Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2)

3.1 Patients

Among patients randomized at baseline to baricitinib 4 mg and 2 mg, respectively, 252/281 (89.7%) and 163/184 (88.6%) in BRAVE-AA1 and 209/234 (89.3%) and 134/156 (85.9%) in BRAVE-AA2 completed 52 weeks of study treatment (ESM Fig. S1). The most common reasons for discontinuation in BRAVE-AA1 and BRAVE-AA2 were patient withdrawal (n = 21 and n = 21, respectively), AEs (n = 8 and n = 11, respectively), and loss to follow-up (n = 11 and n = 9, respectively).

Baseline characteristics were comparable across baricitinib groups in both trials (Table 1). For patients randomized to baricitinib in BRAVE-AA1 and BRAVE-AA2, respectively, mean age was 37.0 and 38.4 years, 58.9% and 63.3% were female, and mean SALT scores at baseline were 85.9 and 85.1. For ClinRO Measures for Eyebrow Hair Loss and Eyelash Hair Loss, respectively, 69.7% and 59.8% in BRAVE-AA1 and 67.9% and 58.7% in BRAVE-AA2 had scores of 2 or 3 (significant gaps or no notable hair) at baseline.

Table 1 Baseline demographics and clinical characteristics3.2 Efficacy

The proportions of patients achieving SALT score ≤ 20 continuously increased over the treatment period, with response rates for patients treated with baricitinib 4 mg and 2 mg, respectively, reaching 40.9% and 21.2% in BRAVE-AA1 and 36.8% and 24.4% in BRAVE-AA2 at Week 52 (Fig. 1, ESM Table S1). Among patients with severe baseline disease (SALT score 50–94) treated with baricitinib 4 mg and 2 mg, respectively, a SALT score ≤ 20 was achieved in 55.6% and 36.4% in BRAVE-AA1 and 46.1% and 35.7% in BRAVE-AA2. Among patients with very severe disease at baseline (SALT score 95–100) in the baricitinib 4 mg and 2 mg groups, respectively, 27.7% and 10.3% in BRAVE-AA1 and 27.7% and 15.1% in BRAVE-AA2 achieved a SALT score ≤20.

Fig. 1figure 1

Proportions of patients achieving SALT score ≤20 through Week 52 in a BRAVE-AA1 and b BRAVE-AA2. A SALT score ≤20 indicates ≤20% scalp hair loss. Bars represent 95% confidence intervals. Non-responder imputation was applied to missing data (prespecified analysis). Week-36 data points reflect results from the placebo-controlled period. SALT Severity of Alopecia Tool

In the baricitinib 4 mg and 2 mg groups, respectively, 29.9% and 14.1% in BRAVE-AA1 and 27.8% and 16.7% in BRAVE-AA2 achieved a SALT score ≤ 10 (ESM Table S1). With the baricitinib 4 mg and 2 mg doses, respectively, SALT50 was achieved at Week 52 in 52.0% and 31.0% in BRAVE-AA1 and 52.6% and 37.2% in BRAVE-AA2; 28.5% and 11.4% in BRAVE-AA1 and 26.1% and 14.1% in BRAVE-AA2 achieved SALT90 at Week 52 (ESM Table S1). Representative photographs of patients who responded to baricitinib in BRAVE-AA1 are presented in Fig. 2.

Fig. 2figure 2

Patient images ©Eli Lilly and Company. SALT Severity of Alopecia Tool

Clinical photographs of patients with alopecia areata at baseline and after 36 weeks and 52 weeks of treatment with baricitinib 4 mg in BRAVE-AA1. SALT scores indicate percentage of scalp hair loss as assessed by the investigator.

Eyebrow and eyelash response rates also increased over the 52-week period. Among patients with ClinRO Measure for Eyebrow Hair Loss baseline scores of 2 or 3 who were treated with baricitinib 4 mg and 2 mg, respectively, 39.4% and 27.9% in BRAVE-AA1 and 49.7% and 16.3% in BRAVE-AA2 improved ≥ 2 points and scored 0 or 1 at Week 52 (Fig. 3, ESM Table S1). Of those with ClinRO Measure for Eyelash Hair Loss baseline scores of 2 or 3 in the baricitinib 4 mg and 2 mg groups, respectively, 40.7% and 21.6% in BRAVE-AA1 and 50.7% and 30.3% in BRAVE-AA2 had ≥ 2-point improvements and achieved scores of 0 or 1 at Week 52 (Fig. 4, ESM Table S1).

