Compositions and uses for treating osteoarthritis

Abstract

Embodiments of the present disclosure relate to methods or uses of enekinragene inzadenovec for treating pain in subjects with osteoarthritis of the knee (OAK). The methods or uses may also include a corticosteroid pretreatment or co-administration. The methods or uses described herein substantially improve subjects' WOMAC pain scores, WOMAC stiffness scores, WOMAC physical function scores, or KOOS scores after the treatment and the effectiveness of the gene therapy may last up to two or three years.

Description

PCRTX.022WO PATENT COMPOSITIONS AND USES FOR TREATING OSTEOARTHRITISField

[0001] The present disclosure relates to compositions and methods for treating pain in subjects with osteoarthritis of the knee (OAK).REFERENCE TO SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled “PCRTX_022WO.xml” created on March 11, 2026, which is 34,854 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.BACKGROUND

[0003] Osteoarthritis (OA) is a serious disease with an unmet medical need for therapies that inhibit structural damage or target the underlying pathophysiology associated with OA. OA is characterized by synovial inflammation, deterioration of articular cartilage, and degenerative changes to peri-articular and subchondral bone (Creamer and Hochberg, Lancet.1997;350(9076):503-8; Goldring and Goldring, J. Musculoskeletal Neuronal Interactions 2006;6(4):376-8). Osteoarthritis is the most common form of arthritis, estimated to affect more than 31 million adults in the United States (US) (Cisternas et al., Arthritis Care Res (Hoboken) 2016;68(5):574~ 80). OA most commonly affects large weight bearing joints like the knees and hips but can also manifest in the shoulders, hands, feet, temporomandibular joint, and spine and is typically accompanied by chronic joint pain, tenderness, stiffness, and limited mobility. As the disease progresses, it becomes increasingly painful, culminating, in many cases, in the need for total joint arthroplasty.

[0004] Because no progression-modifying treatment is available for OA and its associated pain and subjects may live for decades with the disease, the public health and economic burdens of OA are extremely high (Osteoarthritis Action Alliance, “OA prevalence & burden: osteoarthritis prevention and management in primary care,” 2024).

[0005] Mitigating pain and preventing progression of OA represent areas of unmet need (Food and Drug Administration Draft Guidance: “Osteoarthritis: Structural Endpoints for the Development of Drugs, Devices, and Biological Products for Treatment Guidance for Industry (August 2018)”). Treatment options for OAK range from conservative approaches (exercise and weight loss) to total knee replacement (TKR) surgery. Over-the-counter analgesic options such asacetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) have unfavorable riskbenefit profiles for subjects (Fraenkel et al., Arch Intern Med. 2004; 164( 12) : 1299-304), and intraarticular (IA) corticosteroids or hyaluronic acid injections can have short-term analgesic effects (Richards et al., Phys Sportsmed. 2016;44(2): 101-8).

[0006] The interleukin- 1 (IL-1) family consists of 2 agonists, interleukin- 1 agonist alpha and beta (IL-la and II - Ip); 2 receptors, biologically active IL-1 receptor type I (IL-1RI) and decoy IL-1 receptor type II (IL-1RII); and 1 receptor antagonist, interleukin- 1 receptor antagonist (IL-IRa). IL-IRa is a true antagonist of IL-1RI, competitively blocking the binding of both IL-la and IL-ip while having no inherent signaling capabilities.

[0007] A recombinant version of IL-IRa (anakinra; KINERET®) was approved by the FDA in 2001 and is indicated for the reduction of signs and symptoms, for slowing the progression of structural damage in moderate to severe active rheumatoid arthritis (RA), for the treatment of neonatal -onset multisystem inflammatory disease, and for treatment of deficiency of IL-IRa (KINERET (anakinra) [package insert]. Stockholm, Sweden: Swedish Orphan Biovitrum AB; 2024). It is administered daily by subcutaneous injection. The efficacy of anakinra was evaluated in the context of knee OA by IA injection, but improvement in subjects’ OA symptoms could not be sustained for more than a few days (Chevalier et al., Arthritis Rheum. 2009;61 (3):344~ 52). One reason for this may be the challenge of achieving long-term bioavailability in affected joints: IL-IRa has a short half-life and low in vivo stability, and there are physiological mechanisms for rapid clearance of molecules from the synovial fluid.

[0008] A gene therapy approach for long-term gene expression to locally produce IL-IRa in response to inflammation has the potential to deliver sustained relief from symptoms and beneficial modification of the underlying disease after a single IA injection in subjects with OAK. Helper-dependent adenovirus (HDAd) vectors have genomes that are devoid of all viral coding sequences, and contain only the inverted terminal repeats (ITR) required for vector genome replication, and the adenoviral packaging signal ( ) necessary for packaging for the viral genome into the capsid produced by the helper adenovirus. Because of the lack of viral coding sequences, HDAd have a larger cloning capacity, and are thought to illicit a weaker host immune response than adenoviral vectors. Nonclinical pharmacology studies demonstrated the functionality of a helper-dependent, high capacity adenovirus (HCDAd)-IL-lRa vector (also known as PCRX-201 or enekinragene inzadenovec) to produce therapeutic levels of IL-IRa in the presence of inflammation. As HDAd can be more difficult to manufacture than adenoviral vectors, there remains a need for improving and optimizing the doses of HDAd vector-based gene therapy for best clinical outcome.SUMMARY

[0009] One aspect of the present disclosure relates to a method of treating knee osteoarthritis pain in a subject in need thereof, comprising:identifying and / or selecting a subject, or selecting a subject identified as, having at least grade 2 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale; andadministering a pharmaceutical composition comprising at least about 1 X 109(c.g., about 1 x 109GC to about 1 x 1013GC or about 1 x IO10GC to about 1 x 1012GC) viral genome copies (GC) of enekinragene inzadenovec to the subject (e.g., to an osteoarthritic knee of the subject) by a single intra-articular injection, wherein the method improves one or more measurements of knee osteoarthritis pain selected from the group consisting of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, WOMAC stiffness score, WOMAC physical functional score, and Knee Injury and Osteoarthritis Outcome Score (KOOS).

[0010] Another aspect of the present disclosure relates to a method of improving one or more measurements of knee osteoarthritis pain treatment in a subject having grade 2, 3 or 4 severity of knee osteoarthritis and optionally also have synovitis, comprising:identifying and / or selecting a subject, or selecting a subject identified as, having grade 2, 3 or 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale and / or synotivis; andadministering a pharmaceutical composition comprising at least about 1 X 109(e.g., about 1 x 109GC to about 1 x 1013GC or about 1 x 1010GC to about 1 x 1012GC) viral genome copies (GC) of enekinragene inzadenovec by a single intra-articular injection to an osteoarthritic knee of the subject;wherein the measurements of the knee osteoarthritis pain treatment are selected from the group consisting of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (scale 0 to 10), WOMAC stiffness score (scale 0 to 10), WOMAC physical functional score (scale 0 to 68), and Knee Injury and Osteoarthritis Outcome Score (KOOS) (scale 0 to 100), and wherein the method reduces the WOMAC pain score of the osteoarthritic knee by at least 1 to 8 points in the subject, the method reduces the WOMAC stiffness score of the osteoarthritic knee by at least 1 to 8 points in the subject, the method reduces the WOMAC physical function score of the osteoarthritic knee by at least 1 to 68 points, and / or the method increases the KOOS score of the osteoarthritic knee by at least 1 to 100 points.

[0011] In some embodiments of the methods described herein, the methods further comprise identifying and / or selecting a subject, or selecting a subject identified as, having grade 2 severity of knee osteoarthritis based on the Kcllgrcn-Lawrcncc (K / L) scale. In some embodiments, the methods further comprise identifying and / or selecting a subject, or selecting a subject identified as, having grade 3 severity of knee osteoarthritis based on the K / L scale. In some other embodiments, the methods further comprise identifying and / or selecting a subject, or selecting a subject identified as, having grade 4 severity of knee osteoarthritis based on the K / L scale. In some other embodiments, the methods further comprise identifying and / or excluding a subject having grade 4 severity of knee osteoarthritis based on the K / L scale. In any embodiments of the methods describe herein, the pharmaceutical composition comprises about 1 X 109GC to about 1 x 1013GC or about 1 x IO10GC to about 1 x 1012GC of enekinragene inzadenovec. In some further embodiments, the pharmaceutical composition comprises about 1.4 x IO10or about 1.4 X 1011GC of enekinragene inzadenovec. In some embodiments, the pharmaceutical composition for single intra-articular injection is about 5 mL.

[0012] In some embodiments of the methods described herein, the methods further comprise identifying and / or selecting a subject, or selecting a subject identified as, having synovitis prior to the administration of the pharmaceutical composition. In some such embodiments, the methods comprise identifying and / or selecting a subject, or selecting a subject identified as, having synovitis graded at a score of 9 or higher based on an 11-point synovitis scoring method using contrast-enhanced MRI. In some embodiments, the methods further comprise aspirating synovial fluid prior to administering the pharmaceutical composition. In some embodiments, the methods further comprise administering a corticosteroid to the subject by intraarticular injection immediately, or less than 120, 90, 60, 45, 30, 15, 10 or 5 minutes, prior to administering the pharmaceutical composition. In some such embodiments, the corticosteroid is in the form of a suspension (e.g., having a volume of about 1 mL). In some embodiments, the pharmaceutical composition further comprises a corticosteroid (e.g., a glucocorticoid). In one example, the corticosteroid comprises about 40 mg of methylprednisolone acetate.

