Apoptotic cell therapy shows promise in moderate–severe knee osteoarthritis: Findings from the ENX-CL-05-001 study

ENX-CL-05-001 (NCT06233474) is a randomized, double-blind, placebo-controlled phase 2a trial investigating an intra-articular apoptotic cell therapy for the treatment of moderate–severe knee osteoarthritis (OA). In this interview, Professor Philip Conaghan (NIHR Leeds Biomedical Research Centre; University of Leeds, Leeds, UK) spoke with touchIMMUNOLOGY to discuss the clinical burden of primary knee OA, the unmet needs in the treatment paradigm for OA, and the methodology and findings from the late-breaking ENX-CL-05-001 study.

The abstract “LB12: 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)” was presented at the ACR Convergence 2025, October 24–29, Chicago, Illinois.

touchIMMUNOLOGY coverage of ACR 2025:

Q. What is the prevalence and clinical burden of primary knee osteoarthritis, and what unmet needs exist in its treatment?

There are over 360 million people globally with knee osteoarthritis, with numbers rising rapidly with ageing populations. Nonpharmacological treatments are mainly muscle strengthening and weight loss, both of which may be limited by access to appropriate services and adherence over long periods of time.

The main widely recommended pharmacological therapies are topical and oral NSAIDs, but the former are not well utilised and the latter despite effectiveness can have substantial side effects and are not tolerated or contraindicated in up to 50% of people with knee osteoarthritis. Knee replacements do not work for everybody, and the numbers of such operations mean they are becoming a massive burden on health systems. There are a lot of people with poorly treated knee osteoarthritis and we desperately need new treatments.

Q. Why might apoptotic PBMCs be effective in treating OA, particularly regarding macrophage-mediated inflammation?

Allocetra is comprised of apoptotic cells that are capable of immune modulating the function of activated macrophages, by harnessing the naturally occurring property of apoptotic cells to induce a pro-homeostatic inflammatory state. This interaction of the cells with the patient’s macrophages, via distinct receptors, allows to reset inflammatory balance towards resolution of inflammation.

As pro-inflammatory macrophages are the main immune cells promoting the low-grade inflammatory state in OA, modulating their activity by exposure to a large quantity of normal apoptotic cells, can restore homeostasis and resolve the inflammatory state in the joints of OA patients and may confer substantial clinical benefits in these patients.

Q. What were the aims, design and inclusion criteria of the ENX-CL-05-001 study?

Study ENX-CL-05-001 is a randomized, double-blind, multi-centre trial evaluating the safety and efficacy of knee injections of Allocetra in comparison to placebo, in patients with knee osteoarthritis. Patients were required to have sufficiently severe disease to participate, both structurally and symptomatically, and were equally randomized to receive 3 treatments of Allocetra or control. The study utilizes validated and well-accepted assessments, including monitoring of patient reactions following treatment and patient reporting of pain and function. In addition to assessing the overall safety and efficacy of Allocetra, the study included assessments aiming to find a high-responder patient population.

Q. What were the primary and secondary endpoints and how well were they achieved at 3 months?

The primary endpoint evaluated the safety of patients following treatment. No serious adverse events reported were related to Allocetra. Allocetra-treated patients reported some transient local reactions in the knee, which readily resolved within a few days, and therefore the overall safety profile of Allocetra appears favourable and allows us to move ahead with clinical development of this treatment.

The secondary endpoints assessed the effects of Allocetra. At 3 months, patients treated with Allocetra reported an improvement in their knee pain and functionality. Moreover, a target responder population was identified, demonstrating a substantial improvement in knee pain and function in patients aged 60 years and above. In these patients, clinically meaningful and statistically significant improvements were observed in pain and function with a 92% relative improvement over the controls, as well as potential correlations with important markers on imaging, such as the bone marrow lesions.

Q. Based on these results, what are the implications for future development or clinical use of this therapy?

The results demonstrated a meaningful improvement in knee pain and function in patients treated with Allocetra, indicating that the responders may comprise a population enriched for primary age-related osteoarthritis, and also consistent with an age-linked, macrophage-mediated osteoarthritis phenotype. These results will provide a basis for an advanced clinical trial in primary age-related knee osteoarthritis, enabling us to commence a follow-up phase 2b study in this targeted underserved population during 2026.