FormalPara Key Points

Review of drug safety databases through the first year following marketing approval of ruxolitinib cream suggests that ruxolitinib cream is generally well tolerated, without significant systemic adverse events (AEs), and with a low incidence of application site reactions.

Serious AEs associated with class warnings for oral Janus kinase inhibitors were not reported with ruxolitinib cream during the first year post-approval.

1 Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease that can have considerable impact on quality of life [1]. AD is highly pruritic with underlying skin defects, and prevalence in adults varies geographically, ranging from 1 to 8% [2, 3]. In vitiligo, autoimmune pathways target melanocytes, which results in depigmentation [4]. The prevalence of vitiligo also varies geographically, ranging from 0.5 to 2% in adults [5]. Topical treatments such as corticosteroids or calcineurin inhibitors are typically used as treatment for both AD and vitiligo; however, these treatments are off-label for vitiligo [6, 7], and in both diseases, adherence to treatment may be low due to concerns about adverse events (AEs) and limited efficacy [8, 9].

Janus kinases (JAKs) are intracellular signaling enzymes that are implicated in the disease pathogenesis of both AD and vitiligo [10,11,12,13]. Ruxolitinib cream is a topical formulation of ruxolitinib, a selective inhibitor of JAK1 and JAK2 [14]. In 2021, ruxolitinib cream became the first approved topical JAK inhibitor in the United States (US) for the treatment of mild to moderate AD after phase III studies demonstrated improvements in AD-related signs and symptoms, including itch [15, 16]. Just under a year later, ruxolitinib cream became the first agent to be approved for repigmentation in patients with nonsegmental vitiligo after phase III studies demonstrated substantial repigmentation over 52 weeks [8, 16].

Although the safety of ruxolitinib cream was evaluated in phase III clinical trials with long-term extensions before approval (e.g., TRuE-AD1/TRuE-AD2 [NCT03745638/NCT03745651], and TRuE-V1/TRuE-V2 [NCT04052425/NCT04057573]) [17, 18], as with all approved drugs, safety evaluation has extended into the postmarketing setting. Safety assessment from clinical trials provides insight into AEs that may occur in the indicated population [19, 20]. However, as clinical trials typically represent only a subset of the real-world population, postmarketing surveillance is important to identify safety concerns that may not have arisen or been detected during clinical trial evaluation [19].

In the US, the FDA requires ongoing safety evaluation by drug manufacturers, including periodic review of safety databases and reporting of AEs to national registries [19]. Safety information may be reported by healthcare professionals or consumers to drug manufacturers for inclusion in the company-held safety databases, or directly to the FDA through the FDA Adverse Event Reporting System (FAERS) [19,20,21]. Data collected during the clinical trial evaluation stages are used to inform safety-related information included in the US Prescribing Information (USPI) for the drug, which can be revised as necessary based on relevant postmarketing findings [19,20,21]. The USPI requirements include sections such as contraindications, boxed warnings, warnings, precautions, and adverse reactions [19, 22]. Boxed warnings are often applicable to an entire drug class, with an FDA requirement for all approved drugs in that class to display the warning, typically if an association is considered to exist between the mechanism of action of the drug class and the identified safety risk [19, 21].

A post-approval safety study of oral tofacitinib in 4362 patients with active rheumatoid arthritis who were ≥50 years of age with more than one additional cardiovascular risk factor reported a higher incidence of major adverse cardiovascular events (MACE) and cancer with tofacitinib 5 or 10 mg twice daily versus with a tumor necrosis factor inhibitor (MACE: hazard ratio [HR] 1.33, 95% confidence interval [CI] 0.91-1.94; cancers: HR 1.48, 95% CI 1.04-2.09) [23]. The findings of this study resulted in the FDA adding a boxed warning to all JAK inhibitors indicated for the treatment of rheumatoid arthritis and/or other inflammatory conditions, regardless of the route of administration [16, 24]. The boxed warning highlights the increased risk of serious infections, MACE, lymphoma and other malignancies, and thrombosis.

