Abrocitinib: A comprehensive review of its use in dermatology beyond atopic dermatitis

Mechanism of action

Abrocitinib is a selective JAK 1 inhibitor. It inhibits JAK1 binding by blocking the ATP binding site. Abrocitinib is selective for JAK1 over JAK2 (28-fold), JAK 3 (>340-fold), and tyrosine kinase 2 (43-fold). In vitro, the parent compound and its active metabolite show similar selectivity levels for JAK 1. JAK 1/2/3/TyK 2 is expressed in multiple cell types. JAK3 is commonly seen in hematopoietic cells. Various domains facilitate the binding of JAKs to intracellular receptors. Pseudokinase domains play a regulatory role.

• Step 1: When the ligands bind to the cell receptors, there is dimerization which brings the associated JAKs close together. The JAK phosphorylates each other on tyrosine residues and then increases the activity of kinase domains. Then, they phosphorylate the tyrosine residues on the receptor subunit.

• Step 2: Once phosphorylation occurs, it creates a binding site for the SH2 domains of the intracytoplasmic transcription factors. This is known as STAT

• Step 3: The STATs are phosphorylated by JAKs which form hetero/homodimers and the dimer translocates into the nucleus which regulates the target gene expression of inflammatory mediators.

JAK-STAT is the common signal transduction pathway of cellular proliferation, migration, differentiation, and apoptosis [Figure 3].^[4]

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Figure 3:

Mechanism of action of Janus kinase signal transducers and activators transcription inhibitors in cytokine mediation. JAK: Janus Kinase, STAT: Signal transducers and activators of transcription

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Pharmacokinetics

Abrocitinib has 91% oral bioavailability. Systemic drug absorption is not influenced by food. Peak concentrations of the drug are reached within 1 hour of drug intake. The t ½ of the drug is 5 hours.

When taken once daily, the drug reaches steady-state plasma concentrations within 48 hours.

The following are the drug metabolites of abrocitinib –

1. Pyrrolidinone pyrimidine – inactive

2. 2-hydroxypropyl – active

3. 3-hydroxypropyl – active.

The drug undergoes enzymatic metabolism through mostly CYP2C19 (53%), and CYP2C (30%), and a small percentage of the drug is metabolized by CYP3A4 and CYP2B6. When administered with strong CYP2C19 inhibitors, the dose of the drug should be reduced by half. When administered by CYP2C119/2C9 inducers, no dose adjustment is needed.^[4] Patient characteristics including age, weight, sex, race, and CYP2C19/CYP2C9 genotype have no apparent effect on the metabolism of the drug. In adolescent patients, no difference in metabolism has been seen as compared to adult patients. There is no clinically significant difference in the active moiety of the drug in mild or moderate hepatic impairment or in mild renal impairment.

It is contraindicated in patients with severe hepatic impairment, considering the absence of studies in this population.

It has not been evaluated in patients with end-stage renal disease or renal replacement therapy.^[3]

Pharmacodynamics

Reduction in JAK1 activity reduces downstream thrombopoietin production which consequently shows a fall in platelet count peaking at 4 weeks of treatment. The platelet count gradually rises back up starting at 4 weeks of treatment. After 4 weeks of abrocitinib treatment, there is also a dose-dependent increase in low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, and an increase in total cholesterol levels. A 10% rise in LDL cholesterol is seen with 100 mg of abrocitinib and a 15% rise is seen with 200 mg of abrocitinib.^[4,5]

JADE MONO-1, Simpson et al. (July 2020)

A multicenter, double-blind, placebo-controlled, phase 3 trial was conducted in patients with moderate-to-severe AD of age 12 years or above, with a body weight of 40 kg or more. Both 200 mg and 100 mg doses of abrocitinib demonstrated significant efficacy in improving the signs and symptoms of moderate-to-severe AD compared to placebo. By week 12, a significantly greater proportion of patients in the abrocitinib 100 mg and 200 mg groups achieved an Investigator Global Assessment response and at least a 75% improvement in their Eczema Area and Severity Index scores compared to the placebo group. Notable reductions in pruritus were observed as early as the first post-baseline assessment. The 12-week study highlighted a favorable safety profile for abrocitinib, with no reported cases of venous thromboembolism, malignancy, major adverse cardiovascular events, or deaths.^[6]

