Director of the NIHR Leeds Biomedical Research Centre; Prof of Musculoskeletal Medicine for University of Leeds, Honorary Consultant Rheumatologist for LTHT; NIHR Senior Investigator Emeritus

Philip Conaghan, MBBS, PhD

Objectively Measuring Pain and Function in Osteoarthritis, With Philip Conaghan, MBBS, PhD

LEVI-04 meaningfully improved pain and function in people with knee osteoarthritis (OA) in new analyses from a phase 2 trial.

New data on LEVI-04, a first-in-class p75 neurotrophin receptor-Fc fusion protein, were presented by Philip Conaghan, MBBS, PhD, Director, NIHR Leeds Biomedical Research Centre, and Professor of Musculoskeletal Medicine at University of Leeds at the 

American College of Rheumatology (ACR) Convergence 2025

, held October 24–29 in Chicago, Illinois.

LEVI-04 was evaluated in a multicenter, randomized, placebo-controlled phase 2 trial that enrolled 518 adults with radiographically confirmed (Kellgren-Lawrence grade ≥2) and symptomatic knee OA (≥4/10 WOMAC and ≥4/10 average weekly pain). Participants received intravenous placebo or LEVI-04 at doses of 0.3, 1.0, or 2.0 mg/kg at baseline and every 4 weeks through week 16. The study primarily assessed change in WOMAC pain at week 17, with additional assessments of WOMAC function, stiffness, patient global assessment (PGA), and average weekly numerical rating scale (NRS) pain.

Conaghan and colleagues found that LEVI-04 achieved statistically significant improvements in WOMAC pain versus placebo across all doses in a dose-dependent fashion. The investigators also assessed pain on movement with the Staircase-Evoked Pain Procedure (StEPP) and found that a greater proportion of participants treated with LEVI-04 achieved the minimum clinically important difference (MCID) of 2 points in the StEPP versus placebo, with statistical significance observed in the 1.0 and 2.0 mg/kg groups.

 spoke with Conaghan to learn more about the study and the novel StEPP test that shows potential to be used as an objective measure on pain and function for people with knee OA.

"What we see that more people on LEVI-04 for all 3 doses achieved a clinically relevant reduction in that step function. So in other words, they were able to do more steps. Their pain related to steps was reduced, and that's really important for osteoarthritis, which is a disease where all the pain is related to how much you walk," Conaghan said.

Conaghan's disclosures include AbbVie/Abbott, Alfasigma, Eli Lilly, Eupraxia, Formation Bio, Galapagos, Genascence, Grunenthal, Janssen, Kolon TissueGene, Levicept, Medipost, Moebius Medical, Novartis, Orion, Pacira, Sandoz, Stryker, and Takeda.

Conaghan P, Katz N, Bihlet A, et al. LEVI-04, a Novel Neurotrophin-3 Inhibitor, Demonstrates Clinically Meaningful Improvements in Pain and Physical Function across a Range of OA Outcomes, Including the Staircase-Evoked Pain Procedure (StEPP). Presented at: ACR Convergence 2025; October 24-29; Chicago, Illinois. Poster #2101

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Conaghan discussed the potential of StEPP as a measure in clinical trials.

LEVI-04 Improves Pain, Function in Knee Osteoarthritis, with Philip Conaghan, MBBS, PhD

LEVI-04, a first-in-class p75 neurotrophin receptor-Fc fusion protein, has shown promising and clinically meaningful improvements in pain and physical function among patients with moderate-to-severe knee osteoarthritis (OA).

Findings from the multicenter, randomized, placebo-controlled phase 2 trial were presented by Philip Conaghan, MBBS, PhD, Director, NIHR Leeds Biomedical Research Centre, and Professor of Musculoskeletal Medicine at University of Leeds at the 

The trial enrolled 518 adults with radiographically confirmed (Kellgren-Lawrence grade ≥2) and symptomatic knee OA (≥4/10 WOMAC and ≥4/10 average weekly pain). Participants were randomized to receive intravenous placebo or LEVI-04 at doses of 0.3, 1.0, or 2.0 mg/kg at baseline and every 4 weeks through week 16. The primary endpoint was change in WOMAC pain at week 17, with additional assessments of WOMAC function, stiffness, patient global assessment (PGA), and average weekly numerical rating scale (NRS) pain.

