2103: PCRX-201 High-Capacity Adenovirus Serotype 5 Gene Therapy Demonstrates Sustained Clinical Efficacy and Safety in Patients With Knee Osteoarthritis

Background/Purpose: Knee OA is a common disease affecting ~15 million people in the United States. There is an urgent unmet need for additional OA treatments as current treatments provide only short-term pain relief often associated with unwanted side effects and contraindications. Gene therapy using viral vectors has emerged as a novel therapeutic modality with the potential to treat many diseases. PCRX-201 (enekinragene inzadenovec) is a novel high-capacity adenovirus serotype 5 (Ad5) vector carrying a transgene encoding for the inflammation-inducible expression of IL-1 receptor antagonist (IL-1Ra) that is under investigation to treat knee OA via IA injection. This open-label phase 1 trial (NCT04119687) investigated the safety and efficacy of PCRX-201, for which long-term follow-up is ongoing.

Methods: Patients aged 30-80 years (N=72) with painful OA of the index knee and Kellgren/Lawrence (K/L) grade 2, 3, or 4 were eligible. The first group (n=36) received IA injection of PCRX-201 in the target knee at 1 of 3 doses (low: 1.4E10 genome copies [GC]; middle: 1.4E11 GC; high: 1.4E12 GC); the second group (n=36) was pretreated with IA methylprednisolone 40 mg immediately before PCRX-201 administration at the same doses. WOMAC pain (WOMAC-A) and stiffness (WOMAC-B) subscale scores and Knee Injury and Osteoarthritis Outcome Score Activities of Daily Living (KOOS ADL) were measured up to 156 weeks. Anti-Ad5 neutralizing antibody (NAb) titers in serum were measured at baseline before PCRX-201 administration and up to 52 weeks.

Results: Pain and function improvements were observed at all doses and across both the not pretreated and corticosteroid pretreated groups up to 156 weeks after PCRX-201 IA administration (Figure 1). The pretreated group showed greater improvements for WOMAC-A (range of least squares mean [LSM] improvement from baseline across dose levels, 3.37-3.62 [of 10] points; Figure 1A), WOMAC-B (3.31-4.13 [of 10] points; Figure 1B), and KOOS ADL (Figure 1C) than the not pretreated group. Patients in the pretreated group with K/L grades of 2, 3, and 4 showed LSM reductions from baseline in WOMAC-A, with greater numerical reductions observed in those with K/L grade 2 than those with K/L grades 3 or 4 (Figure 1D). Importantly, preexisting serum NAbs did not affect PCRX-201 efficacy as determined by WOMAC-A pain (Figure 2A) and WOMAC-B stiffness (Figure 2B). The most commonly reported treatment-related adverse event (AE), index joint effusion, occurred less frequently for participants in the pretreated (15/36; 42%) than the not pretreated group (24/36; 67%) (Table 1).

Conclusion: A single IA injection of PCRX-201 with corticosteroid pretreatment in patients with knee OA had an acceptable safety profile and sustained clinical efficacy for up to 156 weeks. Preexisting NAbs did not affect PCRX-201 efficacy or safety at all 3 doses, and corticosteroid pretreatment demonstrated greater improvement in the clinical scores than no pretreatment. These results support the ongoing phase 2 study strategy of PCRX-201 with a 10-fold lower dose (1.4E11 GC) and steroid pretreatment.