Silverberg et al. (October 2020)

This phase 3, double-blind, placebo-controlled, parallel-group randomized clinical trial involved patients aged 12 years and older who had moderate-to-severe AD for at least 1 year and an inadequate response to topical therapies administered for a minimum of 4 weeks within the past 6 months. The findings demonstrated that abrocitinib is an effective treatment for AD, with a low incidence of treatment-related adverse effects, making it a promising and safe therapeutic option.^[7]

JADE REGIMEN, Blauvelt et al. (May 2021)

A phase 3 trial investigated the effects of randomized withdrawal of abrocitinib in patients undergoing treatment. This study assessed the necessity of maintaining a consistent dose and the flexibility of the treatment regimen. Patients initially received 200 mg of abrocitinib daily for 12 weeks. Those achieving clear or nearly clear skin then entered a 40-week phase, during which their dose was adjusted to either 200 mg, 100 mg, or a placebo. Patients who experienced an AD flare during this period entered a rescue phase with 200 mg of abrocitinib and a topical treatment to regain disease control. A high rate of relapse was seen with treatment discontinuation but the treatment response seen previously was recaptured with 200 mg of abrocitinib.^[8]

JADE TEEN, Eichenfield et al. (June 2021)

A phase 3 trial was conducted to understand the safety and efficacy of oral abrocitinib in patients between 12 and 17 years of age, with moderate-to-severe AD, not responsive to topical therapy. At week 12, 41.6% in the 100 mg group and 46.2% in the 200 mg group achieved over 75% clearance in dermatitis. 2.1% in the 200 mg group had a serious adverse effect and none in the 100 mg group. The study confirmed that abrocitinib is an effective treatment for AD in adolescents, with a very low incidence of serious adverse effects, consistent with previous results.^[9]

JADE COMPARE, Bieber et al. (October 2021)

The study was a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of two abrocitinib doses in adults with moderate-to-severe AD. Patients were allowed to use more than one topical therapy (low-to-medium potency topical glucocorticoids, topical calcineurin inhibitors, and topical phosphodiesterase 4 inhibitors). Patients 18 years of age or older with at least a 1-year history of AD were included.

The secondary objective was to evaluate and compare the efficacy of abrocitinib, with dupilumab based on reduction in itch at 2 weeks.

Abrocitinib 200 mg or 100 mg once daily had significantly greater reductions in moderate-to-severe atopic compared to placebo at weeks 12 and 16. The 200-mg dose of abrocitinib was superior to dupilumab with respect to relief of pruritus at week 2.

More adverse events were seen with Abrocitinib (Ab) 200 mg dose, compared to the lesser dose. 100 mg of Ab had adverse effects comparable to dupilumab.

The main adverse events with abrocitinib were nausea, acne, nasopharyngitis, and headache.^[10]

JADE EXTEND, Shi et al. (December 2022)

An extended phase 3 study was conducted to assess the effectiveness of abrocitinib in patients who had earlier been treated with dupilumab. After the 12-week study, 76.9% of patients in the 100 mg abrocitinib group who had previously achieved the endpoint with dupilumab also met the endpoint with abrocitinib. Similarly, 83.3% of those in the 200 mg abrocitinib group who initially achieved the endpoint with dupilumab maintained their response. Among patients who did not respond to the initial dupilumab trial, 35.2% in the 100 mg abrocitinib group and 47.2% in the 200 mg group successfully reached the endpoint. These findings demonstrate that abrocitinib is effective in nearly half of the cases where dupilumab was previously ineffective. This could be attributed to abrocitinib’s ability to target cytokines that are more directly involved in the pathophysiology of AD compared to dupilumab.^[11]

JADE EXTEND, Reich et al. (February 2023)