[0013] Another aspect of the present disclosure relates to a method of treating knee osteoarthritis pain in a subject in need thereof, comprising:identifying and / or selecting a subject, or selecting a subject identified as, having grade 2 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale and optionally also have synovitis; andadministering a pharmaceutical composition comprising at least about 1 x 109genome copies (GC) (e.g., about 1 x 109GC to about 1 x 1013GC or about 1 x 1010GC toabout 1 x 1012GC) of enekinragene inzadenovec to the subject by a single intra-articular injection to the subject (i.e., to the osteoarthritic knee of the subject);wherein the pharmaceutical composition further comprises a corticosteroid, or the subject is pretreated with a corticosteroid prior to or immediately prior to the administering of the pharmaceutical composition; andwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction, or a range defined by any two of the preceding values, in the WOMAC pain scores change from baselines of a group of about, or at least about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects, and / or wherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction, or a range defined by any two of the preceding values, in the WOMAC stiffness scores change from baselines of a group of about, or at least about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / or wherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%. 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction, or a range defined by any two of the preceding values, in the WOMAC physical function scores change from baselines of a group of about, or at least about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provides about or at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% increase, or a range defined by any two of the preceding values, in the KOOS scores (one or more subscales including ADL function score, symptom score, pain score, sports and recreation function score, and knee-related QoL score) change from baselines of a group of about, or at least about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects.

[0014] A further aspect of the present disclosure relates to a method of treating knee osteoarthritis pain in a subject in need thereof, comprising:identifying and / or selecting a subject, or selecting a subject identified, as having grade 3 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale and optionally also have synovitis; andadministering a pharmaceutical composition comprising at least about 1 x 109genome copies (GC) (e.g„ about 1 x 109GC to about 1 x 1013GC or about 1 x IO10GC toabout 1 x 1012GC) of enekinragene inzadenovec to the subject by a single intra-articular injection to the subject (i.e., to the osteoarthritic knee of the subject);wherein the pharmaceutical composition further comprises a corticosteroid, or the subject is pretreated with a corticosteroid prior to or immediately prior to the administering of the pharmaceutical composition; andwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction or a range defined by any two of the preceding values, in the WOMAC pain scores change from baselines of a group of about, or at least about 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects, and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction or a range defined by any two of the preceding values, in the WOMAC stiffness scores change from baselines of a group of about, or at least about 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / or wherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%. 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction or a range defined by any two of the preceding values, in the WOMAC physical function scores change from baselines of a group of about, or at least about 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / or wherein the enekinragene inzadenovec and the corticosteroid treatment provides about or at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% increase or a range defined by any two of the preceding values, in the KOOS scores (one or more subscales including ADL function score, symptom score, pain score, sports and recreation function score, and knee-related QoL score) change from baselines of a group of about, or at least about 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects.

[0015] Another aspect of the present disclosure relates to a method of treating knee osteoarthritis pain in a subject in need thereof, comprising:identifying and / or selecting a subject, or selecting a subject identified as, having grade 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale and optionally also have synovitis; andadministering a pharmaceutical composition comprising at least about 1 X 109genome copies (GC) (e.g., about 1 x 109GC to about 1 x 1013GC or about 1 x 1010GC toabout 1 x 1012GC) of enekinragene inzadenovec to the subject by a single intra-articular injection to the subject (i.e., to the osteoarthritic knee of the subject);wherein the pharmaceutical composition further comprises a corticosteroid, or the subject is pretreated with a corticosteroid prior to or immediately prior to the administering of the pharmaceutical composition; andwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction or a range defined by any two of the preceding values, in the WOMAC pain scores change from baselines of a group of about, or at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects, and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction or a range defined by any two of the preceding values, in the WOMAC stiffness scores change from baselines of a group of about, or at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / or wherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%. 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction or a range defined by any two of the preceding values, in the WOMAC physical function scores change from baselines of a group of about, or at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / or wherein the enekinragene inzadenovec and the corticosteroid treatment provides about or at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% increase or a range defined by any two of the preceding values, in the KOOS scores (one or more subscales including ADL function score, symptom score, pain score, sports and recreation function score, and knee-related QoL score) change from baselines of a group of about, or at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects.

[0016] In some embodiments of the methods disclosed herein, the corticosteroid comprises about 40 mg of methylprednisolone acetate. In further embodiments, the corticosteroid is in a second pharmaceutical composition in the form of a liquid or suspension. In further embodiments, the corticosteroid is in the same pharmaceutical composition as the enekinragene inzadenovec. In some embodiments, the WOMAC pain scores, the WOMAC physical function scores, the WOMAC stiffness scores, or the KOOS scores (one or more subscales including ADL function score, symptom score, pain score, sports and recreation function score, and knee-related QoL score) are least squares mean (LSM) scores, measured at, or at least, about 12 weeks afterthe treatment (e.g., 12 weeks, 18 weeks, 24 weeks, 30 weeks, 36 weeks, 42 weeks, 49 weeks, 52 weeks, 78 weeks, 104 weeks, 130 weeks, 156 weeks, 182 weeks, 208 weeks, 234 weeks, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-104 weeks, 52-156 weeks, or 104-208 weeks).

[0017] In some embodiments of the methods disclosed herein, the subject does not have grade 4 severity of knee osteoarthritis based on the K / L scale.

[0018] In any embodiments of the methods described herein, the knee osteoarthritis pain treatment described herein reduces pain in the osteoarthritic knee of the subject, which results in improvements in the one or more measurements of the knee osteoarthritis pain.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIGs. 1 A and IB show the least squares mean (LSM) change from baseline for WOMAC-A pain across 3 doses of enekinragene inzadenovec in the not pretreated and steroid pretreated cohorts respectively through week 156.

[0020] FIGs. 2A and 2B show the LSM change from baseline for WOMAC-B stiffness across 3 doses of enekinragene inzadenovec in the not pretreated and steroid pretreated cohorts respectively through week 156.

[0021] FIGs. 3 A and 3B show the LSM change from baseline in KOOS activities of daily living scores across 3 doses of enekinragene inzadenovec in the not pretreated and steroid pretreated cohorts respectively through week 156.

[0022] FIGs. 4A and 4B show the LSM change from baseline for WOMAC-A pain across K / L grade 2, 3, and 4 in the not pretreated and steroid pretreated cohorts respectively through week 104.

[0023] FIGs. 5A and 5B. show the LSM change from baseline for WOMAC-B stiffness across K / L grade 2, 3, and 4 in the not pretreated and steroid pretreated cohorts respectively through week 104.

[0024] FIGs. 6A and 6B show the LSM change from baseline in KOOS activities of daily living scores across K / L grade 2, 3, and 4 in the not pretreated and steroid pretreated cohorts respectively through week 104.DETAILED DESCRIPTION

[0025] Embodiments of the present disclosure relate to methods or uses of enekinragene inzadenovec for treating pain in subjects with osteoarthritis of the knee (OAK). The method or use includes identifying or selecting a subject having at least grade 2 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale, and administering at least about 1 x1()9genome copies (GC) of enekinragene inzadenovec via a single intra-articular injection. The method or use may further include identifying or selecting a subject having synovitis prior to the treatment. Enekinragene inzadenovec gene therapy may be used in combination with a corticosteroid pretreatment or co-administration. The method or use described herein reduces pain and stiffness and increases and improves the patient’s activities of daily living.Definitions

[0026] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs when read in light of the disclosure. In the disclosure, the singular forms also include the plural unless the context clearly dictates otherwise; as examples, the terms “a,” “an,” and “the” are understood to be singular or plural and the term “or” is understood to be inclusive. By way of example, “an element” means one or more element. Throughout the specification the word “comprising,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0028] As used herein, “enekinragene inzadenovec” (also known as PCRX-201) refers to a novel IL-IRa gene therapy which utilizes the newest generation of adenoviral serotype 5 (Ad5) vectors, termed high capacity adenovirus, which have been engineered to carry the genetic coding sequence for IL-IRa controlled by a nuclear factor-kappa B-inducible promoter. PCRX-201 is a non-replicating, non-integrating HD Ad vector. The genomic component is composed of double-stranded linear DNA approximately 29.3 kilobases (kb) in size. The annotated sequence obtained by next-generation sequencing confirms the key elements in the PCRX-201 genome. The PCRX-201 genome contains minimal adenoviral elements required for amplification and packaging to allow for its manufacturing: left and right inverted terminal repeats (hereafter referred to as “L ITR” and “R ITR”, respectively) and the packaging signal ('P). Approximately 1.1 kb of the PCRX-201 genome is composed of the nucleic acid sequence encoding human IL-IRa, which is inserted on the right end of the genome in reverse (right-to-left) orientation, and the promoter, placed just before the R ITR. The promoter is 5 species-conserved NF-KB binding motif repeats fused to a proximal promoter region of the human ELAM gene, responding to pro-inflammatory cytokines. Approximately 27 kb of the PCRX-201 genome consists of non-coding stuffer sequence composed of human hypoxanthine phosphoribosyltransferase (HPRT) and human cosmid insert, which is inserted to enlarge the PCRX-201 genome to a size which allowsefficient packaging of the vector genome into each viral particle. PCRX-201 genome contains a 534 base pair (bp) sequence of human IL-IRa, which is regulated by a 262 bp sequence of NF-KB -inducible promoter.

[0029] PCRX-201 contains the inflammation-sensitive NF-KB5-ELAM promoter upstream of the IL-IRa cDNA according to SEQ ID NO: 1, as well as ITR and an adenoviral packaging signal. The full vector sequence of PCRX-201 (also referred to as HDAd-human IL-IRa), is shown in SEQ ID NO:2. The human IL-IRa protein has an amino acid sequence according to SEQ ID NO: 3.

