Baricitinib: Therapeutic Potential for Moderate to Severe Atopic Dermatitis
Abstract
Introduction. Atopic dermatitis (AD) is a chronic inflammatory skin disease mediated by multiple signals including the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. The current therapeutic armamentarium consists of a limited number of drugs which may result in insufficient management of AD. Preclinical evidence regarding inhibition of JAK/STAT led to the development of a promising class of therapeutics, namely JAK inhibitors. Baricitinib, a novel JAK1/JAK2 inhibitor, is currently under investigation in AD clinical trials. Areas covered. This review offers an overview of baricitinib and examines clinical efficacy and safety data in patients with moderate-to-severe AD. Expert opinion. Baricitinib showed promising preliminary data in terms of efficacy in phase II and III trials, with a very rapid onset of response and great improvements of itch and sleep disturbances. These aspects, combined with the advantage of an oral formulation, have reduced drug production costs compared to biologic agents and could lead to consideration of baricitinib as a first-line systemic treatment. Also, in some countries, it could be a therapeutic option in cases of contraindication or failure of conventional systemic drugs prior to biologic therapies. Data related to long-term safety and efficacy will be important to refine the place-in-therapy of this drug.
Keywords: atopic dermatitis, baricitinib, JAK, JAK inhibitors, small molecules
Introduction
Atopic dermatitis (AD) is an immune-mediated skin disease with a chronic-relapsing course and multifactorial pathogenesis. AD is the most common inflammatory skin disorder with a worldwide prevalence ranging from 5 to 10% in children and 1-3% in adults. Clinical manifestations are usually associated with intense itching and typically consist of symmetric, erythematous, and scaly papules or plaques, with secondary features of lichenification and excoriation, and a high risk of superimposed infections. The recurrent eczematous lesions are predominantly localized on extensor areas, face, scalp, and diaper area in childhood AD, whereas flexural areas, face, neck, and distal extremities are commonly affected in adolescent and adult AD patients. However, different AD phenotypes have been recently described, some characterized as the result of distinct endotypes according to age, ethnicity, body localization, disease stage, IgE levels, immune pathway activation, and filaggrin mutation. This novel distinction of AD into different subgroups will pave the way for the introduction of a personalized therapeutic approach replacing the traditional “one-size-fits-all” strategy.
No longer considered only a cutaneous disease, AD often precedes other atopic manifestations priming the so-called “atopic march.” Moreover, AD may be associated with a significant increased risk of comorbidities, including cardiovascular, neuropsychiatric, and malignant disorders. Nevertheless, atopic dermatitis might be associated with a profound negative impact on quality of life (QoL), due to constant itch and sleep disturbances. Both social and emotional functioning can be detrimentally affected, leading to work impairment and social isolation.
1.1 AD Pathogenesis
AD pathogenesis consists of a complex mechanism involving genetic and environmental factors, leading to skin barrier dysfunction and immunological impairment. The immune system dysregulation involves both innate and adaptive immunity. Although AD has been conventionally considered mediated by a Th2-skewed adaptive immune response, associated with eosinophil recruitment, mast cell activation, and IgE production from activated B cells, the immune map of the disease is expanded to T cytotoxic 2 cells (Tc2), type 2 innate lymphoid cells (ILC2s), and multiple inflammatory pathways, namely Tc22/Th22, Th17, Th9, and Th1.
In the acute phase of AD, type 2 (Th2-, ILC2-, Tc2-derived) and Th22-derived cytokines (i.e., IL-22) are mostly involved, contributing to skin inflammation, epidermal barrier dysfunction, and itch, while in the chronic stage, the intensification of Th2 and Th22 cytokine axes occurs, with an important contribution of both Th1 and Th17 pathways in sustaining inflammation. Pruritus is mainly induced by IL-31.
