TURALIO^® Risk Evaluation and Mitigation Strategy Program (tREMS): 3-year retrospective hepatic safety assessment

Abstract

Aim: Hepatic safety data assessment from the TURALIO^® (pexidartinib) Risk Evaluation and Mitigation Strategy (tREMS) Program. Methods: Retrospective 3-year assessment (August 2019 to June 2022) of hepatic events from the TURALIO® (pexidartinib) Risk Evaluation and Mitigation Strategy Program. Results: A total of 451 patients, 369 prescribers, 2 wholesalers/distributors and 2 pharmacies were enrolled and certified. Twenty-one (4.7%) patients met the criteria for a hepatic adverse event or laboratory abnormality suggestive of serious and potentially fatal liver injury, all with onset within 2 months of therapy. No new hepatic safety signals were identified. Conclusion: Results are consistent with the phase 3 ENLIVEN trial data. Liver enzyme monitoring, combined with early intervention, including dose modification and discontinuation, conducted in patients treated with pexidartinib mitigate the risk of potential hepatotoxicity.

Plain language summary

Safety findings from the 3-year data collected in the TURALIO^® Risk Evaluation and Mitigation Strategy Program

Pexidartinib (TURALIO^®) is an oral drug that is used to treat adults with tenosynovial giant cell tumor (TGCT) that cannot be fixed with surgery. TGCTs are rare, noncancerous tumors that cause pain, stiffness and difficulty moving. Pexidartinib works by blocking a protein that helps these tumors grow. Before pexidartinib, there were no good treatments for TGCT and surgery often could not remove all the tumors, so they would frequently grow back.

Pexidartinib was approved in 2019 after a clinical trial showed it worked well in adults with TGCT. However, pexidartinib can sometimes cause serious liver harm for some patients. To handle this risk, a program called the tREMS (TURALIO^® Risk Evaluation and Mitigation Strategy) was established to ensure that pexidartinib is used safely.

The tREMS Program teaches doctors, pharmacists and patients about the safe use of pexidartinib and potential liver risks and enrolls patients in a registry to watch their health. Doctors and pharmacies must be certified, and patients need regular liver tests. In the first 3 years, 451 patients and 369 doctors joined the program. Unintended liver issues were found in around 5% of patients, a rate that is about the same as that seen in pexidartinib clinical trials, and no new safety concerns were found. About half of patients with liver issues could reverse them by stopping pexidartinib. No patient had permanent liver damage, needed a transplant or died from liver problems. These results show that the tREMS Program is working well to keep patients with TGCT safe while taking pexidartinib.

Article highlights

• The TURALIO^® Risk Evaluation and Mitigation Strategy (tREMS) Program was established in August 2019 to mitigate the risk of hepatotoxicity associated with the administration of pexidartinib.

• A retrospective 3-year (August 2019 to June 2022) hepatic safety assessment was performed.

• A total of 451 patients, 369 prescribers, 2 wholesalers/distributors and 2 pharmacies were enrolled and certified in the tREMS Program during this period.

• A total of 21 (4.7%) patients met the criteria for a liver adverse event (AE) or laboratory abnormalities suggestive of serious and potentially fatal liver injury, all with event onset within 2 months of therapy.

• Of the 21 patients with liver AEs, 20 permanently discontinued pexidartinib therapy and the dose was interrupted for 1 patient.

• No AEs of irreversible liver injury, transplant or hepatotoxicity-related death were reported during the study period. No new hepatic safety signals were identified.

• These hepatic safety data are consistent with the results from the pexidartinib phase 3 ENLIVEN trial and the known safety profile of pexidartinib.

• These 3-year retrospective hepatic safety assessment data show that the goal of the tREMS Program, to mitigate the risk of serious and potentially fatal liver injury, is being met.

