Summary
Background
Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment ...effect via topical application in patients with AD is unknown.
Objectives
Tofacitinib, a small‐molecule JAK inhibitor, was investigated for the topical treatment of AD.
Methods
In this 4‐week, phase IIa, randomized, double‐blind, vehicle‐controlled study (NCT02001181), 69 adults with mild‐to‐moderate AD were randomized 1:1 to 2% tofacitinib or vehicle ointment twice daily. Percentage change from baseline (CFB) in Eczema Area and Severity Index (EASI) score at week 4 was the primary end point. Secondary efficacy end points included percentage CFB in body surface area (BSA), CFB in EASI Clinical Signs Severity Sum Score, proportion of patients with Physician's Global Assessment (PGA) response and CFB in patient‐reported pruritus. Safety, local tolerability and pharmacokinetics were monitored.
Results
The mean percentage CFB at week 4 in EASI score was significantly greater (P < 0·001) for tofacitinib (−81·7%) vs. vehicle (−29·9%). Patients treated with tofacitinib showed significant (P < 0·001) improvements vs. vehicle across all prespecified efficacy end points and for pruritus at week 4. Significant improvements in EASI, PGA and BSA were observed by week 1 and improvements in pruritus were observed by day 2. Safety/local tolerability were generally similar for both treatments, although more adverse events were observed for vehicle vs. tofacitinib.
Conclusions
Tofacitinib ointment showed significantly greater efficacy vs. vehicle across end points, with early onset of effect and comparable safety/local tolerability to vehicle. JAK inhibition through topical delivery is potentially a promising therapeutic target for AD.
What's already known about this topic?
Atopic dermatitis (AD) is a common, inflammatory skin condition affecting adults and children worldwide with prevalence rates of up to 20% and increasing.
Despite unmet medical need, it has been 15 years since a new AD drug with a novel mechanism of action has been approved, highlighting the need for other effective agents.
Recent clinical and nonclinical data support the potential therapeutic benefit of Janus kinase (JAK) inhibition in treating AD.
What does this study add?
Tofacitinib ointment showed significantly greater efficacy vs. vehicle across all study end points, with early onset of effect, and comparable safety/local tolerability with vehicle.
JAK inhibition through topical delivery is potentially a promising treatment target for AD.
This study provides important information to the medical research community regarding AD treatment options that have a new mechanism of action.
Linked Comment: Damsky and King. Br J Dermatol 2016; 175:861–862.
Summary Background Long‐term safety evaluations of biologics are needed to inform patient management decisions.
Objectives To evaluate the safety of ustekinumab in patients with moderate‐to‐severe ...psoriasis treated for up to 5 years.
Methods Safety data were pooled from four studies of ustekinumab for psoriasis. Rates of adverse events (AEs), serious AEs (SAEs) and AEs of interest infections, nonmelanoma skin cancers (NMSCs), other malignancies and major adverse cardiovascular events (MACE) per 100 patient‐years (PY) of follow‐up were analysed by ustekinumab dose (45 or 90 mg) and by year of follow‐up (years 1–5) to evaluate the dose response and impact of cumulative exposure. Observed rates of overall mortality and other malignancies were compared with those expected in the general U.S. population.
Results Analyses included 3117 patients (8998 PY) who received one or more doses of ustekinumab, with 1482 patients treated for ≥ 4 years (including 838 patients ≥ 5 years). At year 5, event rates (45 mg, 90 mg, respectively) for overall AEs (242·6, 225·3), SAEs (7·0, 7·2), serious infections (0·98, 1·19), NMSCs (0·64, 0·44), other malignancies (0·59, 0·61) and MACE (0·56, 0·36) were comparable between dose groups. Year‐to‐year variability was observed, but no increasing trend was evident. Rates of overall mortality and other malignancies were comparable with those expected in the general U.S. population.
Conclusions No dose‐related or cumulative toxicity was observed with increasing duration of ustekinumab exposure for up to 5 years. Rates of AEs reported in ustekinumab psoriasis trials are generally comparable with those reported for other biologics approved for the treatment of moderate‐to‐severe psoriasis.
What’s already known about this topic?
