Baricitinib for the Treatment of Alopecia Areata

Baricitinib selectively inhibits JAK1 and 2 [29]. Baricitinib exhibited 100-fold selectivity for JAK1 and JAK2 over JAK3. The lower affinity for JAK3 could potentially decrease the immunosuppressive effects expected as a consequence JAK3 inhibition [30]. Baricitinib has an oral bioavailability of approximately 80%. Metabolism is mainly carried out via CYP3A4 [31].The half-life is approximately 12 h. Approximately 75% of the drug is eliminated via urine and 20% via feces. Of the drug eliminated, 69% is unchanged in urine and 15% in feces [29].

Baricitinib is currently approved for the treatment of moderate to severe rheumatoid arthritis (2017/2018, EMA [32] and FDA [33], respectively), moderate to severe atopic dermatitis (2020, EMA [34]), and more recently coronavirus disease 2019 (COVID-19) in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (2022, FDA [35]). In May and June 2022, baricitinib was approved for severe alopecia areata by the EMA [20] and FDA [19], respectively.

3.1 Phase 2 Trials3.1.1 Clinical Efficacy

BRAVE-AA1 (NCT03570749), a phase 2/3 adaptive, placebo (PBO)-controlled, double-blind trial, evaluated the efficacy and safety of oral baricitinib in patients with AA who had ≥ 50% scalp hair loss. A total of 110 patients were randomized 1:1:1:1 to receive baricitinib 1 mg (28 patients), 2 mg (27 patients), or 4 mg (27 patients) once daily (OD) or placebo (28 patients). The trial had two interim analysis after all patients completed 12/16 weeks and 36 weeks of treatment or early discontinuation. The first interim analysis (12/16 weeks) aimed to identify two doses of baricitinib to advance to a second phase 3 trial (BRAVE-AA2) and study’s phase 3 part, and the second analysis to assess the drug's efficacy and safety [36]. More detailed information can be found in Table 1.

Table 1 Baricitinib results in the treatment of AA

The trial included patients with severe AA [Severity of Alopecia Tool (SALT) score of 50–94% of scalp hair loss] or very severe AA (SALT score 95–100%), aged ≥ 18 to ≤ 70 years and ≥ 18 to ≤ 60 years for women and men, respectively, and with a current episode of AA lasting > 6 months to < 8 years, with no spontaneous improvement (≤ 10 point reduction in SALT score) in the past 6 months or lasting > 8 years, but with regrowth episodes in the previous 8 years. Different age limits were set due to differences in the severity and prevalence of androgenetic alopecia (AGA) between the sexes [36].

Patients with “diffuse” AA or other types of alopecia, patients who received topical corticosteroids or topical JAK inhibitors 1 and 4 weeks, respectively, before the start of the study, or intralesional, systemic corticosteroids, or oral JAK inhibitors 8 weeks before randomization, were excluded. During the trial, no other treatments for AA were allowed [36].

In the first interim analysis, the proportion of patients who achieved a ≥ 30% baseline improvement in SALT score (SALT30) at week 12 or ≥ 50% baseline improvement in SALT score (SALT50) at week 16 was used in the decision on the two doses. The primary endpoint in the second interim analysis was the proportion of patients who achieved a SALT score ≤ 20 at week 36 [36].

At week 12, 33.3%, 29.6%, 17.9%, and 10.7% of patients achieved a SALT30 when treated with baricitinib 4 mg, 2 mg, 1 mg, and placebo, respectively. Of patients who completed 16 weeks or discontinued earlier (87 patients), SALT50 response was achieved by 31.8%, 38.1%, 18.2%, and 4.5% patients treated with baricitinib 2 mg (P = 0.057 versus PBO), 4 mg (P = 0.036 versus PBO), 1 mg, and placebo, respectively. On the basis of the results presented, the 2 mg and 4 mg doses were selected for phase 3 studies. Patients on baricitinib 1 mg were transferred to the baricitinib 4 mg group but were not included in subsequent analyses [36].