Keywords: :

• adverse events (AEs)
• hepatotoxicity
• pexidartinib
• Risk Evaluation and Mitigation Strategy (REMS)
• tenosynovial giant cell tumor (TGCT)
• TURALIO^®
• tyrosine kinase inhibitor

1. Background

Pexidartinib (TURALIO^®) is a first-in-class, oral, tyrosine kinase inhibitor developed by Daiichi Sankyo for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations that is not amenable to surgical improvement [1–4]. TGCTs are a rare, locally aggressive, yet infrequently malignant group of tumors in the synovium, bursae and tendon sheath in or outside of joints [5,6]. Overexpression of colony-stimulating factor 1 (CSF1), resulting in downstream recruitment of macrophages expressing CSF1 receptors (CSF-1R), which are the primary cellular component of TGCTs, is the key mechanistic driver of this disease [7,8]. TGCT can be classified as either localized or diffuse and, while the 2 classifications differ in their prognosis, they share typical clinical presentations of pain, stiffness and decreased mobility that can range from a few symptoms to potentially debilitating [5]. Prior to the approval of pexidartinib, there was a significant unmet medical need for systemic agents to treat patients with TGCT. While surgery is the primary approach used to treat patients with TGCT, its usefulness is often limited by the difficulty or inability to completely resect the tumors and the potential involvement of tendons, limbs and neurovascular structures, which lead to further postsurgical morbidity and disease recurrence [9,10].

Based on the positive results from the phase 3 ENLIVEN trial, pexidartinib was approved by the US FDA in August 2019 [2,3] at the recommended dose of 400 mg twice daily on an empty stomach, at least 1 h before or 2 h after a meal or snack. The ENLIVEN trial compared the safety and efficacy of pexidartinib with placebo in 120 symptomatically advanced adult patients with TGCT for whom surgery was not recommended [11]. Patients in the pexidartinib group received a daily 1000-mg oral loading dose of pexidartinib for 2 weeks, followed by a twice-daily 400-mg dose for 22 weeks. At week 25, the proportion of patients achieving an overall response was higher in the pexidartinib group than in the placebo group, 24 of 61 (39%) versus 0 of 59 (0%) patients. Furthermore, patient responses in the pexidartinib group were durable; all responding patients followed for ≥12 months maintained their response.

Regarding hepatic adverse events (AEs), elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) occurred in 67%, 90% and 12% of patients, respectively, a third of which were grade ≥3 events. Laboratory abnormalities suggestive of hepatotoxicity (eg, TBIL of ≥2 × the upper limit of normal [ULN] and AST or ALT ≥3 × ULN) occurred in 4.9% of patients (3 out of 61 patients; upper bound of the 95% CI: 13.7%). In patients who were treated with pexidartinib, the peak ALT elevation ranged from 6 to 9 × ULN, TBIL was 2.5 to 15 × ULN and alkaline phosphatase was ≥2 × ULN [12]. Because of these findings, the pexidartinib label contains a black box warning for hepatotoxicity due to the risk of serious and potentially fatal liver injury [1].

Based on the risk of hepatic AEs in patients with TGCT treated with pexidartinib, its approval in the USA was conditional with the development of a Risk Evaluation and Mitigation Strategy (REMS) Program. The TURALIO^® REMS (tREMS) Program is a drug safety Program instituted by the FDA whereby healthcare professionals guide the use of medications with serious safety concerns to help ensure the benefits of these medications outweigh their risks [13]. Focus is placed on preventing, monitoring and/or managing a specific serious risk by informing, educating and/or reinforcing actions to reduce the frequency and/or severity of an AE [14].

The purpose of this communication is to provide a summary of the hepatic data from the retrospective 3-year (August 2019 to June 2022) assessment of the tREMS Program [14].