1.2 Role of JAK/STAT Signaling Pathway in AD
The Janus kinases (JAK)/signal transducer and activator of transcription (STAT) pathway is a paradigm of receptor-mediated signal transduction, which is essential for both immune and hematopoietic function. The JAK family belongs to the group of cytoplasmic tyrosine kinases and includes four isoforms: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Once activated, JAKs phosphorylate the intracellular domain of the cytokine receptor creating a docking site for STATs. The ultimate effect of the activation of the JAK/STAT pathway is strongly influenced by the isoforms recruited and their complex interaction. Type 2 cytokines (namely IL-4 and IL-13), which are central to AD pathogenesis, act through JAK1/JAK3 and STAT3, STAT5, and STAT6, mediating different steps of AD pathogenesis. By binding the type I IL-4 receptor, IL-4 and IL-13 activate the JAK/STAT pathway, (i) altering the keratinocyte differentiation process leading to skin barrier impairment; (ii) regulating keratinocyte-derived chemokine and antimicrobial peptide production; and (iii) inducing sensory neuronal stimulation. The overall result of JAK-STAT activation is the contribution to both AD skin inflammation and chronic itch. However, the pathogenic role of JAK-STAT signaling is not only related to IL-4 and IL-13, as other key pathogenic mediators such as IL-31 and thymic stromal lymphopoietin (TSLP) transduce their pruritogenic stimuli through JAK-STAT pathways. Collectively, these lines of evidence suggest the central role of JAK/STAT in AD pathogenesis and the therapeutic development of JAK inhibitors in treating human AD.
Material and Methods
A search of the English-language literature regarding the pathogenic role of JAK/STAT pathway dysregulation in AD was carried out, in addition to clinical data on baricitinib therapy. Multiple databases, namely PubMed, Embase, Google Scholar, and Scopus, were consulted using the following terms: baricitinib, INCB028050, olumiant, atopic dermatitis, JAK/STAT pathway, JAK inhibitors. Ongoing clinical trials and preliminary results concerning investigational use of baricitinib in AD were searched on ClinicalTrials.gov. Data from recent international meetings were also taken into account.
Overview of the Market
The choice of AD treatment widely varies depending on various factors. Topical approaches are usually the first-line treatment for mild disease, while phototherapy and systemic agents are recommended for moderate-to-severe patients. Apart from cyclosporine, which is approved for treatment of AD, the remaining immunosuppressive drugs have been used as alternative, off-label therapies. In 2017, the Food and Drug Administration (FDA) approved dupilumab, a fully human monoclonal antibody blocking the shared IL-4 receptor α (IL4Rα) subunit binding to both IL-13 and IL-4, for the treatment of moderate-to-severe AD in both adults and adolescents.
3.1 Emerging Therapies for AD
Several novel therapeutic agents, including biologic agents, topical and oral small molecules, are currently being investigated for AD treatment. Some of these agents are in advanced stages of development: nemolizumab, an anti-IL-31 monoclonal antibody, met the primary endpoint in a phase II trial; lebrikizumab and tralokinumab, both targeting IL-13, are currently under investigation in phase III studies. Tezepelumab, a monoclonal antibody targeting TSLP, and ustekinumab, an anti-IL-12/23 monoclonal antibody, demonstrated controversial results in phase II trials, whereas fezakinumab, an anti-IL-22 monoclonal antibody, has proven to be effective particularly in patients with severe AD (SCORAD > 50) and with high IL-22 serum levels at baseline.
An oral inhibitor of phosphodiesterase 4 (PDE4), apremilast, was investigated in one phase II clinical trial for AD but showed inconsistent results. Conversely, upadacitinib, a selective JAK1 inhibitor, successfully passed phase II and is now being tested in multiple phase III clinical trials, including a phase IIIb versus dupilumab. Abrocitinib, another specific JAK1 inhibitor, is currently investigated in a phase III trial (NCT03422822). Another class of drugs appearing on the AD pipeline landscape comprises oral H4R antihistamines such as ZPL-3893787, tested in phase II.