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Short‐term studies of ustekinumab in patients with moderate‐to‐severe psoriasis indicated a favourable benefit–risk profile. Long‐term safety evaluations are needed to inform patient management decisions.
What does this study add?
•
This report evaluated the largest psoriasis clinical trial cohort to date with the longest duration of follow‐up. Safety outcomes after 5 years of ustekinumab treatment are consistent with shorter‐term reports and are generally comparable with observations from studies of other biologics in patients with psoriasis.
Summary
Background
The interleukin‐17 cytokine family plays a central role in psoriasis pathogenesis.
Objectives
To evaluate the efficacy and safety of brodalumab, a human anti‐interleukin‐17 ...receptor antibody, in treating patients with moderate‐to‐severe plaque psoriasis.
Methods
In this phase III, double‐blind, placebo‐controlled study (NCT01708590; AMAGINE‐1), adult patients in the U.S.A., Canada and Europe were randomized to brodalumab (140 or 210 mg) or placebo every 2 weeks (Q2W), with an additional dose at week 1, for a 12‐week induction phase. At week 12, patients receiving brodalumab who achieved static Physician's Global Assessment 0 or 1 (sPGA success) were rerandomized to the placebo or induction dose. After week 16, patients with sPGA ≥ 3 were re‐treated with the induction dose. After ≥ 12 weeks of retreatment, patients with sPGA 2 for ≥ 4 weeks or sPGA ≥ 3 were rescued with brodalumab 210 mg Q2W. At week 12, patients randomized to brodalumab with sPGA ≥ 2 or placebo received brodalumab 210 mg Q2W. Coprimary end points were the percentage of patients with ≥ 75% improvement in Psoriasis Area and Severity Index score (PASI 75) and sPGA success at week 12.
Results
There were 661 patients randomized: 220 placebo, 219 brodalumab 140 mg and 222 brodalumab 210 mg. At week 12, 60% (140 mg) and 83% (210 mg) vs. 3% (placebo) achieved PASI 75, and 54% (140 mg) and 76% (210 mg) vs. 1% (placebo) achieved sPGA success. The safety profile was considered acceptable.
Conclusions
Brodalumab therapy resulted in significant clinical benefit and an acceptable safety profile in patients with moderate‐to‐severe plaque psoriasis.
What's already known about this topic?
Anti‐interleukin (anti‐IL)‐17 receptor A and anti‐IL‐17A antibodies have been shown to be efficacious in treating patients with moderate‐to‐severe plaque psoriasis.
What does this study add?
This study further demonstrates that brodalumab therapy in patients with moderate‐to‐severe plaque psoriasis results in a high degree of complete skin clearance.
This study also further elucidates the safety profile of brodalumab.
Linked Comment: Ormerod. Br J Dermatol 2016; 175:243–244
Plain language summary available online
Summary
Background Conventional systemic therapies for plaque psoriasis have not fully met the needs of patients, and although current biologic treatments are generally well tolerated, concerns ...exist with respect to long‐term safety. Interleukin (IL)‐17A is believed to be an important effector cytokine in the pathogenesis of psoriasis and is produced by Th17 cells, a class of helper T cells that act outside the established Th1/Th2 paradigm for regulation of innate and adaptive immunity.
Objectives To assess the efficacy and safety of different doses of secukinumab, a fully human anti‐IL‐17A IgG1κ monoclonal antibody, in patients with moderate‐to‐severe plaque psoriasis.
Methods Patients (n = 125) were randomized 1 : 1 : 1 : 1 : 1 to receive subcutaneous doses of placebo (n = 22) or secukinumab 1 × 25 mg (n = 29), 3 × 25 mg (n = 26), 3 × 75 mg (n = 21) or 3 × 150 mg (n = 27) at weeks 0, 4 and 8. After the 12‐week treatment period, patients entered a follow‐up period of 24 weeks. The primary efficacy outcome was at least 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75); secondary outcomes included the Investigator’s Global Assessment (IGA) and PASI 90 and 50 response rates.
