ACTION — Nusinersen is an SMN2directed antisense oligonucleotide It acts by increasing exon inclusion in SMN2 messenger RNA transcripts, which increases the gene’s production of SMN protein Nusinersen is administered intrathecally, which allows the drug to be distributed from the cerebrospinal fluid to the target central nervous system tissues CLINICAL STUDIES — Approval of nusinersen was based on the results of an unpublished, randomized, double-blind, sham-controlled trial, summarized in the package insert, in 121 infants with type SMA who received their first dose at ≤7 months of age Among 82 infants included in an interim analysis, 40% of those in the active-treatment group showed improvement in motor milestones on Section of the Hammersmith Infant Neurologic Exam (HINE-2), the primary endpoint, compared to none of the infants who received a sham injection Motor milestones include ability to kick, head control, rolling, sitting, crawling, standing, and walking Patients were also evaluated using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND); more patients in the active-treatment group had a ≥4-point improvement from baseline (63% vs 3%) and fewer had a ≥4-point worsening (4% vs 40%) Several open-label trials also provided data for approval of nusinersen for treatment of SMA Two of these studies were published: a phase trial in 20 patients with infantile-onset SMA4 and a phase trial in 28 patients 2-14 years old with type or SMA.5 Vol 59 (1517) March 27, 2017 Table Pharmacology Class Route Formulation Metabolism Elimination Half-life (terminal) Antisense oligonucleotide Intrathecal 12 mg/5 mL single-dose vials Exonuclease (3'- and 5')-mediated hydrolysis Probably renal ~135-177 days (CSF); 63-87 days (plasma) In the phase trial, nusinersen significantly increased HINE-2 and CHOP-INTEND scores compared to baseline In the phase trial, nusinersen increased scores on the Hammersmith Functional Motor Scale Expanded (HFMSE) at months and 9-14 months post-dose with no reports of serious adverse events ADVERSE EFFECTS — In the sham-controlled trial, the most common adverse effects of nusinersen were lower respiratory infection, upper respiratory infection, and constipation Observations made during the trial suggest that nusinersen may cause growth retardation Adverse events related to lumbar puncture, including headache, back pain, and post-lumbar puncture syndrome, have occurred.6 Hyponatremia and rash have also been reported Thrombocytopenia, coagulation abnormalities, and renal toxicity have occurred following administration of some antisense oligonucleotides, and decreased platelet levels and elevated urine protein were observed in some nusinersen-treated patients during clinical trials PREGNANCY AND LACTATION — There are no adequate studies of nusinersen in pregnant women No adverse embryofetal effects were observed in mice and rabbits given subcutaneous injections of the drug There are no data on the presence of nusinersen in breast milk DOSAGE, ADMINISTRATION, AND COST — Spinraza is available in single-dose vials containing 12 mg/ mL The recommended dosage is 12 mg administered intrathecally; mL of cerebrospinal fluid should be removed prior to administration Patients may be sedated before treatment Use of imaging techniques (e.g., fluoroscopy) can be considered to guide the intrathecal injection, particularly in patients with prominent scoliosis or surgical hardware When starting treatment with nusinersen, the first doses should be given 14 days apart and the fourth dose 30 days after the third dose Maintenance doses should be administered once every months thereafter Spinraza is only available through one specialty pharmacy The cost of one 5-mL vial of nusinersen is 51 The Medical Letter ® $125,000.7 The drug's website (www.spinraza-hcp.com) includes a 73-page guide to drug reimbursement The manufacturer offers a $0 drug copay and $0 procedure copay program for most patients with nongovernmental insurance For those who are not eligible for the drug copay program, the manufacturer says it will help find a charitable organization that can provide third-party assistance CONCLUSION — The antisense oligonucleotide nusinersen (Spinraza) is the first drug to improve motor function in infants and children with spinal muscular atrophy (SMA) Whether it can prevent respiratory failure and death in infantile-onset SMA and to what extent it can improve disability in older children remain to be determined The cost of the drug may limit its use ■ ▶ Exablate Neuro for Essential Tremor The FDA has approved use of Exablate Neuro (Insightec) for unilateral thalamotomy to treat medicationrefractory essential tremor in patients ≥22 years old Exablate Neuro uses magnetic resonance-guided focused ultrasound (MRgFUS) to create lesions in the ventral intermediate nucleus of the thalamus MRgFUS is also approved in the US for treatment of uterine fibroids and