Efficacy and safety of LEVI-04 in patients with osteoarthritis of the knee: a

# Efficacy and safety of LEVI-04 in patients with osteoarthritis of the knee: a randomised, double-blind, placebo-controlled, phase 2 trial *The Lancet 2026* Articles Efficacy and safety of LEVI-04 in patients with osteoarthritis of the knee: a randomised, double-blind, placebo-controlled, phase 2 trial Philip G Conaghan, Nathaniel Katz, Asger R Bihlet, Ali Guermazi, Dror Rom, Michael C Perkins, Bernadette Hughes, Claire Herholdt, Iwona Bombelka, Simon Westbrook Summary Background Current therapies for osteoarthritis have limitations. LEVI-04 is a p75 neurotrophin receptor (p75NTR) Lancet 2026; 407: 1237–48 fusion protein that inhibits neurotrophin-3. We assessed the ecacy and safety of LEVI-04 in individuals with knee See Comment page 1210 osteoarthritis. Leeds Institute of Rheumatic and Musculoskeletal Medicine, Methods This randomised, placebo-controlled, double-blind, phase 2 trial enrolled participants from Denmark, University of Leeds, Leeds, UK (Prof P G Conaghan MBBS); Hong Kong, Poland, Moldova, and the Czech Republic with painful (≥4/10 Western Ontario and McMaster National Institute for Health Universities Osteoarthritis Index [WOMAC] pain scores) and radiographic knee osteoarthritis. Participants were and Care Research Leeds randomised 1:1:1:1 to receive a monthly intravenous placebo or LEVI-04 0·3 mg/kg, 1·0 mg/kg, or 2·0 mg/kg through Biomedical Research Centre, to week 16, with safety follow-up to week 30. The primary endpoint was change in WOMAC pain from randomisation Leeds, UK (Prof P G Conaghan); Ein Sof Innovation, Wellesley, to week 17 in the intention-to treat population. Safety analyses included all participants who received the study drug. MA, USA (N Katz MD); NBCD, This trial is registered with ClinicalTrials.gov, NCT05618782, and EU Clinical Trials database, EudraCT 2021-006540-28. Søborg, Denmark (A R Bihlet PhD); Department of Findings Between Oct 19, 2022, and Oct 23, 2023, of 1598 participants screened, 518 (292 female and 226 male; mean Radiology, Boston University School of Medicine, age 64·0 years [SD 8·07]) were randomly assigned to receive LEVI-04 0·3 mg/kg (n=130), 1·0 mg/kg (n=130), or West Roxbury, MA, USA 2·0 mg/kg (n=129) or placebo (n=129). One person who did not receive the study treatment was excluded from the (Prof A Guermazi MD); Prosoft safety analysis. At week 17, least squares mean dierence in WOMAC pain versus placebo were −0·51 Clinical, Chesterbrook, PA, USA (95% CI −0·96 to −0·07), p=0·023; −0·62 (−1·07 to −0·17), p=0·015; and −0·79 (−1·24 to −0·35) p=0·0024 in the (D Rom PhD); Levicept, Sandwich, UK (M C Perkins MD, LEVI-04 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg groups, respectively. Eect sizes (standardised mean dierence) at B Hughes PhD, C Herholdt BSc, week 17 were 0·28 (95% CI 0·52 to 0·04), 0·33 (0·58 to 0·09), and 0·43 (0·68 to 0·19) for the 0·3 mg/kg, 1·0 mg/kg, I Bombelka BSc, and 2·0 mg/kg groups, respectively. LEVI-04 showed no increased incidence in serious adverse events, treatment- S Westbrook PhD) emergent adverse events (75 [58%], 86 [66%], 83 [64%] in the 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg dose groups, Correspondence to: respectively, and 87 [67%] placebo), or joint pathologies, including rapidly progressive osteoarthritis. Prof Philip G Conaghan, Leeds Institute of Rheumatic and Musculoskeletal Medicine, Interpretation LEVI-04 was well tolerated and showed significant improvements in pain and function. These results Chapel Allerton Hospital, support supplementing endogenous p75NTR in treating osteoarthritis. Leeds, LS7 4SA, UK p.conaghan@leeds.ac.uk Funding Levicept. Copyright © 2026 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Introduction well as homeostasis of articular chondrocytes.8–10 Novel therapies for the treatment of osteoarthritis are Antibodies to NGF provide analgesia in individuals with urgently required. Current pharmacological options are osteoarthritis but this treatment has been associated with limited by ecacy, tolerability, and adverse eects.1,2 dose-dependent increases in joint safety events, including Nerve growth factor (NGF) and neurotrophin-3 (NT-3) rapidly progressive osteoarthritis.11–13 belong to a family of neurotrophins that regulate LEVI-04 is a fusion protein comprising two extracellular peripheral pain pathways.3,4 NGF binds to tropomyosin domains of the human p75NTR coupled to the fragment receptor kinase A (TrkA) and p75 neurotrophin receptor crystallisable component of human immunoglobulin G1, (p75NTR), whereas NT-3 binds to all neurotrophin acting as a stable analogue of the endogenous receptors (TrkA, TrkB, TrkC, and p75NTR), with highest neurotrophin binding protein, p75NTR. LEVI-04 anity for TrkC and lowest anity for p75NTR.5–7 In supplements circulating concentrations of p75NTR and, addition to its role in pain signalling, NT-3 has a like soluble p75NTR, binds to all the neurotrophins with prominent role in cartilage and bone metabolism, diering anities, with low picomolar anity to NT-3 inducing osteoclastogenesis and resorptive activity.7 In and with low nanomolar and reversible anity to NGF.14 contrast, NGF regulates bone cells, influencing osteoblast LEVI-04 is an antagonist of neurotrophin-induced and osteoclast dierentiation and osteocyte activity, as activation of Trk receptors with and without co-expression Articles Research in context Evidence before this study number of participants with osteoarthritis showed LEVI-04 to We searched PubMed from database inception up to be well tolerated, with a pharmacokinetic profile that supported Nov 27, 2025, using the search terms “p75NTR”, the doses and dose frequency explored in this phase 2 study. “osteoarthritis”, and “randomised clinical trial” for publications Added value of this study in English. This search yielded no results. There remains a huge This is the first clinical study demonstrating analgesic efficacy of unmet need for efficacious and well tolerated therapies for p75NTR supplementation, supporting a novel mechanism of osteoarthritis. Excess neurotrophins are implicated, and action for targeting chronic pain in knee osteoarthritis. previous analgesic therapies targeting nerve growth factor Significant improvements in pain, function, and patient global (NGF) inhibition provided analgesia but were dose-dependently outcomes were shown. LEVI-04 was well tolerated and associated with substantial joint pathologies, including rapidly exhibited a favourable safety profile, especially in terms of joint progressive osteoarthritis. LEVI-04 is a first-in-class fusion safety outcomes, with no increase in joint safety events protein comprising two extracellular domains of the human including rapidly progressive osteoarthritis. p75 neurotrophin receptor (p75NTR) coupled via a glycine linker to the fragment crystallisable