Selective JAK1 Inhibitor Research Articles

Mass balance study of [14C]SHR0302, a selective and potent JAK1 inhibitor in humans

SHR0302, a selective JAK1 inhibitor developed by Jiangsu Hengrui Pharmaceutical Co., was intended for the treatment of rheumatoid arthritis. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of SHR0302 in six healthy Chinese male subjects after a single 8 mg (80 µCi) oral dose of [14C]SHR0302. SHR0302 was absorbed rapidly (T max = 0.505 h), and the average t 1/2 of the SHR0302-related components in plasma was approximately 9.18 h. After an oral dose was administered, the average cumulative excretion of the radioactive components was 100.56% ± 1.51%, including 60.95% ± 11.62% in urine and 39.61% ± 10.52% in faeces. A total of 16 metabolites were identified. In plasma, the parent drug SHR0302 accounted for 90.42% of the total plasma radioactivity. In urine, SHR161279 was the main metabolite, accounting for 33.61% of the dose, whereas the parent drug SHR0302 only accounted for 5.1% of the dose. In faeces, the parent drug SHR0302 accounted for 23.73% of the dose, and SHR161279 was the significant metabolite, accounting for 5.67% of the dose. In conclusion, SHR0302-related radioactivity was mainly excreted through urine (60.95%) and secondarily through faeces (39.61%). The metabolic reaction of SHR0302 in the human body is mainly through mono-oxidation and glucuronidation. The main metabolic location of SHR0302 in the human body is the pyrrolopyrimidine ring.

Efficacy and Treatment Satisfaction of Different Systemic Therapies in Children and Adolescents with Moderate-to-Severe Atopic Dermatitis: A Real-World Study.

For the treatment of moderate-to-severe atopic dermatitis in children and adolescents, the monoclonal antibody dupilumab and the selective JAK-1 inhibitor upadacitinib are two modern systemic therapies approved for long-term treatment. Both drugs have demonstrated high efficacy in randomized controlled trials, although evidence from real-world data in the pediatric population is limited. In a prospective analysis over 24 weeks, we investigated the efficacy, safety and treatment satisfaction of both systemic therapies in 23 patients (16 patients treated with dupilumab; 7 patients treated with upadacitinib). The median age of the patients was 16 years, with a median EASI of 18.8. A significant improvement in the EASI, VAS-itch, CDLQI, POEM and DFIQ from baseline to week 24 was demonstrated for both treatment options. No significant difference was observed between dupilumab and upadacitinib in any of the assessed scores. Less adverse events were recorded in the real-world setting compared with clinical trials. Our results confirm the efficacy and safety of dupilumab and upadacitinib as equivalent treatment options in children and adolescents in a real-world setting.

P724 Upadacitinib is Effective and Safe in Tofacitinib-Experienced Patients with Ulcerative Colitis: A Prospective Real-World Experience

Abstract Background The development and availability of Janus kinus inhibitors (JAKinibs) for moderately to severely active ulcerative colitis (UC) provides new therapeutic options with both novel mechanisms and unique pharmacodynamic benefits. Tofacitinib (tofa) is a non-selective pan-JAKinib that received FDA approval for UC in 2018 and upadacitinib (upa) is a JAK-1 selective inhibitor, that received FDA approval for UC in 2022. It is unknown whether patients who do not respond to tofa will subsequently respond to upa. We report our real-world experience with upa in UC patients with primary or secondary non-response to tofa. Methods We performed a prospective analysis of clinical outcomes on upa in patients with UC and Crohn’s disease (CD) using pre-determined intervals at weeks 0, 2, 4, and 8 as part of a formalized treatment protocol at our institution. We used the SCCAI and HBI, as well as CRP and fecal calprotectin (FCP) to assess efficacy and recorded treatment-related adverse events and serious adverse events (AEs). Here we report our experience in patients treated with upa who have been previously treated with tofa. Results 26 patients (18=UC, 8=CD) with primary or secondary non-response to tofa received upa. (Table 1) In addition to tofa, all of these patients failed at least two biologics prior to upa treatment. In UC: by week 2 60% (6/10) achieved clinical response, and 40% (4/10) achieved clinical remission. By week 4 87.5% (7/8) achieved clinical remission, and 87.5% (6/8) achieved steroid-free remission; FCP decreased by a mean of 649.2 μg/g from baseline (+/- 772.7). At week 8: 100% (8/8) of patients achieved clinical response, 87.5% (7/8) achieved clinical remission, and of all of these (7/7) achieved steroid-free remission; FCP decreased by a mean of 180 μg/g (+/- 721.8) from baseline. One patient had follow-up to week 12 and continued to be in steroid-free remission. (Table 2) In CD: by week 2 2 of 2 patients achieved clinical remission, by week 4 3 of 3 were in clinical remission, 2 of 3 achieved steroid-free remission, and one patient had follow-up to week 8 and he remained in steroid-free remission. (Table 2). 6 patients experienced AEs, with the most common being acne (19.2%). No infections, MACE, or VTE occurred. Conclusion In this prospective real-world experience in medically-resistant patients with UC and CD who previously failed treatment with tofa and at least two biologics, we describe that upa is rapidly effective, inducing both clinical, steroid-free, and biochemical remission with no serious AEs.