This Phase 3 long-term extension study enrolled patients who had participated in previous abrocitinib trials for AD providing long-term safety information for abrocitinib in a population with a median drug exposure of 10.4 months, where approximately 45% of patients had been exposed to the drug for ≥48 weeks. The most frequent adverse events included nasopharyngitis, AD, nausea, upper respiratory tract infections, acne, increased creatine phosphokinase, and herpes simplex.^[12]

Long-term efficacy data showed:

1. Sustained control of AD was seen with abrocitinib without the need for concomitant topical medications.

2. A significant proportion of patients who did not meet formal response criteria by week 12 showed clinically meaningful improvements by week 24.

Serious adverse effects occurred in 7% of patients receiving abrocitinib 200 mg and 5% of those on 100 mg, with study discontinuation in 9% and 7% of patients receiving 200 mg and 100 mg, respectively.

Alopecia areata (AA)

In AA, there is a T-cell-mediated autoimmune destruction of hair follicles with resultant nonscarring patchy hair loss. The extent of involvement varies in the patient and may be restricted to the scalp or involve other hair-bearing areas. The condition carries significant detriment to the patient’s psychological health.

Tofacitinib, a JAK 1 and JAK 3 inhibitor, has been increasingly popular in the treatment of AA. Several case reports and case series have reported successful treatment of AA and alopecia universalis with abrocitinib at 100 mg daily and 200 mg daily doses.

In comparison to other dermatological conditions, a long median time to complete resolution (about 10 months) was noted in AA.^[13-15]

Lichen sclerosus (LS)

LS is a non-specific inflammatory genital dermatosis, and a key regulator is interleukin (IL)-6 which has a pro-inflammatory role. It has been hypothesized that LS has more of an autoimmune disease with a preferable Th1 immune response and increased expression of proinflammatory cytokines specific to Th1-interferon (IFN) gamma-induced immune response. Abrocitinib, as an inflammatory agent, also is considered to reduce the release of IL-6.

A demonstrable effective response was seen in a 50-year-old male with plasma cell balanitis and LS where there was complete remission within 1 month of abrocitinib 100 mg daily.^[16]

Abrocitinib was also used in 10 patients, 7 females, and 3 males, mean age 35.4 years, who had been treated with different topical agents for LS and had an inadequate response. They were given a 100 mg daily dose of abrocitinib, which was continued for 4 months after all patients showed good outcomes. One patient developed dyslipidemia and had a fall in their platelet count at the end of the treatment period. The rest showed no adverse effects.^[17]

Pyoderma gangrenosum (PG)

Abrocitinib has been effectively used in a 16-year-old male with perianal PG. After worsening symptoms with doxycycline, isotretinoin, oral steroids, and cyclosporine A, the patient was started on abrocitinib 100 mg daily. Improvement was seen within a week, and within a month, the ulcer size reduced significantly, with alleviation of swelling and discharge. During the 4-month follow-up period, further improvement was maintained.^[18]

Livedoid vasculopathy (LV)

In a 31-year-old female with LV for over 2 years, when adequate response was not seen with glucocorticoids, thalidomide, hydroxychloroquine, doxycycline, or cyclosporine, the patient was started on 100 mg abrocitinib. There was rapid improvement in pain, swelling, and ulceration with complete remission in 6 weeks.

During the next 12-week follow-up period, when the dose was tapered to 100 mg once every 2 days, there was no recurrence. No adverse effect was noted.^[18]

Hidradenitis suppuritiva (HS)

In a 17-year-old male, with axillary HS with recurrent inflammatory lesions over the 3-year duration, minimal resolution was seen despite prolonged medical and surgical treatment. Following such a poor clinical outcome, the patient was started on abrocitinib at 100 mg once daily.