Fig. 3figure 3

Proportion of patients achieving ClinRO Measure for Eyebrow Hair LossTM 0 or 1 with ≥2-point improvement from baseline through Week 52 among patients with a score of ≥ 2 at baseline in a BRAVE-AA1 and b BRAVE-AA2. A ClinRO score of 0 indicates full coverage and a score of 1 indicates minimal gaps in eyebrows. Bars represent 95% confidence intervals. Non-responder imputation was applied to missing data (prespecified analysis). Week-36 data points reflect results from the placebo-controlled period. ClinRO Clinician-Reported Outcome

Fig. 4figure 4

Proportion of patients achieving ClinRO Measure for Eyelash Hair LossTM 0 or 1 with ≥ 2-point improvement from baseline through Week 52 among patients with a score of ≥ 2 at baseline in a BRAVE-AA1 and b BRAVE-AA2. A ClinRO score of 0 indicates full coverage and a score of 1 indicates minimal gaps in eyelashes. Bars represent 95% confidence intervals. Non-responder imputation was applied to missing data (prespecified analysis). Week-36 data points reflect results from the placebo-controlled period. ClinRO Clinician-Reported Outcome

Results of the post hoc analysis of efficacy outcomes using multiple imputation for missing data are reported in ESM Figs. S2–S4 and ESM Table S2.

3.3 Safety

A total of 280 (patient-years exposure [PYE] = 385.5) and 183 (PYE = 197.9) patients in BRAVE-AA1 and 233 (PYE = 284.8) and 155 (PYE = 168.7) patients in BRAVE-AA2 were exposed to baricitinib 4 mg and 2 mg, respectively. Among patients in the baricitinib 4 mg and 2 mg groups, respectively, treatment-emergent AEs (TEAEs) were reported in 69.6% (IR = 110.8) and 58.5% (IR = 94.5) in BRAVE-AA1 and 77.3% (IR = 159.1) and 74.2% (IR = 168.7) in BRAVE-AA2 (Table 2). Most TEAEs were mild or moderate in severity. The most frequently reported TEAEs were upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection, increased blood creatinine phosphokinase (CPK), and COVID-19 infection (Table 2). There were no patterns in types of SAEs; the most common SAEs were bone fractures due to injury (ESM Table S3). The frequency of discontinuations due to AEs was low and similar across groups (ESM Table S4).

Table 2 Summary of safety outcomes

AEs during the 36-week placebo-controlled period have been previously reported [1]. Newly reported herpes zoster infections that occurred after the placebo-controlled period were localized; all patients recovered, and none discontinued. Herpes simplex infections were all mild or moderate and there were no discontinuations. After the placebo-controlled period, serious infections during the extension phase of BRAVE-AA2 included one (0.4%, IR = 0.3) case each of appendicitis, herpes zoster, and COVID-19 with baricitinib 4 mg; all patients recovered, and none discontinued (ESM Table S3). During the extension period of BRAVE-AA2, one (0.4%, IR = 0.3) COVID-19 infection with baricitinib 4 mg led to study discontinuation. No serious infections or infections leading to discontinuation were reported in BRAVE-AA1. Malignancies reported during the trial extension periods included one (0.5%, IR = 0.5) squamous cell carcinoma after 16 months with baricitinib 2 mg, and one (0.4%, IR = 0.3) ductal carcinoma in situ after 10 months with baricitinib 4 mg in BRAVE-AA1; the latter patient discontinued per protocol. No VTEs, opportunistic infections, cases of tuberculosis, gastrointestinal perforations, or deaths were reported in either trial over the observation period (Table 2).

Most laboratory changes were balanced across baricitinib groups in both studies. Increases in CPK, low-density lipoprotein, and high-density lipoprotein were more frequent with the 4 mg dose (Table 3). CPK increases were mostly Common Terminology Criteria for Adverse Events (CTCAE) [8] grade 1 or 2, and there were no cases of rhabdomyolysis. CTCAE grade 4 neutropenia (neutrophils < 0.5 billion/L) was seen in one baricitinib 4 mg patient in the extension period of BRAVE-AA1; the patient recovered and continued the study. During the trial extension periods, thrombocytosis (platelets > 600 billion/L) occurred in one patient with baricitinib 4 mg in BRAVE-AA1 and one patient with baricitinib 2 mg in BRAVE-AA2; both patients recovered and continued the study. Frequencies of hepatic test abnormalities were consistent with those previously reported [1] and were not associated with TEAEs leading to study drug interruption or discontinuation.

Table 3 Summary of laboratory changes

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