P800 Upadacitinib is effective and safe for Crohn’s Disease: prospective real-world experience

Abstract Background Upadacitinib (upa) is a novel selective JAK-1 inhibitor that has demonstrated efficacy in the treatment of moderate to severe ulcerative colitis (UC) and Crohn’s disease (CD) and has received regulatory approval for UC. We report our prospective real-world experience with upadacitinib in patients with CD. Methods We performed a prospective analysis of clinical outcomes during upa therapy in patients with CD using pre-determined follow-up intervals at weeks 0, 2, 4, and 8 as part of a formalized treatment evaluation protocol at our institution. We used the Harvey Bradshaw Index (HBI), C-reactive protein (CRP) and fecal calprotectin (FCP). Clinically active disease was defined as HBI ≥5. Clinical response was defined as a decrease of ≥ 3 points from baseline HBI. Clinical remission was defined as HBI <5. Corticosteroid free clinical remission (CSFR) was defined as those in clinical remission, not taking any form of systemic corticosteroid at the specific time point. CRP normalization was defined as baseline elevated and then within the normal range for the lab used (Quest Diagnostics (Secaucus, NewJersey) ≤8 mg/L or University of Chicago Medicine ≤5 mg/L). FCP response and remission was assessed at three different cutoffs: less than 250 μg/g, 150 μg/g, and 50μg/g. Adverse events were recorded as treatment-related adverse events (AE) and serious adverse events (SAE). Results 47 patients with CD received ≥4 weeks of upa (Table 1). 100% had previously received anti-TNF therapy and 93.6% had received ≥2 advanced therapies (biologic, small molecule, calcineurin-inhibitor). At weeks 4 and 8, 16/21 (76.2%) and 12/16 (75.0%) achieved clinical response and 14/21 (66.7%) and 11/16 (68.8%) achieved clinical remission by 8 weeks, respectively (Table 2). Of those who were on steroids at baseline, 100% (5/5) achieved CSFR. Results were seen as early as week 2 with clinical remission rates of 52.6%. Mean HBI decreased from 6.7 (SD 4.6) at week 0 to 3.5 (3.7) at week 8 (Figure 1). Mean FCP decreased by 707.0 (SD 1026.0) μg/g at week 0 to 74.6 (SD 56.2) μg/g at week 8. Of those with FCP >150 μg/g at baseline, 100% (4/4) achieved FCP <150 μg/g by week 8 (Table 2). Mean CRP decreased by 12.8 (SD 19.1) mg/L to 4.9 (SD 8.0) mg/L at week 8. Of those with CRP >5 mg/L at week 0, 80% (4/5) achieved CRP <5 mg/L by week 8 (Table 2). 23.4% of patients had an AE after starting upa (Table 3). The most common of these was acne (14.9%). Two AEs led to discontinuation and there was a single possible SAE (anemia which was also multifactorial from severely active Crohn’s ileitis and vitamin B12 deficiency). Conclusion In this large, prospective real-world experience in medically-resistant patients with CD, we describe that upadacitinib is rapidly effective and safe.

P580 Upadacitinib is effective and safe for Ulcerative Colitis: prospective real-world experience

