Cenerimod, a sphingosine-1-phosphate receptor modulator, versus placebo in patients with moderate-to-severe systemic lupus erythematosus (CARE): an international, double-blind, randomised, placebo-controlled, phase 2 trial.

Sphingosine-1-phosphate (S1P) is a signalling molecule that has an inhibitory role in atherosclerosis, inflammation, cell proliferation, and immunity. Cenerimod is a selective S1P1 receptor modulator under investigation for the treatment of systemic lupus erythematosus (SLE). We aimed to determine the efficacy, safety, and tolerability of four doses of cenerimod in adults with moderate-to-severe SLE receiving standard of care background therapy. CARE was a double-blind, randomised, placebo-controlled, phase 2 trial, in adults (aged 18-75 years) with moderate-to-severe SLE (a score of at least 6 out of 105 on the SLE disease activity index-2000, modified to exclude leukopenia [mSLEDAI-2K] score). Participants were recruited from 189 hospitals, specialist centres, and outpatient clinics in 22 countries in Asia Pacific, Latin America, Europe, and the USA. Participants were randomly assigned (1:1:1:1:1), using an interactive response technology via balanced block randomisation (block size of 5) and stratified by oral glucocorticoid dose at randomisation and disease activity at screening, to once-daily oral cenerimod at 0·5 mg, 1·0 mg, 2·0 mg, or 4·0 mg or placebo, in addition to stable background SLE therapy, and followed up for 12 months. After 6 months, participants assigned to cenerimod 4·0 mg were randomly assigned again (1:1) to either cenerimod 2.0 mg or placebo for a further 6 months. The primary endpoint was change from baseline to month 6 in mSLEDAI-2K score, assessed in all participants randomly assigned to treatment (full analysis set). To meet the primary endpoint, the doses had to show a significant improvement over placebo, when adjusting for multiplicity, considering the hierarchical testing strategy, per a prespecified plan. Safety analyses included all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03742037, and is complete. Between Dec 21, 2018, and Aug 25, 2022, 810 patients were screened and 427 were randomly assigned to 0·5 mg (n=85), 1·0 mg (n=85), 2·0 mg (n=86), and 4·0 mg (n=85) cenerimod or placebo (n=86). Median age was 42 years (IQR 33-51), 406 (95%) of 427 participants were women, 21 (5%) were men, and 337 (79%) were White. At month 6, the least squares mean change from baseline in mSLEDAI-2K score was -2·85 (95% CI -3·60 to -2·10) for the placebo group and -3·24 (-3·98 to -2·49; difference vs placebo -0·39 [95% CI -1·45 to 0·68]; p=0·47) for the cenerimod 0·5 mg group, -3·41 (-4·16 to -2·67; difference vs placebo -0·57 [-1·62 to 0·49]; p=0·29) for the 1·0 mg group, -2·84 (-3·58 to -2·09; difference vs placebo 0·01 [-1·05 to 1·08]; p=0·98) for the 2·0 mg group, and -4·04 (-4·79 to -3·28; difference vs placebo -1·19 [-2·25 to -0·12]; p=0·029) for the 4·0 mg group; hence, the primary endpoint was not met. Treatment-emergent adverse events up to 12 months had no clear treatment-related or dose-related pattern across the groups. At month 6, treatment-emergent lymphopenia was reported in one (1%) of 85 patients who received cenerimod 0·5 mg, five (6%) of 85 patients who received 1·0 mg, nine (10%) of 86 patients who received 2·0 mg, 12 (14%) of 84 patients who received 4·0 mg, and no patients who received placebo. Two deaths due to adverse events occurred (both in the cenerimod 1·0 mg group; one due to acute coronary syndrome and the other due to upper gastrointestinal haemorrhage), and were determined to be unrelated to study treatment. The primary endpoint was not met. Cenerimod was well tolerated over 12 months. Cenerimod 4·0 mg is being investigated for the treatment of SLE in two ongoing phase 3 trials (NCT05648500, NCT05672576). Idorsia Pharmaceuticals.

Askanase AD ，D'Cruz D ，Kalunian K ，Merrill JT ，Navarra SV ，Cahuzac C ，Cornelisse P ，Murphy MJ ，Strasser DS ，Trokan L ，Berkani O ... -  《Lancet Rheumatology》

Efficacy and safety of filgotinib as induction and maintenance therapy for Crohn's disease (DIVERSITY): a phase 3, double-blind, randomised, placebo-controlled trial.