2. Methods

The goal of the tREMS Program is to mitigate the risk of serious and potentially fatal liver injury by:

1.	Ensuring that prescribers are educated on the following: • The approved indication for pexidartinib. • The risk of serious and potentially fatal liver injury associated with the use of pexidartinib. • The need for liver monitoring at baseline and periodically during treatment with dose modifications as described in the TURALIO®(pexidartinib) prescribing information (PI). • The need to counsel patients about the risk of serious and potentially fatal liver injury. • Liver monitoring at Baseline and periodically during treatment as described in the Patient Guide and to report signs and/or symptoms of liver injury to the prescriber during therapy.
2.	Ensuring that prescribers adhere to the requirement of baseline and periodic monitoring as described in the TURALIO®(pexidartinib) PI.
3.	Enrollment of all patients in a registry to further assess the safe use and acute, chronic and irreversible hepatotoxicity of pexidartinib.

The tREMS Program consists of (i) a Communication Plan for healthcare providers (HCPs), pharmacies and patients, (ii) Elements to Assure Safe Use (ETASU) and (iii) an Implementation System. A detailed description of the tREMS Program framework has been previously published [15].

The tREMS Program requires certification of both HCPs and pharmacies before the prescribing and dispensing of pexidartinib. Certification includes requirements to review the TURALIO^® (pexidartinib) PI, completion of prescriber training, completion of the prescriber knowledge assessment and enrollment in the tREMS Program measured by completion of the Prescriber Enrollment Form. The Form contains prescriber information, office contact information and prescriber attestations committing to compliance with the requirements of the tREMS Program.

After a patient is diagnosed with TGCT and decides in conjunction with their provider to start pexidartinib, the patient must review the Patient Guide, receive counseling regarding the risk of serious and potentially fatal liver injury, undergo baseline liver function tests and complete a Patient Enrollment Form with their prescriber, certifying their enrollment in the tREMS Program. Only once these conditions are met may patients begin their pexidartinib treatment. These requirements have been set to guarantee that HCPs and patients/caregivers are educated on the risk of hepatotoxicity associated with pexidartinib and to ensure the monitoring of the patient’s liver enzyme levels and dose modification, if necessary, to mitigate the risk of serious and potentially fatal hepatotoxicity [14–16].

Following initiation of treatment with pexidartinib, the Patient Status Form must be completed and submitted for each patient every month for the first 3 months of treatment, months 6, 9 and 12 of treatment and every 6 months thereafter. This form contains patient and prescriber information, hepatic monitoring information and any hepatic laboratory tests, procedures/imaging/referrals performed or requested, and medications prescribed to treat any liver injury. Also, following initiation of pexidartinib treatment, patients are required to undergo weekly liver function tests for the first 8 weeks of treatment. This frequency subsequently decreases stepwise: biweekly for 1 month, then at least every 3 months based on the prescriber’s discretion.

Prescribers are also actively evaluating the patient’s liver function and making modifications to the treatment dose where necessary. There are several pre-established algorithms to guide prescriber dose modification, reduction and discontinuation that are described in the TURALIO^® (pexidartinib) PI [1]. Any AE or laboratory abnormality suggestive of serious or potentially fatal liver injury must be reported to the tREMS Program via a Liver Adverse Event Reporting Form. The Form contains patient and prescriber information, details of the event that triggered the report, hepatic laboratory tests, procedures/imaging/referrals performed or requested, medications prescribed to treat any liver injury and the status of the liver AE [14–16].

Pharmacies are certified after demonstrating knowledge about the process and commitment to oversee the implementation and compliance with the requirements of the tREMS Program.

Before dispensing pexidartinib, the pharmacist should obtain authorization to dispense each prescription by contacting the tREMS Program to verify that the prescriber is certified and the patient is enrolled and authorized to receive the drug; dispense no more than a 30 days’ supply at a time for the first 3 months; report any AEs; distribute, transfer, loan or sell pexidartinib to certified dispensers; and maintain records documenting the tREMS Program trainings, processes and procedures [14–16].

The established system’s processes and procedures were implemented to ensure that pexidartinib was distributed only to certified pharmacies. The relevant staff members involved in its distribution are trained on the tREMS Program requirements and maintain records of all drug distributions.