Abstract Background Upadacitinib (upa) is a novel selective JAK-1 inhibitor that has demonstrated efficacy in the treatment of moderate to severe ulcerative colitis (UC) and Crohn’s disease (CD) and has received regulatory approval for UC. We report a large prospective real-world experience with upa in patients with UC. Methods We performed a prospective analysis of clinical outcomes during upa therapy in patients with UC using pre-determined follow-up intervals at weeks 0, 2, 4, and 8 as part of a formalized treatment protocol. We used the Simplified Clinical Colitis Activity Index (SCCAI), C-reactive protein (CRP) and fecal calprotectin (FCP). Clinically active disease was defined as SCCAI ≥ 3. Clinical response was defined as a decrease of ≥ 3 points from baseline SCCAI. Clinical remission was defined as SCAAI < 3. Corticosteroid free clinical remission (CSFR) was defined as those in clinical remission, not taking systemic corticosteroid at the specific time point. CRP normalization was defined as baseline elevated and then within the normal range for the lab used (Quest Diagnostics (Secaucus, New Jersey) ≤8 mg/L or UChicago Medicine ≤5 mg/L). FCP response and remission was assessed at three different cutoffs: less than 250 μg/g, 150 μg/g, and 50μg/g. Adverse events were recorded as treatment-related adverse events (AE) and serious adverse events (SAE). Results 55 patients with UC received ≥4 weeks of upa (Table 1). 100% had previously received anti-TNF therapy and 81.8% had received ≥2 advanced therapies (biologic, small molecule, calcineurin-inhibitor). At 4 and 8 weeks of treatment, 18/22 (81.8%) and 19/21 (90.5%) achieved clinical response and 17/22 (77.3%) and 17/21 (81.0%) achieved clinical remission, respectively (Table 2). Of those who were on steroids at baseline, 100% (7 of 7) achieved CSFR. Results were seen as early as week 2 with clinical remission rates of 36.0%. Mean SCCAI decreased from 5.3 (SD 3.6) at week 0 to 1.71 (SD 3.96) at week 8 (p = <0.0001, Figure 1). Mean FCP decreased from 1028.5 (SD 1291) μg/g at week 0 to 530.2 (SD 715.1) μg/g (p = 0.0881). Of those with FCP >150 μg/g at baseline, 33.3% (2/6) achieved FCP <150 μg/g by week 8 (Table 2). Mean CRP (mg/L) decreased from 5.1 (SD 5.0) mg/L at week 0 to 2.5 (SD 3.3) mg/L at week 8. Of those with CRP >5 at week 0, 60% (3/5) achieved CRP <5 by week 8 (Table 2). 30.9% of patients had an AE after starting upa (Table 3). The most common of these was acne (23.6%). Two AEs led to discontinuation. There were no SAEs. Conclusion In this large prospective real-world experience in medically-resistant patients with UC, we describe that upadacitinib is rapidly effective and safe, with remission rates that exceed those seen in the pivotal trial.

P074 Interferon-γ promotes antigen processing and presentation pathway in the intestinal epithelium of patients with Crohn’s disease

Abstract Background Interferon-γ (IFN-γ) is a major driver of excessive immune response, leading to intestinal mucosal damage and contributing the pathogenesis of Crohn’s diseases (CD). In contrast to the inflammatory cells and immune system, IFN-γ-induced cellular responses has not been well documented in the intestinal epithelium. The intestinal epithelium consists of multiple cell types and patient-derived intestinal organoid model may be appropriate to evaluate the IFN-γ-induced epithelial cellular responses in patients with CD. Methods To evaluate the IFN-γ-mediated epithelial cellular responses, human small intestinal organoids (enteroids) derived from the controls (n=6) and patients with Crohn’s disease (CD, n=10) were constructed. We focused on the IFN-γ-induced cell death mechanism upregulated in CD enteroids and validated them in surgically resected small intestine in patients with active CD. Results As the concentration of IFN-γ increased in the culture medium, the organoid-forming efficiency decreased steadily, which did not differ between control and CD enteroids. The enteroid viability measured using MTT was estimated to be 83.10 pg/ml for EC50. In control and CD enteroids treated with 100 pg/ml IFN-γ, PANoptosis was the main inflammatory cell death mechanism. Bulk and single-cell RNA sequencing revealed that IFN-γ induced the expression of MHC class II-associated genes, co-inhibitory molecule CD274 (PD-L1), and IDO1 in control and CD enteroids, which may be associated with peripheral tolerance in the absence of exogenous antigens. Gene set enrichment analysis identified an up-regulated antigen processing and presentation pathway with increased expression of MHC class I molecules in IFN-γ-treated CD enteroids compared to IFN-γ-treated control enteroids (normalized enrichment score=2.13, p=0.002, q=0.005). IFN-γ-induced MHC class I pathway could result in T cell-mediated cytotoxicity in CD enteroids. The selective JAK1 inhibitor, upadacitinib, inhibited the IFN-γ-induced PANoptosis and T cell-mediated cytotoxicity in CD enteroids. The expression of HLA-A and B was higher in the inflamed small intestine in patients with CD than those in patients with ischemic enteritis. Conclusion IFN-γ promotes antigen processing and presentation pathway in the intestinal epithelium. In patients with CD, increased expression of MHC class I molecules may induce T cell-mediated cytotoxicity, which could contribute to the development of CD.

