We believe that better is possible for patients suffering with pain and degenerative diseases like osteoarthritis. Hello, I'm Jonathan Slonin, Chief Medical Officer for Pacira BioSciences. I'm excited to share with you our clinical development plan for PCRX-201, an innovative gene therapy targeting an underlying cause and symptoms of osteoarthritis of the knee. Before we begin, let me remind you today's presentation contains forward-looking statements based on current expectations. Such statements may involve certain assumptions, risks, and uncertainties that are beyond our control and could cause actual results to differ materially. A more detailed description of these and other risks can be found in the presentation materials, as well as our latest SEC filings, which are available from the SEC or the Pacira website.
I would also like to remind our listeners that PCRX-201, also known as enekinragene inzadenovec, is currently investigational and not approved by the U.S. Food and Drug Administration. Knee osteoarthritis is a highly prevalent and debilitating condition affecting over 15 million individuals in the United States. With an aging population and an increasing number of younger individuals developing OA, the burden of the disease is expected to rise significantly. In the absence of a disease-modifying treatment, the number of patients progressing to severe disability and total knee arthroplasty, commonly referred to as knee replacement, will pose growing challenges not only for patients but also for the healthcare system. Current treatment options provide only short-term symptomatic relief, are associated with adverse effects from long-term use, and do not address the underlying cause of disease and disease progression.
Based on the high prevalence of OA, its associated morbidity, and the lack of therapies that can reverse, slow, or stop the degradation processes of OA, in 2018, the FDA recognized OA as a serious disease with significant unmet medical need. Patients with knee OA often struggle with routine activities such as climbing stairs, getting in and out of vehicles, or participating in social interactions. Chronic pain can disrupt sleep, limit physical activity, and interfere with work, significantly diminishing overall health and quality of life. The absence of effective disease-modifying therapies has contributed to therapeutic stagnation, leaving many patients with the belief that chronic pain is inevitable and must be endured. Pacira aims to address this gap by developing safe, non-addictive therapies designed to improve outcomes and quality of life for individuals living with knee OA.
PCRX-201, also known as eneikinragene inzadenovec, is one such innovation that uses a novel gene delivery system with unique design elements that we believe will unlock the promise of gene therapy to address unmet medical needs in OA. This investigational therapy targets the well-validated IL-1 pathway with several drugs approved for other inflammatory diseases. These existing therapies have had limited success in treating osteoarthritis because they are unable to achieve the high and durable concentrations of drug inside the joint where it is needed for OA. PCRX-201 offers a solution by delivering a gene to the cells of the knee that expresses interleukin-1 receptor antagonist, or IL-1RA, an anti-inflammatory protein that our body already produces to keep inflammation in check by blocking the Interleukin-1 pathway.
In a robust phase I trial involving 72 patients with moderate to severe OA, PCRX-201 demonstrated unprecedented clinical results, including significant and durable pain relief across all levels of disease severity, lasting at least two years from a single intra-articular injection. These outcomes led to PCRX-201 becoming the first gene therapy in OA to receive the FDA's Regenerative Medicine Advanced Therapy designation, or RMAT, highlighting both the innovativeness and potential impact of this treatment. Additionally, because of the local injection strategy and the efficiency of the high-capacity adenovirus vector employed in PCRX-201, low doses of drug were able to achieve relief in patients. This means PCRX-201 can be manufactured at a scale that can be cost-effective in a common disease like OA.
The combination of targeting a well-validated pathway, achieving impressive initial phase I results, establishing a favorable regulatory designation, and having a line of sight to an economically viable manufacturing approach positions PCRX-201 to be a significant and innovative new modality in OA therapy, perhaps the first in over 20 years. The two-year data from our 72-patient phase I study was presented by Dr. Stanley Cohen at the 2024 American College of Rheumatology annual meeting in Washington, D.C. The data shown here are patient-reported outcomes using the Western Ontario and McMaster Universities Osteoarthritis Index, or WOMAC, scale of OA pain and stiffness from the 36 patients in the corticosteroid pretreatment cohort. Across all three dosages studied, 70% of patients experienced a greater than 50% reduction in pain and stiffness through 78 weeks and a 48%-65% reduction in pain and stiffness through two years.
In this study, efficacy among the three dose levels were not statistically differentiated, likely due to PCRX-201's design for inflammation-inducible expression of IL-1RA. This means that the expression of the therapeutic protein is turned on only when needed and turned off when inflammation is quelled, therefore suppressing the level of dose response. PCRX-201 was well tolerated, with the most common adverse event being a dose-dependent transient knee effusion. These effusions were typically managed with conservative therapy, aspiration, and corticosteroids. This observation led to the expansion of the phase I study to include co-administration of the corticosteroid methylprednisolone acetate at the time of drug administration. This approach led to a reduction in AEs and to an improvement in patient-reported outcomes through 104 weeks. It is noteworthy that generally in gene therapy development, pretreatment of patients with steroids improves product efficacy and durability by improving cellular transduction and gene transfer.