The objective of this analysis was to review the postmarketing safety of ruxolitinib cream, encompassing nearly 14,000 patient-years of treatment during the first year of market approval.

2 Methods

The Incyte global safety database and the FAERS database were queried for all event reports, including AEs (i.e., any unfavorable sign, symptom, or disease) and special situation events (e.g., off-label use, product issues, product availability issues, or dose omission) for ruxolitinib cream. For the Incyte global safety database, the period searched was between 21 September 2021 and 20 September 2022, and for the FAERS database, the data were as of 30 September 2022. Reports were submitted by healthcare professionals or consumers to Incyte for inclusion in the company safety databases or directly to the FDA and could be spontaneous and/or unsolicited, non-interventional and/or solicited, or identified through AEs reported in the literature. Assessment was made based on information made available by the person submitting the report; to the extent possible, attempts were made to obtain missing data and follow-up information as needed for both serious and nonserious reports.

Per the FDA, AEs during the postmarketing period were defined as unanticipated experiences or side effects associated with the use of a drug, whether or not considered related to the product [25]. AEs were defined per the FDA as serious if the patient outcome attributed to the AE resulted in death or was life-threatening; resulted in hospitalization, disability or permanent damage, or congenital anomaly/birth defect; or was another serious, important medical event that jeopardized the patient and could have required medical or surgical intervention to prevent one of the other serious outcomes [26]. The European Medicines Agency (EMA) Important Medical Events (IME) list includes those AEs that should be considered serious for regulatory reporting, regardless of how they are reported to the sponsor [27]. In the Incyte database, if an AE was reported nonserious by FDA criteria but appeared on the EMA IME list, the AE was upgraded and considered serious.

AEs of special interest (AESIs), based on those identified for the oral JAK inhibitor tofacitinib, included serious infections, MACE, thrombosis, mortality, and malignancies. Other special situation reports were excluded from detailed analysis, with the focus on AEs.

3 Results

3.1 Postmarketing Exposure

Total postmarketing exposure with ruxolitinib cream during the first year of approval was estimated to be 13,833 patient-years of treatment.

3.2 Individual Case Safety Reports

A total of 294 postmarketing individual case safety reports (ICSRs) for ruxolitinib cream were identified (Table 1). Most of the ICSRs were from spontaneous sources (74.8%) versus from non-interventional or solicited sources (25.2%). Few of the ICSRs were medically confirmed by a healthcare professional such as a nurse, pharmacist, or physician (24.8%), with the majority being reported by consumers (75.2%).

Table 1 ICSRs and overall demographics of ICSRs for ruxolitinib cream
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Sex was reported for most ICSRs (87.4%). In the ICSRs with sex reported, females (68.5%) were involved more commonly than males (31.5%). Less than one-quarter of the ICSRs reported age (21.8%); where age was reported, the median was 39 years.

3.3 Events

A total of 589 events were received for ruxolitinib cream. Most of the events reported were nonserious (99.3%), only 4 (0.7%) were serious AEs, and there were no fatal AEs. Of the 589 reported events, 329 (55.9%) were special situation events and 260 (44.1%) were AEs.

3.4 Adverse Events (AEs)

3.4.1 Most Frequent AEs

The most frequently (>2%) reported AEs were application site pain, AD, skin irritation, scratch, and condition aggravated (Table 2). Events of AD and condition aggravated mostly described a lack of improvement or worsening of the underlying condition for which the patient was being treated. Application site reactions included application site pain, skin irritation, and scratch.

Table 2 Most frequent adverse events for ruxolitinib cream
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3.4.2 Serious AEs

In the time period analyzed, four serious AEs were reported: ‘skin cancer’ (as reported, n = 2), pericarditis (n = 1), and thrombocytopenia (n = 1). None of the serious AEs contained sufficient information for assessment of possible relatedness to ruxolitinib cream (i.e., key information was missing, such as date of therapy, timing of onset of the AE, medical history of the patient, or concomitant medications received by the patient). Only the report of pericarditis was medically confirmed and was reported as a serious AE, as it resulted in hospitalization. The skin cancer and thrombocytopenia events were initially reported as nonserious AEs but were upgraded to serious IMEs per EMA criteria by Incyte, for regulatory reporting purposes.