P518 Safety of upadacitinib in ulcerative colitis: Long-term data from the phase 3 open-label extension study (U-ACTIVATE)

Abstract Background Upadacitinib (UPA), an oral reversible and selective JAK inhibitor, has demonstrated efficacy, with a well-characterised safety profile, in two replicate induction studies of UPA 45 mg once daily (QD; U-ACHIEVE induction and U-ACCOMPLISH), and a maintenance study of UPA 15 mg or UPA 30 mg QD (U-ACHIEVE maintenance).1 Here, we report safety data from the ongoing, Phase 3, open-label, 288-week long-term extension (LTE) study in patients with ulcerative colitis (UC) who previously participated in the induction studies. Methods Rates of treatment-emergent adverse events (TEAEs) and TEAEs of special interest were calculated by treatment sequence in patients who received ≥1 dose of UPA in the induction studies, maintenance study, or by the data cut-off of 13 December 2021 in the LTE study. Rates are presented as exposure-adjusted event rates (EAERs; events/100 patient-years [PYs]), except for events that typically occur as a single instance, which are presented as exposure-adjusted incidence rates (EAIRs; n/100 PYs). PYs were calculated from the first dose of UPA 45 mg received during induction through to the last UPA dose received or the data cut-off date for ongoing patients. Results Overall, 1,308 patients representing 2,350.2 PYs of UPA exposure were evaluated (mean age: 43 years; female: 38%). Across treatment groups, EAERs of serious TEAEs, severe TEAEs, TEAEs leading to UPA discontinuation, TEAEs with reasonable possibility of being related to UPA, or TEAEs leading to death were numerically similar across all UPA treatment sequences (Table 1). EAERs of serious infections, herpes zoster, neutropenia, hepatic disorder, and creatine phosphokinase elevation were numerically higher with UPA 15 mg and 30 mg vs placebo; and creatine phosphokinase elevation with UPA 30 mg vs UPA 15 mg (Table 2). The EAER of anaemia was numerically lower with UPA 30 mg vs UPA 15 mg and placebo. Of note, no remarkable differences were observed in EAIRs of adjudicated major adverse cardiovascular events, adjudicated venous thromboembolic events, or malignancy (excluding non-melanoma skin cancer). Conclusion: Long-term use of UPA 15 or 30 mg among patients with UC continuing to benefit from prolonged therapy representing 2,350.2 PYs of exposure was well tolerated. The ongoing safety profile of UPA is consistent with previous analyses, with no new safety signals identified compared with previous UC analyses following 52 weeks’ maintenance therapy,1,2 or other immune-mediated indications for which UPA is approved.3,4

DOP38 Upadacitinib Therapy Reduces Crohn’s Disease Symptoms Within the First Week of Induction Therapy

Abstract Background Upadacitinib (UPA), an oral, selective JAK inhibitor demonstrated superior efficacy for clinical remission compared with placebo (PBO) and an acceptable safety profile in patients with moderately to severely active Crohn’s disease (CD) in 2 phase 3 induction trials, U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836).1-2 There remains an unmet need for therapies that provide rapid symptom relief in ambulatory patients with moderate to severe CD experiencing disease flares. This sub-analysis evaluated the efficacy of UPA 45 mg once daily (UPA45) on early symptomatic improvement for the first 15 days of treatment, using pooled data from U-EXCEL and U-EXCEED. Methods U-EXCEL and U-EXCEED were multicentre, double-blind, PBO-controlled trials that enrolled patients who had average daily very soft or liquid stool frequency (SF) ≥4 and/or abdominal pain score (APS) ≥2 at baseline, plus a Simple Endoscopic Score for CD ≥6 (≥ 4 for patients with isolated ileal disease), excluding the narrowing component. Patients (n=1021) were randomized (2:1 ratio) to receive UPA45 (n=674) or PBO (n=347) for 12 weeks. First dose of study drug was administered on day 1. Improvement in daily symptoms of SF and APS, in addition to time to first achievement of daily SF/APS clinical remission were assessed. Results Patients treated with UPA45 experienced a significant improvement in daily symptoms compared with PBO-treated patients, simultaneously achieving SF < 3 and APS ≤ 1 beginning at day 3 (9.6% UPA vs. 5.8% PBO) (P≤0.05, Figure 1A). Difference from PBO was maintained through day 15 (P≤0.05), except for day 4 (P=0.0518). Similar results were found when evaluating each symptom separately, with a higher proportion of patients who received UPA45 achieving either SF < 3, beginning at day 5 (31.6% UPA vs. 23.1% PBO, Figure 1B). UPA-treat patients attained significance for APS ≤ 1 beginning at day 6 (49.1% UPA vs. 39.3% PBO, Figure 1C), compared with patients that received PBO. Differences from PBO were sustained through day 15 for either symptom (P≤0.01 for both endpoints). A greater proportion of patients receiving UPA45 also demonstrated at least a 60% decrease in SF by day 5, compared to PBO, which was maintained through day 15 (P≤0.01, Figure 1D). Patients treated with UPA45 achieved daily SF/APS clinical remission significantly earlier than PBO-treated patients (median time to clinical remission: 13 days UPA45 vs 32 days PBO; P<0.0001, Figure 2). Conclusion Patients who received UPA 45 mg once daily significantly improved daily symptoms of diarrhea or abdominal pain within the first week of treatment and achieved daily clinical remission faster than PBO-treated patients, providing rapid symptom relief.

