The Evolving Story of JAK Inhibitors for Treating Alopecia Areata: A Review of Current Progress and Future Directions

Jeff Donovan, MD, FRCPC, PhD

Donovan Hair Clinic, Whistler, BC, Canada
Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Conflict of interest: Jeff Donovan has received honoraria from Pfizer, maker of abrocitinib, tofacitinib and ritlecitinib.

Abstract:
Oral Janus kinase (JAK) inhibitors now have a position as first-line agents for treating advanced alopecia areata. Oral JAK inhibitors are considerably more effective than topical JAK inhibitors, although topical agents may still have a valuable role for specific subgroups of patients. The US FDA approval of baricitinib in 2022 was an important milestone. Numerous JAK inhibitors are now being intensely studied for use in alopecia areata and several additional medications may also become approved in the near future. Accumulating clinical trial data points to a generally good safety profile for JAK inhibitors when used for patients with alopecia areata. However, long-term data pertaining to the safety and efficacy in this patient population are lacking.

Keywords: alopecia areata, cytokines, hair loss, Janus kinase inhibitors, JAK inhibition

Introduction

The treatment of advanced forms of alopecia areata (AA) is more challenging than the milder forms and patients with advanced AA often require systemic therapy in order to regrow hair. Since the introduction of Janus kinase (JAK) inhibitors to the world over a decade ago, these agents have risen to the top of the treatment ladder to become a bona fide first-line therapeutic option for severe AA.¹ The US FDA approval of baricitinib on June 13, 2022 marked an important new chapter in the field of AA.²

The Janus Kinase (JAK) Pathway

The JAK pathway is an intracellular signaling pathway that mediates the effects of many different pro-inflammatory signaling molecules.³ The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway consists of three main components: 1) the cell surface receptor, 2) the intracellular JAK and 3) the downstream regulatory signals of JAKs known as STAT. There are four members of the JAK family: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Current JAK inhibitor medications block one, two, three or all of the JAK enzymes. JAK1, JAK3 and TYK2 have a role in mediating signals in a wide range of inflammatory disorders. JAK2 not only mediates signals related to inflammation but also mediates signals for a range of inflammatory cytokines that involve hematopoiesis. Newer JAK inhibitors that lack the ability to inhibit JAK2 are of particular interest as they may have fewer hematologic side effects.

Clinical Studies of JAK Inhibitors: Pre-FDA Approval Era

Initial studies in 2014 using mouse models of AA revealed that JAK-STAT signaling had a key role in the development of autoreactive CD8+ T-cells targeting the hair follicle.⁴ These studies also confirmed that use of JAK inhibitors promoted hair regrowth in affected animals and more revolutionary – also in humans affected by AA. Three patients with AA treated with oral ruxolitinib experienced near complete hair growth after 5 months of treatment.⁴

In 2014, a second JAK inhibitor, tofacitinib, was reported to be helpful for treating AA in humans.⁵ A patient presenting with both plaque psoriasis and advanced AA exhibited complete regrowth of scalp hair after 3 months of treatment and full regrowth of all body hair after 8 months of treatment.⁵

Since 2014, there have been many case reports, retrospective case series, open label trials and randomized control trials (RCT) reporting the benefits of JAK inhibitors for some, but not all, patients with various types of AA. Most of the larger RCTs have studied JAK inhibitors for patients with severe AA (currently defined as ≥50% scalp hair loss).

Meta-analyses Confirm Efficacy of JAK Inhibitors

In 2019, Phan and Sebaratnam performed a systematic review and meta-analysis examining the benefits of JAK inhibitors for treating AA.⁶ Studies of tofacitinib, ruxolitinib and baricitinib from 30 studies and 289 patients were included in the analysis. A good response was defined as 50-100% hair growth and a partial response was defined as 5-50% hair growth. The proportion of patients achieving a good response was 45.7% and the proportion of patients with partial responses was 21.4% The mean time to initial hair growth was 2.2 ± 6.7 months. Children and adults treated with JAK inhibitors appeared to benefit in a similar manner.