At week 36, a significantly higher proportion of patients achieved a SALT ≤ 20 in the baricitinib 4 mg and 2 mg group compared with PBO (51.9%, 33.3% versus 3.6%, P = 0.016 and P = 0.001, respectively). Patients treated with baricitinib 4 mg and 2 mg had a significantly greater percent change from baseline in SALT score (least square mean ± standard error) than PBO (− 58.1 ± 7.8, P < 0.001; − 48.2 ± 7.9, P < 0.001; and − 11.7 ± 7.8; respectively). The SALT 10 score was achieved significantly higher in patients in the baricitinib 4 mg (40.7%, P = 0.008) and baricitinib 2 mg (25.9%, P = 0.046) group compared with the PBO (0%). SALT50, SALT75, SALT90, and SALT100 responses were significantly higher in patients treated with baricitinib 4 mg compared with PBO. The more detailed results can be found in Table 1 [36].

3.1.2 Safety

The most frequently observed adverse events (AEs) in patients taking baricitinib were nausea, acne, and upper respiratory tract infection. Treatment-emergent adverse events occurred in 77.8%, 70.4%, and 60.7% of patients on baricitinib 4 mg, 2 mg, and PBO, respectively. In none of the treated groups was there a serious adverse event or death. No thromboembolic events, malignancies, serious infections, or major adverse cardiovascular events were observed [36].

3.2 Phase 3 Trials3.2.1 Clinical Efficacy

BRAVE-AA1 (NCT03570749) and BRAVE-AA2 (NCT03899259) are parallel-group, randomized, double-blind, 36-week, placebo-controlled trials that included 654 and 546 patients, respectively [17]. BRAVE-AA1 was an adaptive phase 2–3 trial as indicated earlier, but the results of the phase 3 part are included here (Table 1). The trials have the same eligibility criteria (already mentioned above) and primary and secondary endpoints. The primary outcome was a SALT score of 20 or less at week 36. Patients were randomized in a 3:2:2 ratio to receive oral baricitinib 4 mg, 2 mg, or placebo OD for 36 weeks [17].

At week 36, the percentage of patients achieving a SALT20 score was 38.8%, 35.9% in the baricitinib 4 mg group, 22.8%, 19.4% in the baricitinib 2 mg group, and 6.2%, 3.3% in the PBO group, in BRAVE-AA1 and BRAVE-AA2, respectively [17]. In BRAVE-AA1 and BRAVE-AA2, the difference between the baricitinib 4 mg group and the PBO group was 32.6 percentage points in both studies [95% confidence interval (CI) 25.6–39.5 and 25.6–39.6, respectively], and the difference between baricitinib 2 mg and placebo was 16.6 and 16.1 percentage points, respectively (95% CI 9.5–23.8 and 9.1–23.2, respectively) (P < 0.001 for each dose versus placebo in both studies) [17]. The results of the baricitinib 4 mg treated group were significantly superior compared with placebo in all the outcomes within the graphical test scheme, in BRAVE-AA1 [37]. In BRAVE-AA2, the baricitinib 4 mg group also differed significantly compared with the placebo, except for SALT10 at week 24 and the two subsequent secondary endpoints. In BRAVE-AA1, the graphical test procedure failed at SALT20 at week 16 in patients on baricitinib 2 mg and a ClinRO Measure for Eyelash Hair Loss score of 0 or 1 with a decrease of at least 2 points from baseline at week 36 did not pass the graphical test scheme. Meanwhile, in BRAVE-AA2, the baricitinib 2 mg group failed the graphical test procedure on the ClinRO measure for eyebrow hair loss at week 36. Additionally, the results of the eight subsequent outcomes did not differ significantly compared with the PBO [17].