[0030] PCRX-201 is a nonreplicating, nonintegrating vector and does not contain any adenoviral sequences, except for the L ITR, R ITR and the adenoviral packaging signal. In some embodiments, the adenoviral delivery and expression system according to the present disclosure can comprise a nucleic acid sequence of the adenoviral-based biological delivery and expression system comprising the promoter, the nucleic acid sequence encoding the IL-IRa, the left and the right inverted terminal repeats, the adenoviral packaging signal and the non-viral, non-coding staffer nucleic acid sequences as set forth in SEQ ID NO: 2, or a biologically effective part thereof. The nucleic acid sequence set forth in SEQ ID NO: 2 describes a human helper-dependent adenoviral vector bearing human IL-IRa gene. In some embodiments, the system of the disclosure has any one of at least 96%, 97%, 98%, or 99% sequence identity with the vector set forth in SEQ ID NO: 2. In some embodiments, the genome includes or consists of a nucleic acid that is, or is at least, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 2, excluding the sequences of the promoter and the nucleic acid sequence encoding the protein from the comparison between the genome and SEQ ID NO: 2. In some embodiments, the genome includes or consists of a nucleic acid wherein the nucleic acid sequences of the left and right inverted terminal repeats, the adenoviral packaging signal, and the non-viral and non-coding staffer portions of the genome is, or is at least, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 2. In some embodiments, the nucleic acid encodes an IL-IRa protein including or consisting of an amino acid sequence that is, or is at least, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical or homologous to a sequence selected from SEQ ID NO: 3, or a biologically active fragment thereof, or a homolog thereof from any other species. Additional information regarding enekinragene inzadenovec and doses thereof may be found in WO 2013 / 114199, WO 2021 / 055860, and WO 2024 / 182549, each of which are incorporated by reference in its entirety.

[0031] The term “genome copies” or “GC” refers to the number of copies of a therapeutic gene.

[0032] The term “Kellgren-Lawrence scale” or “K / L scale” is a system used to classify the severity of knee osteoarthritis in the index knee based on X-ray findings. “K / L Grade” or K-L Grade” 2, 3, or 4 arc defined as follows:Grade 2: Definite osteophytes and possible narrowing of joint space.Grade 3: Moderate multiple osteophytes, definite nano wing of joint space, some sclerosis, and possible deformity of bone ends.Grade 4: Large osteophytes, marked narrowing, severe sclerosis, and definite deformity of bone ends.

[0033] The term “synovitis” refers to inflammation of the synovium, which is the connective tissue lining the inside of the joint capsule.

[0034] The term “Average Daily Pain score,” Numerical Rating System,” or “NRS” is an 11 -point scale for patients to rate their pain intensity, ranging from 0 to 10 where 0 represents “no pain” and 10 represents “worst pain imaginable.”

[0035] The term “Western Ontario and McMaster Universities Osteoarthritis Index” or “WOMAC” is a self-assessment questionnaire that measures subscales of pain (WOMAC-A), stiffness (WOMAC-B), and physical function (WOMAC-C) in people with osteoarthritis (Bellamy et al. J Rheumatol. 1988; 15(12): 1833-40). The terms “WOMAC pain” and “WOMAC-A” are used interchangeably herein. The terms “WOMAC stiffness” and “WOMAC-B” are used interchangeably herein. The terms “WOMAC physical function” and “WOMAC-C” are used interchangeably herein. The WOMAC pain score has a range of 0-10. The WOMAC stiffness score has a range of 0 to 10. The WOMAC physical function score has a range of 0 to 68. Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations.

[0036] The term “Knee Injury and Osteoarthritis Outcome Score” or “KOOS” is a patient-reported score that measures subscales of pain, symptoms, activities of daily living (ADL), sport and recreation function, and quality of life (Roos et al. Health Qual Life Outcomes.2003:1:64; Roos et al. Cartilage. 2011;2(2): 122-36). The KOOS evaluates both short-term and long-term consequences of knee injury. It includes 42 items in 5 separately scored subscales: pain, other symptoms, function in daily living (ADL), function in Sport and Recreation (Sport / Rec), and knee-related Quality of Life (QoL). The terms “activities of daily living,” “ADL,” and “function / daily living” are used interchangeably herein. The KOOS score in each subscale is a percentage score from 0 to 100, 0 representing extreme knee problems and 100 representing no knee problems.

[0037] The term “synovitis score” refers to 11 -point synovitis scoring method using contrast-enhanced MRI (Geurmazi et al. Ann Rheum Dis. 2011 May;70(5):805-l 1) as follows:• Moderate synovitis: Score of 9 to 12• Severe synovitis: Score > 13.

[0038] The term “treat,” “treatment,” or “treating,” as used herein refers to administering a pharmaceutical composition / formulation for prophylactic and / or therapeutic purposes. The term “prophylactic treatment” refers to treating a patient who is not yet suffering from a disease, but who is susceptible to, or otherwise at risk of, a particular disease, whereby the treatment reduces the likelihood that the patient will develop a disease. The term “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease.

[0039] As used herein, “pharmaceutical composition” has its plain and ordinary meaning as understood by one of skill in the art in view of the present disclosure. The pharmaceutical composition need not be a single dosage form, and in some embodiments the corticosteroid and the adenoviral-based delivery and expression system (e.g., enekinragene inzadenovec) are in separate dosage forms (e.g., two separate liquids) such that they can be administered separately. In some embodiments, the pharmaceutical composition is a single dosage form (e.g., liquid) that contains both the corticosteroid and enekinragene inzadenovec.Methods of Treating Knee Osteoarthritis Pain

[0040] Some embodiments of the present disclosure relate to a method of treating knee osteoarthritis pain in a subject in need thereof, including identifying and / or selecting a subject (e.g., identifying and / or selecting a subject, or selecting a subject identified as) a subject having at least grade 2 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale; and administering a pharmaceutical composition comprising about or at least about 1 x 107. 1 x 108. or 1 x 109genome copies (GC) 109(e.g., about 1 x IO9GC to about 1 x 1013GG or about 1 x 1010GC to about 1 x 1012GC) of enekinragene inzadenovec to the subject by a single intra-articular injection to the subject.

[0041] Some embodiments of the present disclosure relate to a method of reducing Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (scale 0-10) of an osteoarthritic knee of a subject having grade 2, 3 or 4 severity of knee osteoarthritis and optionally also have synovitis, comprising:identifying and / or selecting a subject (e.g., identifying and / or selecting, or selecting a subject identified as) a subject having grade 2, 3 or 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale and optionally also synovitis; andadministering a pharmaceutical composition comprising at least about 1 x 109genome copies (GC) (e.g., about 1 x 109GC to about 1 x 1013GC or about 1 x 1010GC toabout 1 x 1012GC) of enekinragene inzadenovec by a single intra-articular injection to the osteoarthritic knee of the subject;wherein the method reduces the subject's WOMAC pain score by at least 1 to 8 points (e.g., the reduction in score is or at least is 1, 2, 3, 4, 5, 6, 7, 8 or 9 points, or a range defined by any two of the preceding values, optionally 1-8 points, 2-7 points, 3-6 points, 4-8 points, 5-8 points, 3-7 points, 4-7 points, 2-5 points, or 2-6 points) in the subject.

[0042] Some embodiments of the present disclosure relate to a method of reducing WOMAC stiffness score (scale 0-10) of an osteoarthritic knee in a subject having grade 2, 3 or 4 severity of knee osteoarthritis and optionally also have synovitis, comprising:identifying and / or selecting a subject (e.g., identifying and / or selecting, or selecting a subject identified as) a subject having grade 2, 3 or 4 severity of knee osteoarthritis based on the Kellgren- Lawrence (K / L) scale and optionally also synovitis; andadministering a pharmaceutical composition comprising at least about 1 X 109genome copies (GC) (e.g., about 1 x IO9GC to about 1 x 1013GC or about 1 x IO10GC to about 1 x 1012GC) of enekinragene inzadenovec by a single intra-articular injection to the osteoarthritic knee of the subject;wherein the method reduces the subject’s WOMAC stiffness score by at least 1 to 8 points (e.g., the reduction in score is, or at least is 1, 2, 3, 4, 5, 6, 7, or 8 points, or a range defined by any two of the preceding values, optionally 1-8 points, 2-7 points, 3-6 points, 4-5 points, 3-8 points, 1-5 points, or 3-5 points) in the subject.

[0043] Some embodiments of the present disclosure relate to a method of reducing WOMAC physical function score (scale 0-68) of an osteoarthritic knee in a subject having grade 2, 3 or 4 severity of knee osteoarthritis and optionally also have synovitis, comprising:identifying and / or selecting a subject (e.g., identifying and / or selecting, or selecting a subject identified as) having grade 2, 3 or 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale and optionally also have synovitis; and administering a pharmaceutical composition comprising at least about 1 x 109genome copies (GC) (e.g., about 1 x 109GC to about 1 x 1013GC or about 1 x 1010GC to about 1 X 1012GC) of enekinragene inzadenovec by a single intra-articular injection to the osteoarthritic knee of the subject;wherein the method reduces the subject’s WOMAC physical function score of the osteoarthritic knee by at least 1 to 68 points (e.g., the reduction in score is, or at least is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 32, 34, 36,38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, or 68 points, or a range defined by any two of the preceding values, optionally 1-50 points, 5-55 points, 10-60 points, SOSO points, 35-55 points, 40-60 points, 5-40 points, 10-35 points, or 15-30 points) in the subject.

[0044] Some embodiments of the present disclosure relate to a method of increasing Knee Injury and Osteoarthritis Outcome Score (KOOS) of an osteoarthritic knee in a subject having grade 2, 3 or 4 severity of knee osteoarthritis and optionally also synovitis, comprising:identifying and / or selecting a subject (e.g., identifying and / or selecting, or selecting a subject identified as) having grade 2, 3 or 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale and optionally also have synovitis; and administering a pharmaceutical composition comprising at least about 1 X 109genome copies (GC) (e.g., about 1 x 1010GC to about 1 x 1012GC) of enekinragene inzadenovec by a single intra-articular injection to the osteoarthritic knee of the subject;wherein the KOOS score comprises five subscales selected from the group consisting of activities of daily living (ADL) function score, symptom score, pain score, sports and recreation function score, and knee-related quality of life (QoL) score, and wherein the method increases one or more subscale of the subject’s KOOS score by at least 1 to 100 points (e.g., the increase in score is, or at least is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 points, or a range defined by any two of the preceding values, optionally 5-85, 10-80, 15-75, 20-70, 25-65, 30-60, 40-50, 1-50, 5-45, 10-40, 15-35, 20-30, 40-70, 45-75, 50-80, or 55-85) in the subject.