component of human Implications of all the available evidence immunoglobulin G1. LEVI-04 provides analgesia via LEVI-04 has the potential to provide clinically meaningful supplementation of the endogenous p75NTR binding protein analgesia without the treatment-limiting side effects of current and inhibition of neurotrophin-3 activity. A phase 1 study therapies and without the serious joint safety side effects seen (NCT03227796) conducted in healthy volunteers and a small with anti-NGF antibodies. of p75NTR. However, the responses induced by brain- Participants derived neurotrophic factor, NT-4 and NGF, in cells Adults aged 40–80 years with a history of knee pain on expressing Trk receptors and cells co-expressing Trk most days for at least 3 months before screening and receptors and p75NTR are not fully inhibited by LEVI-04. confirmed osteoarthritis of the target knee were enrolled. In contrast, NT-3-induced activity in cells expressing Diagnosis was confirmed radiographically as TrkA and TrkC receptors is fully inhibited by LEVI-04 and Kellgren–Lawrence grade 2 or greater (scale 0–4, read close to full inhibition is seen with p75NTR centrally) and by American College of Rheumatology co-expression.14 clinical and radiographic diagnostic criteria.15 The target We hypothesised that modulating neurotrophin excess knee had to score at least 20/50 (4/10 on transformed with p75NTR supplementation would maintain NGF 0–10 scale) on the Western Ontario and McMaster signalling and provide pain relief without side eects Universities Osteoarthritis Index (WOMAC) numerical such as rapidly progressive osteoarthritis. This phase 2 rating scale (NRS) version 3.1 pain subscale at screening trial evaluated the ecacy, safety, and tolerability of and baseline visits, with average daily pain NRS scores of LEVI-04 compared with placebo in participants with knee between 4·0 and 9·0 (range 0–10, 10 indicating the worst osteoarthritis. pain), with mean variability (SD) of 1·5 or less, collected on at least six of the last 7 days before randomisation Methods using a daily electronic diary. Participants had to be Study design willing to withdraw from all analgesic medication for This was a multiple-arm, multicentre, prospective, osteoarthritis. parallel group, randomised, double-blind, placebo- Exclusion criteria focused on comorbidities or controlled, phase 2 study of LEVI-04 intravenous concomitant medication that could interfere with infusion for the treatment of knee osteoarthritis. assessment of target knee pain, systemic illness known Participants were enrolled at 13 clinical research centres to be significantly associated with arthritis or joint in Denmark, Hong Kong, Poland, Moldova, and the pathology aecting any joint, and pathological conditions Czech Republic. Regulatory and ethical approvals were significantly aecting joint and bone health. Full list of obtained in each country. The trial participation involved inclusion and exclusion criteria are provided in the ten study visits over a 30-week period, following a appendix (pp 3–5). See Online for appendix screening period of up to 56 days (two study visits). The study was conducted in accordance with all applicable Randomisation and masking regulations, including the International Council for Participants were randomised (block size of four centrally Harmonisation of Technical Requirements for balanced across the study) by an interactive web-based Pharmaceuticals for Human Use guidelines on current randomisation system to one of four treatment arms: good clinical practice, and the Declaration of Helsinki as LEVI-04 0·3 mg/kg, 1·0 mg/kg, 2·0 mg/kg, or placebo, amended in October 2013. All participants provided in a 1:1:1:1 ratio (figure 1). Study site sta and participants written informed consent. did not have access to the random allocation sequence. 1238 Articles The treatment was prepared at each site by an unblinded screening, but once the target knee was selected at delegate who was not involved in other aspects of the baseline, only pain in that knee was rated throughout the study. The placebo was indistinguishable from the active study. Pain scores (NRS) for the previous 24 h were treatment. Participants, study site investigators, study collected daily using an electronic diary, starting from the site personnel giving the interventions, those assessing screening period and continuing throughout the trial. outcomes, and those analysing the data were unaware of Standing x-rays of bilateral knees (posteroanterior the treatment allocation. fixed-flexion), hips (pelvis anteroposterior weight-bearing and mediolateral view), and shoulders (Grashey’s view), Procedures followed by MRI (1·5 T) of bilateral knees, were obtained After the screening period and randomisation, study visits during screening and read by an independent central were performed at weeks 0, 2, 4, 5, 8, 12, 16, 17, 20, and 30 reader to confirm eligibility (see imaging inclusion and (with week 2 and week 30 being telephone visits). exclusion criteria, appendix pp 3–5). Follow-up MRI of Participants received monthly intravenous infusions of the target knee and follow-up x-rays of bilateral knees, LEVI-04 or saline control (placebo) during the first hips, and shoulders were performed at week 20. 16 weeks. All on-site visits involved safety assessments, Blood samples for anti-drug antibodies were taken including blood monitoring, electrocardiograms (ECGs), pre-dose at visits on day 1, and week 4 and week 20. and vital signs. Ecacy measures were conducted at visits Rescue medication (paracetamol [acetaminophen] one week after dose 2 (week 5) and dose 5 (week 17). 1000 mg per dosing with a maximum total of 4000 mg Ecacy assessments at these visits were the WOMAC, per 24 h) was permitted, dispensed at sites, and use patient global assessment (PGA), and an evoked pain-on- recorded via an electronic daily diary. movement assessment, the Staircase-Evoked Pain Procedure (StEPP), in which participants rate their pain on Outcomes a scale of 0–10 (with 10 being the worst pain) after climbing The primary endpoint was the change in WOMAC NRS 3.1 up and down a single standardised step on alternate legs a pain subscale from baseline to week 17. Secondary total of 24 times.16 Pain was assessed in both knees during ecacy endpoints included change in WOMAC pain 1598 participants assessed for eligibility 1080 ineligible 836 did not meet inclusion criteria 102 declined to participate 142 other reasons 518 randomly assigned 130 assigned to LEVI-04 0·3 mg/kg 130 assigned to LEVI-04 1·0 mg/kg 129 assigned to LEVI-04 2·0 mg/kg 129 assigned to placebo 1 did not receive allocated intervention (venous access not successful) 10 discontinued intervention 9 discontinued intervention 11 discontinued intervention 13 discontinued intervention 5 withdrawal by participant 4 withdrawal by participant 5 withdrawal by participant 