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In a trial comparing enfortumab vedotin and a PD-1 inhibitor with chemotherapy in patients with untreated advanced or metastatic urothelial cancer, progression-free and overall survival nearly doubled with the experimental treatment.

In a phase 3 trial, participants with early Alzheimer’s disease who received the monoclonal antibody lecanemab had less decline on measures of cognition and function at 18 months than those who received placebo.

Mirikizumab, a humanised monoclonal antibody that inhibits IL-23p19, is effective in moderate-to-severe ulcerative colitis. We aimed to evaluate the efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn's disease. VIVID-1 was a global phase 3, randomised, double-blind, double-dummy, placebo-controlled and active-controlled, treat-through study. The study enrolled adult patients at 324 sites (hospitals or medical centres, clinical practices, and clinical research sites) in 33 countries across Europe, Asia, North America, Central America, South America, and Australia. Adult patients with moderately-to-severely active Crohn's disease and previous inadequate response, loss of response, or intolerance to one or more approved biological therapies or conventional therapies were randomly assigned 6:3:2 to receive mirikizumab 900 mg intravenously at weeks 0, 4, and 8, then 300 mg subcutaneously every 4 weeks from weeks 12 to 52; ustekinumab about 6 mg/kg intravenously at week 0, then 90 mg subcutaneously every 8 weeks from weeks 8 to 52; or placebo. The coprimary endpoints assessing superiority of mirikizumab over placebo were composite endpoints: patient-reported outcome (PRO) clinical response at week 12 and endoscopic response at week 52 (endoscopic response-composite), and PRO clinical response at week 12 and Crohn's Disease Activity Index (CDAI) clinical remission at week 52 (CDAI clinical remission-composite). The adjusted risk differences were calculated, and the comparison was performed by the Cochran–Mantel–Haenszel test. Non-responder imputation was used. VIVID-1 was registered on ClinicalTrials.gov, NCT03926130, and is now complete. Between July 23, 2019, and Aug 23, 2023, 1150 patients were randomly assigned and received study treatment (safety population); 1065 patients were included in the efficacy population and received mirikizumab (n=579), ustekinumab (n=287), or placebo (n=199). Both coprimary endpoints were met: endoscopic response-composite was reached in 220 (38·0%) of 579 patients on mirikizumab versus 18 (9·0%) of 199 on placebo (99·5% CI 20·6–36·8; p<0·0001); CDAI clinical remission-composite was reached in 263 (45·4%) of 579 patients on mirikizumab versus 39 (19·6%) of 199 patients on placebo (99·5% CI 15·9–35·6; p<0·0001). The incidence rates of overall adverse events and discontinuations in patients treated with mirikizumab were lower compared with placebo. The most common adverse event across the three groups was COVID-19. Serious adverse events were reported in 65 (10·3%) of 630 patients on mirikizumab, 33 (10·7%) of 309 patients on ustekinumab, and 36 (17·1%) of 211 patients on placebo. There were three deaths during VIVID-1, one in the ustekinumab group, and two in the placebo group, including one in a placebo non-responder who switched to mirikizumab after week 12. None of the deaths were considered related to the study drug. The safety of mirikizumab in Crohn’s disease was consistent with its known favourable profile. Mirikizumab was safe and effective as induction and maintenance treatment for patients with moderately-to-severely active Crohn's disease who had intolerance, inadequate response, or loss of response to standard therapy. Eli Lilly and Company.

Angiopoietin-like 3 is an inhibitor of lipoprotein lipase. Evinacumab is a monoclonal antibody that inhibits angiopoietin-like 3, activating lipoprotein lipase. In patients with hypercholesterolemia that is refractory to statin and PCSK9 inhibitor therapy, the use of evinacumab reduced plasma lipid levels by more than 50% at the maximum dose.