There is a need for efficacious therapies for patients with Crohn's disease that are better tolerated and more durable than available treatments. We aimed to evaluate the efficacy and safety of filgotinib, an oral Janus kinase 1 preferential inhibitor, for treating Crohn's disease. This phase 3, double-blind, randomised, placebo-controlled trial was conducted in 371 centres in 39 countries. Eligible patients were aged 18-75 years with moderately to severely active Crohn's disease for at least 3 months before enrolment. Patients were enrolled into one of two induction studies on the basis of their experience with biological agents (induction study A included biologic-naive and later biologic-experienced patients and induction study B included biologic-experienced patients). In both induction studies, patients were randomly assigned (1:1:1), using an interactive web response system, to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once daily for 11 weeks. Patients who received filgotinib and had two-item patient-reported outcome (PRO2) clinical remission or an endoscopic response at week 10 were re-randomised (2:1) to receive their induction dose or placebo orally, once daily to the end of week 58 in the maintenance study. Co-primary endpoints were PRO2 clinical remission and an endoscopic response at week 10 (induction studies) and week 58 (maintenance study). PRO2 clinical remission was defined as an abdominal pain subscore of not more than 1 and a liquid or very soft stool frequency subscore of not more than 3 (from eDiary data) and endoscopic response was defined as a reduction of at least 50% in Simple Endoscopic Score for Crohn's disease from induction baseline (from central reading of endoscopy). For the induction studies, efficacy was assessed in all randomly assigned patients who received at least one dose of study drug. For the maintenance study, efficacy was assessed in all patients from either filgotinib treatment group in the induction studies who reached PRO2 clinical remission or an endoscopic response at week 10, and who were re-randomised and received at least one dose of study drug in the maintenance study. Patients who received placebo throughout the induction and maintenance studies were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of study drug. This trial is complete and is registered with ClinicalTrials.gov, NCT02914561. Between Oct 31, 2016, and Nov 11, 2022, 2634 patients were screened, of whom 1372 were enrolled (induction study A: n=707, induction study B: n=665, and maintenance study: n=481). There were 346 (49%) women and 358 (51%) men in induction study A, 356 (54%) women and 303 (46%) men in induction study B, and 242 women (51%) and 236 men (49%) in the maintenance study. Significantly more patients had PRO2 clinical remission at week 10 with filgotinib 200 mg than with placebo in induction study B (29·7% vs 17·9%, difference 11·9%; 95% CI 3·7 to 20·2, p=0·0039) but not induction study A (32·9% vs 25·7%, 6·9%; -1·4 to 15·2, p=0·0963); there was no significant difference for endoscopic response (induction study A: 23·9% vs 18·1%, difference 5·5%; 95% CI -2·0 to 12·9, p=0·1365; induction study B: 11·9% vs 11·4%, 0·1%; -6·5 to 6·6, p=0·9797). At week 58, both co-primary endpoints were reported in greater proportions of patients who received filgotinib 200 mg than in those who received placebo (PRO2 clinical remission: 43·8% vs 26·4%, difference 16·8%; 95% CI 2·0 to 31·6, p=0·0382; endoscopic response: 30·4% vs 9·4%, difference 20·6%; 95% CI 8·2 to 33·1, p=0·0038). Co-primary endpoints were not met for filgotinib 100 mg in any study. In the induction studies, the most frequently reported treatment-emergent adverse events (TEAEs; ≥5% of patients in any group) were abdominal pain; arthralgia; an exacerbation, flare, or worsening of Crohn's disease; headache; nasopharyngitis; nausea; and pyrexia. In the maintenance study, the most frequently reported TEAEs (≥5% of patients in any filgotinib or associated placebo group) were those reported in the induction studies (except for headache) and abdominal distension, upper abdominal pain, anaemia, and flatulence. Serious TEAEs were reported in 49 patients in induction study A (18 [8%]) of 222 patients in the filgotinib 200 mg group, 16 [7%] of 245 patients in the filgotinib 100 mg group, and 15 [6%] of 237 patients in the placebo group), 81 patients in induction study B (19 [9%] of 202 patients in the filgotinib 200 mg group, 36 [16%] of 228 patients in the filgotinib 100 mg group, and 26 [11%] of 229 patients in the placebo group), and 49 patients in the maintenance study (13 [11%] of 118 patients in the filgotinib 200 mg-filgotinib 200 mg group, five [9%] of 56 patients in the filgotinib 200 mg-placebo group, 14 [13%] of 104 patients in the filgotinib 100 mg-filgotinib 100 mg group, three [5%] of 55 patients in the filgotinib 100 mg-placebo group, and 14 [10%] of 145 patients in the placebo-placebo group). No deaths were reported during the induction and maintenance studies. Filgotinib 200 mg did not meet the co-primary endpoints of clinical remission and an endoscopic response at week 10, but did meet the co-primary endpoints at week 58. Filgotinib treatment was well tolerated, and no new safety signals were reported. Galapagos.