7 withdrawal by participant 3 had an adverse event 2 had an adverse event 4 had an adverse event 4 had an adverse event 1 physician decision 1 physician decision 1 physician decision 2 protocol violation 1 lost to follow-up 1 lost to follow-up 1 lost to follow-up 1 other reason 130 included in intention-to-treat 130 included in intention-to-treat 129 included in 129 included in intention-to-treat analysis analysis intention-to-treatanalysis analysis 127 included in modified 126 included in modified 126 included in modified 127 included in modified intention-to-treat analysis intention-to-treat analysis intention-to-treat analysis intention-to-treat analysis 114 included in per-protocol 116 included in per-protocol 116 included in per-protocol 110 included in per-protocol analysis analysis analysis analysis* 129 included in safety analysis 130 included in safety analysis 129 included in safety analysis 129 included in safety analysis 1 excluded from analysis (did not receive treatment) Figure 1: Trial profile Articles subscale from baseline to week 5 and change from of 0∙0189 to account for three comparisons against a baseline to week 5 and week 17 in WOMAC physical common control. Overall type-1 error was two-sided 0∙05. function and stiness subscales, PGA, and StEPP. The drop-out rate was assumed to be 15%, distributed Changes in average weekly NRS pain score from baseline evenly over the duration of the study. A predefined to week 5 and week 17, the proportion of participants interim analysis to confirm the adequacy of sample size achieving 30% and 50% reduction in WOMAC pain and variability assumptions was planned for when the subscale at week 5 and week 17, the area under the curve first 208 participants either completed the week 5 visit or of average daily NRS pain from baseline to week 20, and discontinued after randomisation, with approximately rescue medication usage during the trial were all pre- 80 participants passing week 17. The prespecified options specified secondary ecacy endpoints. The change from were to continue the study with the originally planned baseline in WOMAC pain at week 17 was also assessed by sample size or recruit up to an additional 208 participants Kellgren–Lawrence grade. (a 50% increase) to a maximum of 624 participants, with Post-hoc ecacy analyses included the proportion of the objective of achieving 90% power. All study personnel participants achieving 70% reduction and 90% reduction remained unaware of the interim analysis, and the in WOMAC pain subscale at week 5 and week 17, and statistician who performed the interim analysis was change from baseline in daily pain NRS scores on day 1 recused from any interactions with study personnel until through to day 10. the database lock of May 28, 2024. Safety was assessed from the screening visit up to All data collected were used in the final analysis. week 30 (follow-up safety phone visit). Adverse events Missing data for the primary endpoint were imputed between treatment arms (count and severity) were using multiple imputations methodology. Imputations recorded and analysed. Any serious adverse event was were performed separately for each treatment and only reported as soon as site sta became aware of it. The the primary endpoint results for non-missing visits safety profile of LEVI-04 was assessed through analysis of (baseline, week 5, and week 17) were used to impute the adverse events, physical examination findings, including visits with missing results. Neither site nor any other vital signs, laboratory tests and procedures, ECGs during additional covariates were used in the multiple screening and before each dosing, and radiographic and imputation modelling. Missing data attributable to MRI imaging at screening and week 20 (or as indicated reasons plausibly related to treatment (eg, adverse events clinically). Joint safety surveillance was in line with that or lack of ecacy) were not assumed to be missing at used in anti-NGF antibody studies. Adverse events of random and were imputed using the jump-to-control special interest included new or worsening peripheral principle. All other missing data were considered neuropathy or abnormal peripheral sensation, and joint missing at random and imputed using the randomised events. Joint events, detected by treatment-blinded treatment assignment as the projected treatment eect. central reader on x-ray or MRI, or upon investigator The primary population of all ecacy analyses was the request as a result of an unexplained increase in joint intention-to-treat population defined as all randomised pain, were reviewed by an independent Adjudication participants. The modified intention-to-treat analysis set Committee (appendix p 2). included all participants from the intention-to-treat Self-reported mean change from baseline in Boston analysis set who had baseline and at least one post- Carpal Tunnel Questionnaire by treatment, subscale, and treatment WOMAC pain sub-score assessment available. timepoint (intention-to-treat analysis set) were assessed The per-protocol analysis set included all participants from at week 8 and week 20. The presence and impact of the modified intention-to-treat analysis set who had been autonomic symptoms were assessed using the Survey for treated according to the trial protocol and had an absence Autonomic Symptoms (SAS), stratified by treatment, of major clinical trial protocol deviations (determined in a timepoint (week 8 and week 20), and gender (intention- blinded manner). Sensitivity analyses for assessing the to-treat analysis set). jump-to-control imputation of the primary population were performed using observed data. Additionally, the Statistical analysis modified intention-to-treat and per-protocol populations The sample size calculations assumed an SD of 19∙2 and were analysed without imputation using only observed a reduction in the WOMAC pain score that was 10 units data. more than the placebo group in a minimum of one dose The primary ecacy analyses of continuous data were group (scale 0–100, all transformed to 0–10). With a analysed using the analysis of covariance (ANCOVA) sample size of 416, the power to detect at least model of the change from baseline in score, with one statistical dierence from placebo ranged from 86% treatment, study centre, and baseline score as covariates. (only one dose dierent from placebo) to 90% (reductions The final primary endpoint analysis was conducted of 10, 7∙5, and 5 greater than placebo in the high, mid, between the three treatment arms and placebo using a and low dose groups, respectively). These power simple inverse normal combination test with weights calculations were based on an adjusted critical value due of 1/2 on the interim Z, and 1/2 on the post-interim to Dunnett’s test at a per-comparison two-sided α z-statistics. A step-down Dunnett’s test was used to 1240 Articles control