Results After 12 weeks of treatment, secukinumab 3 × 150 mg and 3 × 75 mg resulted in significantly higher PASI 75 response rates vs. placebo (82% and 57% vs. 9%; P < 0·001 and P = 0·002, respectively). Higher PASI 75 response rates compared with placebo were maintained throughout the follow‐up period with these dosages week 36, 26% (n = 7) and 19% (n = 4) vs. 4% (n = 1), respectively, with a gradual decline of PASI 75 response over time after the dosing period. IGA response rates were significantly higher in the 3 × 150 mg group vs. placebo at week 12 (48% vs. 9%; P = 0·005) and were consistently higher for the 3 × 150 mg and 3 × 75 mg groups vs. placebo at all time points from week 4 onward. The PASI 90 response rate was significantly higher in the 3 × 150 mg group vs. placebo (52% vs. 5%) at week 12 and remained higher during the follow‐up period. Secukinumab was well tolerated. Two cases of neutropenia (≤ grade 2) were reported in the 3 × 150 mg cohort.
Conclusions Treatment with subcutaneous secukinumab 3 × 75 mg and 3 × 150 mg met the primary outcome of PASI 75 response achievement after 12 weeks, demonstrating efficacy in moderate‐to‐severe psoriasis.
What’s already known about this topic?
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Conventional systemic therapies for plaque psoriasis have not fully met patient needs; biologics, although effective and generally well tolerated, have a still‐developing long‐term safety profile.
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Monoclonal antibodies against interleukin (IL)‐17A have shown early promise.
What does this study add?
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In this study, the investigational anti‐IL‐17 monoclonal secukinumab (3 × 150 mg, 3 × 75 mg subcutaneously) produced significantly higher rates of 75% improvement from baseline in Psoriasis Area and Severity Index score vs. placebo, and was well tolerated in moderate‐to‐severe plaque psoriasis.
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Secukinumab may offer new therapeutic options in plaque psoriasis.
Summary
Background
Plaque psoriasis is a chronic and often debilitating skin disorder and proinflammatory cytokines are known to play a key role in the disease process.
Objectives
To evaluate the ...safety and efficacy of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate‐to‐severe psoriasis in a randomized, double‐blind, placebo‐controlled, dose‐ranging phase 2b study.
Methods
Patients were randomized (n = 271) to receive placebo or oral baricitinib at 2, 4, 8 or 10 mg once daily for 12 weeks (Part A). Dose adjustment for 12 additional weeks was based on percentage improvement in the Psoriasis Area and Severity Index (PASI) score. The primary end point was Psoriasis Area and Severity Index (PASI) 75% (PASI‐75) at 12 weeks for North American patients (n = 238); secondary end points were safety and efficacy measures in the entire population.
Results
At week 12, more North American patients in the 8‐mg (43%) and 10‐mg (54%) baricitinib groups than in placebo group (17%; P < 0·05) achieved PASI‐75. All baricitinib‐treated groups had greater mean changes from baseline in their PASI scores (P < 0·05) at 12 weeks and (except 2 mg) had higher rates of PASI‐50 than the placebo group; statistically significant PASI‐90 responses were achieved in the 8‐mg and 10‐mg groups at 8 and 12 weeks. More than 81% of PASI‐75 responders maintained their scores through 24 weeks. During Part A, study discontinuations due to adverse events (AEs) were 0%, 0%, 2·8%, 6·3% and 5·8% and treatment‐emergent AE rates were 44%, 50%, 47%, 58% and 64% for placebo and 2‐, 4‐, 8‐ and 10‐mg baricitinib groups, respectively. No opportunistic infections were observed in any treatment group. Dose‐dependent changes in laboratory values were observed.
Conclusions
Patients with moderate‐to‐severe psoriasis treated with baricitinib for 12 weeks achieved significant improvements in PASI‐75.
What's already known about this topic?
Psoriasis is a common, chronic, immune‐mediated inflammatory skin disease.
Key cytokines involved in the pathogenesis of psoriasis use the Janus kinase–signal transducer and activator of transcription (JAK‐STAT) pathway.
New safe and effective therapies are needed for patients.
What does this study add?
Baricitinib, a selective JAK1/JAK2 inhibitor, demonstrates clinical efficacy in the treatment of psoriasis.