[0045] In some embodiments of the methods described herein, the patient has synovitis. In some embodiments, the patient has synovitis graded at a score of 9 or higher based on an 11-point synovitis scoring method using contrast-enhanced MRI (Gcurmazi ct al. Ann Rheum Dis.2011 May;70(5):805-ll) as follows:• Moderate synovitis: Score of 9 to 12• Severe synovitis: Score > 13Patient selection

[0046] In some embodiments of the methods described herein, the subject has had painful symptoms associated with OA of the knee for at least 12 months prior to the enekinragene inzadenovec treatment. In some embodiments, the subject has had index knee pain on most days (>15 days) over the last month prior to the start of the enekinragene inzadenovec treatment. In some embodiments, the subject meets American College of Rheumatology (ACR) criteria (clinical and radiological) for OA (Altman et al. Arthritis Rheum. 1986 Aug;29(8): 1039-49) as follows:• Knee pain• At least 1 of the following:o Age > 50 yearso Morning stiffness < 30 minuteso Crepitus on knee motion• Osteophytes

[0047] In some embodiments of the methods described herein, the subject has grade 2 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale. In some embodiments, the subject has grade 3 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale. In some further embodiments, the subject has grade 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale. In other embodiments of the methods described herein, a subject that has grade 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale is excluded.Patient Exclusions

[0048] In some embodiments of the methods described herein, the subject does not have any current or prior diagnosis of autoimmune connective tissue disorders, secondary OA conditions, benign synovial tumors, gout / pseudogout, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or arthritis associated with inflammatory bowel disease.

[0049] In some embodiments of the methods described herein, the subject does not have any active systemic or local infection, including infection of the index knee. In some embodiments, the subject does not have an unstable index knee joint within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months of being selected or identified or before the start of the enekinragene inzadenovec treatment. In some embodiments the subject does not have a history of chronic diseases that would require oral, intravenous, intramuscular, and / or intranasal steroid treatments within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after the start of enekinragene inzadenovec treatment.

[0050] In some embodiments of the methods described herein, the subject has not previously been treated with, or is being concomitantly treated with one or more of the following medications:• Approved or investigational IA drug / biologic in index knee within 1, 2, 3, 4, 5, or 6 months before the start of the enekinragene inzadenovec treatment • Any gene therapy treatment within 1, 2, or 3 years before the start of the enekinragene inzadenovec treatment• IA corticosteroid in any joint within 1, 2, or 3 months before the start of the enekinragene inzadenovec treatmentIn some embodiments of the methods described herein, the subject does not have bilateral OAK and average pain in the contralateral knee greater than 4 on the 0 to 10 NRS scale.Enekinragene inzadenovec

[0051] In some embodiments of the methods described herein, the pharmaceutical composition comprises about or at least about 1 x 1071 x 10s, or 1 x 109genome copies (GC) of enekinragene inzadenovec. In some embodiments, the pharmaceutical composition is a liquid. In some embodiments, enekinragene inzadenovec is in a buffer including TRIS 10 mM, NaCl 75 mM, Polysorbate 80 0.02% (v / v), sucrose 5% (w / v), MgCh 1.0 mM, EDTA 100 pM, ethanol 0.5% (v / v), and L-histidine 10 mM. In some embodiments, the concentration of enekinragene inzadenovec is, is at least, oris no more than 1.4xl07, 2.8xl07, 7.0xl07, 1.4xl08, 2.8xl09, 7.0xl09, 1.4xlO10, 2.8xlO10, 7.OxlO10, 1.4x10", 2.8x10", 7.0x10", 1.4xl012, 2.8xl012, 7.0xl012, 1.4xl013, 2.8xl013, 7.0xl013or a range defined by any two of the preceding values, optionally 1.4xl07to 7.0xl013, 1.4xl07to 7.0xl012, 1.4xl07to 7.0x10", 1.4xl08to 7.0x10", 1.4x10sto 7.OxlO10, 1.4xl08to 7.0xl09, or 1.4xl09to 7.OxlO10genome copies (GC) of the vector per ml of the pharmaceutical composition. In some embodiments, the concentration of enekinragene inzadenovec is, is at least, or is not more than, 11.4xl07, 2.8xl07, 7.0xl07, 1.4x10s, 2.8xl09, 7.0xl09, 1.4xlO10, 2.8xlO10, 7.OxlO10, 1.4x10", 2.8x10", 7.0x10", 1.4xl012, 2.8xl012, 7.0xl012, 1.4xl013, 2.8xl013, 7.0xl013or a range defined by any two of the preceding values, optionally 1.4xl07to 7.0xl013, 1.4xl07to 7.0xl012, 1.4xl07to 7.0x10", 1.4xl08to 7.0x10", 1.4xl08to 7.OxlO10, 1.4x10sto 7.0xl09, or 1.4xl09to 7.OxlO10viral particles (VP) of vector per ml of the pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid having a volume that is, is at least, or is not more than, 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 ml, or a range defined by any two of the preceding values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 mb, for example, 1.0, 2.0, 2.5 or 5.0 mL, or optionally 5.0 mL. In some embodiments, the concentration of enekinragene inzadenovec is reduced to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 30%-80%, 20%-70%, 30%-60%, 40-50%, 50%-90%, of a typical and / or publicly disclosed concentration of enekinragene inzadenovec for administration by the same route of administration to the same species of animal for treatment of the same or similar disease or disorder. In some further embodiments, the pharmaceutical composition comprises about 1010GC to about 1012GC of enekinragene inzadenovec. In some embodiments, the pharmaceutical composition comprises about 1.4 x 1010or about 1.4 x 10" GC of enekinragene inzadenovec. In some embodiments, the pharmaceutical composition comprises about 2.8 x 109or about 2.8 x 1010GC of enekinrageneinzadenovec per mL of solution. The pharmaceutical composition may be prepared with a supplied diluent containing an isotonic, sterile, aqueous solution of sodium chloride (NaCl; 0.9% w / w) to form a 5 mL sterile suspension intended for intra-articular injection. In one example, the pharmaceutical composition for single intra-articular injection is about 5 mL. The concentration of enekinragene inzadenovec can be calculated based on the volume of the pharmaceutical composition and the total GC of enekinragene inzadenovec. For example, when the pharmaceutical composition is about 5 mL and comprises about 1.4 X IO10or about 1.4 X 1011GC of enekinragene inzadenovec, the concentration of enekinragene inzadenovec in the pharmaceutical composition is about 2.8 x IO9or about 2.8 x IO10GC / mL, respectively.

[0052] In some embodiments of the methods described herein, the methods further comprise aspirating synovial fluid prior to administering the pharmaceutical composition. “Prior to’’ means within about 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 15 minutes, or 5 minutes before the administration of enekinragene inzadenovec. In some embodiments, the methods further comprise administering a corticosteroid to the subject by intra-articular injection prior to, or immediately prior to administering the pharmaceutical composition. “Immediately prior to” means within 2 hours, 1 hour, 45 minutes, 30 minutes, 15 minutes, 5 minutes, 2 minutes, or 1 minute. In some embodiments, the methods comprise aspirating synovial fluid prior to administering a corticosteroid, immediately prior to administering the pharmaceutical compound. The same needle used for IA injection of the pharmaceutical composition may also be used for aspirating synovial fluid and administering a corticosteroid, thereby allowing for a single injection with syringe replacement. In some embodiments, a 21 -gauge needle or larger may be used for both injections. In some embodiments, the corticosteroid is a glucocorticoid, a mineralocorticoid, or both, for example, the corticosteroid may have predominantly glucocorticoid or mineralocorticoid activity, or the activity of the corticosteroid may be both as a glucocorticoid or mineralocorticoid. In some embodiments, corticosteroid is a combination of one or more glucocorticoids, one or more a mineralocorticoids, or both a glucocorticoid and a mineralocorticoid. In some embodiments, the corticosteroid comprises or is selected from the group consisting of: beclomethasone, betamethasone, budesonide, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, fludrocortisone, deoxycorticosterone, aldosterone, ciclesonide, fluticasone, flunisolide, mometasone, salts thereof, esters thereof, and combination thereof. In some embodiments, the corticosteroid is methylprednisolone or ester thereof. In some embodiments, the corticosteroid is methylprednisolone acetate. In some embodiments, the corticosteroid is in a second pharmaceutical composition. In some embodiments, the corticosteroid is, is at least, is not more than, 0.001, 0.01, 0.1, 1.0, 5.0, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000,2500, or 5000, or a range defined by any two of the preceding values, optionally 0.001-5000, 0.001-0.1, 0.001-10, 0.1-100, 1.0-100, 1.0-50, 30-300, 25-60, 30-50, 100-1000, 500-5000 mg / mL, or 40 mg / mL, of the second pharmaceutical composition. In some embodiments, the second pharmaceutical composition containing the corticosteroid is a liquid or suspension having a volume that is, is at least, or is not more than, 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10 mL, or a range defined by any two of the preceding values, optionally 0.1-10, 0.1-5, 1.0-10, 1.0-5.0, 2.5-7.5, or 4.0-6.0 mL, for example, 1.0, 2.0, 2.5 or 5.0 ml, or 1.0 mL. In one embodiment, the corticosteroid is 40 mg methylprednisolone acetate in 1.0 mL liquid or suspension form (having a concentration of 40 mg / mL). In some such embodiments, about 0.5-1 mL flush of 0.9% sterile saline may be performed after administering the corticosteroid. Alternatively, the corticosteroid and enekinragene inzadenovec may be in the same pharmaceutical composition for co-administration. In some such embodiments, about 1-2 mL flush of 0.9% sterile saline may be performed after administering the pharmaceutical composition.

[0053] Formulations: In some embodiments, enekinragene inzadenovec is formulated in a buffer composed of about 1-20 mM, TRIS, about 50-100 mM NaCl, 0.01-1% weight / volume (w / v) Polysorbate 80, 1-10% (w / v) sucrose, 0.1-10 mM MgCl2, 50-500 pM EDTA, 1-5% volume / volume (v / v) ethanol, and 5-50mM L-histidine. In some embodiments, PCRX201 can be formulated in a buffer composed of 10 mM TRIS, 75 mM NaCl, 0.02% (weight / volume (w / v) Polysorbate 80, 5% (w / v) sucrose, 1.0 mM MgCh, 100 pM EDTA, 0.5% (volume / volume (v / v) of ethanol), and 10 mM L-histidine. In some embodiments, the product can be a clear to slightly opalescent, colorless suspension with no visible particulates. In some embodiments, the formulation further comprises a corticosteroid described herein. In some embodiments, the concentration of the corticosteroid is 5-10, or 8 mg / mL for co-administration.

