PracticeUpdate Conference Series: IID 2018

" …selective induction of T cell exhaustion using Janus kinase inhibitors offers a mechanistic explanation of the success of this treatment strategy to reverse autoimmune diseases such as alopecia areata. " areata, and reversed established disease in the C3H/HeJ model. T cell receptor clonality after 24 weeks of treatment.

Indeed, the investigators observed high expression of the coinhibitory receptors PD-1 and Tim-3, known markers of T cell exhaustion expressed on effector/mem- ory CD8-positive T cells of treated mice. They also observed decreased interfer- on-g production in these mice. Dr. Dai concluded that selective induction of T cell exhaustion using Janus kinase inhibitors offers a mechanistic explanation of the success of this treatment strategy to reverse autoimmune diseases such as alopecia areata. The Janus kinase inhibitor tofacitinib A vi Bitterman, MD, of Columbia University Medical Center in New York, explained that alopecia areata is a common autoimmune disease in which the immune system targets the hair follicle, resulting in nonscarring alopecia. Dr. Bitterman’s group has demonstrated that CD8-positive natural killer G2D- positive T cells are necessary and sufficient to induce alopecia areata. They also identified γ chain cytokines and interferon pathways as key molecular circuits. They showed that tofacitinib abrogated γ chain cytokine and interferon pathways suc- cessfully, prevented the onset of alopecia

Extending these observations to the clinic, Dr. Bitterman and colleagues conducted a small open-label study of oral tofacitinib in 12 patients with moderate to severe alopecia areata. Following limited response to the initial 5 mg twice-daily dose, the dose was escalated to 10 mg twice daily in nonre- sponding subjects. In all, 8 of 12 patients demonstrated hair regrowth of at least 50%, 3 patients demonstrated partial hair regrowth (<50%), and 1 patient demonstrated no regrowth. Gene expression profiling of scalp tissue andAlopeciaAreataDisease Severity Index scores correlated with clinical response. To investigate T cell dynamics in response to tofacitinib treatment, the investigators performed high-throughput T cell recep- tor β chain sequencing of scalp biopsy tissue, and found a marked decrease in

Many of the T cell clones expanded at baseline were either decreased in fre- quency or had disappeared from the scalp after treatment. All responders showed a reduction in expanded scalp CD8-positive T cell clones after treatment, whereas this reduction was not observed in nonresponders. Dr. Bitterman concluded that this open- label study of oral tofacitinib demonstrated dramatic clinical responses in moderate to severe alopecia areata. These responses correlated with normalization of gene expression profiles and a decrease in T cell receptor clonality in scalp skin. These mechanistic findings provided a strong rationale for larger, placebo-con- trolled clinical trials of Janus kinase inhibitors for alopecia areata.

www.practiceupdate.com/c/68652

ƒ ƒ Baseline disease severity, PASI <20: ixekizumab n=85, usteki- numab n=107 ƒ ƒ Baseline disease severity, PASI ≥20: ixekizumab n=51, usteki- numab n=59 Response was significantly greater with ixekizumab than with ustekinumab in: ƒ ƒ Biologic-naïve patients (PASI 90: 76.3% vs 62.4%, P = .022; PASI 100: 55.1% vs 39.7%, P = .017) ƒ ƒ Biologic-experienced patients for PASI 90 (77.8% vs 40.0%, P = .028) ƒ ƒ Patients weighing ≤100 kg (PASI 90: 77.9% vs 62.0%, P = .013; PASI 100: 53.8% vs 38.8%, P = .032) ƒ ƒ Patients with baseline PASI ≥20 (PASI 90: 90.2% vs 57.6%) ƒ ƒ Patients weighing >100 kg (PASI 90: 74.2% vs 51.1%, P = .057; PASI 100: 48.4% vs 26.7%, P = .08) ƒ ƒ Patients with baseline PASI <20 (PASI 90: 68.2% vs 59.8%, P = .291; PASI 100: 48.2% vs 37.4%, P = . 143) Response was consistently higher with ixekizumab across patient subgroups at week 52, including in difficult-to-treat patients, for example, biologic-experienced patients or those with more severe disease.

ƒ ƒ 2% of patients treated with ixekizumab achieved PASI 100 vs 23.5% of those treated with ustekinumab (P = .001) Additionally, 86.6% of patients treated with ixekizumab achieved static Physician’s Global Assessment score 0 or 1 vs 69.3% of those treated with ustekinumab after 24 weeks (P < .001). The majority of treatment-emergent adverse events were mild or moderate. There were no statistically significant differences between treatment groups in overall treatment-emergent adverse events. The safety profile of ixekizumab was consistent with previous clinical trials. In the present subgroup review, patients were randomized 1:1 to receive approved dosing of ixekizumab (160 mg initial dose, 80 mg every 2 weeks to week 12, and every 4 weeks thereafter, total n=136); or ustekinumab (45 mg in patients weighing ≤100 kg or 90 mg in patients weighing >100 kg at weeks 0 and 4, and every 12 weeks thereafter, n=166). Efficacy at week 52 was measured as the percentage of patients who achieved PASI 90/100 in patient subgroups of prior biologic use and analyzed using nonresponder imputation and Fisher’s exact test: ƒ ƒ Prior biologic use: ixekizumab n=18, ustekinumab n=25 ƒ ƒ No prior biologic use: ixekizumab n=118, ustekinumab n=141 ƒ ƒ Weight ≤100 kg: ixekizumab n=104, ustekinumab n=121 ƒ ƒ Weight >100 kg: ixekizumab n=31, ustekinumab n=45

www.practiceupdate.com/c/68651

IID 2018 • PRACTICEUPDATE CONFERENCE SERIES 19