Background/Purpose: IL-1 contributes significantly to osteoarthritis (OA) pathology, driving inflammation and cartilage degradation. Prior therapies targeting IL-1 have shown limited success due to inadequate drug delivery and retention in joints. GNSC-001, a recombinant adeno-associated virus (rAAV) encoding the IL-1 receptor antagonist (IL-1Ra) transgene, is designed to provide sustained, local inhibition of IL-1 activity after a single intra-articular (IA) injection. The DONATELLO Phase 1b trial was initiated to evaluate the safety, dosing and pharmacodynamic effects of GNSC-001. Effects of immune conditioning with short regimens of corticosteroids (CS) were also investigated. Results from the 12-month primary follow-up period are reported.

Methods: Consented participants (40-75 years, Kellgren Lawrence grades 2-3, target knee pain WOMAC ≥20/50) were randomized (1:1:1:1:1) into five groups: (1: n=12) GNSC-001 1×10¹² vector genomes (vg); (2: n=11)) GNSC-001 1×10¹² vg + oral CS (prednisone 60mg/day tapered over 6 weeks); (3: n=10) GNSC-001 1×10¹³ vg; (4: n=10) GNSC-001 1×10¹³ vg + oral CS and (5: n=10) placebo (PBO). An open-label group (6: n=14) with target knee effusions at baseline, received GNSC-001 1×10¹³ vg with IA methylprednisolone (80mg) plus oral prednisone (60mg/day for 3 days). All subjects received ultrasound-guided IA injections on Day 1. Visits, including synovial fluid (SF) draws to measure IL-1Ra expression and exploratory patient reported outcomes (PROs) occurred at Months 1, 3, 6, and 12, with planned 48-month safety follow-up.

Results: At study completion (Month 12), 67 subjects (78% female, mean age 60.9 ± 8.5 years, mean BMI 28.6 ± 4.3 kg/m²) had been dosed across the 6 groups. No deaths or related treatment-emergent serious adverse events were reported. Treatment-Emergent Adverse Events (TEAEs) were balanced in Groups 1-5, trending higher in Group 6. Target knee AEs (TKAEs) across Groups 1-6 were mostly mild-moderate, with one graded as a ‘severe’ event (recurrent knee effusion in Group 6). TKAEs included arthralgia, swelling, effusion, and stiffness. TEAEs and TKAEs at 12 months are summarized in Table 1. GNSC-001 treated groups 1, 2, 4 and 5 had elevated SF IL-1Ra levels compared to baseline and PBO (Table 2). PROs in GNSC-001 treated groups showed sustained improvement from baseline in most subjects.

Conclusion: This trial met its primary and secondary objectives, with GNSC-001 demonstrating a favorable safety profile and sustained IL-1Ra expression in SF. Corticosteroid immune conditioning was associated with increased IL-1Ra expression. Exploratory PROs in GNSC-001 treated groups showed improvements from baseline in a majority of subjects. These data support further clinical development of GNSC-001 as a promising therapeutic strategy addressing unmet clinical needs for treatment of knee OA.

Table 1: Treatment Emergent and Target Knee Adverse Events, Groups 1-6.

* Related AE are all AE classified as either Possibly, Probably or Definitely related.

** Only applies to cohorts receiving oral steroids.

Table 2: IL-1Ra Expression.

Numbers denote % subjects expressing IL-1Ra in synovial fluid in target range (>500pg/ml)

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evaluate-safety-tolerability-and-pharmacodynamics-of-a-single-intra-articular-injection-of-gnsc-001-gene-therapy-in-subjects-with-knee-osteoarthritis-12-month-results-from-donatello/