A core requirement for the tREMS Program is the FDA-mandated REMS assessment, annually for the first 3 years since product approval and every 2 years thereafter, to determine whether the program’s goals are being met and/or whether modifications to any of its components are needed. The scope of this assessment includes prescriber/patient knowledge and understanding of potential risks associated with pexidartinib treatment and methods to ensure its safe use. Additional data are collected and evaluated, including the total number of enrolled prescribers/patients, patterns of pexidartinib utilization, prescriber behaviors, AEs and patient outcomes [14].

The 3-year cumulative hepatic data collected from HCPs, patients, pharmacies and distributors participating in the tREMS Program were analyzed. Summary statistics were used to describe the results for this hepatic safety assessment [14].

3. Results

During the 3-year assessment period, a total of 451 patients were enrolled in the tREMS Program; of these, 426 received ≥1 dispense of pexidartinib. The program also certified and enrolled 369 prescribers, 2 wholesalers/distributors and 2 pharmacies (Table 1) [14].

Table 1. Characteristics of the tREMS enrollees

Characteristic	Enrolled (n = 451)	Active^a (n = 426)
Male, n (%)	184 (40.8)	174 (40.8)
Female, n (%)	267 (59.2)	252 (59.2)
Mean age (SD), y	45.1 (15.75)	45.1 (15.56)

a Patients who received at least 1 dispense of TURALIO^® during the 3-year assessment period.

SD: Standard deviation; tREMS: TURALIO^® Risk Evaluation and Mitigation Strategy.

Prescribers and pharmacies were required to report any liver AEs by completing and submitting a Liver Adverse Event Reporting Form. A total of 95 Forms were submitted from 69 patients. The most frequently reported serious AEs (>0.3%) in all patients enrolled in the tREMS Program were elevated transaminases (ie, AST, ALT), gamma-glutamyl transferase and blood bilirubin, which are AEs that are already included in the pexidartinib label [14].

A total of 21 of the 451 (4.7%) patients met the criteria for liver AE or laboratory abnormalities suggestive of serious and potentially fatal liver injury. All 21 patients had hepatic event onset within 2 months of initiating therapy. Of the 21 patients reporting hepatic events, the number of patients by total daily dose were as follows: 13 at 800 mg, 3 at 600 mg, 3 at 400 mg and 1 at 200 mg. The dose at event onset was not reported for 1 patient.

Of the 21 patients meeting the criteria for liver AE or laboratory abnormalities, 11 patients met the laboratory criteria of ALT/AST >3 × ULN and TBIL >2 × ULN; 2 of 21 patients had ALT/AST >10 × ULN (with or without TBIL >2 × ULN) and 8 patients had alkaline phosphatase >2 × ULN with gamma-glutamyl transferase >2 × ULN (without meeting other Liver Injury Event of Concern/liver AE reporting criteria). Of the 11 patients meeting the criteria of ALT/AST >3 × ULN and TBIL >2 × ULN, 6 also met the criteria of ALT/AST >10 × ULN (with or without TBIL >2 × ULN). Hepatic events in 11 of the 21 patients completely resolved, while the events in 10 patients had not fully resolved as of data cut-off for this review [14].

Of the 21 patients, 20 permanently discontinued pexidartinib treatment and treatment was interrupted for 1 patient. A total of 19 of the 21 cases were assessed by an external hepatologist; causality was assessed as: possible in 10, probable in 4 or unable to assess because of missing/incomplete information in 5 cases. The nature of the injury was assessed as mixed/cholestatic in 14, hepatocellular in 2, initially hepatocellular and then became a cholestatic injury in 2 and unable to assess because of missing/incomplete information in 3 cases [14].

All hepatic events reported from all sources indicated that the pattern of hepatic injury was consistent with what was observed in the ENLIVEN trial [11,14]. There were no cases of irreversible liver injury, and no new safety signals were identified [14].

