Clowse MEB, Isenberg DA, Merrill JT
… +16 more, Dörner T, Petri M, Vital EM, Morand EF, Touma Z, Askanase AD, Ioannou Y, Brookes S, Gaiha-Rohrbach J, Koch ED, Zibian N, Martin C, Jimenez T, Nelde A, Stach C, PHOENYCS GO Study Investigators’ Group
BACKGROUND: Dapirolizumab pegol is a novel CD40 ligand inhibitor. In this phase 3 trial, we aimed to evaluate the efficacy and safety of dapirolizumab pegol in patients with systemic lupus erythematosus (SLE). METHODS: P...BACKGROUND: Dapirolizumab pegol is a novel CD40 ligand inhibitor. In this phase 3 trial, we aimed to evaluate the efficacy and safety of dapirolizumab pegol in patients with systemic lupus erythematosus (SLE). METHODS: PHOENYCS GO was a 48-week, randomised, double-blind, placebo-controlled, phase 3 trial conducted in 177 centres (hospitals, private practices, and trial centres) in 25 countries. Patients aged 16 years or older with moderate-to-severe, active SLE despite standard-of-care medication were randomly assigned (2:1), via an interactive web response system, to intravenous dapirolizumab pegol 24 mg/kg or placebo every 4 weeks in addition to standard of care. Patients, investigators, and funders were blinded to treatment assignments. The primary outcome was British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response at week 48. Efficacy analyses were conducted on a modified intention-to-treat population. Safety analyses included all randomly assigned patients who received at least one study medication dose. This trial is registered with ClinicalTrials.gov (NCT04294667) and is completed. FINDINGS: Between Aug 12, 2020, and June 8, 2023, 643 patients were screened and 321 patients were randomly assigned to dapirolizumab pegol (n=213) or placebo (n=108) plus standard of care. All randomly assigned patients received at least one dose of study medication. Six patients were excluded due to non-compliance of one site with Good Clinical Practice guidelines; therefore, the full-analysis set included 315 patients (293 female, 22 male). A significantly greater proportion of patients receiving dapirolizumab pegol (50% [103/208]) versus placebo (35% [37/107]) had BICLA response at week 48 (p=0·011; difference 14·6; 95% CI 3·3-25·8). Treatment-emergent adverse events occurred in 83% (176/213) of patients receiving dapirolizumab pegol versus 75% (81/108) receiving placebo. Serious treatment-emergent adverse events occurred in 10% (21/213) of patients receiving dapirolizumab pegol versus 15% (16/108) receiving placebo. Hypersensitivity reactions during infusion occurred in 3% (6/213) of patients receiving dapirolizumab pegol. Serious infections occurred in 4% (8/213) and 6% (6/108) of patients receiving dapirolizumab pegol and placebo, respectively. One thromboembolic event (myocardial infarction) occurred in one patient in the dapirolizumab pegol group and one death (gangrene-related sepsis) occurred in another patient in the dapirolizumab pegol group. INTERPRETATION: Dapirolizumab pegol was associated with significant improvement in disease activity in patients with SLE. These findings support the further investigation of dapirolizumab pegol as a treatment option for SLE. FUNDING: UCB and Biogen.