Across all doses, LEVI-04 achieved statistically significant improvements in WOMAC pain versus placebo, with effect sizes that met or exceeded those typically reported for NSAIDs. Improvements increased with higher doses, underscoring a dose-response relationship. Clinical meaningfulness was further supported by results from the Staircase-Evoked Pain Procedure (StEPP), a standardized measure of pain on movement. A greater proportion of participants treated with LEVI-04 achieved the minimum clinically important difference (MCID) of 2 points in the StEPP versus placebo, with statistical significance observed in the 1.0 and 2.0 mg/kg groups.

Phase 3 studies are now being planned to confirm the efficacy and safety of LEVI-04 and further evaluate its long-term impact on pain and functional outcomes in knee OA. 

 spoke with Conaghan to learn more about LEVI-04 and its potential advantages for people with osteoarthritis.

Conaghan discussed the potential of LEVI-04 for knee osteoarthritis at ACR 2025.

Apoptotic Cell Therapy Shows Promising Benefits for Older Adults With Knee OA, with Philip Conaghan, MBBS, PhD

Apoptopic cell therapy (Enlivex Therapeutics) has demonstrated promising safety and efficacy in older adults over the age of 60 with moderate-to-severe knee osteoarthritis.

The cell therapy was evaluated in the multicenter, randomized, double-blind, placebo-controlled phase 2a ENX-CL-05-001 trial (NCT06233474), findings from which were presented by Philip Conaghan, MBBS, PhD, Director, NIHR Leeds Biomedical Research Centre, and Professor of Musculoskeletal Medicine at University of Leeds at the 

The study enrolled 129 patients with Kellgren-Lawrence grade 2–3 disease, who received 3 knee injections over 28 days and were followed for 12 months. Conaghan and colleagues found that numerical rating scale (NRS) pain improvement was 24% higher with apoptotic cell therapy than placebo, and WOMAC pain and function improvements were also numerically higher than placebo, however, these did not reach statistical significance. A predefined age-related responder group (≥60 years; 53.5% of participants) did demonstrate clear benefits with apoptotic cell therapy.

At 3 months, patients aged 60 and older reported a 72% relative improvement in WOMAC pain (–27.82 vs –16.22; 

 = .03), a 109% improvement in function (–26.45 vs –12.63; 

 = .007), and a 92% improvement in total WOMAC score (

 = .012) compared with placebo. For patients ≥65 years, effects were even more pronounced, with the total WOMAC improvement reaching –27.14 vs –6.03 (

 = .0004). These clinically meaningful benefits were accompanied by consistent trends in NRS pain reduction and durability through month 6.

In terms of safety, there were some adverse events, mostly transient effusions, after injection that were more frequent with apoptotic cell therapy (89.6%; n = 60) than placebo (71.6%; n = 48%).

spoke with Conaghan to learn more about the potential of apoptotic cell therapy to provide a therapeutic benefit for knee OA, the importance of age- and phenotype-driven targeting, and how the field may finally be moving closer to precision therapy for osteoarthritis.

"I think a problem for all OA trials has been finding the subgroup, the phenotype, or the endotype, that might be responsive to a given therapy, and that's thought to be the reason why certain therapies haven't worked. So this was interesting that there's a very strong age signal," Conaghan said.

Conaghan P, Husøy B, Rovsing C, et al. Randomized, Double-Blind, Placebo-Controlled Phase IIa Trial of an Innovative Intra-Articular Apoptotic Cell Therapy in Knee Osteoarthritis (OA): 3-Month Positive Outcomes and Identification of Responder Population (NCT06233474). Presented at: ACR Convergence 2025; October 24-29; Chicago, Illinois. Poster #LB12

Conaghan discussed findings from the ENX-CL-05-001 phase 2a trial at the ACR Convergence.

Philip Conaghan, MBBS, PhD

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