Safety, biodistribution, and exploratory clinical outcomes of a novel intra-articular IL-1Ra gene therapy (PCRX-201) in moderate-to-severe knee osteoarthritis: 2-year results of a phase 1 study

Objectives The objective of this study is to investigate the safety, biodistribution, and exploratory clinical outcomes of enekinragene inzadenovec (PCRX-201), a high-capacity, nonintegrating, nonreplicating adenovirus serotype 5 vector expressing interleukin-1 receptor antagonist under the control of an inflammation-inducible promoter, in patients with moderate-to-severe knee osteoarthritis. Methods This open-label phase 1 trial (NCT04119687) enrolled participants aged 30 to 80 years with symptomatic (Western Ontario and McMaster Universities Osteoarthritis [WOMAC] pain score ≥ 5 and ≤ 9 [0-10–point scale]) and radiographic (Kellgren-Lawrence grade 2-4) knee osteoarthritis. In part 1, participants received a single intra-articular injection of PCRX-201 at 1 of 3 doses (n = 36). In part 2, participants received intra-articular methylprednisolone acetate immediately before PCRX-201 at the same dose (n = 36). Outcomes at week 104 included safety (primary endpoint), biodistribution (secondary endpoint), clinical outcomes (exploratory patient-reported endpoint), and immunogenicity. Data were analysed as observed. Results Transient treatment-related knee effusion was the most common adverse event and occurred less frequently in participants receiving glucocorticoid pretreatment (13/36 [36.1%]) than in those who did not (22/36 [61.1%]). Very limited biodistribution was detected outside the knee; only 2 participants had detectable PCRX-201 in plasma on days 1 and 4 postinjection. By week 104, 33/72 (45.8%) of participants had discontinued the study; however, those remaining showed sustained improvements with PCRX-201 for the exploratory outcomes of pain, stiffness, and function across doses and groups, regardless of preexisting neutralising antibody levels, with greater improvements observed in the glucocorticoid-pretreated group. Conclusions A single intra-articular injection of PCRX-201 demonstrated safety and localised distribution within the knee. Exploratory patient-reported clinical outcomes suggest promise and support further investigation of PCRX-201.