for pain palliation of bone metastases TREATMENT OF ESSENTIAL TREMOR — Essential tremor is a common neurological disorder that causes involuntary and rhythmic shaking, especially of the hand, head, neck, and voice The tremor is not life threatening, but it can be distressing and make performance of everyday activities difficult The most effective drugs used to treat essential tremor are the beta blocker propranolol (Inderal, and others) and (off-label) the anticonvulsant primidone (Mysoline, and generics); they reduce tremor by about 60% in about 50% of patients The anticonvulsant topiramate (Topamax, and others) is a commonly used alternative Botulinum toxin injections have been used to treat head and voice tremor.1,2 Surgical ablation of the ventral intermediate nucleus of the thalamus is an option for drug-refractory cases Both deep brain stimulation from implanted electrodes and radiofrequency thalamotomy have been highly effective in suppressing tremor and so immediately Both methods require a craniotomy Deep brain stimulation causes fewer side effects such as speech, gait, and cognition disturbances, and it is reversible 52 Vol 59 (1517) March 27, 2017 TW Prior et al Newborn and carrier screening for spinal muscular atrophy Am J Med Genet A 2010; 152A:1608 MA Farrar et al Emerging therapies and challenges in spinal muscular atrophy Ann Neurol 2016 Dec 27 (epub) SJ Kolb and JT Kissel Spinal muscular atrophy Neurol Clin 2015; 33: 831 RS Finkel et al Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study Lancet 2016; 388:3017 CA Chiriboga et al Results from a phase study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy Neurology 2016; 86:890 M Haché et al Intrathecal injections in children with spinal muscular atrophy: nusinersen clinical trial experience J Child Neurol 2016; 31:899 WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly March 5, 2017 Reprinted with permission by First Databank, Inc All rights reserved ©2017 www.fdbhealth.com/policies/drug-pricing-policy Gamma knife thalamotomy uses radiation to ablate the ventral intermediate nucleus and does not require a craniotomy It has improved tremor in several studies, but its benefits may take weeks to months to become apparent and serious delayed adverse effects have been reported.1 MRgFUS THALAMOTOMY — Exablate Neuro uses magnetic resonance-guided high-intensity focused ultrasound waves to heat focal areas in the ventral intermediate nucleus of the thalamus to approximately 130-140°F (~55-60°C) and ablate them.3,4 THE PROCEDURE — Prior to treatment, CT and MRI scans of the patient’s head are taken to determine skull thickness and density and to locate the target area The patient’s head is shaved, treated with a local anesthetic, and immobilized with a stereotactic frame During the procedure, cold water circulates around the head to keep the skull cool because bone temperature can rise during application of ultrasound energy.3 Sublethal low-energy sonications are delivered initially to test targeting accuracy and patient response Once targeting accuracy is confirmed, the energy is gradually increased to temperatures sufficient for tissue ablation (~55-60° C) and the patient is assessed for reduction in tremor The patient remains awake and can respond to questions during treatment CLINICAL STUDIES — Approval of Exablate Neuro was based on the results of a randomized, double-blind, sham-controlled trial in 76 patients with moderate to severe essential tremor that had not responded to treatment with at least two drug regimens Patients The Medical Letter ® were randomized to unilateral focused ultrasound thalamotomy or to sham treatment Three months after the procedure, mean contralateral hand-tremor scores improved from baseline by 47% in patients who received unilateral focused ultrasound thalamotomy and by 0.1% in those who received sham treatment; a 40% improvement in hand-tremor scores in treated patients was maintained at 12 months after the procedure Total disability scores decreased by 62% from baseline and quality-of-life scores decreased by 46% at months in patients who received the active treatment compared to a 3% reduction for both measures in the sham group Only minimal improvements were observed in head, neck, and voice tremors and no improvement was seen in ipsilateral hand tremors.5 MRgFUS fails to achieve adequate heating for successful treatment in some patients, which may be related to skull characteristics In a retrospective study of 25 patients who had undergone MRgFUS, skull volume was negatively correlated with maximal temperatures while skull density ratio (the ratio of cortical to cancellous bone) was positively correlated with maximal temperatures.6 In the pivotal trial, a criterion for enrollment was a skull density ratio ≥0.45 ADVERSE EFFECTS — Exablate Neuro is only approved for unilateral thalamotomy Bilateral thalamotomy has been associated with