More recently, Yan et al.⁷ performed another systematic review and meta-analysis. They included 14 studies (5 RCTs and 9 non-RCTs) from 1845 patients. A good response was defined as the achievement of Severity of Alopecia Tool score of 50% improvement (SALT50) and a complete response was defined as a SALT90 (90% improvement in SALT score compared with baseline). The SALT is the severity of alopecia tool score and ranges from 100 in the case of complete hair loss to 0 in the case of complete hair regrowth.

In the RCT data examining baricitinib and the experimental JAK inhibitors brepocitinib and ritlecitinib, oral JAK inhibitors were found to have a better response rate compared to controls, although topical JAKs did not perform better than controls. When evaluating the non-RCT data involving tofacitinib and ruxolitinib, pooled data showed a good response in 63% of patients using oral JAKs and in 28% of those using topical JAKs. Overall, the Yan et al. study suggested that oral JAK inhibitors can be expected to help patients reduce SALT scores by an average of 30-50%.⁷ It appears that all of the currently studied JAK inhibitors are fairly similar in effectiveness although this may change as more data accumulates and newer JAK inhibitors are studied. Data on JAK inhibitors also showed that many patients lose hair again when they reduce or stop treatment. Many studies have shown that relapses occur within 3 months after stopping treatment.^6,8,9-11

The FDA Approval of Baricitinib

Orally administered baricitinib is a reversible and selective JAK1 and JAK2 inhibitor. The FDA approval of baricitinib on June 13, 2022 marked an important landmark date in the field of AA.

It was the pivotal phase 3 trials of baricitinib that ultimately supported the drug’s FDA approval.¹² The two trials, termed BRAVE-AA1 and BRAVE-AA2, included 654 and 546 patients, respectively. Each trial randomly assigned patients with severe AA to daily treatments consisting of either placebo, 2 mg or 4 mg of baricitinib, with the primary outcome being the percentage of patients achieving a SALT score of ≤20. The average baseline SALT score in these studies was approximately 85 indicating that a large proportion of patients with advanced AA were included in these trials. After 36 weeks of treatment, the primary outcome was achieved by 35.9-38.8% of patients in the 4 mg group, 19.4-22.8% in the 2 mg group, and 3.3-6.2% of placebo patients.

Extended follow-up data from patients in the BRAVE-AA1 and BRAVE-AA2 trials using continuous therapy through 52 weeks (1 year) showed that the 4 mg group had 36.6-40.9% of patients achieve a SALT score of ≤20, while the 2 mg group had 21.1-24.4%.¹³

Longer Term Baricitinib Data

Senna et al.¹⁴ recently presented longer term data on the efficacy of baricitinib in patients with severe AA following 104 weeks (2 years) of continuous therapy. Several findings are particularly important to note. First, some patients were not able to maintain their good 52 week results and lost hair between weeks 52 and 104. About 10-20% of patients who met the SALT ≤20 cut off at week 52 experienced slight hair loss in the second year of treatment. These patients did not meet the SALT ≤20 cut off at week 104 despite meeting the target at week 52. Therefore, good results are not maintained in all AA patients treated with baricitinib.

Second, a small proportion of patients experience good regrowth in the first 4-10 months after starting baricitinib and then lose some amount of hair as the 1 year mark approaches.¹⁴ These patients are called “mixed responders”. Mixed responders are more likely to be patients that have a longer duration of AA and more likely to have more severe hair loss at the start of treatment. It is evident from these results that a small proportion of patients with severe AA or longer duration AA will experience confusing and frustrating periods of hair regrowth followed by hair loss while using baricitinib. About 40% of mixed responders end up growing back hair and achieving a SALT ≤20 score at week 104, but 60% of mixed responders do not achieve this density again. Therefore, not all AA patients who experience hair loss after a period of good regrowth will recapture their hair density even with a longer duration of treatment.

Third, the 104 week data showed that further improvements in eyebrow and eyelash density can be expected from week 52 to week 104.¹⁴ Patients with AA using baricitinib can be advised that the eyebrow and eyelash density they achieve at week 52 are not necessarily representative of the final density they will achieve.