In this 12-week phase 2 trial, a humanized anti–interleukin-17 monoclonal antibody was effective for chronic plaque psoriasis. Larger studies of longer duration are necessary to assess the safety and efficacy of long-term treatment. Psoriasis vulgaris (plaque psoriasis) is a chronic, frequently painful, and often debilitating skin disorder. The estimated prevalence of diagnosed psoriasis in the United States is 3%, with approximately 17% of these patients having moderate-to-severe plaque psoriasis. 1 Psoriasis is characterized by inflammation and keratinocyte hyperproliferation 2 thought to be the pathological consequence of a T-cell–mediated immune response to an as-yet unidentified autoantigen. Studies have shown that a subgroup of CD4+ T cells, type 17 helper T (Th17) cells, may play a specific pathological role in psoriasis. 3 Type 17 helper T cells secrete a number of proinflammatory cytokines, including interleukin-17A, a member of . . .

Background To investigate the safety, pharmacokinetics, preliminary efficacy, pharmacodynamics, and immunogenicity of QX002N, an interleukin-17 A monoclonal antibody, in Chinese patients with active ankylosing spondylitis (AS). Methods In this phase 1b, double-blind, placebo-controlled, multiple ascending dose study, eligible patients with active AS were randomized into three dose (40, 80, or 160 mg) cohorts, with a 4:1 ratio in each cohort to subcutaneously receive either QX002N or a placebo once every 2 weeks with six doses in total. All patients were followed for 14 weeks (98 days) after the last dose. The primary endpoints were the safety and pharmacokinetics of QX002N, and the secondary endpoints included its preliminary efficacy, pharmacodynamics, and immunogenicity. Results Thirty patients ( n  = 10 in each cohort) were included, with 24 receiving QX002N and 6 receiving a placebo. A total of 85 adverse drug reactions, predominantly Grade 1–2, were identified in 20 out of 24 patients (83.3%) who took QX002N. The exposure to QX002N increased proportionally with the dose escalating from 40 mg to 160 mg. Patients taking 160 mg QX002N achieved higher response rates (ASAS20: 87.6% at Week 8 [Day 56]); ASAS40: 50.0% at Week 12 [Day 78]), than those taking 40-mg or 80-mg QX002N. An increase in interleukin-17 A and a decrease in interleukin-6 levels in the serum, with decreases in the erythrocyte sedimentation rate and high-sensitivity C-reactive protein levels, were observed. Anti-drug antibodies were detected in only one of 24 patients taking QX002N. Conclusions Subcutaneous administration of QX002N demonstrates a favorable safety profile, with linear pharmacokinetic characteristics. Promising clinical responses in pharmacodynamics and preliminary efficacy have been observed. Immunogenicity does not appear to be a concern. Trial registration This study was registered with Chinadrugtrials.org.cn (CTR20201277), the data of registration was in 20 Jul, 2020. Key points QX002N, an anti-interleukin-17 A monoclonal antibody, was evaluated in this Phase 1b, multiple ascending dose study to assess its safety, efficacy, pharmacodynamics, pharmacokinetics, and immunogenicity in patients with AS. In the QX002N 160-mg group, 87.6% (7/8) of the patients achieved an ASAS20 response after the final dose. An increase in the concentrations of total interleukin-17 A and a decrease in interleukin-6 from the baseline were observed in all dose groups, along with a substantial decrease in the erythrocyte sedimentation rate and the levels of high-sensitivity C-reactive protein. The safety profiles observed in patients receiving multiple doses of QX002N up to 160 mg support future investigations of QX002N as a potential treatment for AS in Phase 2 and 3 clinical trials.

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV) 1 . However, eradication of the virus in individuals with HIV has not been possible to date 2 . Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication 3 . Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives. Combination therapy of broadly neutralizing monoclonal antibodies can provide long-term virological suppression in individuals infected with HIV without antiretroviral therapy.

Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer's disease. We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.).