type-1 error and compare the three active arms Safety data, including joint safety events, were with placebo. The same ANCOVA model used for the summarised descriptively overall and by treatment group primary endpoint was used to assess the treatment eect using the safety analysis set (all participants who had been on continuous secondary endpoints, but without administered at least one dose of trial treatment). weighting for the interim analysis, and without a Participants were analysed according to the actual step-down test. Logistic regression analysis was used to treatment they received. No statistical inference was assess the treatment eect on the binary ecacy applied to safety endpoints. The incidence rate, severity, endpoints such as responder rate. The logistic regression and relationship to treatment for all adverse events were model included main eect treatment and covariates summarised by Medical Dictionary for Regulatory study centre and baseline value. Point estimates for the Activities version 25.0 system organ classes and preferred pairwise comparison and corresponding CIs and term. Descriptive statistics were presented for clinical p values were provided. WOMAC pain scores (0–50 scale) laboratory tests, vital signs, and physical examinations. were transformed to a 0–10 scale. For the primary NBCD was responsible for medical monitoring, endpoint, eect size was calculated as Cohen’s d17 from operational management, site monitoring, and data an analysis of covariance of pooled interim and post- management. Statistical analyses were performed by interim data. Prosoft Clinical (Chesterbrook, PA, USA) using SAS LEVI-04 0·3 mg/kg LEVI-04 1·0 mg/kg LEVI-04 2·0 mg/kg Placebo (n=130) (n=130) (n=129) (n=129) Age, years 63·2 (7·68) 64·5 (8·37) 63·1 (8·26) 65·4 (7·80) Sex Female 67 (52%) 80 (62%) 69 (53%) 76 (59%) Male 63 (48%) 50 (38%) 60 (47%) 53 (41%) Ethnicity Hispanic or Latino 0 1 (1%) 1 (1%) 0 Not Hispanic or not Latino 130 (100%) 128 (98%) 128 (99%) 129 (100%) Not reported 0 0 0 0 Unknown 0 1 (1%) 0 0 Race American Indian or Alaska Native 1 (1%) 0 0 0 Asian 12 (9%) 15 (12%) 17 (13%) 22 (17%) White 117 (90%) 115 (88%) 112 (87%) 107 (83%) BMI, kg/m 30·3 (4·50) 29·4 (4·40) 29·3 (4·31) 30·3 (4·65) Selected medical history Hypertension 70 (54%) 55 (42%) 63 (49%) 62 (48%) Hypercholesterolaemia 26 (20%) 30 (23%) 25 (19%) 24 (19%) Type 2 diabetes 10 (8%) 11 (8%) 13 (10%) 12 (9%) WOMAC pain subscale score Target knee 5·74 (1·12) 5·80 (1·05) 5·76 (1·07) 5·82 (1·03) Non-target knee 3·98 (1·97) 3·73 (1·96) 3·79 (2·05) 3·95 (2·12) Kellgren–Lawrence grade, target knee 0 and 1 0 0 0 0 2 22 (17%) 30 (23%) 34 (26%) 25 (19%) 3 64 (49%) 60 (46%) 60 (47%) 65 (50%) 4 44 (34%) 40 (31%) 35 (27%) 39 (30%) Kellgren–Lawrence grade, non-target knee* 0 13 (10%) 5 (4%) 7 (6%) 8 (6%) 1 12 (9%) 20 (16%) 16 (13%) 17 (13%) 2 33 (26%) 42 (33%) 30 (24%) 32 (25%) 3 47 (36%) 48 (38%) 50 (40%) 50 (39%) 4 24 (19%) 12 (9%) 23 (18%) 20 (16%) Data are n (%) or mean (SD). WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index numerical rating scale. Sex, ethnicity, and race were self-reported by participants. *Patient numbers for Kellgren–Lawrence grade of non-target knees were 129, 127, 126, 127 across the LEVI-04 0·3 mg/kg, 1·0 mg/kg, 2·0 mg/kg dose groups, and placebo, respectively, due to existing arthroplasties. Table 1: Demographics and baseline characteristics of the intention-to-treat population Articles (version 9.44). Both organisations are independent of the in 255 individuals), insucient pain in the target knee trial sponsor. This trial was registered with (151 individuals), and Kellgren–Lawrence grade less ClinicalTrials.gov, NCT05618782, and the EU Clinical than 2 in the target knee (108 individuals). The interim Trials database, EudraCT 2021-006540-28. analysis estimated a conditional power of 85% with no change to the sample size, or 90% with a 25% increase. Role of the funding source Therefore, according to the predefined interim analysis The study funder was involved in the study design, data plan, the independent statistician recommended a collection, data interpretation, and writing of the report. 25% increase in the sample size. In total, 517 received at least one dose of treatment (safety analysis set), and Results 475 participants (92%) completed the study. Between Oct 19, 2022, and Oct 23, 2023, 1598 participants Participant demographic and baseline characteristics were screened and 518 were randomly assigned to receive were similar across the treatment groups (table 1). The LEVI-04 0·3 mg/kg (n=130), LEVI-04 1·0 mg/kg (n=130), mean age of participants was 64·0 years (SD 8·07), LEVI-04 2·0 mg/kg (n=129), or placebo (n=129); the 292 (56%) were female and 226 (44%) were male, and the intention-to-treat analysis set (figure 1). The main mean BMI was 29·8 (SD 4·48) kg/m². All participants reasons for exclusion were radiology findings other than had evidence of target knee osteoarthritis with a Kellgren–Lawrence grade (including meniscal root tear Kellgren–Lawrence grade 2 or greater. Target knee LEVI-04 0·3 mg/kg (n=130) LEVI-04 1·0 mg/kg (n=130) LEVI-04 2·0 mg/kg (n=129) Placebo (n=129) WOMAC pain, week 5 N 127 124 125 127 LSM change from baseline (SE) −2·24 (0·15) −2·18 (0·15) −2·43 (0·16) −1·57 (0·15) LSM difference (95% CI) −0·67 (−1·09 to −0·26) −0·62 (−1·04 to −0·20) −0·87 (−1·29 to −0·45) ·· p value 0·0016 0·0038 <0·0001 ·· WOMAC pain, week 17 (primary endpoint, multiple imputations) N 130 130 129 129 LSM change from baseline (SE, SD)* −2·77 (0·16, 1·86) −2·87 (0·17, 1·88) −3·05 (0·17, 1·89) −2·26 (0·17, 1·87) LSM difference (95% CI) −0·51 (−0·96 to −0·07) −0·62 (−1·07 to −0·17) −0·79 (−1·24 to −0·35) ·· Adjusted p value† 0·023 0·015 0·0024 ·· WOMAC physical function, week 5 N 127 124 125 127 LSM change from baseline (SE) −1·72 (0·15) −1·81 (0·15) −2·14 (0·15) −1·16 (0·15) LSM difference (95% CI) −0·56 (−0·96 to −0·15) −0·64 (−1·05 to −0·23) −0·98 (−1·38 to −0·57) ·· p value 0·0073 0·0021 <0·0001 ·· WOMAC physical function, week 17 N 118 119 116 113 LSM change from baseline (SE) −2·40 (0·16) −2·49 (0·16) −2·75 (0·16) −1·84 (0·16) LSM difference (95% CI) −0·56 (−1·00 to −0·12) −0·65 (−1·09 to −0·21) −0·90 (−1·34 to −0·46) ·· p value 0·012 0·0038 <0·0001 ·· WOMAC stiffness, week 5 N 127 124 125 127 LSM change from baseline (SE) −1·92 (0·16) −1·98 (0·16) −2·35 (0·16) −1·15 (0·16) LSM difference (95% CI) −0·77 (−1·21 to −0·33) −0·83 (−1·27 to −0·39) −1·20 (−1·64 to −0·76) ·· p value 0·0006 0·0003 <0·0001 ·· WOMAC stiffness, week 17 N 118 119 116 113 LSM change from baseline (SE) −2·60 (0·18) −2·82 (0·18) −3·20 (0·18) −1·75 (0·19) LSM difference (95% CI) −0·85 (−1·34 to −0·35) −1·07 (−1·56 to −0·57) −1·45 (−1·95 to −0·95) ·· p value 0·0009 <0·0001 <0·0001 ·· From an ANCOVA model with main effect treatment and covariates study centre and baseline score with missing scores imputed using multiple imputations