3.2 JAK Inhibitors: A New Promising Class of Therapeutics
Alterations of the JAK/STAT pathway and their relation to the pathophysiology of many chronic immune-mediated disorders have been thoroughly investigated, and JAK inhibitors shed light on their therapeutic potential in treating various inflammatory skin disorders. By blocking one or more members of the JAK family, JAK inhibitors exert anti-inflammatory, immunosuppressive, and antiproliferative properties. Currently, two generations of JAK inhibitors exist: the first generation, including tofacitinib, ruxolitinib, and baricitinib, blocks multiple JAKs, while the second generation is more selective, blocking a single JAK, narrowing the inhibitory range of cytokines.
Introduction to the Compound
Baricitinib (LY3009104, previously known as INCB028050) is an orally administered small molecule, already approved for the treatment of moderate to severe rheumatoid arthritis (RA). Noteworthy, a black-box warning has been included because of the occurrence of serious infections, such as herpes zoster and tuberculosis reactivation, malignancies, arterial and venous thromboses, observed during analysis of phase II and III trials on patients affected by moderate-to-severe RA. However, given its emerging therapeutic potential, baricitinib is currently under investigation for the treatment of other chronic immune-mediated diseases such as moderate-to-severe psoriasis, systemic lupus erythematosus, chronic graft versus host disease, and atopic dermatitis.
4.1 Chemistry
The chemical name of baricitinib is {1-(ethylsulfonyl)-3-[4-(7Hpyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. The empirical formula of baricitinib is C16H17N7O2S and the molecular weight is 371.42 g/mol.
4.2 Pharmacodynamics
Baricitinib is capable of selectively inhibiting both JAK1 and JAK2 tyrosine kinases, with half-maximum inhibitory concentrations (IC50) of 5.9 and 5.7 nmol/L, respectively. To a lesser extent, it also inhibits the other two members of Janus kinases, TYK2 and JAK3 (IC50 of 53 and approximately 560 nmol/L, respectively). In human T-cell assays, strong inhibition of STAT3 phosphorylation resulted in suppression of IL-6 and IL-23 signaling, and a subsequent decreased production of MCP-1, IL-17, and IL-22.
4.3 Pharmacokinetics and Metabolism
Drug plasma concentration, following oral administration, typically peaks after 1.5 hours. Additionally, baricitinib demonstrated dose-proportional pharmacokinetics, with minimal systemic accumulation after repeated doses. Absolute drug bioavailability is about 79%, which is reduced by up to 14% by the co-administration of a high-fat and high-calorie meal, without significant impact on clinical effect. Up to 50% of baricitinib binds to plasma proteins, and less than 10% of the drug’s plasma dose undergoes transformation through CYP3A4 cytochrome.
A phase I trial (NCT01870388) evaluated baricitinib pharmacokinetics in patients with liver disease. In detail, eight subjects with hepatic impairment classified as Child-Pugh score A or B (mild or moderate impairment, respectively) and eight healthy controls underwent treatment with 4 mg baricitinib daily for one week. No serious adverse events or deaths occurred in any arm, while nausea and neutrophil count decrease (classified as non-serious adverse events) were slightly more frequent in patients with moderate liver impairment (1/8, 12.5% versus 0% in healthy controls).
The drug is mainly excreted unchanged through renal and gastrointestinal elimination (75% and approximately 20% of the dose, respectively). Co-administration with the potent organic anion transporter 3 (OAT3) inhibitor probenecid is associated with a clinically relevant increase in baricitinib serum levels and with a 69% decrease in renal clearance. Patients with mild or moderate renal impairment (creatinine clearance of 30–60 mL/min) have been studied to assess dosing adjustments,been studied to assess dosing adjustments, and it was found that exposure to baricitinib increases in these patients. Consequently, dose reduction is recommended for individuals with moderate renal impairment, while baricitinib is not recommended in patients with severe renal impairment or end-stage renal disease.
Clinical Efficacy
5.1 Preclinical Evidence
Preclinical studies have demonstrated that baricitinib is effective in suppressing the JAK/STAT signaling pathway, which is central to the pathogenesis of atopic dermatitis. In vitro and in vivo models have shown that baricitinib reduces the production of inflammatory cytokines such as IL-4, IL-13, and IL-22, all of which are implicated in the development and maintenance of AD lesions. These findings provided the rationale for clinical trials investigating baricitinib in patients with moderate-to-severe AD.