Inflammation mediated by interleukin-6 (IL-6) is strongly associated with cardiovascular risk. Here we evaluated clazakizumab, a monoclonal antibody targeting the IL-6 ligand, in a phase 2b dose-finding study. Adults with cardiovascular disease and/or diabetes receiving maintenance dialysis with high-sensitivity C-reactive protein (hs-CRP) ≥ 2 mg l −1 at baseline were randomized to receive clazakizumab (2.5 mg, 5 mg or 10 mg, n  = 32 per dose group) or placebo ( n  = 31) every 4 weeks. The primary endpoint was the change from baseline in hs-CRP to week 12, expressed as the geometric mean ratio. Clazakizumab treatment signficantly reduced serum hs-CRP concentrations at week 12 by 86%, 90% and 92% relative to placebo in patients randomized to 2.5 mg, 5 mg or 10 mg clazakizumab, respectively (all P  < 0.0001), meeting the primary outcome. With regard to secondary endpoints, clazakizumab treatment reduced serum fibrinogen, amyloid A, secretory phospholipase A2, and lipoprotein(a) concentrations, as well as increased mean serum albumin concentrations at 12 weeks, relative to placebo. The proportion of patients who achieved hs-CRP < 2.0 mg l −1 was 79%, 82% and 79% in the 2.5 mg, 5 mg and 10 mg clazakizumab groups, respectively, compared with 0% of placebo-treated patients. With regard to safety, no cases of sustained grade 3 or 4 thrombocytopenia or neutropenia were observed. Serious infections were seen with similar frequency in the placebo, clazakizumab 2.5 mg and clazakizumab 5 mg groups, but were numerically more frequent in the clazakizumab 10 mg group. The results of this trial indicate that in patients receiving maintenance dialysis, clazakizumab reduced inflammatory biomarkers associated with cardiovascular events. ClinicalTrials.gov registration: NCT05485961 . In a randomized clinical trial, treatment using a monoclonal antibody targeting interleukin-6 (IL-6) in patients with cardiovascular disease and/or diabetes who were receiving maintenance kidney dialysis reduced levels of inflammatory biomarkers at 12 weeks, including C-reactive protein, paving the way for a phase 3 trial.

Sjögren's disease is a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease. This randomised, double-blind, placebo-controlled, phase 2b study, conducted at 71 sites in 23 countries, enrolled patients aged 18 years or older fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) 2016 criteria. In the dose-ranging cohort 1, patients with a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or higher were randomly assigned (1:1:1:1) to subcutaneous iscalimab 150 mg, 300 mg, 600 mg, or placebo. In the proof-of-concept cohort 2, patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher were randomly assigned (1:1) to iscalimab 600 mg or placebo. The sponsor, investigator, site personnel, and patients were masked to the treatment assignment. The primary objectives were to demonstrate a dose–response relationship of iscalimab based on the change in ESSDAI from baseline to week 24 in cohort 1 by Multiple Comparison Procedure—Modelling (MCP-Mod), and to assess the effect of iscalimab 600 mg on ESSPRI at week 24 in cohort 2. All the efficacy analyses included all patients who were randomly assigned, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03905525), and is complete. Between Oct 1, 2019, and Feb 28, 2022, 460 patients were screened; 173 patients were assigned to cohort 1 (44 to iscalimab 150 mg, 43 to 300 mg, 43 to 600 mg, and 43 to placebo) and 100 to cohort 2 (50 to each group). In cohort 1, the MCP step showed a significant dose–response relationship for placebo-adjusted ESSDAI change from baseline in one of four models (Linlog model, one-sided p=0·0041). ESSDAI decreased from baseline to week 24 with all three doses of iscalimab; 150 mg and 600 mg doses showed statistically significant improvement (placebo-adjusted least squares [LS] mean difference –3·0 [95% CI –4·9 to –1·1]; p=0·0025 for 150 mg and –2·9 [–4·9 to –1·0]; p=0·0037 for 600 mg). In cohort 2, ESSPRI showed a trend towards improvement with iscalimab 600 mg (placebo-adjusted LS mean change from baseline –0·57 points [95% CI –1·30 to 0·15]; p=0·12). Serious adverse events were reported in nine patients in cohort 1 (one [2%] of 43 in the placebo group, one [2%] of 44 in the iscalimab 150 mg group, three [7%] of 42 in the 300 mg group, four [9%] of 44 in the 600 mg group) and four patients in cohort 2 (two [4%] of 50 in each group). No deaths occurred over the 24-week period. The study met the primary objective of demonstrating a significant dose–response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials. Novartis Pharma.