[0054] In some embodiments of the methods described herein, the methods further comprise determining or receiving information on the subject’ s baseline WOMAC pain score prior to the treatment. In some such embodiments, the treatment (enekinragene inzadenovec alone, or enekinragene inzadenovec in combination with a corticosteroid) reduces the subject’s WOMAC pain score by at least 1 point from the subject’s baseline WOMAC pain score. In some further embodiments, the method reduces the subject's WOMAC pain score (scale 0-10) by 1 to 9 or 1 to 8 points, by or at least by 1 to 9 or 1 to 8 points (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9 points, or a range defined by any two of the preceding values, optionally 1-8 points, 2-7 points, 2-6 points, 2-5 points, 3-5 points, 3-6 points, 3-7 points, 4-6 points, 4-7 points, 2-8 points, 3-8 points, 4-8 points, 5-8 points, 1-5 points, or 3-5 points) from the subject’s baseline WOMAC pain score, wherein the subject’s WOMAC pain score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeksafter the treatment. In some such embodiments, the method reduces the subject’s WOMAC pain score by 2-6 points, 2-5 points, 3-5 points, 3-6 points, 4 points or 5 points from baseline at about 12 weeks after treatment. In some such embodiments, the method reduces the subject’s WOMAC pain score by 3-6 points, 3-5 points, 4 points or 5 points from baseline at about 24 weeks after treatment. In some such embodiments, the method reduces the subject’s WOMAC pain score by 3-7 points, 3-5 points, 3-6 points, 4-7 points, 4 points or 5 points from baseline at about 52 weeks after treatment. In some such embodiments, the method reduces the subject’s WOMAC pain score by 2-6 points, 2-5 points, 3-6 points, 3 points or 4 points from baseline at about 104 weeks after treatment. In some further embodiments, the method reduces the subject’s WOMAC pain score by about, or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%, reduction of the subject’s WOMAC pain score from the subject’s baseline WOMAC score, wherein the subject’s WOMAC pain score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some such embodiments, the method provides about 30% to about 90%, about 50% to about 60%, or about 70% to about 80% reduction of the subject WOMAC pain score from baseline at about 12 weeks after treatment. In some such embodiments, the method provides about 30% to about 90%, about 50% to about 70%, or about 70% to about 80% reduction of the subject WOMAC pain score from baseline at about 24 weeks after treatment. In some such embodiments, the method provides about 40% to about 90%, about 50% to about 60%, or about 70% to about 80% reduction of the subject WOMAC pain score from baseline at about 52 weeks after treatment. In some such embodiments, the method provides about 20% to about 90%, about 40% to about 50%, or about 60% to about 70% reduction of the subject WOMAC pain score from baseline at about 104 weeks after treatment. In some further embodiments, the subject’s WOMAC pain score is measured after, or after at least, about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-156 weeks, or 104-208 weeks, of treatment. In some further embodiments, the treatment provides a reduction in the WOMAC pain scores change from baseline of a group of about or at least about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 2 severity of knee osteoarthritis based on the K / L scale. In some further embodiments, the treatment provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%. or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%, reduction in the WOMAC pain scores change from baseline of a group of about, or at least about 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 3 severity of knee osteoarthritis based on the K / L scale. In some further embodiments, the treatment providesabout or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%, reduction in the WOMAC pain scores change from baseline of a group of about, or at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 4 severity of knee osteoarthritis based on the K / L scale. In some further embodiments, the subject’s WOMAC pain score is measured at, or at least, about 12, 16, 26, 40 or 52 weeks after the treatment. In some further embodiments, the subject’s WOMAC pain score is measured after, or after at least, about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-156 weeks, or 104-208 weeks, of treatment. In any embodiments, the subjects’ WOMAC pain scores are measured as the least squares mean (LSM) scores. In some embodiments, the standard error (SE) of LSM mean improvement from baseline WOMAC pain scores is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, or 0.9, or a range defined by any two of the preceding values. SE can be calculated as SE = Standard Deviation (SD) / square root of the sample size (n). In further embodiments, the treatment efficacy outcome measurement has a 95% confidence interval (CI).

[0055] In some embodiments of the methods described herein, the methods further comprise determining or receiving information on the subject’s baseline WOMAC stiffness score prior to the treatment. In some such embodiments, the treatment (enekinragene inzadenovec alone, or enekinragene inzadenovec in combination with a corticosteroid) reduces the subject’s WOMAC stiffness score by at least 1 point from the subject’s baseline WOMAC stiffness score. In some further embodiments, the method reduces the subject’s WOMAC stiffness score (scale 0-10) by or at least by 1, 2, 3, 4, 5, 6, 7, 8 or 9 points, or a range defined by any two of the preceding values, optionally 1-8 points, 3-8 points, 2-7 points, 4-6 points, 1-5 points, or 3-5 points, from the subject’s baseline WOMAC stiffness score, wherein the subject’s WOMAC stiffness score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some such embodiments, the method reduces the subject’s WOMAC stiffness score by 2-7 points, 2-5 points, 4-7 points, 3-5 points, 3-6 points, 4 points or 5 points from baseline at about 12 weeks after treatment. In some such embodiments, the method reduces the subject’s WOMAC stiffness score by 2-6 points, 2-5 points, 3-6 points, 4 points or 5 points from baseline at about 24 weeks after treatment. In some such embodiments, the method reduces the subject’s WOMAC stiffness score by 3-7 points, 3-5 points, 3-6 points, 4-7 points, 4 points or 5 points from baseline at about 52 weeks after treatment. In some such embodiments, the method reduces the subject’s WOMAC stiffness score by 2-7 points, 2-5 points, 3-7 points, 4 points or 5 points from baseline at about 104weeks after treatment. In some further embodiments, the method reduces the subject’s WOMAC stiffness score by about, or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%, reduction of the subject’s WOMAC stiffness score from baseline, wherein the subject’s WOMAC pain score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some such embodiments, the method provides about 30% to about 90%, about 50% to about 60%, or about 70% to about 80% reduction of the subject WOMAC stiffness score from baseline at about 12 weeks after treatment. In some such embodiments, the method provides about 30% to about 90%, about 50% to about 70%, or about 70% to about 80% reduction of the subject WOMAC stiffness score from baseline at about 24 weeks after treatment. In some such embodiments, the method provides about 40% to about 90%, about 50% to about 60%, or about 70% to about 80% reduction of the subject WOMAC stiffness score from baseline at about 52 weeks after treatment. In some such embodiments, the method provides about 20% to about 90%, about 40% to about 50%, or about 60% to about 70% reduction of the subject WOMAC stiffness score from baseline at about 104 weeks after treatment. In some further embodiments, the subject’s WOMAC stiffness score is measured after, or after at least, about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-156 weeks, or 104-208 weeks, of treatment. In some further embodiments, the treatment provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%, reduction in the WOMAC stiffness scores change from baseline of a group of about or at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 subjects having grade 2 severity of knee osteoarthritis based on the K / L scale. In some further embodiments, the treatment provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%, reduction in the WOMAC stiffness scores change from baseline of a group of about or at least about 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 subjects having grade 3 severity of knee osteoarthritis based on the K / L scale. In some further embodiments, the treatment provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%, reduction in the WOMAC stiffness scores change from baseline of a group of about or at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 subjects having grade 4 severity ofknee osteoarthritis based on the K / L scale. In some such embodiments, the subject’s WOMAC stiffness score is measured at, or at least, about 12 weeks (such as 12, 16, 26, 40, or 52 weeks) after the treatment. In some further embodiments, the subject’s WOMAC stiffness score is measured after, or after at least, about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-156 weeks, or 104-208 weeks of treatment. In any embodiments, the subjects’ WOMAC stiffness scores are measured as the least squares mean (LSM) scores. In some embodiments, the standard error (SE) of LSM mean improvement from baseline WOMAC stiffness scores is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, or 0.9, or a range defined by any two of the preceding values. SE can be calculated as SE = Standard Deviation (SD) / square root of the sample size (n). In further embodiments, the treatment efficacy outcome measurement has a 95% confidence interval (CI).

[0056] In some embodiments of the methods described herein, the methods comprise or further comprise determining or receiving information on the subject’s baseline WOMAC physical function score prior to the treatment. In some such embodiments, the treatment (enekinragene inzadenovec alone, or enekinragene inzadenovec in combination with a corticosteroid) reduces the subject’s WOMAC stiffness score by at least 1 point from the subject’s baseline WOMAC physical function score. In some further embodiments, the method reduces the subject’s WOMAC physical function (scale 0 to 68) score by 1 to 68, by or at least by 1 to 34 points, for example by 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 or 34 points, or a range defined by any of the two preceding values, optionally 10-34, 12-32, 14-30, 8-34, 6-34, 16-32, 18-30, 20-28 or 22-26, from the subject’s baseline WOMAC physical function score, wherein the subject’s WOMAC physical function score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some embodiments, the treatment provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%, reduction in the WOMAC physical function scores change from baseline of a group of about or at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 subjects having grade 2 severity of knee osteoarthritis based on the K / L scale. In some further embodiments, the treatment provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%, reduction in the WOMAC physical function scores change from baseline of a group of about or at least about 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 subjects having grade 3 severity of knee osteoarthritis based on the K / L scale. Insome further embodiments, the treatment provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%, reduction in the WOMAC physical function scores change from baseline of a group of about or at least about 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 subjects having grade 4 severity of knee osteoarthritis based on the K / L scale. In some such embodiments, the subject’s WOMAC physical function score is measured at, or at least, about 12 weeks (such as 12, 16, 26, 40, or 52 weeks) after the treatment. In some further embodiments, the subject’s WOMAC stiffness score is measured after, or after at least, about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-104 weeks, 52-156 weeks, or 104-208 weeks, of treatment. In any embodiments, the subjects’ WOMAC physical function scores arc measured as the least squares mean (LSM) scores. In some embodiments, the standard error (SE) of LSM mean improvement from baseline WOMAC physical function scores is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, or 0.9, or a range defined by any two of the preceding values. SE can be calculated as SE = Standard Deviation (SD) / square root of the sample size (n). In further embodiments, the treatment efficacy outcome measurement has a 95% confidence interval (CI).