Xiong A, Yao W, Zheng W
… +33 more, Yu Y, Chen P, Zhong H, Ge J, Wang H, Chen B, Wang H, Fan Y, Yang Y, Pu X, Song X, Wang Q, Du X, Huang Z, Li X, Luo H, Yao Y, Yu Q, Su C, He L, Jiang G, Cui J, Liu C, Yi T, Che G, Liu Z, Zhang L, Zhou M, Fang Y, Wei Y, Qing Y, Jin X, Zhou C
BACKGROUND: Sacituzumab tirumotecan (sac-TMT), a trophoblast cell-surface antigen 2-targeting antibody-drug conjugate, combined with programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors, has shown pr...BACKGROUND: Sacituzumab tirumotecan (sac-TMT), a trophoblast cell-surface antigen 2-targeting antibody-drug conjugate, combined with programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors, has shown promising antitumour activity as first-line therapy for non-small-cell lung cancer (NSCLC) in early-phase studies. Our aim was to evaluate the efficacy and safety of sac-TMT plus pembrolizumab as first-line treatment for patients with PD-L1-positive advanced NSCLC without targetable genomic alterations. METHODS: In this randomised, open-label, phase 3 trial (OptiTROP-Lung05) conducted across 68 hospitals in China, eligible patients had locally advanced or metastatic NSCLC without targetable genomic alterations and a PD-L1 tumour proportion score (TPS) of 1% or greater. Patients were randomly assigned (1:1) to receive sac-TMT (4 mg/kg on days 1, 15, and 29) plus pembrolizumab (400 mg fixed dose on day 1), or pembrolizumab alone, administered intravenously every 6 weeks. The primary endpoint was progression-free survival, as assessed by blinded independent central review in the intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT06448312). Recruitment is complete, with the trial ongoing and the final analysis to be reported later. FINDINGS: Between June 7, 2024, and March 27, 2025, 741 patients were screened and 413 eligible patients were randomly assigned to receive sac-TMT plus pembrolizumab (n=208) or pembrolizumab alone (n=205). At the prespecified interim analysis, conducted after a median follow-up of 10·5 months (IQR 8·7-12·5), median progression-free survival was significantly longer with sac-TMT plus pembrolizumab than with pembrolizumab alone (not reached vs 5·7 months; stratified hazard ratio [HR] 0·35 [95% CI 0·26-0·47]; p<0·0001). The progression-free survival benefit was broadly consistent across subgroups, including patients with PD-L1 TPS of 1-49% (HR 0·28 [95% CI 0·19-0·41]) and those with PD-L1 TPS of 50% or greater (HR 0·47 [0·29-0·77]). Grade 3 or higher treatment-emergent adverse events occurred in 115 (55%) of 208 patients in the sac-TMT plus pembrolizumab group and 64 (31%) of 204 patients in the pembrolizumab group. INTERPRETATION: Among patients with PD-L1-positive advanced NSCLC without targetable genomic alterations, first-line treatment with sac-TMT plus pembrolizumab significantly prolonged progression-free survival compared with pembrolizumab alone. Therefore, sac-TMT plus pembrolizumab has the potential to redefine first-line treatment for patients with PD-L1-positive advanced NSCLC without targetable genomic alterations. FUNDING: Sichuan Kelun-Biotech Biopharmaceutical.
Alzheimer's disease is the leading cause of dementia and among the top ten leading causes of death in high-income countries. Exponential advances in epidemiology, genetics, diagnostic imaging and fluid biomarkers, treatm...Alzheimer's disease is the leading cause of dementia and among the top ten leading causes of death in high-income countries. Exponential advances in epidemiology, genetics, diagnostic imaging and fluid biomarkers, treatment, and prevention in the last decade reinforce the notion that we are entering a new era in the clinical management of Alzheimer's disease. However, far from triumphalism, this momentum should be accelerated to achieve the goals of preventing Alzheimer's disease and arresting its progression. In this Seminar, we summarise this progress and highlight unmet needs and areas of research priority.