methodology. ANCOVA=analysis of covariance. LSM=least squares mean. WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index numerical rating scale. *SD=SE*sqrt(n). †p values are from separately analysing interim and post-interim participants. Z statistics from the interim and post-interim comparisons against placebo are created using the inverse normal transformation of the t statistics and combined using a weighted sum and used for an overall comparison against placebo. p values are adjusted according to a step-down Dunnett’s test. Table 2: Primary and selected secondary efficacy endpoints at week 5 and week 17 in the intention-to-treat population 1242 Articles Kellgren–Lawrence grades at baseline were grade 2 (21%), grade 3 (48%), and grade 4 (31%). Overall target knee baseline mean WOMAC pain subscale score was 5·78 (SD 1·07). All doses of LEVI-04 met the primary endpoint, demonstrating greater improvements in change from –1 baseline in WOMAC pain than placebo at week 17: least squares mean change from baseline were −2·77 (SD 1·86), −2·87 (1·88), and −3·05 (1·89) in the LEVI-04 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg groups, respectively, –2 versus −2·26 (1·87) with placebo. The least squares mean dierences from placebo in the LEVI-04 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg groups, respectively, were −0·51 (95% CI −0·96 to −0·07), p=0·023; –3 −0·62 (−1·07 to −0·17), p=0·015; and −0·79 (−1·24 to −0·35), p=0·0024 (table 2). Modified intention- to-treat and per-protocol analyses showed consistent results (data not shown). Limited influence of missingness on treatment eect estimation was –4 confirmed in sensitivity analyses of observed data (no imputation). The eect sizes (standardised mean dierence) of each dose group versus placebo at week 17 were 0·28 (95% CI 0·52 to 0·04), 0·33 (0·58 to 0·09), and 0·43 (0·68 to 0·19) for the 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg groups, respectively. LEVI-04 also met the secondary endpoints, of WOMAC physical function and WOMAC stiness at week 5 and week 17 for all doses (table 2). The dierences between all LEVI-04 dose groups and placebo were significant at all timepoints for WOMAC physical function: p=0·0073, p=0·0021, and p<0·0001 for LEVI-04 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg, respectively, at week 5; and p=0·012, p=0·0038, and p<0·0001, respectively, at week 17. Similarly, for WOMAC stiness, the dierences between the LEVI-04 dose groups and placebo were significant at both week 5 and week 17 for all doses and timepoints (p=0·0006, p=0·0003, and p<0·0001 at week 5, and p=0·0009, p<0·0001, and p<0·0001 at week 17, for LEVI-04 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg, respectively). Additional secondary endpoints are shown in figure 2. All LEVI-04 doses showed significant improvement in Figure 2: Least squares mean change from baseline in (A) PGA score and (B) StEPP score through to week 17 in the intention-to-treat population PGA and in the StEPP pain intensity scores compared PGA=patient global assessment. StEPP=Staircase-Evoked Pain Procedure. with placebo at week 5 and week 17 (figure 2). Responder *p<0·05; **p<0·01; ***p<0·001. p values are adjusted according to a step-down analyses showed that a significantly higher proportion Dunnett’s test. of participants in all LEVI-04 groups experienced at least 30% reduction in WOMAC pain scores versus placebo Mean change from baseline in average weekly NRS at week 5 (80 of 127, p<0·0006 in the 0·3 mg/kg; 74 of score was significantly improved for the 2·0 mg/kg 124, p<0·0033 in the 1 mg/kg; and 77 of 125, p<0·0001 LEVI-04 group compared with placebo at week 5 in the 2 mg/kg dose groups), although at week 17 this (p=0·028) and week 17 (p=0·0036). There was a trend for dierence was not significant (appendix p 7). The numerically greater reductions in the LEVI-04 0·3 mg/kg proportion of participants who experienced at least and 1·0 mg/kg dose groups versus placebo, but the 50% reduction in WOMAC pain scores compared with dierences were not significant (appendix p 8). Reduction placebo was significantly higher in all LEVI-04 groups at in the mean area under the curve of average daily pain week 5 (45 of 127, p=0·0027 for 0·3 mg/kg; 44 of 124, was statistically significant (p=0·0066) for the LEVI-04 p=0·0037 for 1 mg/kg; and 57 of 125, p<0·0001 for 2·0 mg/kg group compared with placebo (appendix p 8). 2·0 mg/kg), indicating sustained duration of eect The average daily rescue medication use in all dose from weeks 5 to 17 with these doses (figure 3A). groups was low, with no significant dierences observed )AGP( enilesab morf egnahc naem serauqs tsaeL A –1 –2 –3 –4 )PPEtS( enilesab morf egnahc naem serauqs tsaeL Placebo 0·3 mg/kg 1·0 mg/kg 2·0 mg/kg ** *** *** * *** *** B *** *** *** * ** *** 0 5 10 15 20 Time (weeks) Articles for LEVI-04 groups compared with placebo (appendix p 9). Similarly, dierences in the mean proportion of days on rescue medication with LEVI-04 were not statistically significant versus placebo (appendix p 9). 80 Further post-hoc analyses showed improvements in outcomes with LEVI-04 versus placebo. A significantly higher proportion of participants in all LEVI-04 groups ** 58 ** versus placebo achieved at least 70% reduction in 60 56 WOMAC pain scores at week 17 (p=0·004, p=0·003, and *** 50 46 p=0·001 in the 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg dose groups, respectively), and the proportion of * * 38 40 35 36 participants achieving at least 90% reduction in mean WOMAC pain scores was significant for the 2·0 mg/kg dose group versus placebo at week 17 (p=0∙022; figure 3). 20 18 LEVI-04 showed a rapid time to reduction in least squares mean change from baseline in daily NRS pain score, with a significant dierence versus placebo by day 3 for the 1·0 mg/kg and 2·0 mg/kg dose groups (p=0·028 and p=0·017, respectively; appendix p 7). Similar improvements in WOMAC pain scores were observed with LEVI-04 treatment across all Kellgren–Lawrence grades (2–4) at week 17 (appendix p 10). LEVI-04 was well tolerated, with a similar frequency of observed serious adverse events, treatment-emergent adverse events, and joint pathologies, including rapidly progressive osteoarthritis, between the treatment groups (table 3). The incidence of treatment-emergent adverse events reported as severe, treatment-related, causing discontinuation, or of special interest was low, with similar rates between active LEVI-04 and placebo treatment groups (table 3). The most common treatment- emergent adverse events across the LEVI-04 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg dose groups, and placebo, respectively, were: arthralgia, 11 (9%), 15 (12%), 15 (12%), and 20 (16%); nasopharyngitis, six (5%), eight (6%), 13 (10%), and 13 (10%); and back pain, three (2%), five (4%), eight (6%), and three (2%) participants (table 