[0057] In some embodiments of the methods described herein, the methods further comprise determining or receiving information on the subject’s baseline KOOS score prior to the treatment, wherein the KOOS score comprises five subscales selected from the group consisting of activities of daily living (ADL) function score, symptom score, pain score, sports and recreation function score, and knee-related quality of life (QoL) score. In some such embodiments, the treatment (enekinragene inzadenovec alone, or enekinragene inzadenovec in combination with a corticosteroid) increases the subject’s KOOS ADL function score by at least 1 point from the subject’s baseline KOOS ADL function score. In some further embodiments, the treatment increases the subject’s KOOS ADL function score by 1 to 100 points (scale 0 to 100), by or at least by 5 to 61 points, for example 1, 2, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60 points, or a range defined by any of the two preceding values, optionally 10-60 points, 12-58 points, 14-56 points, 8-60 points, 5-55 points, 6-60 points, 16-46 points, 18-44 points, 20-42 points, 22-40 points, 24-38 points, or 26-36 points, from the subject’s baseline KOOS ADL function score, wherein the subject’s KOOS ADL function score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some such embodiments, the method increases the subject’s KOOS ADL function score by 15-50, 15-40, 15-35, 20-50, 25, 27 or 35 points from baseline at about 12 weeks after treatment. Insome such embodiments, the method increases the subject’s KOOS ADL function score by 15-45, 15-40, 20-45, 28 or 33 points from baseline at about 24 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS ADL function score by 20-55, 23-46, 24-45, 26-53, 34, 35 or 40 points from baseline at about 52 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS ADL function score by 14-55, 14-38, 22-44, 23-51, 26, 33, or 37 points from baseline at about 104 weeks after treatment. In some embodiments, the treatment provides about or at least about 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, or 300%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, 50%-90%, 35%-200%, 45%-180%, 50%-170%, 60%-160%, 70%-150%, 80-120%, 50%-150%, 100%-200%, 150%-250%, or 200%-300% increase in the subject's KOOS ADL function score from baseline, wherein the subject's KOOS ADL function score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some such embodiments, the method provides about 10% to about 165%, about 40% to about 140%, about 35% to about 125%, about 50% to about 165%, about 80%, about 90%, or about 110% increase of the subject’s KOOS ADL function score from baseline at about 12 weeks after treatment. In some such embodiments, the method provides the method provides about 35% to about 150%, about 35% to about 135%, about 55% to about 150%, about 40% to about 130%, about 90%, about 100%, or about 105% increase of the subject’s KOOS ADL function score from baseline at about 24 weeks after treatment. In some such embodiments, the method provides the method provides about 50% to about 185%, about 55% to about 155%, about 60% to about 155%, about 90%, about 105%, about 110%, or about 125% increase of the subject’s KOOS ADL function score from baseline at about 52 weeks after treatment. In some such embodiments, the method provides the method provides about 20% to about 175%, about 20% to about 125%, about 45% to about 145%, about 50% to about 175%, about 70%, about 95%, or about 110% increase of the subject’s KOOS ADL function score from baseline at about 104 weeks after treatment. In some further embodiments, the treatment provides about or at least about 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%. 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, or 300%, or a range defined by any two of the preceding values, optionally about 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, 50%-90%, 35%-200%, 45%-180%, 50%-170%, 60%-160%, 70%-150%, 80-120%, 50%-150%, 100%-200%, 150%-250%, or 200%-300% increase in the KOOS ADL function scores change from baseline of a group of about or at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 subjects having grade2 , 3 or 4 severity of knee osteoarthritis based on the K / L scale. In some such embodiments, the subject’s KOOS ADL function score is measured at, or at least, about 12 weeks (such as 12, 16, 26, 40, or 52 weeks) after the treatment. In some further embodiments, the subject’s KOOS ADL function score is measured after, or after at least, about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-104 weeks, 52-156 weeks, or 104-208 weeks of treatment. In any embodiments, the subjects’ KOOS ADL function scores are measured as the least squares mean (LSM) scores. In some embodiments, the standard error (SE) of LSM mean improvement from baseline KOOS ADL function scores is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1. 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, or 0.9, or a range defined by any two of the preceding values. SE can be calculated as SE = Standard Deviation (SD) / square root of the sample size (n). In further embodiments, the treatment efficacy outcome measurement has a 95% confidence interval (CI).

[0058] In some further embodiments, the treatment (enekinragene inzadenovec alone, or enekinragene inzadenovec in combination with a corticosteroid) increases the subject’s KOOS symptom score by at least 1 point from the subject’s baseline KOOS symptom score. In some further embodiments, the treatment increases the subject’s KOOS symptom score by 1 to 100 points(scale 0 to 100), by or at least by 5 to 50 points, for example 1, 2, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, or 50 points, or a range defined by any of the two preceding values, optionally 10-60 points, 12-58 points, 14-56 points, 8-60 points, 5-55 points, 6-60 points, 6-50 points, 6-40 points, 16-46 points, 18-44 points, 20-42 points, 22-40 points, 24-38 points, or 26-36 points, from the subject’s baseline KOOS symptom score, wherein the subject’s KOOS symptom score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some such embodiments, the method increases the subject’s KOOS symptom score by 6-36, 14-32, 6-24, 14-36, 23, 15, or 25 points from baseline at about 12 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS symptom score by 11-34, 15-34, 13-30, 11-33, 22, or 25 points from baseline at about 24 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS symptom score by 11-40, 16-36, 11-29, 17-40, 20, 26, or 28 points from baseline at about 52 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS symptom score by 13-39, 13-34, 13-33, 14-39, 23, or 26 points from baseline at about 104 weeks after treatment. In some embodiments, the treatment provides about or at least about 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, or 300%, or a range defined by any two of the preceding values, optionally about10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, 50%-90%, 35%-200%, 45%-180%, 50%-170%, 60%-160%, 70%-150%, 80-120%, 50%-150%, 100%-200%, 150%-250%, or 200%-300% increase in the subject’s KOOS symptom score from baseline, wherein the subject’s KOOS symptom score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some further embodiments, the treatment provides about or at least about 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%. 290%, or 300%, or a range defined by any two of the preceding values, optionally about 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, 50%-90%, 35%-200%, 45%-180%, 50%-170%, 60%-160%, 70%-150%, 80-120%, 50%-150%, 100%-200%, 150%-250%, or 200%-300% increase in the KOOS symptom scores change from baseline of a group of about or at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 subjects having grade 2 , 3 or 4 severity of knee osteoarthritis based on the K / L scale. In some such embodiments, the subject’s KOOS symptom score is measured at, or at least, about 12 weeks (such as 12, 16, 26, 40, or 52 weeks) after the treatment. In some further embodiments, the subject’s KOOS symptom score is measured after, or after at least, about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-104 weeks, 52-156 weeks, or 104-208 weeks of treatment. In any embodiments, the subjects’ KOOS symptom scores are measured as the least squares mean (LSM) scores. In some embodiments, the standard error (SE) of LSM mean improvement from baseline KOOS symptom scores is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3. 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, or 0.9, or a range defined by any two of the preceding values. SE can be calculated as SE = Standard Deviation (SD) / square root of the sample size (n). In further embodiments, the treatment efficacy outcome measurement has a 95% confidence interval (CI).

[0059] In some further embodiments, the treatment (enekinragene inzadenovec alone, or enekinragene inzadenovec in combination with a corticosteroid) increases the subject’s KOOS pain score by at least 1 point from the subject’s baseline KOOS pain score. In some further embodiments, the treatment increases the subject’s KOOS pain score by 1 to 100 points (scale 0 to 100), by or at least by 5 to 60 points, for example 1, 2, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60 points, or a range defined by any of the two preceding values, optionally 10-60 points, 12-58 points, 14-56 points, 8-60 points, 5-55 points, 6-60 points, 6-50 points, 6-40 points, 10-55 points, 16-46 points, 18-44 points, 20-42 points, 22-40 points, 24-38 points, or 26-36 points, from the subject’s baseline KOOS pain score, wherein the subject’s KOOS pain score is measured at, or at least, about 12, 16, 20, 24, 38CK 52 weeks after the treatment. In some such embodiments, the method increases the subject’s KOOS pain score by 13-43, 17-38, 13-33, 18-43, 23, 27, or 30 points from baseline at about 12 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS pain score by 19-44, 22-42, 20-44, 30, or 32 points from baseline at about 24 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS pain score by 24-54, 24-46, 23-43, 28-54, 35, 33 or 41 points from baseline at about 52 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS pain score by 18-52, 18-41, 20-43, 24-52, 29, 32, or 38 points from baseline at about 104 weeks after treatment. In some embodiments, the treatment provides about or at least about 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, or 300%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, 50%-90%, 35%-200%, 45%-180%, 50%-170%, 60%-160%, 70%-150%, 80-120%, 50%-150%, 100%-200%, 150%-250%, or 200%-300% increase in the subject’s KOOS pain score from baseline, wherein the subject’s KOOS pain score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some further embodiments, the treatment provides about or at least about 10%, 20%, 25%, 30%, 35%, 40%, 45%. 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%. 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, or 300%, or a range defined by any two of the preceding values, optionally about 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, 50%-90%, 35%-200%, 45%-180%, 50%-170%, 60%-160%, 70%-150%, 80-120%, 50%-150%, 100%-200%, 150%-250%, or 200%-300% increase in the KOOS pain scores change from baseline of a group of about or at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 subjects having grade 2 , 3 or 4 severity of knee osteoarthritis based on the K / L scale. In some such embodiments, the subject’s KOOS pain score is measured at, or at least, about 12 weeks (such as 12, 16, 26, 40, or 52 weeks) after the treatment. In some further embodiments, the subject’s KOOS pain score is measured after, or after at least, about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-104 weeks, 52-156 weeks, or 104-208 weeks of treatment. In any embodiments, the subjects’ KOOS pain scores are measured as the least squares mean (LSM) scores. In some embodiments, the standard error (SE) of LSM mean improvement from baseline KOOS pain scores is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, or 0.9, or a range defined by any two of the preceding values. SE can be calculated as SE = Standard-TIDeviation (SD) / square root of the sample size (n). In further embodiments, the treatment efficacy outcome measurement has a 95% confidence interval (CI).