BACKGROUND: Prasinezumab has previously shown potential for reducing the progression of motor signs (Movement Disorder Society-sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III) in p...BACKGROUND: Prasinezumab has previously shown potential for reducing the progression of motor signs (Movement Disorder Society-sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III) in patients with early-stage Parkinson's disease who were treatment-naive or receiving monoamine oxidase type B (MAO-B) inhibitors. The aim of the PADOVA trial was to evaluate the efficacy and safety of prasinezumab in a broader population of patients receiving stable symptomatic medication. METHODS: This phase 2b, multicentre, double-blind, parallel-group, placebo-controlled, randomised, superiority trial recruited participants with early-stage Parkinson's disease (age 50-85 years, 3 months to 3 years from diagnosis, Hoehn and Yahr stage 1 or 2) on stable symptomatic medication from 110 centres in nine countries in Europe and North America. Participants were individually randomly assigned (1:1) via permuted blocks (stratified by symptomatic medication [levodopa or MAO-B inhibitor]) to intravenous prasinezumab (1500 mg) or placebo every 4 weeks for at least 76 weeks and until the target number of motor progression events was reached. Participants, investigators, and clinical assessors were masked to group assignment. The primary endpoint was time to a confirmed motor progression event (≥5-point increase in MDS-UPDRS Part III off-medication score), assessed in the full analysis set (all randomly assigned participants according to the treatment to which they were assigned). Safety and tolerability were assessed in all randomly assigned participants who received at least one dose of study drug, with participants grouped according to treatment received. The trial is registered with ClinicalTrials.gov (NCT04777331) and EudraCT (2020-004997-23), and is active, not recruiting. FINDINGS: Between May 5, 2021, and March 22, 2023, 787 individuals were screened. 586 were enrolled and randomly assigned (n=293 per group; mean age 64·2 years [SD 7·3]; 214 [37%] female and 372 [63%] male); 550 completed double-blind treatment (prasinezumab, n=277; placebo, n=273). The primary endpoint was not met; the primary analysis showed a non-significant delay in motor progression with prasinezumab versus placebo (hazard ratio 0·84 [95% CI 0·69-1·01]; p=0·066); median time to confirmed motor progression in the prasinezumab group was 61·1 weeks (95% CI 52·3-71·9), compared with 49·7 weeks (40·1-58·1) in the placebo group. The incidence of one or more serious adverse events was similar between groups (prasinezumab, 34 [12%] of 292; placebo, 34 [12%] of 290) and three recorded deaths were unrelated to the study drug (prasinezumab, n=1 [<1%]; placebo, n=2 [1%]). INTERPRETATION: Although PADOVA did not meet the primary endpoint, prespecified exploratory evidence suggests clinical activity of prasinezumab in early-stage Parkinson's disease, supporting continued investigation in the ongoing phase 3 PARAISO trial (NCT07174310). FUNDING: F Hoffmann-La Roche.
BACKGROUND: Tau PET imaging has emerged as a critical biomarker for Alzheimer's disease, informing diagnosis, staging, and therapeutic selection. We investigated whether PET tracer selection alters tau detection. METHODS...BACKGROUND: Tau PET imaging has emerged as a critical biomarker for Alzheimer's disease, informing diagnosis, staging, and therapeutic selection. We investigated whether PET tracer selection alters tau detection. METHODS: We conducted a prospective, multicentre, non-randomised, within-participant comparison of [F]flortaucipir (Tauvid), currently used in clinical settings in the USA and Europe, and [F]MK6240, an investigational tau PET tracer. Participants were recruited from eight north American sites and underwent tau PET, amyloid-β (Aβ) PET, and detailed cognitive assessments. Tau PET with both agents was acquired within a 45-day window. Coprimary outcomes were the discriminative accuracy for Alzheimer's disease-related cognitive impairment and the frequency of tau positivity in early medial temporal lobe (MTL) and late neocortical regions. The study is registered with ClinicalTrials.gov, NCT05361382. FINDINGS: Between March 2, 2022, and Aug 27, 2025, 775 individuals were enrolled, with 682 completing all procedures (373 [55%] female, 309 [45%] male; 38 [6%] aged 19-27 years, 214 [31%] aged 50-65 years, and 430 [63%] aged 65-89 years). 32 (5%) participants identified as Hispanic or Latino. 637 (93%) identified as White, 24 (4%) as Black or African American, 16 (2%) as Asian, and five (1%) as other. In addition, 49 (7%) individuals were identified as being from a rural area. [F]MK6240 showed greater accuracy than [F]flortaucipir in distinguishing Alzheimer's disease from non-Alzheimer's disease impairment (area under the curve 0·93, 95% CI 0·89-0·95 vs 0·86, 0·75-0·91; p<0·0001). Among the older adults, tau positivity status was concordant in 560 (87%) for MTL and 603 (94%) for neocortical regions. In cognitively unimpaired participants, [F]MK6240 identified twice as many MTL-positive cases as [F]flortaucipir (n=54 [15%] vs n=23 [6%]). Prevalence ratio in Aβ-positive was 2·43 (95% CI 1·50-3·94; p=0·0003), identifying 23 additional cases per 100. Among discordant cases, 75 (89%) were [F]MK6240-positive only and had higher Aβ burden (p<0·0001), APOEε4 frequency (p<0·0001), and cognitive impairment (p=0·0043) than those negative on both tracers. Neocortical tau positivity was more frequent with [F]MK6240 than with [F]flortaucipir in cognitively impaired individuals (80 [28%] vs 46 [16%]). Prevalence ratio in Aβ-positive was 1·74 (95% CI 1·32-2·29; p<0·0001), identifying 15 additional mild cognitive impairment and 21 dementia cases per 100. INTERPRETATION: Tau PET tracer selection influences the frequency of detection of tau pathology across the ageing and Alzheimer's disease spectrum. Compared with [F]flortaucipir, [F]MK6240 identified more individuals with tau pathology in cognitively unimpaired and cognitively impaired individuals, with direct implications for patient stratification in clinical trials and more precise guidance for therapeutic decision-making. FUNDING: National Institute on Aging.