With treatment, there was a significant reduction in the pain and size of abscesses. Excellent improvement was seen in 2 weeks, and the drug was continued for 6 weeks, then reduced to a dose of 100 mg every 2 days. No lesions were reported during a follow-up period of 10 weeks.^[18]

Lichenoid amyloidosis

Significant lesional improvement with symptomatic betterment was seen in 2 patients (53-year-old female and 59-year-old female) with daily abrocitinib 100 mg on treatment for 2–4 months, and sustained improvement was seen when the drug was tapered to once in 2–3 days.^[19]

Porokeratosis

Abrocitinib has been effective in the treatment of eruptive pruritic papular porokeratosis with rapid resolution of pruritus. Increased IL-31 cells are seen in the lesional skin. Dysregulated keratinocyte proliferation also causes a Th2 inflammatory response which further upregulated IL-31. Abrocitinib through JAK1 blockage inhibits IL-31 by over 85%. In a 75-year-old male with porokeratosis for 60 years, rapid relief in itching was seen in 24 hours followed by subsidence of skin lesions within 30 days of treatment.^[20]

Hailey–Hailey disease (HHD)

HHD is a rare genodermatosis with a mutation in the ATP2Cl gene that causes impaired Ca+2 transport signaling. It presents as painful erythematous, blistering skin at sites of friction, that will then erode with crusting, scaling, and hypertrophic vegetative growths. The primary skin barrier defects in HHD lead to cytokine-mediated secondary Th2 inflammation. The use of JAK inhibitors inhibits the Th2- mediated IL-4 and IL-13 signaling, which also helps in Ca+2 mobilization in keratinocytes.^[21]

A 41-year-old male with HHD was successfully treated with 4 weeks of abrocitinib 100 mg daily.^[22]

Necrobiosis lipoidica

A 53-year-old female with extensive NBL for over 10 years, treated previously with steroids, calcineurin inhibitors, psoralens, and hydroxychloroquine, was treated with oral abrocitinib. Treatment was started with 200 mg abrocitinib once daily for 11 months.^[23]

Vitiligo

Vitiligo is due to the autoimmune destruction of melanocytes by self-reactive CD8+ T lymphocytes. CD8+ T cells produce IFN gamma which then causes JAK-STAT phosphorylation. JAK inhibitors, both in topical form (ruxolitinib 1.5%, tofacitinib 2%, ifidancitinib 0.46%, delgocitinib) and oral form (tofacitinib, baricitinib), have proven to be effective in treatment.^[1]

A 61-year-old male with active acrofacial vitiligo, inadequate response to topical tacrolimus 0.1%, was treated with 100 mg daily abrocitinib and had significant repigmentation. After 2 months, there was no recurrence of the patches, and was successfully maintained on topical Tacrolimus, with repigmentation developing 4 months after abrocitinib stoppage.^[24,25]

In a case series, Xu et al. treated 11 patients of refractory progressive vitiligo, between 26 and 59 years of age (mean age 35.9 years, mean disease duration 17.7 years) – 2 males and 9 females – with Abrocitinib 100 mg daily for 16 weeks. Favorable clinical outcomes were seen in all, with disease stability achieved. 10 patients continued treatment with 100 mg every alternate day for 2 months, along with narrow-band ultraviolet B therapy. Headache, dizziness, and nausea were noted in 3 patients.^[26]

Oral lichen planus (LP)

LP is an inflammatory condition with T-cell-predominant lymphocytic reactions. Reticulated white patches are seen over the oral mucosa associated with burning or increased gustatory sensitivity in oral LP.

JAK-STAT cytokines have been proposed to play a definitive role in disease pathogenesis. JAK inhibitors have demonstrated effectiveness in the treatment of oral LP, including tofacitinib, baricitinib, and upadacitinib.^[26]

A 58-year-old male, who had failed to show effective response to other immunosuppressants, responded well to abrocitinib 200 mg once daily for 7 days, followed by 100 mg daily, with improvement in 3 months.^[27]

Allergic contact dermatitis (ACD)

ACD is a delayed type IV hypersensitivity reaction where diffuse eczematous lesions manifest within hours to days after exposure to a contact allergen.^[28] Complete clearance was reported in a 37-year-old male with ACD to Compositae species, where 100 mg abrocitinib was given daily for 8 weeks.^[29]