[0060] In some further embodiments, the treatment (cnckinragcnc inzadcnovcc alone, or enekinragene inzadenovec in combination with a corticosteroid) increases the subject’s KOOS sports and recreation function score by at least 1 point from the subject’s baseline KOOS sports and recreation function score. In some further embodiments, the treatment increases the subject’s KOOS sports and recreation function score by 1 to 100 points (scale 0 to 100), by or at least by 5 to 65 points, for example 1, 2, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 55, 60, or 65 points, or a range defined by any of the two preceding values, optionally 10-60 points, 12-58 points, 14-56 points, 8-60 points, 10-60 points, 5-55 points, 6-60 points, 6-50 points, 6-40 points, 16-46 points, 18-44 points, 20-42 points, 22-40 points, 24-38 points, or 26-36 points, from the subject’s baseline KOOS sports and recreation function score, wherein the subject’s KOOS sports and recreation function score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some such embodiments, the method increases the subject’s KOOS sports and recreation function score by 11-50, 17-45, 11-37, 18-50, 24, 30 or 35 points from baseline at about 12 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS sports and recreation function score by 18-50, 22-50, 16-42, 30, or 35 points from baseline at about 24 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS sports and recreation function score by 17-56, 24-53, 17-44, 21-56, 30, 35, 38 or 40 points from baseline at about 52 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS sports and recreation function score by 18-60, 20-51, 18-47, 23-60, 32, 35 or 40 points from baseline at about 104 weeks after treatment. In some embodiments, the treatment provides about or at least about 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, or 300%, or a range defined by any two of the preceding values, optionally about 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, 50%-90%, 35%-200%, 45%-180%, 50%-170%, 60%-160%, 70%-150%, 80-120%, 50%-150%, 100%-200%, 150%-250%, or 200%-300% increase in the subject’s KOOS sports and recreation function score from baseline, wherein the subject's KOOS sports and recreation function score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some further embodiments, the treatment provides about or at least about 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, or 300%, or a range defined by any two of the preceding values, optionally about 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, 50%-90%, 35%-200%, 45%-180%, 50%-170%, 60%-160%, 70%-150%, 80-120%, 50%-150%, 100%-200%, 150%-250%, or 200%-300% increase in the KOOS sports and recreation function scores change from baseline of a group of about or at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 subjects having grade 2 , 3 or 4 severity of knee osteoarthritis based on the K / L scale. In some such embodiments, the subject’s KOOS sports and recreation function score is measured at, or at least, about 12 weeks (such as 12, 16, 26, 40, or 52 weeks) after the treatment. In some further embodiments, the subject’s KOOS sports and recreation function score is measured after, or after at least, about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-104 weeks, 52-156 weeks, or 104-208 weeks of treatment. In any embodiments, the subjects’ KOOS sports and recreation function scores are measured as the least squares mean (LSM) scores. In some embodiments, the standard error (SE) of LSM mean improvement from baseline KOOS sports and recreation function scores is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, or 0.9, or a range defined by any two of the preceding values. SE can be calculated as SE = Standard Deviation (SD) / square root of the sample size (n). In further embodiments, the treatment efficacy outcome measurement has a 95% confidence interval (CI).

[0061] In some further embodiments, the treatment (enekinragene inzadenovec alone, or enekinragene inzadenovec in combination with a corticosteroid) increases the subject’s KOOS QoL score by at least 1 point from the subject's baseline KOOS knee-related QoL score. In some further embodiments, the treatment increases the subject’s KOOS QoL score by 1 to 100 points (scale 0 to 100), by or at least by 5 to 60 points or 10 to 55 points, for example 1, 2, 4, 5, 6, 8, 10, 12, 14. 16. 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 55, or 60 points, or a range defined by any of the two preceding values, optionally 10-60 points, 12-58 points, 14-56 points, 8-60 points, 10-60 points, 5-55 points, 6-60 points, 6-50 points, 6-40 points, 16-46 points, 18-44 points, 20-42 points, 22-40 points, 24-38 points, or 26-36 points, from the subject’s baseline KOOS QoL score, wherein the subject’s KOOS QoL score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some such embodiments, the method increases the subject’s KOOS QoL score by 13-43, 17-39, 13-33, 17-43, 23, 28, or 30 points from baseline at about 12 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS QoL score by 18-44, 19-41, 19-40, or 30 points from baseline at about 24 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS QoL score by 20-50, 22-46, 20-42, 24-52, 30, 35, or 38 points from baseline at about 52 weeks after treatment. In some such embodiments, the method increases the subject’s KOOS QoL score by 20-48, 18-44, 18-42, 18-48, 30, or 33 points from baseline at about 104 weeks after treatment. In someembodiments, the treatment provides about or at least about 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, or 300%, or a range defined by any two of the preceding values, optionally about 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, 50%-90%, 35%-200%, 45%-180%, 50%-170%, 60%-160%, 70%-150%, 80-120%, 50%-150%, 100%-200%, 150%-250%, or 200%-300% increase in the subject’s KOOS QoL score from baseline, wherein the subject’s KOOS QoL score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment. In some further embodiments, the treatment provides about or at least about 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, or 300%, or a range defined by any two of the preceding values, optionally about 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, 50%-90%, 35%-200%, 45%-180%, 50%-170%, 60%-160%, 70%-150%, 80-120%, 50%-150%, 100%-200%, 150%-250%, or 200%-300% increase in the KOOS QoL scores change from baseline of a group of about or at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 subjects having grade 2 , 3 or 4 severity of knee osteoarthritis based on the K / L scale. In some such embodiments, the subject's KOOS QoL score is measured at, or at least, about 12 weeks (such as 12, 16, 26, 40, or 52 weeks) after the treatment. In some further embodiments, the subject’s KOOS QoL score is measured after, or after at least, about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-104 weeks, 52-156 weeks, or 104-208 weeks of treatment. In any embodiments, the subjects’ KOOS QoL scores are measured as the least squares mean (LSM) scores. In some embodiments, the standard error (SE) of LSM mean improvement from baseline KOOS QoL scores is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, or 0.9, or a range defined by any two of the preceding values. SE can be calculated as SE = Standard Deviation (SD)Zsquare root of the sample size (n). In further embodiments, the treatment efficacy outcome measurement has a 95% confidence interval (CI).

[0062] In any embodiments of the methods described herein, the treatment method (enekinragene inzadenovec alone, or enekinragene inzadenovec in combination with a corticosteroid) reduces the level of one or more inflammatory biomarkers selected from the group consisting of high-sensitivity C-reactive protein (hs-CRP), TNFa, IL-1, IL- ip, IL-6, IL-8 and IL-10. In any embodiments of the method described herein, the treatment improves the one or more measuments of knee osteoarthritis pain treatment as described herein regardless of a subject’s preexisting baseline adenovirus type 5 neutralizing antibodies (anti-Ad5 Nabs) level prior to thetreatment. In some embodiments, the presence of the baseline anti-Ad5 NAbs does not impact or substantially impact the subject’s WOMAC pain score, WOMAC stiffness score, WOMAC physical function score, or KOOS scores (one or more subscales including ADL function score, symptom score, pain score, sports and recreation function score, and knee-related QoL score) of the subject. In any embodiments of the method described herein, the treatment reduces the synovitis score of the subject. In any embodiments of the methods disclosed herein, the method excludes subject who does not have synovitis. In other words, the subject needs to have active synovitis to receive the treatment described herein.

[0063] Some additional embodiments of the present disclosure relate to a method of treating knee osteoarthritis pain in a subject in need thereof, comprising:identifying and / or selecting a subject (e.g., identifying and / or selecting, or selecting a subject identified as) having grade 2 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale and optionally also have synovitis; and administering a pharmaceutical composition comprising at least about 1 x 109genome copies (GC) of enekinragene inzadenovec (e.g., 1 x IO10GC to about 1 x 1012GC or 1.4 x IO10or about 1.4 x 1011GC) to the subject by a single intra-articular injection to the subject;wherein the pharmaceutical composition further comprises a corticosteroid, or the subject is pretreated with a corticosteroid prior to or immediately prior to the administering of the pharmaceutical composition; andwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction, or a range defined by any two of the preceding values (e.g., 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%), in the WOMAC pain scores change from baselines of a group of at least 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects, and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction, or a range defined by any two of the preceding values (e.g., 10%-90%, 10%-50%, 20% to 70%, 40% to 60%. 30%-80%. or 50%-90%), in the WOMAC stiffness scores change from baselines of a group of at least 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%. 50%. 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction, or a range defined by any two of thepreceding values (e.g., 10%-90%, l()%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%), in the WOMAC physical function scores change from baselines of a group of at least 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provides about or at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250% or 300% increase, or a range defined by any two of the preceding values (e.g., 10%- 90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, 50%-90%, 100%-200%, 120%-180%, 140%-160%, 100%-120%, 120%-140%, 140%-160%, 160-180%, 180%-200%, 150%- 300%, 150%-250%, 200%-300%, or 250%-300%), in one or more subscales of the KOOS scores change from baselines of a group of at least 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects. In some such embodiments, the KOOS score comprises five subscales selected from the group consisting of activities of daily living (ADL) function score, symptom score, pain score, sports and recreation function score, and knee-related quality of life (QoL) score.