BACKGROUND: Alzheimer's disease neuropathology, characterised by amyloid β (Aβ) and phosphorylated-tau (p-tau) protein accumulation, has primarily been assessed with biomarkers in clinical samples of older adults. Less i...BACKGROUND: Alzheimer's disease neuropathology, characterised by amyloid β (Aβ) and phosphorylated-tau (p-tau) protein accumulation, has primarily been assessed with biomarkers in clinical samples of older adults. Less is known about plasma biomarkers of Alzheimer's disease neuropathology and their associations with cognitive outcomes in midlife in diverse community-based samples. Our goal was to address these gaps. METHODS: In this cohort study, we analysed participants who were retained in the US Coronary Artery Risk Development in Young Adults (CARDIA) Study with available plasma biomarkers at year 35 (2020-22). We excluded participants without cognitive measures and individuals with probable dementia. Cognition in five domains was measured with standardised tests at years 30 and 35; accelerated cognitive decline in each domain was defined as a 5-year decline at least 1·5 SD greater than the cohort mean change. Plasma Aβ42, Aβ40, and p-tau217 concentrations were assayed with the use of the Fujirebio Lumipulse G1200 analyser and used to calculate the p-tau217-to-Aβ42 ratio (p-tau217/Aβ42) and Aβ42-to-Aβ40 ratio (Aβ42/40). Alzheimer's disease neuropathology status (ie, negative, intermediate, or positive) was defined based on amyloid PET-validated cutpoints for each biomarker (p-tau217/Aβ42, p-tau217, and Aβ42/40). Associations of Alzheimer's disease neuropathology with cognition (Z scores) and accelerated decline were evaluated with the use of multivariable linear and logistic regression. FINDINGS: From the 2248 CARDIA participants who completed the year 35 visit, we randomly selected 1500 participants for plasma biomarker measurement. We excluded three participants with poor biomarker assay quality, 143 without cognitive measures, and four with probable dementia resulting in a final cohort of 1350. The mean participant age was 61 years (SD 3·6, range 53·0-69·0); 779 (58%) participants were women, 571 (42%) were men, 613 (45%) were Black, and 737 (55%) were White. Alzheimer's disease neuropathology positivity was present in 86 (6%) participants based on p-tau217/Aβ42, 196 (15%) based on Aβ42/40, and 48 (4%) based on p-tau217, and was associated with worse performance on processing speed (standardised cognitive difference comparing Alzheimer's disease neuropathology positive to negative for Aβ42/40, p-tau217, and p-tau217/Aβ42 -0·54 to -0·25; p values 0·0001 to 0·0048) and executive function (-0·42 to -0·19; p values 0·0070 to 0·049). Alzheimer's disease neuropathology positivity was also associated with increased odds of accelerated decline on verbal memory (Aβ42/40: odds ratio 4·31, 95% CI 1·71-10·9, p-tau217/Aβ42: 2·44, 1·16-5·13) and processing speed (p-tau217: 3·98, 1·71-9·3; p-tau217/Aβ42: 3·35, 1·77-6·35) compared with Alzheimer's disease neuropathology negativity. There was no association for global cognition or fluency. Although not consistent, some effect modification was observed, with stronger associations among women and Black participants and individuals with APOE ∈4. INTERPRETATION: Alzheimer's disease neuropathology is relatively uncommon in midlife but associated with worse cognitive performance and accelerated decline and might have stronger association among some groups. Early Alzheimer's disease neuropathology detection with the use of plasma biomarkers might enable timely prevention and intervention in midlife adults including risk reduction and pharmacological therapies. FUNDING: National Heart, Lung, and Blood Institute (75N92023D00002, 75N92023D00003, 75N92023D00004, 75N92023D00005, and 75N92023D00006), National Institute on Aging (R01AG063887, R01AG091431, R35AG071916, and K99AG083211), and the Alzheimer's Association (AARFD-23-1150636).