Baricitinib was generally well-tolerated in the BRAVE-AA1 and BRAVE-AA2 trials. In data recently presented by King and colleagues,¹⁵ there were no new safety signals with the 104 week data. Among 1303 patients with alopecia studied on 2 mg and 4 mg doses to date (with a mean 1.6 years of evaluation), serious adverse events occurred in 5% of patients. Serious infections occurred in 1.2% of patients. One case of a major cardiac adverse event (MACE), 1 deep vein thrombosis/pulmonary embolism (DVT/TE), 2 nonmelanoma skin cancers, 5 malignancies other than non-melanoma skin cancer (including B cell lymphoma, breast cancer, chronic lymphocytic leukemia, malignant melanoma and melanoma in situ) and 1 case of gastrointestinal perforation were documented in the trials, but were adjudicated to be unrelated to the study drug. There was 1 DVT that was felt to be related to the drug. There were no deaths.

Overall, COVID-19, upper respiratory tract infections (URTI), headache, acne, urinary tract infections (UTI) and increases in creatinine phosphokinase (CPK) were the most commonly reported adverse events. Extended study data showed that 18% of patients receiving 4 mg had elevation of low-density lipoprotein (LDL) cholesterol, 5% had elevation of CPK, 2.3% had elevated alanine aminotransferase (ALT) and herpes zoster occurred in 1.6%.¹⁵

Baricitinib is now marketed in the US under the trade name Olumiant™. The recommended dosage is 2 mg once-daily. Patients are recommended to increase the dosage to 4 mg once-daily if treatment response is not adequate. For patients with nearly complete or complete scalp hair loss, the recommended starting dose is 4 mg once-daily rather than 2 mg once-daily.

New Directions with Baricitinib

The FDA approval of baricitinib marks the beginning, rather than the end, of rigorous study for the use of this medication in patients with AA. In the years to come, the number of patients using these medications will dramatically increase. In addition to better understanding the long-term risks and benefits, we will also gain further insight if any particular patient subgroup can actually reduce the dose of the JAK inhibitor once full regrowth is achieved.

Despite the well-known risk of hair loss when doses of JAK inhibitors are reduced and despite the possibility that some patients with AA who do lose hair do not regrow hair back when they increase the dose again, the baricitinib product monograph indicates that patients using 4 mg “reduce the dose to 2 mg once-daily when an adequate response has been achieved.” This may be poor advice for some patients with AA. Various JAK inhibitor studies, for example, have suggested that patients who decrease their JAK inhibitor dose and then experience hair loss are not always able to regrow back hair to the exact same high density after restarting treatment.¹⁶ This also appears to be the case for patients using baricitinib. For example, King and colleagues¹⁷ recently evaluated the effect of reducing baricitinib from 4 mg to 2 mg in patients who achieved a SALT ≤20 cut off score at week 52. About one-half of patients (52.4%) who reduced from 4 mg to 2 mg were able to maintain a SALT ≤20 density. However, the remaining 47.6% of patients lost hair and no longer maintained sufficient hair density to meet the SALT ≤20 cut off. The risk of hair loss seems too great to follow the recommendations of the product monograph in every patient.

Furthermore, it is clear that reducing the baricitinib dose with a plan to simply resume the 4 mg dose if hair loss occurs, does not come with a guarantee that the patient will eventually get their hair back again. Recent studies in 7 patients who lost hair following a baricitinib dose reduction showed that 5 patients (71.4%) were able to regrow hair and once again achieve a SALT ≤20 after 36 more weeks of follow up.¹⁷ Two of the 7 patients (28.6%), however, did not get back to the SALT ≤20 density they once had.

More studies are needed before universally recommending dose reductions in all patients once full hair regrowth is achieved. It is possible that the recommendations for dose reductions found in the current baricitinib product monograph will be modified over time. If not, it is possible that they may be ignored if the standard of practice among hair loss experts ultimately moves in the direction of maintaining a large proportion of patients on a 4 mg dose once full regrowth occurs.

Finally, it is possible that the definition of severe AA may change over time. As reviewed above, baricitinib received FDA approval for patients with severe AA, defined as patients with ≥50% loss of scalp hair. It is increasingly recognized, however, that using scalp hair coverage alone to define “severe” AA is inadequate and excludes a large proportion of patients who fit a more encompassing definition of what constitutes severe AA.¹⁸ A recent expert focus group proposed that one must consider not only the hair density but the pattern of hair loss, location of hair loss, nail involvement, duration, quality of life and prior treatment responses in determining if someone should best be classified as having severe AA. It is possible that the criteria to more broadly define severe AA, and therefore the formal indications for drug approval, could change over time.