a higher rate of adverse effects.1 In the double-blind trial, the most common adverse effects reported during the procedure were head discomfort (30%), dizziness (21%), and nausea (20%) The most common postoperative adverse effects were paresthesias and gait disturbances, which occurred in 38% and 36% of patients, respectively, in the active treatment group, and these effects persisted at 12 months in 14% and 9% of patients Other possible side effects of MRgFUS include damage to areas surrounding the focal point, hemorrhage requiring emergency treatment, skin ulceration, scar formation, and blood clots.7 Treatment with Exablate Neuro is contraindicated in patients who cannot undergo an MRI scan, such as those with implanted metallic devices Pregnancy, advanced kidney disease, severe hypertension, and a history of bleeding abnormalities also preclude treatment with the device It is not recommended for patients with a history of stroke or brain tumors or in those taking an anticoagulant Vol 59 (1517) March 27, 2017 CONCLUSION — Magnetic resonance-guided focused ultrasound unilateral thalamotomy using Exablate Neuro significantly improved contralateral hand tremor in patients with drug-refractory essential tremor, but postoperative paresthesias and gait disturbances were common and persisted for at least one year in some patients This procedure has not been compared to deep brain stimulation, which is also effective in reducing tremor and, unlike thalamotomy, is reversible ■ TA Zesiewicz et al Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology 2005; 64:2008 TA Zesiewicz et al Evidence-based guideline update: treatment of essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology Neurology 2011; 77:1752 P Ghanouni et al Transcranial MRI-guided focused ultrasound: a review of the technologic and neurologic applications AJR Am J Roentgenol 2015; 205:150 Exablate Model 4000 Type Information for prescribers Available at: www.accessdata.fda.gov/cdrh_docs/pdf15/p150038c pdf Accessed March 16, 2017 WJ Elias A randomized trial of focused ultrasound thalamotomy for essential tremor N Engl J Med 2016; 375:730 WS Chang et al Factors associated with successful magnetic resonance-guided focused ultrasound treatment: efficiency of acoustic energy delivery through the skull J Neurosurg 2016; 124:411 FDA Summary of safety and effectiveness data (SSED) Available at www.accessdata.fda.gov/cdrh_docs/pdf15/P150038B pdf Accessed March 16, 2017 ▶ Obeticholic Acid (Ocaliva) for Primary Biliary Cholangitis Obeticholic acid (Ocaliva – Intercept), a farnesoid X receptor agonist, has been approved by the FDA for treatment of primary biliary cholangitis; it is indicated for use in combination with ursodeoxycholic acid (ursodiol, UDCA; Urso, and others) in adults with an inadequate response to UDCA and as monotherapy in adults unable to tolerate UDCA Obeticholic acid is the second drug to be approved for this indication; UDCA was the first Ocaliva: oh cal' i va Pronunciation Key Obeticholic acid: oh bet" i koe' lik as' id PRIMARY BILIARY CHOLANGITIS — Primary biliary cholangitis, formerly called primary biliary cirrhosis, is a rare progressive autoimmune disease of the intralobular bile ducts that can lead to fibrosis, cirrhosis, and liver failure.1 It most commonly affects women >40 years old STANDARD TREATMENT — UDCA, a naturally occurring hydrophilic bile acid, replaces toxic 53 The Medical Letter ® hydrophobic bile acids that accumulate in the liver, promotes choleresis, inhibits apoptosis of hepatocytes, and has immunomodulatory effects It has been shown to reduce the risk of cirrhosis and liver transplantation and improve survival, but about one-third of patients have an inadequate response Budesonide, methotrexate, rituximab, fibrates, and other drugs have been added to UDCA when monotherapy fails, but the benefits are unclear.2 MECHANISM OF ACTION — Obeticholic acid is a derivative of the primary human bile acid chenodeoxycholic acid (CDCA); it is a more potent agonist of the farnesoid X receptor (FXR) than CDCA Stimulation of FXRs, which are expressed in enterohepatic tissue, suppresses bile acid synthesis and promotes bile acid transport out of hepatocytes Table Pharmacology Class Formulation Route Tmax Metabolism Elimination Farnesoid X receptor (FXR) agonist 5, 10 mg tablets Oral 1.5 hours, active conjugates 10 hours Conjugated with taurine and glycine and secreted into bile In feces (87%) after deconjugation in the ileum and colon CLINICAL STUDIES — Approval of obeticholic acid was based on studies using alkaline phosphatase (ALP) levels as a surrogate endpoint.3 Obeticholic acid has not yet been shown to improve clinical outcomes in patients with primary biliary cholangitis In a 12-month, double-blind, phase trial, 216 patients with primary biliary cholangitis and an ALP level ≥1.67 times the upper limit of normal (ULN) or an abnormal total bilirubin level