5.2 Phase II Clinical Trials
The first phase II, randomized, double-blind, placebo-controlled trial of baricitinib in adults with moderate-to-severe atopic dermatitis demonstrated promising results. Patients were assigned to receive either baricitinib or placebo, in addition to topical corticosteroids. Baricitinib-treated patients showed significant improvements in the Eczema Area and Severity Index (EASI) scores, Investigator’s Global Assessment (IGA), and patient-reported outcomes such as pruritus and sleep disturbances. The onset of action was rapid, with notable improvements observed as early as one week after initiation of therapy. Importantly, baricitinib was generally well tolerated, with most adverse events being mild or moderate in severity.
5.3 Phase III Clinical Trials
Subsequent phase III studies further confirmed the efficacy and safety of baricitinib in a larger population. In these trials, baricitinib was evaluated as monotherapy or in combination with topical corticosteroids. The results consistently showed that baricitinib led to significant improvements in clinical signs and symptoms of AD compared to placebo. Patients receiving baricitinib experienced greater reductions in EASI and IGA scores, as well as improvements in quality of life measures. The rapid onset of itch relief was particularly notable, as pruritus is one of the most burdensome symptoms for AD patients. The safety profile remained favorable, with infections, headache, and elevated creatine phosphokinase being the most commonly reported adverse events. Serious adverse events were rare and comparable between the baricitinib and placebo groups.
Safety and Tolerability
Baricitinib has been generally well tolerated in clinical trials for atopic dermatitis. The most common adverse events included upper respiratory tract infections, headache, and mild increases in creatine phosphokinase levels. Herpes simplex and herpes zoster infections were reported, but their incidence was low. Laboratory abnormalities, such as changes in blood counts and liver enzymes, were infrequent and usually reversible upon discontinuation or dose adjustment. The risk of serious infections, malignancies, and thromboembolic events observed in rheumatoid arthritis trials led to the inclusion of a black-box warning in the prescribing information. However, in the AD population, the incidence of these events has been low, although long-term safety data are still being collected.
Discussion
Baricitinib represents a significant advancement in the systemic treatment of moderate-to-severe atopic dermatitis. Its oral administration, rapid onset of action, and favorable efficacy and safety profile make it an attractive alternative to conventional systemic therapies and biologic agents. Baricitinib’s mechanism of action targets multiple cytokine pathways implicated in AD, offering a broader anti-inflammatory effect compared to agents that block a single cytokine. This may translate into better disease control for patients with complex or refractory disease.
Baricitinib may be particularly useful in patients who have contraindications to or have failed conventional systemic therapies such as cyclosporine or methotrexate. Additionally, its oral formulation may improve adherence and convenience compared to injectable biologics. However, careful patient selection and monitoring are essential, especially in those with a history of infections, malignancy, or thromboembolic disorders.
Expert Opinion
The introduction of baricitinib and other JAK inhibitors into the therapeutic landscape of atopic dermatitis marks a new era in the management of this challenging disease. Baricitinib’s efficacy in rapidly improving skin lesions, reducing pruritus, and enhancing quality of life has been demonstrated in clinical trials. Its safety profile appears acceptable, though long-term data are needed to fully establish its risk-benefit ratio. The cost-effectiveness of baricitinib, especially compared to biologic agents, may also support its use as a first-line systemic therapy in some settings.
Future studies should focus on the long-term safety of baricitinib, its use in pediatric populations, and its effectiveness in real-world clinical practice. Ongoing research into biomarkers and disease endotypes may further refine patient selection and optimize therapeutic outcomes.
In conclusion, baricitinib offers a promising new option for patients with moderate-to-severe atopic dermatitis, particularly those who are inadequately controlled with existing therapies. Its rapid efficacy, oral administration, and manageable safety profile position it as a valuable addition to the armamentarium against atopic dermatitis.