Possible New JAK Inhibitor Approvals in the Future

Although the FDA has approved baricitinib for the treatment of advanced AA, a number of new JAK inhibitor drug approvals are possible in the near future, including ritlecitinib and deuruxolitinib.

Ritlecitinib

Ritlecitinib is the first in a new class of kinase inhibitors that have high selectivity for Janus kinase 3 (JAK3) and members of the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family.

The randomized, double-blind ALLEGRO phase 2b/3 study addressed the use ritlecitinib in 718 patients ≥12 years of age with severe AA.¹⁹ Patients were randomized to receive ritlecitinib 50 mg, 30 mg, 10 mg or placebo (with or without 1 month of initial treatment with once-daily ritlecitinib 200 mg, 50 mg, 30 mg, 10 mg or placebo). The primary endpoint was the proportion of patients achieving a SALT score ≤20 at week 24. The study showed statistically greater proportions of patients treated with ritlecitinib 30 mg and 50 mg (with or without a loading dose) achieving this study endpoint compared to placebo. Overall, approximately 22-31% of patents achieved this target at week 24. By week 48 of the study, approximately 35-40% of patients in the higher dosing groups achieved a SALT ≤20.

Ritlecitinib was found to be well tolerated by both adult and adolescent patients. Adverse events (AEs) were experienced by 82% of patients and serious AEs by 2% of patients – with similar rates across the active treatment groups. The most common AEs seen in the ALLEGRO studies were nasopharyngitis, headache, herpes zoster and URTI. There were no MACE, deaths or opportunistic infections. There was one case of pulmonary embolism and two cases of breast cancers in the ritlecitinib 50 mg group. The case of pulmonary embolism and one of the cases of breast cancer were not felt to be related to ritlecitinib treatment. The other case of breast cancer, however, was felt to be related to treatment – this was a 58 year-old female participant diagnosed with breast cancer on day 198.

Both the FDA and European Medicines Agency are reviewing the application for formal approval of ritlecitinib and a decision is expected in 2023.

Deuruxolitinib

Deuruxolitinib (formerly CTP-543) selectively inhibits JAK1 and JAK2. THRIVE-AA1 was a randomized, muliticenter double-blind, placebo-controlled clinical trial involving 706 adult patients aged 18-65 years with severe AA.²⁰ THRIVE-AA2 was similar in design with 517 patients.²¹ Patients were randomized to receive either 8 mg twice-daily or 12 mg twice-daily of deuruxolitinib or placebo for 24 weeks. The primary endpoint was the percentage of patients achieving a SALT score of ≤20 at 24 weeks.

In THRIVE-AA1, the proportion of patients achieving a SALT score of ≤20 at week 24 was 41.5% in the 12 mg twice-daily dose group and 29.6% in the 8 mg twice-daily dose group, compared to 0.8% of patients in the placebo group. The treatment difference for both dose groups, relative to placebo, was statistically significant. In the THRIVE-AA2, the proportion of patients achieving a SALT score of ≤20 at week 24 was 38.3% in the 12 mg twice-daily dose group and 33.0% in the 8 mg twice-daily dose group, compared to 0.8% of patients in the placebo group. The most common side effects were headache, acne, URTI, increased creatine kinase levels, COVID-19 infection and nasopharyngitis.

In early May 2023, the FDA intervened in the clinical trials of deuruxolitinib.²² Specifically, the FDA halted use of deuruxolitinib 12 mg twice-daily in clinical trials on account of a trial participant developing a pulmonary embolism while receiving deuruxolitinib 12 mg twice-daily. The individual was participating in one of the deuruxolitinib long-term open label extension studies. The company recently stated that clinical trial participants receiving 12 mg twice-daily were switched to 8 mg twice-daily.²² Given that there have been no thrombotic events reported to date for 8 mg twice-daily dosing, the FDA has not placed this regimen on hold and clinical trials of the 8 mg twice-daily dose are continuing.