3). Serious treatment-emergent adverse events were reported in seven participants: none, one (1%), three (2%), and three (2%) in the LEVI-04 0·3 mg/kg, 1·0 mg/kg, 2·0 mg/kg, and placebo groups, respectively. All serious treatment-emergent adverse events were considered unrelated to the study medication, and none resulted in death. A total of 13 participants reported 17 treatment- emergent adverse events leading to study discontinuation (table 3). Of the 17 treatment-emergent adverse events, eight (five participants) were considered related to study medication (LEVI-04 0·3 mg/kg, mild rash, moderate joint eusion, mild joint eusion, moderate arthralgia, mild arthralgia, and moderate muscle weakness; LEVI-04 1·0 mg/kg, moderate microscopic colitis and mild skin burning sensation). No clinically important observations were noted in physical examinations, vital signs, Figure 3: Proportion of participants achieving (A) at least 50%, laboratory parameters, ECG findings, or x-ray results. (B) at least 70%, and (C) at least 90% reduction in WOMAC pain score Concerning the Boston Carpal Tunnel Questionnaire, no through week 17 in the intention-to-treat population change in functional status subscale score or symptom WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index numerical rating scale. *p<0·05; **p<0·01; ***p<0·001. severity subscale score was observed at week 8 or week 20 1244 noitcuder %05 gniveihca stneitap fo noitroporP erocs niap CAMOW ni A 0·3 mg/kg 1·0 mg/kg 2·0 mg/kg Placebo 60 40 3 ** 1 3 ** 0 3 ** 2 * 19 20 17 17 9 noitcuder %07 gniveihca stneitap fo noitroporP erocs niap CAMOW ni B 60 20 * 11 8 9 5 4 2 2 noitcuder %09 gniveihca stneitap fo noitroporP erocs niap CAMOW ni C 5 17 Time (weeks) Articles LEVI-04 0·3 mg/kg LEVI-04 1·0 mg/kg LEVI-04 2·0 mg/kg Placebo (n=129) (n=130) (n=129) (n=129) Any treatment-emergent adverse event 75 (58%) 86 (66%) 83 (64%) 87 (67%) Study medication-related* treatment-emergent adverse events 9 (7%) 9 (7%) 8 (6%) 10 (8%) Serious treatment-emergent adverse events 0 1 (1%) 3 (2%) 3 (2%) Severe treatment-emergent adverse events 0 3 (2%) 4 (3%) 4 (3%) Treatment-emergent adverse events leading to study discontinuation 3 (2%) 2 (2%) 4 (3%) 4 (3%) Treatment-emergent adverse event of special interest† 5 (4%) 10 (8%) 7 (5%) 4 (3%) Abnormal peripheral sensation 3 (2%) 4 (3%) 2 (2%) 1 (1%) Traumatic fracture 0 2 (2%) 3 (2%) 1 (1%)‡ Total joint replacement§ 1 (1%)¶ 1 (1%)¶ 1 (1%) 0 Subchondral insufficiency fracture§ 0 1 (1%)‡ 0 1 (1%) Suspected neuropathy 1 (1%) 0 0 0 Narrowing of joint space width (rapidly progressive osteoarthritis type 1)§ 0 2 (2%)|| 1 (1%)|| 1 (1%)|| Non-traumatic fracture 1 (1%) 0 0 0 Destructive arthropathy (including rapidly progressive osteoarthritis type 2§ 0 0 0 0 Osteonecrosis§ 0 0 0 0 Bone marrow infiltration 0 0 0 0 Treatment-emergent adverse events in ≥5% participants in any treatment group (preferred term) Arthralgia 11 (9%) 15 (12%) 15 (12%) 20 (16%) Nasopharyngitis 6 (5%) 8 (6%) 13 (10%) 13 (10%) Back pain 3 (2%) 5 (4%) 8 (6%) 3 (2%) Headache 4 (3%) 3 (2%) 8 (6%) 6 (5%) COVID-19 5 (4%) 2 (2%) 4 (3%) 8 (6%) Upper respiratory tract infection 4 (3%) 4 (3%) 5 (4%) 7 (5%) Pain in extremity 3 (2%) 7 (5%) 5 (4%) 5 (4%) Data are n (%). Participants experiencing multiple adverse events are only counted once within a given cell. *Adverse events with missing relatedness are considered related. †Participants experiencing multiple adverse events are only counted once within a given cell. ‡Osteoarthritis present at baseline. §All joint events Kellgren–Lawrence grade 2–4 on entry, all total joint replacements Kellgren–Lawrence grade 4 on entry. ¶Elective surgery. ||Meniscal extrusion reported. Table 3: Treatment-emergent adverse events in the safety population (appendix p 11). Similarly, for the SAS, no change from events with LEVI-04 at any dose. Rapidly progressive baseline was observed in SAS score at week 8 or week 20 osteoarthritis type 1 was reported in none, two (2%), (appendix p 12). one (1%), and one (1%) participants in the LEVI-04 The incidence rates of treatment-emergent adverse 0·3 mg/kg, 1·0 mg/kg, 2·0 mg/kg, and placebo groups, events of special interest are reported in table 3. The respectively (table 3). There were two subchondral most frequently reported was abnormal peripheral insuciency fractures reported, one in a shoulder joint in sensation with three (2%), four (3%), two (2%), and the 1 mg/kg group (1%), and one in a knee joint in the one (1%) participant reporting this event in the LEVI-04 placebo group (1%). There were no events of rapidly 0·3 mg/kg, 1·0 mg/kg, 2·0 mg/kg, and placebo groups, progressive osteoarthritis type 2. Three participants had respectively. There were no patterns related to the time of joint replacements during the 30-week study period (one in onset or duration of these events, and most resolved each active arm, 1%), all of which were Kellgren–Lawrence spontaneously. One non-traumatic fracture of L4/L5 in a grade 4 on study entry. One participant had surgery female participant aged 70 years with longstanding 3 weeks after starting the study and was adjudicated as lumbar pain and osteoporosis was reported (0·3 mg/kg normal progression of osteoarthritis, one was on a waiting group). Six traumatic fractures, all classified as unrelated, list before the study start (protocol deviation), and one was were reported as adverse events of special interest performed during the follow-up period. (two, three, and one in the LEVI-04 1·0 mg/kg, Detection of anti-drug antibodies was low (<2% of 2·0 mg/kg, and placebo groups, respectively). None of participants treated with LEVI-04). Anti-drug antibodies these were reported to be associated with prior dizziness to LEVI-04 were detected at randomisation in two (2%), or changes in proprioception. five (4%), and two (2%) participants, and at week 20 Irrespective of the Adjudication Committee decision in zero, four (3%), and two (2%) participants in the regarding normal or rapid progression of osteoarthritis, all LEVI-04 0·3 mg/kg, 1·0 mg/kg, and 2·0 mg/kg groups, cases reviewed by the Committee are reported. There was respectively. All positive anti-drug antibody results were no increase in the observed incidence of joint-related at the limit of detection (data not shown). Articles Discussion progressive osteoarthritis type 2 (the subchondral bone- This is the first report of a trial of supplementation of destructive phenotype) or other joint findings, and no p75NTR in individuals with osteoarthritis. The primary events in healthy joints (graded as Kellgren–Lawrence endpoint, the mean change from baseline in WOMAC grade 0 or 1 at study entry). By contrast, in studies with pain scores compared with placebo at week 17, was met anti-NGF antibodies of similar treatment duration, rapidly for all LEVI-04 dose groups. Significant improvements progressive osteoarthritis type 