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The serotonin-receptor modulator pimavanserin reduces psychosis in patients with Parkinson’s disease. In a randomized discontinuation trial involving patients with psychosis related to several types of dementia, the frequency of relapse over a period of 26 weeks was 13% with pimavanserin and 28% with placebo.

In this randomized noninferiority trial involving patients with rheumatoid arthritis, cardiovascular events and cancers occurred more frequently with tofacitinib than with a TNF inhibitor, and noninferiority of tofacitinib with respect to these end points was not established.

In three phase 3 trials involving patients with ulcerative colitis, tofacitinib (an oral, small-molecule Janus kinase inhibitor) was more effective as induction and maintenance therapy than placebo. Infections were more common with tofacitinib. Ulcerative colitis is characterized by an increased frequency of bowel movements and bloody diarrhea, which has a negative effect on quality of life. 1 Current therapies for ulcerative colitis include mesalamine, glucocorticoids, thiopurines, and antagonists to tumor necrosis factor (TNF) and α4β7 integrin. 1 – 5 Many patients do not have a response to these therapies or have a response that is not sustained. Additional treatment options with new mechanisms of action are needed to increase efficacy rates. The Janus kinase (JAK) family comprises four intracellular tyrosine kinases — JAK1, JAK2, JAK3, and nonreceptor tyrosine-protein kinase 2 — that activate signal transducers and . . .

Daily use of atogepant (a small-molecule, calcitonin gene–related peptide receptor antagonist) at any of three doses resulted in greater reductions in migraine days per month over a period of 12 weeks than did placebo. Nausea and constipation were side effects in approximately 5% of the participants who received atogepant.

In a randomized trial, patients who received evobrutinib, an inhibitor of Bruton’s tyrosine kinase, at 75 mg daily had significantly fewer enhancing lesions on MRI during weeks 12 through 24 than those who received placebo. However, there was no significant between-group difference for either a lower or a higher dose of evobrutinib, or in the annualized relapse rate or disability progression at any dose.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate. ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non-inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98·34% CI of the difference between comparators was larger than −13·0%. This trial is registered with ClinicalTrials.gov, number NCT02187055. 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98·34% CI −6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (−6 [−14 to 3]) or tofacitinib and methotrexate (−8 [−16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year. Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination. Pfizer Inc.

Patients with newly diagnosed advanced ovarian cancer were randomly assigned to receive daily niraparib, a PARP inhibitor, or placebo as maintenance therapy after having had a response to platinum-based chemotherapy. Progression-free survival was significantly longer in the niraparib group than in the placebo group, with some increase in the frequency of myelosuppression and nausea.

Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II–IV mantle cell lymphoma, aged 18–65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1–5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1–4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1–19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258. Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84–92) versus 72% (67–79; hazard ratio 0·52 [one-sided 98·3% CI 0–0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67–79) versus 86% (82–91; hazard ratio 1·77 [one-sided 98·3% CI 0–3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3–5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3–5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. Janssen and Leukemia & Lymphoma Society.

Treatment of psoriatic arthritis with the oral Janus kinase inhibitor tofacitinib for 3 months was more effective than placebo in reducing joint manifestations, as determined by the American College of Rheumatology 20% response rate, but was associated with herpes infections.

Alectinib, a potent ALK tyrosine kinase inhibitor, was more effective and somewhat less toxic than crizotinib when used as primary therapy in patients with ALK -positive non–small-cell lung cancer. Importantly, it reduced the risk of CNS relapse.