The company developing deuruxolitinib reports that it also intends to utilize this data from the THRIVE-AA1 and THRIVE-AA2 trials as the basis of a New Drug Application submission to the FDA in 2023.

New JAK Inhibitor Clinical Trials and Studies

In the last 8 years, we have progressed from studies of tofacitinib, ruxolitinib and baricitinib to trials that also include ritlecitinib, deuruxolitinib and a variety of other JAK inhibitors. A large number of registered clinical trials of various JAK inhibitors are currently underway (Table 1).

New case reports of selective JAK inhibitors to treat AA are increasingly reported in the literature (Table 2). These JAK inhibitors were developed with the goal to more precisely induce inhibition of JAK pathway components and reduce unwanted AEs. The main benefit of the selective JAK inhibitors is avoiding JAK2 inhibition and the hematologic side effects that come from JAK2 inhibition.

The JAK1 selective inhibitors abrocitinib and upadacitinib were both FDA approved in 2022 for the treatment of moderate to severe atopic dermatitis. Findings are now emerging in case reports of benefits in the treatment of AA.^23-32 Filgotinib, approved in Europe and Japan for treating rheumatoid arthritis, has also recently been reported to help AA.³³ The TYK2 selective inhibitor deucravacitinib is Health Canada and FDA approved for psoriasis and will soon enter a trial for AA. A summary of several JAK inhibitors and their study in AA is summarized in Table 2.

Topical JAK Inhibitors

Topical JAK inhibitors have been studied for off label use in adults and children and for various sites including scalp, eyebrows and eyelashes. Studies pertaining to the benefits of topical JAK inhibitors for treating scalp AA are inconsistent. Some studies suggest a benefit whereas others do not. Even the vehicle selected by the pharmacy to compound the JAK inhibitor can have a dramatic effect on patient outcomes. This only adds to the challenges of fully studying the benefits of topical JAK inhibitors.³⁴

Two recent meta-analyses demonstrated that topical JAK inhibitors are far less effective than oral JAK inhibitors for treating scalp AA.^6,7 The 2022 meta-analysis by Yan et al.⁷ found there was no significant difference in efficacy outcomes between topical JAK inhibitors and placebo when RCT studies were examined. When examining the non-RCT studies, the authors found that topical JAK inhibitors induced minimal hair regrowth but the authors felt that the improvement was too little to be clinically meaningful or to be distinguished from the spontaneous remission and placebo effect. Topical JAK inhibitors may be of more benefit in treating eyebrow loss or eyelash loss than scalp hair loss, although more detailed studies are needed.

JAK Inhibitors for Treatment of Pediatric AA

There are no FDA approved treatments for children with AA and the current FDA approval of baricitinib does not extend to include children or adolescents. New clinical trials are increasingly opting to include adolescents in their study population (Table 1).

Children and adolescents appear to respond to JAK inhibitor treatment just as well as adults.⁶ A meta-analysis by Chen et al.³⁴ examined 10 pediatric studies and 69 patients, reporting 68.5% of patients overall were considered good responders and 7.7% were partial responders. Similar to what is seen in adults, the use of oral JAK inhibitors was linked to a much better response than topical medications. Behrangi et al.³⁵ also published a systematic review and meta-analysis of topical and oral tofacitinib use in pediatric patients. They included observational studies from 59 patients ranging in age from 4-19 years. The meta-analysis showed good/complete response by 55% and 41% experienced partial response. Oral administration was significantly more efficacious than topical application. Even though topical JAK inhibitors seem less effective than oral JAK inhibitors in children, more studies are needed to better define how well they work.

Options for Patients Who Do Not Respond Well to JAK Inhibitors

About 25-30% of patients with advanced AA respond extremely well to JAK inhibitor therapy. However, a significant proportion of patients with severe AA are not able to achieve full regrowth with any of our currently available JAK inhibitors. It remains to be elucidated why some patients do not benefit to the same degree from JAK inhibitors and why others seem to be complete nonresponders. Although patients with extremely long duration of disease (especially more than 10 years) and patients with more advanced disease (alopecia totalis/universalis vs. localized) have lower response rates to JAK inhibitors, other factors are not well understood.