3.4.3 AEs of Special Interest

With the exception of two ICSRs of skin cancer, no AESIs were reported with ruxolitinib cream. As noted previously, these skin cancer reports were initially reported as nonserious but were upgraded to serious by Incyte based on EMA criteria (Table 3). The skin cancer events were not medically confirmed, medical history and/or concurrent conditions were not reported, diagnostic evaluation including skin biopsy results and final diagnosis were not provided, and despite repeated attempts at follow-up, reports did not contain sufficient information for medical assessment of relatedness to ruxolitinib cream.

Table 3 AESIs for JAK inhibitors reported with ruxolitinib cream
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3.4.4 US FDA Adverse Event Reporting System (FAERS) Database

In the FAERS database, seven ICSRs were found, of which three were serious and four were nonserious. The three serious ICSRs described the same events of pericarditis, thrombocytopenia, and skin cancer that were captured in the Incyte database. The four nonserious ICSRs described events of (1) diarrhea, asthenia, and vomiting; (2) drug hypersensitivity; (3) skin exfoliation (in the context of dry skin) and eczema; and (4) visual impairment, rash, rash erythematous, pruritus, product use in unapproved indication, ovarian disorder, skin burning sensation, and injection site urticaria (in a case describing concurrent use of both dupilumab and ruxolitinib cream).

4 Discussion

This review of safety data available for ruxolitinib cream in the first year after its approval suggests that ruxolitinib cream is generally well tolerated for the treatment of AD or vitiligo.

The AEs that were most commonly reported included application site reactions such as application site pain, skin irritation, and scratch (approximately 8% of all reported events). AD and condition aggravated, together representing approximately 5% of all reported events, reflected worsening of the underlying condition or a lack of improvement. We had a preponderance of women involved in these postapproval safety reports, consistent with historical trends of spontaneous safety reporting [28].

There were no reports of serious AEs associated with the class warning for oral JAK inhibitors during the first year following approval, such as risk of serious infections, MACE, lymphoma or other malignancies, or thrombosis, except two skin cancers that were initially reported as nonserious without sufficient information for evaluation.

A possible explanation for the absence of serious AESIs associated with ruxolitinib cream is the low systemic bioavailability of ruxolitinib (6.22%) following application of 1.5% ruxolitinib cream twice daily in patients with AD [29]. Importantly, in phase III studies in AD, the mean steady-state plasma concentration of ruxolitinib following application of 1.5% ruxolitinib cream (35.7 nM) has been shown to be a fraction of the proxy parameter (thrombopoietin-stimulated phosphorylated STAT3 inhibition, 281 nM) used to assess potential JAK-related myelosuppression [14, 29]. Similarly, in patients with vitiligo, ruxolitinib cream is associated with low systemic bioavailability [30].

Insufficient information was available to assess any potential associations between ruxolitinib cream and the serious AEs of skin cancer, pericarditis, or thrombocytopenia. Indeed, based on the rate of these events in the general population and the increased risk of nonmelanoma skin cancer in patients with AD, the rate of these events likely reflects the background rates in the target population [31,32,33,34]. Three of the four serious AEs found in the Incyte global safety database were also reported in the FAERS database, reinforcing the value of the company-held global safety database. Longer-term data will be needed to fully assess these risks.

The limitations of this review include those associated with passive safety surveillance systems, including reports containing minimal clinical information, underreporting, reporting bias, and challenges in determining a causal association between a reported AE and a specific drug [35, 36]. As such, results should be interpreted with caution.

5 Conclusions

The serious AEs associated with the oral JAK inhibitor class warning were not reported with ruxolitinib cream in the first year post-approval. These safety data support that ruxolitinib cream is well tolerated, without significant systemic AEs and with a low incidence of application site reactions. Longer-term data are required to confirm these findings.