4. Discussion

The tREMS Program is a closed system for distribution, prescription and dispensing of pexidartinib, in which education and certification of distributors, pharmacies and HCPs were required. In addition, HCPs were required to counsel patients about the risk of serious and potentially fatal liver injury, to monitor liver function at baseline and periodically during the treatment and to report any sign or symptom of liver injury during treatment with pexidartinib. All prescribers were certified after successful completion of the tREMS Education Program [15,16]. The patient data collected were inclusive of demographic and safety information; efficacy data were not collected.

The 3-year retrospective cumulative safety assessment results from the tREMS Program show that it is preventing and managing the risk of serious and potentially fatal liver injury in patients receiving pexidartinib. These results were consistent with those observed in the ENLIVEN trial and included in the TURALIO^® (pexidartinib) label [1,17,18]. Not only was the pattern of hepatic injury reported consistent with what was observed in the phase 3 study, but the hepatic AEs reported were also as expected and were primarily observed within 2 months of initiating treatment. There were no cases of irreversible liver injury, and no new safety signals were identified [11,14,18]. Pexidartinib, as the first approved systemic therapy for patients with TGCT, is a valuable treatment option; however, it is important that HCPs monitor the patient’s liver function as recommended in the TURALIO^® (pexidartinib) PI [1,19].

Additionally, treatment with pexidartinib appeared to be appropriately discontinued, interrupted or reduced where laboratory data were available to assess and most patients recovered where outcome data were reported. No new liver AE signals were identified over the assessment period. Furthermore, among patients experiencing AEs, >90% were nonserious and manageable by their HCP [14].

5. Conclusion & implications of these findings

Based on these safety data collected from the tREMS Program, careful monitoring of liver enzyme levels combined with early intervention using dose modifications and discontinuation are being actively conducted to mitigate the risk of potential hepatotoxicity. In addition, these results demonstrate that the educational materials for HCPs and patients are effective. Cumulative assessment of the tREMS Program results do not provide any evidence that impacts the known safety profile of pexidartinib, hence no additional safety measures are required at this time.

Overall, the results of this assessment indicate that the goal of the tREMS Program, to mitigate the risk of serious and potentially fatal liver injury, is being met to ensure the safe use of pexidartinib.

Author contributions

All authors provided substantial and equal contributions (a) to the conception and design of this research; for the analysis and interpretation of data; AND (b) towards drafting the work and revising it critically for important intellectual content; AND (c) for final approval of the version to be published; AND (d) are in agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Financial disclosure

Drs. Dharmani, Fofah, Rajper and Wooddell are employees of Daiichi Sankyo, Inc. Dr. Fallon is an employee of Daiichi Sankyo UK Ltd. Dr. Salas was an employee at Daiichi Sankyo, Inc. at the time of study initiation until completion. All authors, except Dr. Fofah, own restricted stock units of Daiichi Sankyo, Inc.

Writing disclosure

Editorial assistance for the development of this manuscript was provided by Alanna Kahhan and Shannon Simcox, of Lumanity Scientific Inc. and was financially supported by Daiichi Sankyo, Inc.

Ethical conduct of research

This short communication was written based on the analysis of deidentified patient records and does not involve the collection, use or transmittal of individually identifiable data, thus institutional review board approval was not necessary.

Acknowledgments

This analysis from the TURALIO® REMS was funded by Daiichi Sankyo, Inc. By submitting this manuscript for consideration, the authors affirm that neither the submitted manuscript nor any similar manuscript, in whole or in part, other than an abstract, is under consideration, in press, published or reported elsewhere.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Additional information

Funding

Drs. Dharmani, Fofah, Rajper and Wooddell are employees of Daiichi Sankyo, Inc. Dr. Fallon is an employee of Daiichi Sankyo UK Ltd. Dr. Salas was an employee at Daiichi Sankyo, Inc. at the time of study initiation until completion. All authors, except Dr. Fofah, own restricted stock units of Daiichi Sankyo, Inc.