Vermeire S ，Schreiber S ，Rubin DT ，D'Haens G ，Reinisch W ，Watanabe M ，Mehta R ，Roblin X ，Beales I ，Gietka P ，Hibi T ，Hospodarskyy I ，Ritter T ，Genovese MC ，Kwon P ，Santermans E ，Le Brun FO ，Barron R ，Masior T ，Danese S ... -  《The Lancet Gastroenterology & Hepatology》

Erratum: Eyestalk Ablation to Increase Ovarian Maturation in Mud Crabs.

《Jove-Journal of Visualized Experiments》

Vanzacaftor-tezacaftor-deutivacaftor versus elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials.

The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis. Vanzacaftor-tezacaftor-deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry. We aimed to evaluate the efficacy and safety of vanzacaftor-tezacaftor-deutivacaftor compared with standard of care elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older. In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor-tezacaftor-ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively. Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening. They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period. All participants received matching placebo tablets to maintain the treatment blinding. Randomisation was done using an interactive web-response system and stratified by age, FEV1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103. The primary endpoint for both trials was absolute change in FEV1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor-tezacaftor-deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was -3·0 or higher). Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period. Safety was assessed in all participants who received at least one dose of study drug during the treatment period. These trials are registered with ClinicalTrials.gov, NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete. In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=202) or vanzacaftor-tezacaftor-deutivacaftor (n=196). Median age was 31·0 years (IQR 22·6-38·5), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White. In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=289) or vanzacaftor-tezacaftor-deutivacaftor (n=284). Median age was 33·1 years (IQR 24·5-42·2), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White. The absolute change in least squares mean FEV1 % predicted from baseline through week 24 for Trial VX20-121-102 was 0·5 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·3 (0·3) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference of 0·2 percentage points [95% CI -0·7 to 1·1]; p<0·0001), and for Trial VX20-121-103, was 0·2 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·0 (0·2) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference 0·2 percentage points [95% CI -0·5 to 0·9]; p<0·0001). Most adverse events were mild or moderate, with the most common being infective pulmonary exacerbation (133 [28%] of 480 participants in the pooled vanzacaftor-tezacaftor-deutivacaftor group vs 158 [32%] of 491 in the pooled elexacaftor-tezacaftor-ivacaftor group), cough (108 [23%] vs 101 [21%]), COVID-19 (107 [22%] vs 127 [26%]), and nasopharyngitis (102 [21%] vs 95 [19%]). Vanzacaftor-tezacaftor-deutivacaftor is non-inferior to elexacaftor-tezacaftor-ivacaftor in terms of FEV1 % predicted, and is safe and well tolerated. Once daily dosing with vanzacaftor-tezacaftor-deutivacaftor reduces treatment burden, potentially improving adherence, compared with the twice daily regimen of the current standard of care. The restoration of CFTR function and the potential variants treated are also considerations that should be compared with currently available CFTR modulators. Vertex Pharmaceuticals.

Keating C ，Yonker LM ，Vermeulen F ，Prais D ，Linnemann RW ，Trimble A ，Kotsimbos T ，Mermis J ，Braun AT ，O'Carroll M ，Sutharsan S ，Ramsey B ，Mall MA ，Taylor-Cousar JL ，McKone EF ，Tullis E ，Floreth T ，Michelson P ，Sosnay PR ，Nair N ，Zahigian R ，Martin H ，Ahluwalia N ，Lam A ，Horsley A ... -  《-》

Efficacy, safety, and target engagement of dazukibart, an IFNβ specific monoclonal antibody, in adults with dermatomyositis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial.