Giovannoni G, Airas L, Bove R
… +20 more, Cutter GR, Czarnecki M, Drulovic J, Hobart J, Kuhle J, Montalban X, Selmaj KW, Tur C, Wolinsky JS, Baldinotti A, Bonati U, Craveiro L, Giacobino C, Manfrini M, Schneble HM, Stevenson P, Wang Q, Yang K, Oh J, ORATORIO-HAND study group
BACKGROUND: The ORATORIO trial showed that ocrelizumab reduced the risk of disability progression versus placebo in patients with primary progressive multiple sclerosis (PPMS). We aimed to elucidate the effect of ocreliz...BACKGROUND: The ORATORIO trial showed that ocrelizumab reduced the risk of disability progression versus placebo in patients with primary progressive multiple sclerosis (PPMS). We aimed to elucidate the effect of ocrelizumab in older and more disabled patients with PPMS, particularly regarding hand function preservation. METHODS: ORATORIO-HAND was a multicentre, double-blind, randomised, placebo-controlled, phase 3b study with 138 sites across 22 countries. Patients with PPMS aged 18-65 years and Expanded Disability Status Scale (EDSS) score of 3·0-8·0 were randomly assigned 1:1 to intravenous ocrelizumab 600 mg or placebo every 6 months for 144 weeks or until a prespecified number of progression events occurred. Masking was achieved by use of a placebo solution administered in the same manner as ocrelizumab. Double-blinding across all periods was maintained through separation of investigators responsible for efficacy and safety assessments. MRI scans were evaluated by a masked central reader, and laboratory parameters that could reveal treatment allocation were masked to site personnel until the primary analysis. Two coprimary estimands were defined, with the endpoint of time to onset of 12-week composite confirmed disability progression (12W-cCDP) in 9-Hole Peg Test or EDSS evaluated in all randomly assigned patients, and the same endpoint evaluated in a subset of patients with MRI activity at baseline. This study is registered with ClinicalTrials.gov, NCT04035005 and is ongoing and not recruiting. FINDINGS: Between Aug 12, 2019, and Dec 10, 2024, of 1360 patients assessed for eligibility, 1013 were randomly assigned (ocrelizumab [n=505]; placebo [n=508]). The proportion of patients with 12W-cCDP was 165 (33%) of 505 with ocrelizumab and 205 (40%) of 508 with placebo (hazard ratio, 95% CI 0·70 0·57-0·86; relative risk reduction=30%; p=0·0007). In the MRI-active subgroup, a significant risk reduction was also observed in 12W-cCDP (risk reduction=55%; p<0·0001). The overall safety profile was similar in both groups. More infections (245 [48%] of 506 vs 226 [45%] of 506) were observed with ocrelizumab, but not after COVID-19 was excluded (38% vs 37%). Rates of serious adverse events and serious infections were similar between groups. INTERPRETATION: Ocrelizumab was superior to placebo in delaying disability progression, with stronger effect on hand function, in a broad PPMS population including older patients and those with more advanced disease, while maintaining a manageable safety profile. FUNDING: F Hoffmann-La Roche.