Selective Janus kinase 1 inhibition resolves inflammation and restores hair growth offering a viable treatment option for alopecia areata.

Janus Kinase (JAK) inhibition has recently demonstrated therapeutic efficacy in both restoring hair growth and resolving inflammation in Alopecia Areata (AA). These effects are dose dependent and mainly efficacious at ranges close to a questionable risk profile. We explored the possibility to separate the beneficial and adverse effects of JAK inhibition by selectively inhibiting JAK1 and thereby avoiding side effects associated with JAK2 blockade. The C3H/HeJ mouse model of AA was used to demonstrate therapeutic efficacy in vivo with different regimens of a selection of JAK inhibitors in regards to systemic versus local drug exposure. Human peripheral blood lymphocytes were stimulated in vitro to demonstrate translation to the human situation. We demonstrate that selective inhibition of JAK1 produces fast resolution of inflammation and complete restoration of hair growth in the C3H/HeJ mouse model of AA. Furthermore, we show that topical treatment does not restore hair growth and that treatment needs to be extended well beyond that of restored hair growth in order to reach treatment-free remission. For translatability to human disease, we show that cytokines involved in AA pathogenesis are similarly inhibited by selective JAK1 and pan-JAK inhibition in stimulated human peripheral lymphocytes and specifically in CD8+ T cells. This study demonstrates that systemic exposure is required for efficacy in AA and we propose that a selective JAK1 inhibitor will offer a treatment option with a superior safety profile to pan-JAK inhibitors for these patients.

JAK inhibitors differentially modulate B cell activation, maturation and function: A comparative analysis of five JAK inhibitors in an in-vitro B cell differentiation model and in patients withrheumatoid arthritis.

Janus kinase (JAK) inhibitors have been approved for the treatment of several immune-mediated diseases (IMIDs) including rheumatoid arthritis (RA) and psoriatic arthritis and are in clinical trials for numerous other IMIDs. However, detailed studies investigating the effects of different JAK inhibitors on B cells are missing. Within this study, we therefore aimed to characterize the effect of JAK inhibition on the B cell compartment. To this end, we investigated the B cell compartment under JAK inhibition and compared the specific effects of the different JAK inhibitors tofacitinib (pan-JAK), baricitinib (JAK1/2), ruxolitinib (JAK1/2), upadacitinib (JAK1/2) as well as filgotinib (selective JAK1) on in-vitro B cell activation, proliferation, and class switch recombination and involved pathways. While B cell phenotyping of RA patients showed an increase in marginal zone (MZ) B cells under JAK inhibition, comparison with healthy donors revealed that the relative frequency of MZ B cells was still lower compared to healthy controls. In an in-vitro model of T-cell-independent B cell activation we observed that JAK1/2 and selective JAK1 inhibitor treatment led to a dose-dependent decrease of total B cell numbers. We detected an altered B cell differentiation with a significant increase in MZ-like B cells and an increase in plasmablast differentiation in the first days of culture, most pronounced with the pan-JAK inhibitor tofacitinib, although there was no increase in immunoglobulin secretion in-vitro. Notably, we further observed a profound reduction of switched memory B cell formation, especially with JAK1/2 inhibition. JAK inhibitor treatment led to a dose-dependent reduction of STAT3 expression and phosphorylation as well as STAT3 target gene expression and modulated the secretion of pro- and anti-inflammatory cytokines by B cells. JAK inhibition has a major effect on B cell activation and differentiation, with differential outcomes between JAK inhibitors hinting towards distinct and unique effects on B cell homeostasis.