Nipple and areola eczema

Nipple eczema is seen in patients with AD, with a pathogenic role of the same Th2 inflammatory pathways. A 28-year-old male, recently recovered from severe acute respiratory syndrome coronavirus 2 infection, with background atopy, presented with complaints of nipple eczema. Dermatitis had limited response to emollients, steroids, calcineurin inhibitors, and phototherapy. He was started on 100 mg abrocitinib once daily and pruritus reduced remarkably within 24 hours. Treatment was continued for 12 weeks and the lesions completely cleared. No relapse was seen in 3 months after treatment cessation.^[30]

Prurigo nodularis (PN)

PN occurs with hyperplasia of intraepidermal neuronal fibers with proinflammatory cytokine release such as IL-4, IL-17, IL-22, and IL-31. An increase in expression of STAT 3/6 has been seen in lesional biopsies which underline the therapeutic role of JAK-STAT inhibitors. Tofacitinib and baricitinib have been demonstrated to be useful in the treatment of PN.^[31]

A 62-year-old female, with a 2-year history of PN, had complete resolution with 2 months of 100 mg abrocitinib and topical ruxolitinib, triamcinolone, and crisaborole. Unsatisfactory responses had been seen with dupilumab.^[32]

Hand eczema

Eczema of the hands is a chronic and recurrent dermatoses that significantly affect the quality of life. JAK inhibitors are considered beneficial in the treatment of hand eczema. In a case series of 12 patients, 7 males and 5 females, mean age 46.3 ± 14.1 years, abrocitinib 100 mg once daily was administered and significant improvement was seen at week 16, with over 90% clearance in the lesions. 7/12 patients experienced adverse effects including nausea, headache, dizziness, and blurred vision – none of which required stoppage of the drug.^[33] Other similar instances of abrocitinib use include a case of refractory hand and feet eczema treated successfully,^[34] and a series of 17 patients, of which 13, showed over 90% clearance by week 16.^[35]

Pruritus of unknown origin

Chronic pruritus of unknown origin or CPUO is a condition where there is persistent itching for over 6 weeks, without any identifiable cause. It involves both local and systemic type 2 inflammation which targets the type 2 cytokines (IL-4 and IL-13) thereby causing itch sensation over the sensory neurons. Dupilumab has been used to treat CPUO successfully. Kwatra et al. reported a case series wherein 10 patients with CPUO were treated with 200 mg abrocitinib once daily for 12 weeks, and all had favorable clinical outcomes. However, 2/10 patients developed mild adverse effects including scalp folliculitis, acneform eruptions, and herpes labialis.^[35]

Netherton syndrome

Netherton syndrome is a genodermatosis involving the skin, hair, and immune system. An underlying increase in serum immunoglobulin E levels and hypereosinophilia is seen, which is similar to AD. It is regulated by activated kallikreins which are serine proteases that cause overexpression of proallergic and proinflammatory cytokines. Persistent increased levels of kallikrein 5 induce an overexpression of proinflammatory Th2 and Th17 activity.^[36,37]

A 28-year-old female with Netherton syndrome was treated with dupilumab but had a recurrence of lesions. She was switched to abrocitinib, and there was rapid and complete clearance in 3 weeks with 200 mg daily for 1 week. Since the patient complained of nausea and lightheadedness, it was tapered to 100 mg daily.^[38]

Previous treatment included steroids, methotrexate, cyclosporine, and secukinumab.

Table 3 gives an overview of the various dermatoses in which oral abrocitinib has been used with the clinical outcome and observed adverse effects.^[39-55]

Cost of treatment

The upfront price of abrocitinib is presumably more than other drugs for moderate-to-severe AD, but treatment with abrocitinib has shown that it saves 11000–13000 dollars annually per patient while factoring in the finances saved through reduction in doctors’ visits and improved work quality of life. Overall, this increases the cost-effectiveness of abrocitinib in moderate-to-severe AD.