2 was reported25–27 and joint with LEVI-04 were also observed across secondary safety events occurred in healthy joints,27 suggesting NGF endpoints, including patient-reported and observed inhibition, even over a short duration, has detrimental function, stiness, and PGA. The severity of knee pain eects on joint health. All three of the joint replacements has been associated with the severity of Kellgren–Lawrence that occurred during the 30-week period in this study were grade;18 LEVI-04 treatment demonstrated similar ecacy in knees that were Kellgren–Lawrence grade 4 at baseline, across all Kellgren–Lawrence grades (Kellgren–Lawrence and two were elective. grade 2–4). Osteoarthritis is a chronic condition requiring Interpreting the clinical meaningfulness of these long-term treatment and biological therapies may be analgesic responses requires interpretation of a range of associated with development of an immune response to outcomes, as outlined by the IMMPACT guidelines.19,20 the treatment. The incidence of anti-drug antibodies in For the two highest doses of LEVI-04, the magnitude of this study was low, similar to pre-dose levels, supporting between-group dierences in WOMAC pain scores was the absence of immunogenicity of LEVI-04. Incidence of similar to that in previous trials of existing therapies, and anti-drug antibodies will continue to be monitored in the eect sizes—another measure of meaningfulness— future trials. were in the range of those previously reported for eective Limitations of this phase 2 study included absence of a therapies, with the higher doses above the 0·37 threshold quality-of-life measure, and a safety follow-up period of that reflects the median reported minimum clinically only 13 weeks after the primary endpoint. Greater ethnic important dierence.21 Furthermore, the reduction in and race diversity within the patient population would daily pain score from baseline was rapid (within 3 days). have allowed for improved generalisability. Longer term In terms of responder analyses, a 30% reduction in pain is treatment is needed to show any potential benefits or considered clinically meaningful;22 significantly more harms. If successful in subsequent trials, further participants on the top two LEVI-04 doses achieved at least evaluations will determine the place of this therapy in 50% reduction in WOMAC pain compared with placebo cost-eective care pathways. at weeks 5 and week 17. Sustained duration of eect was NT-3 is associated with pain,28,29 but also has important seen with the top two doses, although not for the lowest eects on bone metabolism. NT-3 enhances dose in the at least 30% responder analysis. expres sion of matrix metalloproteinase-9 and matrix Evoked pain has been proposed as a more sensitive metalloproteinase-13, and can augment osteoclastogenesis assessment for determining treatment eects.16 In the and bone resorption directly by activating the extracellular StEPP assessment, the improvement versus placebo was signal-regulated kinase 1/2 cascade and receptor activator significant for all LEVI-04 doses at week 5 and week 17. for nuclear factor κB ligand-induced increased expression This measure of pain on movement reflects the impact of of osteoclastogenic signals in dierentiating osteoclasts, osteoarthritis on daily functioning, and the ecacy of and indirectly by inducing osteoclastogenic signals in LEVI-04 on this measure parallels the significant osteoblasts.7 NT-3 also induces cartilage proteases, leading improvements seen in PGA scores. to cartilage degradation.7 Consequently, it is plausible that In this study, LEVI-04 was well tolerated with no observed inhibition of NT-3, could have an eect on structural safety concerns. Incident rates of treatment-emergent progression, in addition to treating the symptoms of knee adverse events were similar in the active treatment and osteoarthritis, which will be explored further in placebo groups. There was no increased incidence of subsequent trials. As LEVI-04 is a large molecule, it is treatment-related adverse events or serious adverse events peripherally restricted in most individuals and likely to compared with placebo. Few participants (five) discontinued have limited central nervous system adverse events. It has the study due to treatment-emergent adverse events. a non-opioid mechanism of action, mitigating the The incidence of joint pathologies was not increased, potential for addiction. with a low number of events of rapidly progressive Our results support the potential of LEVI-04 as a novel osteoarthritis type 1 recorded across the treatment and treatment for knee osteoarthritis, improving pain and placebo groups; background rates of approximately 3% physical function, and reducing disease burden, coupled might be expected over a 12-month period.23 At baseline, with an acceptable side eect profile. Longer duration all knees with rapidly progressive osteoarthritis had phase 3 trials will seek to replicate clinical ecacy and moderate-to-severe meniscal extrusion, which is assess long-term joint health. associated with progression of osteoarthritis.24 Importantly, Contributors there was no dose-dependence of incidence of rapidly PGC, NK, AG, ARB, DR, MCP, BH, CH, and SW were responsible for progressive osteoarthritis type 1, no cases of rapidly the study design. ARB, AG, and NK were involved in design of the data 1246 Articles acquisition tools. PGC, AG, ARB, MCP, CH, IB, and SW accessed, 2 Kloppenburg M, Namane M, Cicuttini F. Osteoarthritis. Lancet reviewed, and verified the data. DR is an employee of an independent 2025; 405: 71–85. statistics company (Prosoft) and conducted the statistical analysis. 3 Sharma D, Feng X, Wang B, et al. NT-3 contributes to The team were blinded to all data until after database lock, which was chemotherapy-induced neuropathic pain through TrkC-mediated performed by NBCD, according to GCP compliant procedures. CCL2 elevation in DRG neurons. EMBO Rep 2024; 25: 2375–90. All authors participated in data interpretation. All authors had final 4 Sun S, Diggins NH, Gunderson ZJ, Fehrenbacher JC, White FA, responsibility for the decision to submit the manuscript for publication, Kacena MA. No pain, no gain? The eects of pain-promoting provided critical feedback on the manuscript, approved the final neuropeptides and neurotrophins on fracture healing. Bone 2020; manuscript for submission, and were accountable for the accuracy and 131: 115109. integrity of the manuscript. 