To understand the context of the clinical response observed in this study, a range of placebo responses across numerous OA studies, including multiple routes of drug administration, is provided here. This range of placebo response is not intended to convey any claims of efficacy by separation from placebo, as this will be assessed directly in phase II and III clinical studies. Literature references for this placebo response range are provided at the end of this presentation. Because the dose response with respect to efficacy was not statistically separated, and because the most common AE was dose-dependent, the phase II study will further explore the low and mid doses used in phase I. This is an illustrative example of the probable clinical development plan for PCRX-201.
Phase II will include two parts, differentiated by patient numbers and gene therapy manufacturing process, with part B using a manufacturing process intended for commercial scale-up. Gene therapy development and regulatory submission are significantly de-risked when the commercially represented materials are incorporated as soon as possible in clinical development. It is typically expected to have two well-controlled phase III studies when studying common diseases like OA, as depicted here. We will continue to engage with the FDA under the auspices of our RMAT designation as more clinical data become available to refine and optimize the pivotal clinical study design. Additionally, due to unique properties of our gene therapy platform and immune response to the delivery vector, we will explore the ability to dose other joints in a phase II bilateral dosing study, which will be incorporated into the BLA submission for PCRX-201.
The ability to redose the same joint will be studied as a phase III extension. This two-part phase II study is a randomized double-blind active-controlled study assessing the safety and tolerability in patients with painful OA of the knee. Dosing of patients has begun, and we expect to have top-line interim data from the first part of the study before the end of 2026. Part A of the phase II clinical trial will utilize PCRX-201 material produced using the same manufacturing process employed during the phase I study. Part B will incorporate PCRX-201 manufactured via a process aligned with the intended commercial production pathway. Evaluating both formulations under a unified clinical protocol is expected to facilitate manufacturing optimization and inform phase III dose selection.
Co-administration of methylprednisolone acetate in phase I was associated with a reduction in adverse events, improved long-term pain and function outcomes, and accelerated resolution of immune responses. Consequently, methylprednisolone acetate will be administered concurrently with either PCRX-201 or saline placebo in this study. The primary endpoint of the study is to evaluate the safety profile of PCRX-201. Secondary endpoints include assessment of patient-reported outcomes related to pain, physical function, and health-related quality of life, utilizing validated instruments including WOMAC, COOS, and EQ-5D-5L questionnaires. The phase II protocol includes a broad representative OA patient population with painful OA and active synovitis. The carefully considered inclusion and exclusion criteria should minimize spurious interfering factors while maximizing the addressable population participating in this study. For example, many OA studies limit participation to Kellgren-Lawrence or KL grade II and III radiographic measures of OA severity.
In the phase I study of PCRX-201, even KL4 patients, the most advanced stage of OA disease, had meaningful improvement in pain and function. The PCRX-201 phase II study includes KL2, III, and IV subjects with predefined limits on the number of each KL grade in the randomization plan. This study's primary endpoints focus on safety, specifically the incidence of treatment-emergent adverse events, adverse events of specific interest, and serious adverse events. Secondary endpoints include assessment of biodistribution, immunogenicity characterization, and patient-reported outcome measures of efficacy. The primary endpoint of the study will be 52 weeks with interim top-line analysis prior to week 52 and long-term follow-up through five years. Part A of the study will enroll 45 subjects randomized in a 1:1:1 ratio across three treatment cohorts with stratification based on KL grade.
Each subject will receive either PCRX-201 or saline placebo co-administered with 40 mg of methylprednisolone at the time of intra-articular injection. Enrollment for Part A commenced in February 2025 with multiple patients already dosed. This is a multi-center study involving up to 15 clinical trial sites. Part B follows the same randomization plan and dosing but uses PCRX-201 made using the new scalable commercial manufacturing process with a study population of 90 patients across the three cohorts. Additional clinical sites will be activated to support the increased enrollment target. In 2025, PCRX-201 has several important communication milestones. In April, we will present the two-year phase I data stratified by KL grade at the Osteoarthritis Research Society International Conference in South Korea. In May, at the American Society of Gene and Cell Therapy Conference in New Orleans, we will present our insights into immunogenicity and impact on future dosing strategy.
The ASGCT programming committee selected our work as a podium presentation. In addition, we will be presenting a full symposium on the high-capacity adenoviral vector platform used in PCRX-201. Professor Brendan Lee from the Baylor College of Medicine, a leading innovator in the application of HCAD and gene therapy in human disease, will join Pacira and GQ Bio colleagues in explaining the opportunities this exciting new platform provides in bringing gene therapy to the masses in common diseases. In June, we will present our three-year data from the phase I study. Very few OA studies reach such a milestone for study duration, and we are excited to share this long-term follow-up data. We thank you for your interest in Pacira and PCRX-201. We are excited to advance PCRX-201 because we know better is possible for patients suffering from osteoarthritis.