Baricitinib was well tolerated over the 24‐week trial period.
Linked Comment: Albrecht and Gerdes. Br J Dermatol 2016; 174: 1183–1184.
Summary
Background
Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis.
Objectives
To determine the 16‐week efficacy and safety of two oral tofacitinib doses vs. placebo in ...patients with moderate‐to‐severe chronic plaque psoriasis.
Methods
Patients in two similarly designed phase III studies (OPT Pivotal 1, NCT01276639, n = 901; OPT Pivotal 2, NCT01309737, n = 960) were initially randomized 2 : 2 : 1 to tofacitinib 10 or 5 mg or placebo, twice daily. Coprimary efficacy end points (week 16) included the proportion of patients achieving Physician's Global Assessment (PGA) of ‘clear’ or ‘almost clear’ (PGA response) and the proportion achieving ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75).
Results
Across OPT Pivotal 1 and OPT Pivotal 2, 745 patients received tofacitinib 5 mg, 741 received tofacitinib 10 mg and 373 received placebo. At week 16, a greater proportion of patients achieved PGA responses with tofacitinib 5 and 10 mg twice daily vs. placebo (OPT Pivotal 1, 41·9% and 59·2% vs. 9·0%; OPT Pivotal 2, 46·0% and 59·1% vs. 10·9%; all P < 0·001). Higher PASI 75 rates were observed with tofacitinib vs. placebo (OPT Pivotal 1, 39·9%, 59·2% and 6·2%, respectively, for tofacitinib 5 and 10 mg twice daily and placebo; OPT Pivotal 2, 46·0%, 59·6% and 11·4%; all P < 0·001 vs. placebo). Adverse event (AE) rates appeared generally similar across groups; rates of serious AEs, infections, malignancies and discontinuations due to AEs were low. Twelve patients reported herpes zoster across the tofacitinib treatment groups in both studies vs. none in the respective placebo groups. The most common AE across groups was nasopharyngitis.
Conclusions
Oral tofacitinib demonstrated significant efficacy vs. placebo during the initial 16 weeks of treatment in patients with moderate‐to‐severe psoriasis. Safety findings were consistent with prior studies.
What's already known about this topic?
The management of moderate‐to‐severe chronic plaque psoriasis has benefited from the introduction of biological therapies, but unmet needs still remain.
Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis.
A phase IIb study demonstrated that oral tofacitinib is efficacious and well tolerated in the treatment of patients with plaque psoriasis over a 12‐week period.
What does this study add?
These phase III studies demonstrated that oral tofacitinib 5 and 10 mg twice daily is efficacious and well tolerated in the treatment of plaque psoriasis in a large, global patient population over a 16‐week period.
These studies provide support for tofacitinib as an innovative oral systemic option for the treatment of patients with psoriasis in the future.
Summary
Background Tofacitinib is a novel, oral Janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis.
Objectives This Phase 2b, 12‐week, dose‐ranging study ...(A3921047, NCT00678210) aimed to characterize the exposure–response, efficacy and safety of tofacitinib vs. placebo in patients with moderate‐to‐severe chronic plaque psoriasis.
Methods One hundred and ninety‐seven patients were randomized. The primary endpoint was the proportion of patients achieving a ≥ 75% reduction in the Psoriasis Area and Severity Index (PASI 75) score at week 12.
Results At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice‐daily groups: 25·0% (2 mg; P < 0·001), 40·8% (5 mg; P < 0·0001) and 66·7% (15 mg; P < 0·0001), compared with placebo (2·0%). Significant increases in the proportion of PASI 75 responses were seen by week 4 and were maintained at week 12. Exposure–response over the 0–15 mg tofacitinib twice‐daily dose range was successfully characterized. PASI 50, PASI 90 and Physician’s Global Assessment response rates were also higher for tofacitinib vs. placebo. The most frequently reported adverse events (AEs) were infections and infestations: 22·4% (2 mg twice daily), 20·4% (5 mg twice daily), 36·7% (15 mg twice daily) and 32·0% (placebo). Discontinuations due to AEs were 6·0%, 2·0%, 4·1% and 6·1% of patients in the placebo, and 2, 5 and 15 mg twice‐daily tofacitinib groups, respectively. Dose‐dependent increases from baseline in mean serum high‐density lipoprotein, low‐density lipoprotein and total cholesterol, and decreases in haemoglobin and neutrophils were observed.