In prior years, the strategy to address poor responses has been to increase the dose of the JAK inhibitor.³⁶ However, data showing an increased risk of thrombosis as well as other side effects with tofacitinib 10 mg twice-daily compared to 5 mg twice-daily has dramatically reduced the tendency of clinicians to use higher doses of JAK inhibitors.

Some studies have suggested that if a patient fails one JAK inhibitor, it can still be worthwhile to switch to another JAK inhibitor drug.³⁷ Finally, it will be important to understand why some patients initially respond to JAK inhibitors and then lose benefits over time. Our current AA clinical trials are not long enough in duration to adequately understand the phenomenon of waning treatment responses. The 104 week baricitinib extension studies discussed above reminds us that there is a significant proportion of patients (i.e., 10-20%) who experience waning of results over time.¹⁴

Long-term Safety

Studies of JAK inhibitors in patients with AA generally point to good safety of these agents. It would appear that the prevalence of specific side effects are fairly similar among various JAK inhibitors when used by AA patients. This may change over time as studies with greater numbers of patients and longer duration are conducted.

The 2019 meta-analysis by Phan et al.⁶ reported JAK inhibitor side effects included URTI (18.2%), UTI (2.2%), lipid abnormalities (11.8%) leucopenia (1%) and transaminitis (1.6%). A 2022 metaanalysis by Yan et al.⁷ reported generally good safety from use of these agents. In RCTs examining the use of baricitinib, ritlecitinib and brepocitinib, there was no significant difference between JAK inhibitors and placebo in the risk of experiencing treatmentemergent AEs, serious AEs, URTI, headache or nasopharyngitis. However, acne was approximately three times more common with baricitinib than with placebo. Yan et al.⁷ showed the highest risk was observed for URTI (37.05%), followed by diarrhea (19.65%), acne (9.31%), UTI (6.98%), headache (6.33%) and folliculitis (4.48%).

The ORAL Surveillance Study

Recent published results from the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance trial have affected the entire JAK inhibitor prescribing community.³⁸

The ORAL Surveillance trial was a randomized trial evaluating the safety and efficacy of tofacitinib as compared with a tumor necrosis factor (TNF) inhibitor in patients with rheumatoid arthritis who were ≥50 years of age and had at least one additional cardiovascular (CV) risk factor. The primary endpoints of the study were the risk of MACE (death from CV causes, nonfatal myocardial infarction, or nonfatal stroke) and cancer. A 33% increase in MACE and 48% increase in cancer was noted in tofacitinib users compared to TNF inhibitors.³⁸

On account of these findings, the FDA has placed new boxed warnings on certain JAK inhibitors used in inflammatory conditions including baricitinib, upadacitinib and tofacitinib and abrocitinib. The boxed warning includes information about the risk for serious infections, mortality, cancer, CV events and thrombosis.

Whether or not the findings from the ORAL Surveillance trial of rheumatoid arthritis patients are directly applicable to patients with AA and whether these findings are broadly applicable to all JAK inhibitors is still unknown.

There is a tremendous amount of work ahead to address all the safety issues related to JAK inhibitors. However, the news for patients with AA appears to be reasonably good based on the short duration clinical studies that have been performed to date. Studies lasting many years, rather than many months, will ultimately be needed. The data from the 104 week baricitinib trials¹⁴ are a step in the right direction to understanding the long-term effects of JAK inhibitors specifically in AA patients.

Conclusion

JAK inhibitors are now a first-line treatment option for patients with advanced AA. This is supported by a several studies including an ever increasing number of well-designed randomized, placebo-controlled trials. Baricitinib represents the first of what will likely be many JAK inhibitors that will be used to treat severe AA. Oral JAK inhibitors are superior to topical JAK inhibitors but a role for topical JAK inhibitors in the management of some aspects of AA treatment (eyebrows, eyelashes, pediatric AA) cannot be excluded. There are still many issues we do not fully understand including the long-term safety and efficacy of JAK inhibitors. Appropriate patient assessment and counselling will not only help identify individuals who may benefit most from these medications but will also help exclude those who may be at risk for side effects (Table 3). These issues will be important for us all to follow in the future.

Purchase Article PDF for $1.99