Intra-Articular FX201 Gene Therapy Shows Promise for Osteoarthritis

Scott Kelley, MD

This week, at the American Society of Gene & Cell Therapy (ASGCT) Virtual Meeting, investigators reported on the safety and potential efficacy of FX201 gene therapy for osteoarthritis.

FX201, or humantakinogene hadenovec, is a helper-dependent adenovirus serotype 5 that expresses Interleukin (IL)-1 receptor (IL-1Ra) antagonist as an intra-articular gene therapy

“FX201 is designed to produce IL-1Ra in the presence of inflammation via a nuclear factor-kappa B-responsive promoter,” indicated the researchers, led by Scott Kelley, MD, Chief Medical Officer of Flexion Pharmaceuticals. “Previous work demonstrated safety and efficacy of FX201 in preclinical models of osteoarthritis.”

Kelley and team conducted a Phase 1 open-label, single ascending dose trial in order to assess the therapy’s safety, tolerability, biodistributions, and preliminary clinical activity in patients with moderate-to-severe osteoarthritis in the knee. This ongoing trial follows IND-enabling toxicology studies and clinical-scale cGMP production.

The most recent findings represent 24-week data from the low-dose cohort (n = 5). Patient ages ranged from 30-80 years old, and all had Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain scores ≥ 4.0 - ≤ 9.0.

Further, these patients had Kellgren-Lawrence Grade 2-3 radiographic severity and experienced failure of ≥2 other treatments.

As such, a dose of 1.4E10 genome copies of FX201 was administered to the knee in question via ultrasound-guided intra-articular injection. The investigators assessed systemic biodistribution and shedding through quantification of vector copies in plasma, urine, and injection site swabs.

“No evidence of systemic biodistribution in plasma or shedding in urine or skin samples was observed in any patient,” they reported.

Clinical activity of the gene therapy was evaluated through measurements of changes in pain (WOMAC-A) and function (Knee Injury and Osteoarthritis Outcome Score [KOOS] Function in daily living).

Kelley’s team thus observed variable clinical activity with reduction in pain and improvement in activity. Nonetheless, 3 patients experienced substantial improvements in WOMAC-A pain intensity (as assessed by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials [IMMPACT])) at week 8, and 2 patients had similar improvements at weeks 12 and 24.

“Substantial pain relief persisting to 24 weeks following low-dose FX201 is encouraging and supports evaluating tolerability and responses with higher doses of FX2021,” they wrote.

Overall, the therapy was considered well-tolerated among the patients, with 2 patients experiencing self-limited Grade 2 index-knee adverse events (pain, swelling, effusion). The investigators indicated these events may have been possibly related to conservative treatment management.

The team is expected to update their results in the future, especially as follow-up of the mid-dose cohort nears completion.

The study, “Interim Data from the First-in-Human Phase 1 Trial of FX201, an Intra-Articular, Helper-Dependent Adenoviral Gene Therapy for Osteoarthritis - Safety, Tolerability, Biodistribution, and Preliminary Evaluation of Clinical Activity in 5 Patients,” was presented at ASGCT 2021.