Efficacy and Safety of JAK1 Inhibitor Abrocitinib in Atopic Dermatitis.

Abrocitinib is a JAK1 selective inhibitor recently approved for the treatment of moderate-to-severe atopic dermatitis in adults. It has demonstrated efficacy and safety in several clinical trials, both in children and adults, in monotherapy, and compared with dupilumab. The expected EASI-75 response rate estimates at week 12 are 62.9% (95% CrI 42.5-79.9%) for abrocitinib 200 mg and 43.0% (95% CrI 24.8-64.0%) for abrocitinib 100 mg. Abrocitinib has shown a faster effect than dupilumab as regards early alleviation of itch. Because of the incomplete target selectivity of JAK inhibitors, when abrocitinib treatment is considered, laboratory screening is necessary, latent tuberculosis must be screened for, active infections are a contraindication, and special caution must be exerted in treating elderly patients and those predisposed to thromboembolic events. Even though recent meta-analyses of clinical trials have not shown that atopic dermatitis, or its treatment with JAK inhibitors or dupilumab, modify the risk of deep venous thrombosis or pulmonary embolism, long-term follow-up studies will better define the safety profile of abrocitinib.

Alopecia Universalis in an Adolescent Successfully Treated with Upadacitinib-A Case Report and Review of the Literature on the Use of JAK Inhibitors in Pediatric Alopecia Areata.

Alopecia areata (AA) is a cell-mediated autoimmune disease in which a cytotoxic T-cell response against hair follicles occurs. AA has been demonstrated to frequently co-exist with atopic dermatitis (AD), and the coincidence of atopy predisposes to a more severe course of the disease. To date, therapeutic options in AA, especially in the pediatric population, are mainly limited to corticosteroids, irritants, sensitizers, and immunosuppressive agents. Recently, innovative therapies have emerged, among which Janus kinase (JAK) inhibitors, effective in both AD and AA, appear to be the most promising. Here, a 14-year-old girl with alopecia universalis (AU) and mild AD is demonstrated, who was successfully treated with a selective JAK1 inhibitor, upadacitinib, which has been approved for the treatment of AD in adults and children aged 12years and older. Resolution of eczema and complete hair regrowth was achieved after 3months of therapy. Apart from transient mild leukopenia at weeks 4 and 8, no adverse events were noted. Data in the literature on the efficacy and safety of JAK inhibitors in the treatment of AA in the pediatric population is based on single case reports and case series. So far, topical tofacitinib and ruxolitinib, as well as systemic tofacitinib, ruxolitinib, and baricitinib have been used off-label in this indication in children. Upadacitinib is another effective treatment option with a good benefit-risk ratio for patients with AA, including cases coexisting with AD.

Update on the role of upadacitinib in the treatment of adults with moderately to severely active ulcerative colitis.

With further knowledge of the pathogenesis of inflammatory bowel disease, small oral molecules have become available, including the Janus kinase (JAK) inhibitors. Upadacitinib (UPA) is a selective JAK1 inhibitor and has become the newest drug in this class, with recent approval for the management of moderate-to-severe ulcerative colitis. The large phase III program (including the U-ACHIEVE and U-ACCOMPLISH parallel induction trials and the U-ACHIEVE Maintenance trial) demonstrated superiority over placebo, for all primary and secondary endpoints including key clinical, endoscopic, and histological outcomes utilizing 45 mg orally (po) once daily (OD) during induction and either 30 mg or 15 mg po OD in maintenance. From a safety perspective, UPA has proven to be a safe and well-tolerated medication across immune-mediated diseases with manageable adverse risks such as an increase in herpes zoster. Proper discussion and patient profiling are essential when positioning UPA, considering efficacy and potential risks associated with this highly effective medication.