5 Richner M, Ulrichsen M, Elmegaard SL, Dieu R, Pallesen LT, Vaegter CB. Peripheral nerve injury modulates neurotrophin Declaration of interests signaling in the peripheral and central nervous system. Levicept provided support for medical writing. PGC has done Mol Neurobiol 2014; 50: 945–70. consultancies or speaker bureaus for AbbVie, Eli Lilly, Enlivex, 6 Szobota S, Mathur PD, Siegel S, Black KA, Uri Saragovi H, Formation Bio, Genascence, Grunenthal, Kolon TissueGene, Levicept, Foster AC. BDNF, NT-3 and Trk receptor agonist monoclonal Moebius, Novartis, Orion, Pacira, Stryker & Takeda, and received antibodies promote neuron survival, neurite extension, and synapse support for attending meetings or travel from Novartis. NK is a restoration in rat cochlea ex vivo models relevant for hidden hearing consultant to Levicept, AbbVie, Biogen, Consano, EicOsis, Genentech, loss. PLoS One 2019; 14: 0224022. Grünenthal, GSK, Latigo Biotherapeutics, the Merck Group, Mesoblast, 7 Su YW, Chim SM, Zhou L, et al. Osteoblast derived- Noven Pharmaceuticals, Rapport Therapeutics, Scilex Pharmaceuticals, neurotrophin 3 induces cartilage removal proteases and osteoclast- Sparian Biosciences, TLC BioSciences, Formation Bio (formerly mediated function at injured growth plate in rats. Bone 2018; 116: 232–47. TrialSpark), and Vertex Pharmaceuticals. ARB is an employee and shareholder of NBCD who were contracted by Levicept to provide 8 Dietz BW, Nakamura MC, Bell MT, Lane NE. Targeting nerve growth factor for pain management in osteoarthritis – clinical medical monitoring, operational management, site monitoring, data ecacy and safety. Rheum Dis Clin North Am 2021; 47: 181–95. management for the study. AG is a shareholder of Boston Imaging Core 9 Jiang Y, Tuan RS. Role of NGF-TrkA signaling in calcification of Lab, and a consultant for Levicept, Novartis, Kolon TissueGene, articular chondrocytes. FASEB Journal 2019; 33: 10231–39. Medipost (UK), Formation Bio, Paradigm Biopharmaceuticals, Scarcell 10 Zhao L, Lai Y, Jiao H, Huang J. Nerve growth factor receptor limits Therapeutics, Coval Biopharma (Shanghai), 4Moving Biotech, Peptinov, inflammation to promote remodeling and repair of osteoarthritic Pacira BioSciences, and holds stock or stock options in Boston Imaging joints. Nat Commun 2024; 15: 3225. Core Lab. DR received payment from NBCD to perform statistical 11 Carrino JA, McAlindon TE, Schnitzer TJ, et al. Characterization of analysis of the study and received consulting fees from Levicept for adverse joint outcomes in patients with osteoarthritis treated with ad-hoc analyses and review of the study results. MCP is a consultant to subcutaneous tanezumab. Osteoarthritis Cartilage 2023; Levicept, received Levicept support to attend the British Society of 31: 1612–26. Rheumatology meeting, owns stock in Centessa Pharmaceuticals, and 12 DiMartino SJ, Mei J, Schnitzer TJ, et al. A phase III study to holds stock options for Levicept. BH is a consultant for and received evaluate the long-term safety and ecacy of fasinumab in patients payments for study-related meetings and relevant scientific meetings with pain due to osteoarthritis of the knee or hip. from Levicept, owns stock in Pfizer and Glaxo, and holds stock options Osteoarthr Cartil Open 2024; 6: 100533. in Levicept. CH is an employee of and holds stock options in Levicept. 13 Sanga P, Katz N, Polverejan E, et al. Long-term safety and ecacy of IB is an employee of Levicept. SW is Chief Scientific Ocer, founder of, fulranumab in patients with moderate-to-severe osteoarthritis pain: and holds stock options in Levicept. a phase II randomized, double-blind, placebo-controlled extension study. Arthritis Rheumatol 2017; 69: 763–73. Data sharing 14 Westbrook SL, af Forselles K. Pharmacology of LEVI-04, a novel The study sponsor will receive requests for individual participant data that treatment for OA. [Abstract]. Arthritis Rheumatol 2025; 77 (suppl 9). underlie the results reported in this Article, after de-identification, from https://acrabstracts.org/abstract/pharmacology-of-levi-04-a-novel- qualified researchers whose proposed use of the data has been approved treatment-for-oa/ (accessed Nov 21, 2025). by a Review Committee. The study protocol is available in the appendix 15 Altman R, Asch E, Bloch D, et al. Development of criteria for the (pp 13–109). Data requests can be submitted to: info@levicept.com. classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Acknowledgments Committee of the American Rheumatism Association. The study was designed and sponsored by Levicept UK. The protocol Arthritis Rheum 1986; 29: 1039–49. was developed by Levicept with assistance from the authors of this paper. 16 Treister R, Suzan E, Lawal OD, Katz NP. Staircase-evoked pain Study oversight was provided by NBCD, Denmark, which was may be more sensitive than traditional pain assessments in responsible for medical monitoring, operational management, site discriminating analgesic eects. Clin J Pain 2019; 35: 50–55. monitoring, and data management. Radiographic central reading was 17 Cohen J. Statistical Power Analysis for the Behavioral Sciences. performed by Ali Guermazi. The Adjudication Committee (Joint Safety New York: Routledge, 1988, second edition. https://doi. Advisory Committee) was Marc Hochberg, John Carrino, and Edwin Oei. org/10.4324/9780203771587. Imaging services were provided by Image Analysis Group, London, UK; 18 Wang K, Kim HA, Felson DT, et al. Radiographic knee osteoarthritis Nordic Bioscience, Denmark, supplied clinical safety laboratory services; and knee pain: cross-sectional study from five dierent racial/ and Prosoft Clinical, USA, conducted biostatistics and medical writing ethnic populations. Sci Rep 2018; 8: 1364. services. PGC is supported in part through the National Institute for 19 Dworkin RH, Turk DC, McDermott MP, et al. Interpreting the Health and Care Research (NIHR) Leeds Biomedical Research Centre clinical importance of group dierences in chronic pain clinical (NIHR203331). The views expressed are those of the authors and not trials: IMMPACT recommendations. Pain 2009; 146: 238–44. necessarily those of the UK National Health Service, the NIHR, or the 20 Smith SM, Dworkin RH, Turk DC, et al. Interpretation of chronic UK Department of Health. The authors thank Kerry af Forselles for pain clinical trial outcomes: IMMPACT recommended providing a critical review of this manuscript. Medical writing and considerations. Pain 2020; 161: 2446–61. editorial assistance was provided by Cherry Bwalya of Cherry B 21 da Costa BR, Reichenbach S, Keller N, et al. Eectiveness of non- Enterprises, funded by Levicept. 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The ecacy, tolerability, and 29 Zhou XF, Deng YS, Xian CJ, Zhong JH. Neurotrophins from dorsal joint safety of fasinumab in osteoarthritis pain: a phase IIb/III root ganglia trigger allodynia after spinal nerve injury in rats. double-blind, placebo-controlled, randomized clinical trial. Eur J Neurosci 2000; 12: 100–05. Arthritis Rheumatol 2019; 71: 1824–34. 1248 --- [PDF原文](https://sci-net.xyz/storage/7932541/f1fd9981d538ce3fb5482e397d6edf3a569a8230e9f1870da59a6dead91a1203/Efficacy-and-safety-of-LEVI-04-in-patients-with-osteoarthritis-of-the-knee-a-randomised-double.pdf) DOI: 10.1016/S0140-6736(26)00131-5