Hauser SL, Giovannoni G, Montalban X
… +22 more, Oh J, Bar-Or A, Sormani MP, Weber MS, Stoll S, Nicholas JA, Nehrych T, Bonek R, Selmaj K, Maciejowski M, Zecevic D, Raposo C, Owen R, Bonati U, Madjar K, Harfst E, Wang Q, Raievska A, Manfrini M, Schneble HM, Kappos L, MUSETTE and GAVOTTE Study Groups
BACKGROUND: Ocrelizumab is a humanised anti-CD20 monoclonal antibody approved for people with relapsing (RMS) or primary progressive multiple sclerosis (PPMS). In a post-hoc analysis of phase 3 trials in RMS and PPMS usi...BACKGROUND: Ocrelizumab is a humanised anti-CD20 monoclonal antibody approved for people with relapsing (RMS) or primary progressive multiple sclerosis (PPMS). In a post-hoc analysis of phase 3 trials in RMS and PPMS using a 600 mg dose, higher exposure to ocrelizumab was associated with greater B-cell depletion and lower risk of confirmed disability progression. Here, we prospectively assessed the efficacy and safety of a high dose of ocrelizumab in patients with RMS or PPMS. METHODS: Two multicentre, double-blind, phase 3 controlled trials were conducted to compare high-dose ocrelizumab with the approved 600 mg dose of the drug in patients with RMS (MUSETTE) and PPMS (GAVOTTE) aged 18-56 years. MUSETTE involved 122 centres in 21 countries and GAVOTTE involved 149 centres in 22 countries. Participants were randomly assigned 2:1, with a permuted-block randomisation method, to high-dose ocrelizumab (1200 mg or 1800 mg for baseline body weight <75 kg or ≥75 kg, respectively) or 600 mg ocrelizumab. Patients, investigators, and the sponsor were blinded to treatment allocation. Patients received ocrelizumab infusions every 24 weeks for a minimum 120 weeks and until a prespecified minimum number of confirmed disability events (MUSETTE, 205; GAVOTTE, 357) had occurred. In both trials, the primary endpoint was time to onset of 12-week composite confirmed disability progression (cCDP), assessed by prespecified increases in Expanded Disability Status Scale, Timed 25-Foot Walk Test, or 9-Hole Peg Test scores. Efficacy endpoints were evaluated in all randomised participants and safety endpoints were evaluated in participants who received at least one ocrelizumab infusion. These studies are registered with ClinicalTrials.gov: MUSETTE, NCT04544436; GAVOTTE, NCT04548999. FINDINGS: Participants in MUSETTE were enrolled between Nov 26, 2020, and Aug 30, 2022; participants in GAVOTTE were enrolled between Dec 3, 2020, and May 15, 2023. In MUSETTE, 860 patients were randomly assigned (high-dose ocrelizumab, n=577; 600 mg ocrelizumab, n=283) and had median overall treatment duration of 184·4 weeks. In GAVOTTE, 753 patients were randomly assigned (high-dose ocrelizumab, n=500; 600 mg ocrelizumab, n=253) and had median overall treatment duration of 174·1 weeks. In MUSETTE, the percentage of patients with 12-week cCDP was 34% (198 of 577) with high-dose ocrelizumab versus 37% (104 of 283) with 600 mg ocrelizumab (hazard ratio [HR] 0·93 [95% CI 0·73-1·18]; p=0·53). In GAVOTTE, the percentage of patients with 12-week cCDP was 47% (235 of 500) with high-dose ocrelizumab versus 49% (124 of 253) with 600 mg ocrelizumab (HR 0·95 [95% CI 0·76-1·18]; p=0·64). Safety profiles were similar for the high-dose ocrelizumab and 600 mg ocrelizumab; in MUSETTE, rates of adverse events (552 [96%] of 577 and 267 [94%] of 283), serious adverse events (77 [13%] of 577 and 34 [12%] of 283), and fatalities (four [1%] of 577 and one [<1%] of 283) were comparable, as were rates of adverse events (447 [90%] of 499 and 230 [91%] of 254), serious adverse events (61 [12%] of 499 and 29 [11%] of 254), and fatalities (two [<1%] of 499 and three [1%] of 254) in GAVOTTE. INTERPRETATION: In both studies, high-dose ocrelizumab did not further improve control of disability progression in either RMS or PPMS, and no new safety concerns were identified. FUNDING: F Hoffmann-La Roche.