Dermatomyositis is a chronic autoimmune disease with distinctive cutaneous eruptions and muscle weakness, and the pathophysiology is characterised by type I interferon (IFN) dysregulation. This study aims to assess the efficacy, safety, and target engagement of dazukibart, a potent, selective, humanised IgG1 neutralising monoclonal antibody directed against IFNβ, in adults with moderate-to-severe dermatomyositis. This multicentre, double-blind, randomised, placebo-controlled, phase 2 trial was conducted at 25 university-based hospitals and outpatient sites in Germany, Hungary, Poland, Spain, and the USA. Adults aged 18-80 years with skin-predominant dermatomyositis were enrolled during stages 1, 2, and 2a, and had to have a Cutaneous Dermatomyositis Disease Area and Severity Index-Activity (CDASI-A) score of 14 or more and at least one unsuccessful systemic treatment with standard of care; whereas those with muscle-predominant dermatomyositis were enrolled in stage 3 and had to have active moderate muscle involvement. Patients were randomly assigned using an interactive response technology system to dazukibart 600 mg or placebo in stage 1; dazukibart 600 mg, dazukibart 150 mg, or placebo in stage 2; dazukibart 600 mg then placebo, dazukibart 150 mg then placebo, placebo then dazukibart 600 mg, or placebo then dazukibart 150 mg in stage 2a; and dazukibart 600 mg then placebo or placebo then dazukibart 600 mg in stage 3. For stage 2a and stage 3, treatments were switched at week 12. Patients, investigators, outcome assessors, and funders were masked to the treatment assignment. Dazukibart and placebo were administered intravenously on day 1 every 4 weeks, up to and including week 8 (stages 1 and 2, and stages 2a and 3 for patients starting dazukibart), or on week 12 every 4 weeks, up to and including week 20 (stages 2a and 3 for patients who started placebo and switched to dazukibart). The primary outcome for the skin-predominant cohorts was the change from baseline in CDASI-A score at week 12 assessed in the full analysis set (FAS; stage 1) and the pooled skin FAS (stages 1, 2, and 2a), and safety in the muscle-predominant cohort. This study is registered with ClinicalTrials.gov, NCT03181893. Between Jan 23, 2018, and Feb 23, 2022, 125 adults were assessed and 50 were excluded. 75 patients were randomly assigned and treated (15 to dazukibart 150 mg, 37 to dazukibart 600 mg, and 23 to placebo). Most patients were female (53 [93%] of 57 in the skin-predominant cohort vs 13 [72%] of 18 in the muscle-predominant cohort and four [7%] vs five [28%] were male). In the FAS in stage 1 at week 12, the mean change from baseline in CDASI-A for dazukibart 600 mg was -18·8 (90% CI -21·8 to -15·8; placebo-adjusted difference -14·8 [-20·3 to -9·4]; p<0·0001). In the pooled skin FAS at week 12, the mean change from baseline in CDASI-A for the dazukibart 600 mg group was -19·2 (-21·5 to -16·8; placebo-adjusted difference -16·3 [-20·4 to -12·1]; p<0·0001), whereas the dazukibart 150 mg group was -16·6 (-19·8 to -13·4; placebo-adjusted difference -13·7 [-18·3 to -9·0]; p<0·0001). Treatment-emergent adverse events occurred in 12 (80%) of 15 patients in the dazukibart 150 mg group versus 30 (81%) of 37 in the dazukibart 600 mg group versus 18 (78%) of 23 in the placebo group, with the most common being infections and infestations (two [13%] vs 12 [32%] vs seven [30%]). Four (11%) patients in the dazukibart 150 mg group and one (4%) in the placebo group reported serious adverse events. One patient in stage 3 received dazukibart 600 mg then placebo and died during follow-up due to haemophagocytic lymphohistiocytosis and macrophage activation syndrome. Dazukibart resulted in a pronounced reduction in disease activity and was generally well tolerated, supporting IFNβ inhibition as a highly promising therapeutic strategy in adults with dermatomyositis. Pfizer.

Fiorentino D ，Mangold AR ，Werth VP ，Christopher-Stine L ，Femia A ，Chu M ，Musiek ACM ，Sluzevich JC ，Graham LV ，Fernandez AP ，Aggarwal R ，Rieger K ，Page KM ，Li X ，Hyde C ，Rath N ，Sloan A ，Oemar B ，Banerjee A ，Salganik M ，Banfield C ，Neelakantan S ，Beebe JS ，Vincent MS ，Peeva E ，Vleugels RA ... -  《-》