Data from the long-term extension periods of BRAVE-AA1 and BRAVE-AA2, after 52 weeks, have recently been published. At 52 weeks, an increase in the proportion of patients achieving a SALT score ≤ 20 and a SALT score ≤ 10 was shown, most pronounced in patients on baricitinib 4 mg. SALT score ≤ 20 was achieved in 21.2% and 24.4% of patients under baricitinib 2 mg and 40.9% and 36.8% under baricitinib 4 mg in BRAVE-AA1 and BRAVE-AA2, respectively. SALT ≤ 10 was achieved in 14.1% and 16.7% of patients under baricitinib 2 mg and 29.9% and 27.8% under baricitinib 4 mg in BRAVE-AA1 and BRAVE-AA2, respectively [38]. Over the 52-week period, the trials also showed that eyebrow and eyelash response rates increased. At week 52, 27.9% and 16.3% of patients with baseline ClinRO Measure for Eyebrow Hair Loss scores of 2 or 3 had an improvement ≥ 2 points and a ClinRO Measure for Eyebrow Hair Loss score of 0 or 1 on baricitinib 2 mg and 39.4 % and 49.7% of patients on baricitinib 4 mg, in BRAVE-AA1 and BRAVE-AA2, respectively. At week 52, 21.6% and 30.3% of patients with baseline ClinRO Measure for Eyelash Hair Loss scores of 2 or 3 had an improvement ≥ 2 points and a ClinRO Measure for Eyebrow Hair Loss score of 0 or 1 on baricitinib 2 mg and 40.7% and 50.7% of patients on baricitinib 4 mg, in BRAVE-AA1 and BRAVE-AA2, respectively [38].

3.2.2 Safety

In BRAVE-AA1, AEs occurred in 59.6%, 50.8%, and 51.3% of patients treated with baricitinib 4 mg, 2 mg, and placebo, respectively. In BRAVE-AA2, AEs occurred in 68.4%, 66.1%, and 63.0% of patients treated with baricitinib 4 mg, 2 mg, and PBO, respectively. The proportions of patients who discontinued the study regimen due to AEs were low and were similar between study groups [17]. Serious AEs occurred in 2.1%, 2.2%, and 1.6% of patients on baricitinib 4 mg, 2 mg, and PBO, respectively, in BRAVE-AA1, and 3.4%, 2.6%, and 1.9%, respectively, in BRAVE-AA2. In both studies, acne and the incidence of urinary tract infections were more common in the baricitinib-treated groups. At least one infection was seen in 31.4% of patients on baricitinib 4 mg, 25.1% on baricitinib 2 mg, and 28.0% on PBO in BRAVE-AA1, and 29.6%, 37.4%, and 29.2% under baricitinib 4 mg, 2 mg, and PBO, respectively, in BRAVE-AA2 (Table 1). Herpes zoster infections occurred in 0.7%, 0.5%, and 0.5% of patients on baricitinib 4 mg, 2 mg, and PBO, respectively, in BRAVE-AA1, and 1.3%, 1.9%, and 0.6%, respectively. respectively, in BRAVE-AA2. All herpes zoster infections were localized [17]. There were no opportunistic infections, venous thromboembolic events, or gastrointestinal perforations in any of the studies. In BRAVE-AA1, a patient with cardiovascular risk factors suffered a myocardial infarction on baricitinib 2 mg. In BRAVE-AA2, one case of prostate cancer was reported in a patient on a PBO and one case of B-cell lymphoma in a patient on baricitinib 4 mg [17]. In BRAVE-AA1, one patient with a history of gastrointestinal bleeding experienced grade 4 anemia (defined as a hemoglobin level < 6.5 g/dl) when treated with baricitinib 4 mg and had to discontinue the study. In both studies, elevated levels of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol were observed in approximately 25% and 40% of baricitinib-treated patients, respectively [17]. The recently published 52-week data showed that the most frequent treatment-emergent AEs included headache, upper respiratory tract infection, nasopharyngitis, urinary tract infection, COVID-19 infection, acne, and creatine phosphokinase elevation. The frequency of discontinuations due to AEs was low and similar between groups. During the BRAVE-AA1 extension phase, there was one case of herpes zoster, COVID-19, and appendicitis on baricitinib 4 mg, all patients recovered, and none discontinued. During the BRAVE-AA2 extension period, a COVID-19 infection in one patient on baricitinib 4 mg led to study discontinuation. In BRAVE-AA1, squamous cell carcinoma and ductal carcinoma in situ were reported after 16 months and 10 months in a patient on baricitinib 2 mg and 4 mg, respectively. No opportunistic infections, tuberculosis, venous thromboembolism (VTE), gastrointestinal perforations, or deaths were reported in any of the studies during the extension period. Most laboratory changes were similar between the baricitinib groups in both studies and similar to those reported in the 36-week data [38].

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