Conclusion Short‐term treatment with oral tofacitinib results in significant clinical improvement in patients with moderate‐to‐severe plaque psoriasis and is generally well tolerated.
Recent progress in the understanding of percolation theory points to cation-disordered lithium-excess transition metal oxides as high-capacity lithium-ion cathode materials. Nevertheless, the oxygen ...redox processes required for these materials to deliver high capacity can trigger oxygen loss, which leads to the formation of resistive surface layers on the cathode particles. We demonstrate here that, somewhat surprisingly, fluorine can be incorporated into the bulk of disordered lithium nickel titanium molybdenum oxides using a standard solid-state method to increase the nickel content, and that this compositional modification is very effective in reducing oxygen loss, improving energy density, average voltage, and rate performance. We argue that the valence reduction on the anion site, offered by fluorine incorporation, opens up significant opportunities for the design of high-capacity cation-disordered cathode materials.The performance of lithium-excess cation-disordered oxides as cathode materials relies on the extent to which the oxygen loss during cycling is mitigated. Here, the authors show that incorporating fluorine is an effective strategy which substantially improves the cycling stability of such a material.
Summary
Background
MSB11022 is a proposed adalimumab biosimilar.
Objectives
To compare the efficacy, safety and immunogenicity of MSB11022 with reference adalimumab.
Methods
AURIEL‐PsO was a ...double‐blind randomized controlled equivalence trial, in which patients with moderate‐to‐severe chronic plaque‐type psoriasis were randomized 1 : 1 to MSB11022 or reference adalimumab. The primary end point was ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with a prespecified equivalence interval of ± 18%. Patients with a ≥50% improvement in PASI at week 16 were eligible to enter a double‐blind extension period: patients receiving MSB11022 continued treatment, and patients receiving reference adalimumab were rerandomized 1 : 1 either to continue reference adalimumab or to switch to MSB11022. Other efficacy end points and safety, immunogenicity and pharmacokinetic parameters were evaluated at scheduled visits up to weeks 52 (efficacy and immunogenicity), 54 and 66 (safety).
Results
In total, 443 patients were randomized. The difference in PASI 75 response rates at week 16 between the treatment arms was −1·9%, and the 95% confidence interval (−7·8% to 4·1%) was within the prespecified equivalence interval. No notable difference in the incidence of treatment‐emergent adverse events was observed between treatment arms up to the end of the trial, and no new safety signals were observed. Following treatment switch at week 16, no clinically meaningful differences in safety or immunogenicity were seen between treatment arms through to the end of the observation period.
Conclusions
Therapeutic equivalence between MSB11022 and reference adalimumab was demonstrated. AURIEL‐PsO provides evidence to support the similarity of both products with regard to efficacy, safety and immunogenicity.
What's already known about this topic?
Adalimumab is a fully human antitumour necrosis factor‐α monoclonal antibody, indicated for the treatment of multiple inflammatory disorders, including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel diseases and ankylosing spondylitis.
MSB11022 is a proposed adalimumab biosimilar that has shown structural and functional similarity to the reference product in an extensive analytical comparability exercise.
MSB11022 has demonstrated bioequivalence and comparable safety and immunogenicity profiles in a phase I study in healthy volunteers.
What does this study add?
This phase III study confirmed equivalent efficacy for MSB11022 and reference adalimumab in patients without any immunomodulation comedication in moderate‐to‐severe chronic plaque‐type psoriasis at week 16.
The efficacy, safety and immunogenicity of MSB11022 and reference adalimumab were similar over the respective observation periods (week 52 for efficacy and immunogenicity, week 66 for safety).
A switch from reference adalimumab to MSB11022 at week 16 did not impact efficacy, safety or immunogenicity.
Linked Comment: Borroni and Costanzo. Br J Dermatol 2020; 182:266.
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