A Phase I Study to Evaluate the Safety and Pharmacokinetics of SHR0302 Base Ointment in Healthy Adult Volunteers

Introduction: SHR0302 is a highly selective JAK1 inhibitor. This study aimed to investigate the safety, tolerability, and pharmacokinetics of single and multiple-dose topical skin application of SHR0302 base ointment in healthy adult subjects. Methods: This phase I clinical trial (registration number: CTR20192188) consisted of two parts. Part 1 was a single-dose ascending study with four dose levels in 32 healthy Australian adults (8 subjects in each dose group). All Australian subjects were randomized 3:1 to a single-dose topical skin application of SHR0302 base ointment or placebo. The dose escalated from 1% SHR0302 base ointment on 3% of body surface area (BSA) to 2% SHR0302 base ointment on 20% of BSA. Part 2 combined single and multiple-dose ascension studies with two dose levels in 20 healthy Chinese adults (10 subjects in each dose group). All Chinese subjects were randomized 4:1 to a combination of single and multiple doses for consecutive 10 days of topical application of 1% SHR0302 base ointment on 20% BSA or 2% SHR0302 base ointment on 20% BSA. The safety and pharmacokinetics of the SHR0302 base ointment were evaluated. Results: The incidence of treatment-emergent adverse events (TEAEs) in both parts was comparable between the SHR0302 base ointment group and the vehicle group (part 1: 33.3% vs. 37.5%; part 2: 56.3% vs. 75.0%). All TEAEs were transient, recovered, and equally well-tolerated in the two racial groups. The overall absorption of the SHR0302 base ointment was slow after topical application, with T_max>10 h. After a single dose of the SHR0302 base ointment, drug exposure in healthy Australian and Chinese subjects increased nonlinearly with the increase in the administration area and drug content. Drug exposure increased in a less-than-dose-proportional manner within the dose range tested. Due to differences in the clinical practice of topical application, the T_max of the drug in Australian subjects was earlier than in Chinese subjects, but the overall extent of absorption seemed comparable in Australian and Chinese subjects (with comparable AUC_0-t). Conclusion: The SHR0302 base ointment (either single or multiple doses) was well tolerated and safe, with no racial disparity. Key Message: The SHR0302 base ointment (either single or multiples doses) was well tolerated and safe.

Ruxolitinib cream for the short-term treatment of mild-moderate atopic dermatitis

ABSTRACT Introduction Atopic dermatitis (AD) is a chronic, recurrent, itchy inflammatory skin disease with a vast influence on a patient’s quality of life (QoL). Mild-moderate AD was classically managed with the use of topical corticosteroid (TCS) and calcineurin inhibitors (TCI). It was proven that the JAK pathway plays an important role in the development of AD. The introduction of topical JAK inhibitors may revolutionize the classical approach to the management of mild-to-moderate atopic dermatitis. Areas covered This review discussed the role of the JAK pathway in the development and exacerbations of AD with an emphasis on the newly introduced, topical selective JAK1 and JAK2 inhibitor – Ruxolitinib (RUX) cream. It provides an extensive review of pharmacokinetics and pharmacodynamics, efficacy, and safety of RUX cream in clinical trials. Expert opinion Results from phase II and two phase III clinical trials have shown that RUX cream could be a promising topical treatment of mild-moderate AD. Its favorable safety profile and good efficacy make RUX cream a beneficial modality for patients with chronic TCSs and TCIs use. Future studies on younger patients and with a longer observational period are necessary to adequately assess the efficacy and safety of RUX cream in the whole AD population.

New approaches to tackle cytopenic myelofibrosis.

Myelofibrosis (MF) is a clonal hematopoietic stem cell neoplasm characterized by constitutional symptoms, splenomegaly, and risks of marrow failure or leukemic transformation and is universally driven by Jak/STAT pathway activation. Despite sharing this pathogenic feature, MF disease behavior can vary widely. MF can generally be categorized into 2 distinct subgroups based on clinical phenotype: proliferative MF and cytopenic (myelodepletive) MF. Compared to proliferative phenotypes, cytopenic MF is characterized by lower blood counts (specifically anemia and thrombocytopenia), more frequent additional somatic mutations outside the Jak/STAT pathway, and a worse prognosis. Cytopenic MF presents unique therapeutic challenges. The first approved Jak inhibitors, ruxolitinib and fedratinib, can both improve constitutional symptoms and splenomegaly but carry on-target risks of worsening anemia and thrombocytopenia, limiting their use in patients with cytopenic MF. Supportive care measures that aim to improve anemia or thrombocytopenia are often ineffective. Fortunately, new treatment strategies for cytopenic MF are on the horizon. Pacritinib, selective Jak2 inhibitor, was approved in 2022 to treat patients with symptomatic MF and a platelet count lower than 50 × 109/L. Several other Jak inhibitors are in development to extend therapeutic benefits to those with either anemia or thrombocytopenia. While many other novel non-Jak inhibitor therapies are in development for MF, most carry a risk of hematologic toxicities and often exclude patients with baseline thrombocytopenia. As a result, significant unmet needs remain for cytopenic MF. Here, we discuss clinical implications of the cytopenic MF phenotype and present existing and future strategies to tackle this challenging disease.

Cross-specialty identification of the JAK1 inhibitor trial agent filgotinib as a potential therapy for alopecia areata.

First report of alopecia areata responding to the selective JAK1 inhibitor filgotinib. This case is a patient with coinciding Crohn’s disease that had failed multiple biologics. It serves as a real-world example of how shared decision making between physicians can greatly improve patient outcomes. It highlights that sharing patient registry datasets between specialties will have great benefits, for example in repurposing of JAK inhibitors for other conditions.

The effect of food on the pharmacokinetics of WXFL10203614, a potential selective JAK1 inhibitor, in healthy Chinese subjects.

Objective: This study was performed to investigate the effect of food on the pharmacokinetics (PK) of WXFL10203614 in healthy Chinese subjects. Methods: This was a randomized, open-label, single-dose, two-treatment (fed vs fasted), two-period, two-sequence, crossover study. 14 eligible subjects were averagely randomized into 2 sequences and then received 10mg WXFL10203614 under fasted or fed condition. In each period, the blood samples were collected from 0h (pre-dose) and serially up to 72h post-dose, and plasma concentrations were detected using the high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. The effect of food on the PK profile and safety of WXFL10203614 were assessed. Results: 70 subjects were screened, and 14 subjects (10 male and 4 female) were enrolled and completed the study. Under the fasted condition, WXFL10203614 was absorbed rapidly with a Tmax of 0.98h. The absorption rate was slower, Tmax delayed by 2.98h, and the Cmax decreased by 16.3% when WXFL10203614 administered after the high-fat and high-calorie diet, other PK parameters were not affected. The 90% confidence intervals (CIs) for the ratio (fed/fasted) of geometric means of the Cmax, AUC0-t and AUC0-∞ were 0.73-1.01, 0.90-1.03 and 0.90-1.03, indicating that the high-fat and high-calorie diet might impact the absorption process of WXFL10203614. Although the Cmax was slightly decreased, there was no significant difference in the Cmax under fasted and fed conditions. Thus, it was not considered clinically significant owing to the small magnitude of changes in Cmax. All Treatment-emergent adverse events (TEAEs) were mild and resolved spontaneously without treatment. Conclusion: Food had no clinically relevant effects on drug system exposure of WXFL10203614. It was well tolerated under fasted and fed conditions in healthy Chinese subjects, so WXFL10203614 could be administered orally with or without food. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html, identifier CTR20191636.

The Effect of Upadacitinib on Lipid Profile and Cardiovascular Events: A Meta-Analysis of Randomized Controlled Trials

Our aim was to systematically investigate the effect of upadacitinib, an oral JAK-1 selective inhibitor, on lipid profile and cardiovascular disease risk. PubMed, PubMed Central and ClinicalTrials.gov databases were searched for relevant randomized controlled trials (RCTs) up to 31 July 2022. We performed a qualitative synthesis of published RCTs to investigate the associations of upadacitinib with lipoprotein changes, along with a quantitative synthesis of MACE and mean lipoprotein changes where there were available data. Nineteen RCTs were eligible for the present systematic review, which included 10,656 patients with a mean age of 51 years and a follow-up period of 12-52 weeks. Increases in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were noted upon upadacitinib administration (3-48 mg/day) in 15 studies, while the LDL-C:HDL-C ratio remained unchanged. The pooled analyses of three placebo-controlled RCTs (n = 2577) demonstrated that upadacitinib at 15 mg increased the LDL-C by 15.18 mg/dL (95% CI: 7.77-22.59) and HDL-C by 7.89 mg/dL (95% CI: 7.08-8.69). According to the pooled analysis of 15 placebo-controlled RCTs (n = 7695), upadacitinib had no effect on MACE (risk ratio, RR: 0.62; 95% CI: 0.24-1.60). A sub-analysis focusing on upadacitinib at 15 mg (12 studies, n = 5395) demonstrated similar results (RR: 0.67; 95% CI: 0.19-2.36). Treatment with upadacitinib increases both LDL-C and HDL-C levels. Nevertheless, upadacitinib had no significant effect on the cardiovascular disease risk during a ≤52-week follow-up.

Immunomodulators in Mechanically Ventilated Patients With COVID-19: Lessons Learned From Underpowered Trials.

Immunomodulators in Mechanically Ventilated Patients With COVID-19: Lessons Learned From Underpowered Trials.