[0064] Some additional embodiments the present disclosure relate to a method of treating knee osteoarthritis pain in a subject in need thereof, comprising:identifying and / or selecting a subject (e.g., identifying and / or selecting, or selecting a subject identified as) having grade 3 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale and optionally also have synovitis; and administering a pharmaceutical composition comprising at least about 1 X 109genome copies (GC) (e.g., 1 x 1010GC to about 1 x 1012GC or 1.4 x 1010or about 1.4 x 1011GC) of enekinragene inzadenovec to the subject by a single intra-articular injection to the subject;wherein the pharmaceutical composition further comprises a corticosteroid, or the subject is pretreated with a corticosteroid prior to or immediately prior to the administering of the pharmaceutical composition; andwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction, or a range defined by any two of the preceding values (e.g., 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%), in the WOMAC pain scores change from baselines of a group of at least 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects, and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%. 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction, or a range defined by any two of thepreceding values (e.g., 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%), in the WOMAC stiffness scores change from baselines of a group of at least 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%. 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction or a range defined by any two of the preceding values (e.g., 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%) in the WOMAC physical function scores change from baselines of a group of at least 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provides about or at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250% or 300% increase, or a range defined by any two of the preceding values (e.g., 10%- 90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, 50%-90%, 100%-200%, 120%-180%, 140%-160%. 100%-120%, 120%-140%, 140%-160%, 160-180%, 180%-200%, 150%- 300%, 150%-250%, 200%-300%, or 250%-300%), in one or more subscales of the KOOS scores change from baselines of a group of at least 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects. In some such embodiments, the KOOS score comprises five subscales selected from the group consisting of activities of daily living (ADL) function score, symptom score, pain score, sports and recreation function score, and knee-related quality of life (QoL) score.

[0065] Some embodiments of the present disclosure relate to a method of treating knee osteoarthritis pain in a subject in need thereof, comprising:identifying and / or selecting a subject (e.g., identifying and / or selecting, or selecting a subject identified as) having grade 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale and optionally also synovitis; andadministering a pharmaceutical composition comprising at least about 1 x 109genome copies (GC) of enekinragene inzadenovec (e.g., 1 x IO10GC to about 1 x 1012GC, or 1.4 X 1010or about 1.4 X 1011GC) to the subject by a single intra-articular injection to the subject;wherein the pharmaceutical composition further comprises a corticosteroid, or the subject is pretreated with a corticosteroid prior to or immediately prior to the administering of the pharmaceutical composition; andwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%. 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction, or a range defined by any two of thepreceding values (e.g., 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%), in the WOMAC pain scores change from baselines of a group of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects, and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%. 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction, or a range defined by any two of the preceding values (e.g., 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%), in the WOMAC stiffness scores change from baselines of a group of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction, or a range defined by any two of the preceding values (e.g., 10%-90%, 10%-50%, 20% to 70%, 40% to 60%, 30%-80%, or 50%-90%), in the WOMAC physical function scores change from baselines of a group of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provides about or at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250% or 300% increase, or a range defined by any two of the preceding values (e.g., 10%- 90%, 10%-5()%, 20%-70%, 40%-60%, 30%-80%, 50%-90%, 100%-200%, 120%-180%, 140%-160%, 100%-120%, 120%-140%, 140%-160%, 160-180%, 180%-200%, 150%- 300%, 150%-250%, 200%-300%, or 250%-300%), in one or more subscales of the KOOS scores change from baselines of a group of at least 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects. In some such embodiments, the KOOS score comprises five subscales selected from the group consisting of activities of daily living (ADL) function score, symptom score, pain score, sports and recreation function score, and knee-related quality of life (QoL) score.

[0066] In any embodiments of the methods described herein, the subjects’ WOMAC pain scores, WOMAC stiffness scores, WOMAC physical function scores, and / or KOOS scores are measured as the least squares mean (LSM) scores.

[0067] In any embodiments of the methods disclosed herein, the enekinragene inzadenovec treatment reduces the level of one or more inflammatory biomarkers selected from the group consisting of high-sensitivity C-reactive protein (hs-CRP), TNFa, IL-1, IL- 1 , IL-6, IL-8 and IL- 10. In some embodiments, the levels of the one or more inflammatory biomarkers described herein are decreased by about, or at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%, or a range defined by any two of the preceding values (e.g., 2%-40%, 5%-35%, 10%-30%, 15%-25%, 25%-35%, 35%-45%, 45%-50%, !%-!()%, 10%-20%, or 20%-30%) after the enekinragene inzadenovec treatment. In further embodiments, the cnckinragcnc inzadenovec treatment reduces the pain in the ostcoarthritic knee of the subject and improves the one or more measurements of knee osteoarthritis pain as described herein regardless of a subject’s preexisting baseline anti-Ad5 neutralizing antibody (NAb) level prior to the treatment. In other words, the subject’s preexisting anti-Ad5 NAb titer does not affect or substantially affect the treatment. In some such embodiments, the methods further comprise determining or receiving information on the subject’s baseline anti-Ad5 titer prior to the enekinragene inzadenovec treatment. In other instance, the method does not require determining or receiving information on the subject’s baseline anti-Ad5 titer prior to the enekinragene inzadenovec treatment. In further embodiments, the enekinragene inzadenovec treatment reduces the synovitis score of the subject. In some such embodiments, the synovitis score of the subject is reduced by about or at least about 1, 2, 3, 4, or 5 points as measured by synovitis scoring method using contrast-enhanced MRI as described herein. In some such embodiments, the synovitis score of the subject is reduced by about or at least about 1, 2, 3, 4, or 5 points as measured by synovitis scoring method using contrast-enhanced MRI as described herein. In some such embodiments, the average of median synovitis score is reduced by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% after the enekinragene inzadenovec treatment. In any embodiments of the methods described herein, the enekinragene inzadenovec treatment described herein includes the corticosteroid pretreatment or cotreatment as described herein. In some embodiments of the methods disclosed herein, the corticosteroid comprises about 40 mg of methylprednisolone acetate. In some embodiments, the corticosteroid is in a second pharmaceutical composition in the form of a liquid or suspension. In other embodiments, the corticosteroid is in the same pharmaceutical composition as the enekinragene inzadenovec. In some embodiments, the WOMAC pain scores, WOMAC stiffness scores, WOMAC physical function scores or KOOS scores are measured at, or at least, about 12 weeks after the treatment (e.g., about or at least about 12, 18, 24, 30, 36, 42, 48, 52, 78, 104, 130, 156, 182, 208, 234, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-104 weeks, 52-1 6 weeks, or 104-208 weeks). In some embodiments, the standard error (SE) of LSM mean improvement from baseline WOMAC pain scores, WOMAC stiffness scores, WOMAC physical function scores and / or KOOS scores is about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, or 0.9, or a range defined by any two of the preceding values. SE can be calculated as SE = Standard Deviation (SD) / square root of the sample size (n). In further embodiments, the treatment efficacy outcome measurement has a 95% confidence interval (CI).

[0068] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The references cited herein are not admitted to be prior art to the claimed disclosure. In the case of conflict, the present Specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of the disclosure will be apparent from the following detailed description and claims. The following references disclose methods, compositions, doses, routes of administration, and sequences related to the present disclosure, and which disclosures are incorporated by reference herein, and which references are each incorporated herein by reference in their entireties: WO 2013 / 114199, WO 2014 / 115022, WO 2021 / 055860, WO 2023 / 028492, and WO 2024 / 182549.EXAMPLES

[0069] The examples below are non-limiting and are merely representative of various aspects of the present disclosure.Example 1

[0070] In this example, an open-label, two-part, phase 1 study (NCT04119687) in subjects with osteoarthritis of the knee and the analysis of the clinical study results are summarized here.Study Design

[0071] Eligible participants were adults aged 30 to 80 years with moderate to severe knee osteoarthritis (OA). Eligible participants had K / L grade 2, 3, or 4 OAK, prior treatment failure of two or more other therapies for OAK, and baseline WOMAC pain score > 5.0 and < 9.0 out of 10.0. The first cohort received ultrasound-guided IA injection of 5 mL of PCRX-201 to the index knee joint at ascending doses of 1.4 x 1010GC (low-dose), 1.4 x 1011GC (mid-dose), and 1.4 x 1012GC (high-dose). The second cohort of patients received a 1 mL intra-articular injection of methylprednisolone (40 mg / mL) just before PCRX-201 administration at the above doses to explore the benefit of immune modulation to maximize vector tolerability and transduction. Outcomes up to 156 weeks included safety, WOMAC pain (WOMAC- A) and stiffness (WOMAC-B) scores, and the Knee Injury and Osteoarthritis Outcome Score (KOOS).Results

[0072] FIGs. 1A and IB show the LSM change from baseline for WOMAC-A pain across 3 doses in the not pretreated and steroid pretreated cohorts through week 156. FIGs. 2A and 2B show the LSM change from baseline for WOMAC-B stiffness across 3 doses in the notpretreated and steroid pretreated cohorts through week 156. For each of FIGs. 1A, IB, 2A and 2B, the sample sizes from top to bottom correspond to the low-dose, mid-dose and high-dose groups, respectively.

[0073] As shown in FIGs. 1A and IB, at 104 weeks, a 48% to 65% reduction from baseline pain was observed in the steroid pretreated cohort across all dose levels, and a 41% to 58% reduction from baseline pain was observed in the not pretreated cohort across all dose levels. Additionally, > 50% of participants in the not pretreated cohort have a pain response (defined as > 50% reduction in WOMAC-A from baseline) by 24 weeks. > 40% of participants in the steroid pretreated cohort have a pain response as early as 2 to 8 weeks, and > 70% of participants had a pain response by 16 weeks. At 156 weeks, the LSM improvement from baseline for WOMAC-A score for the steroid pretreated cohort was 3.4 to 3.6 points (51% to 53% reduction from baseline pain). WOMAC-A scores between 104 and 156 weeks for higher doses in the steroid pretreated cohort exhibited a larger LSM change from baseline compared with lower doses.

[0074] As shown in FIGs. 2A and 2B, at 104 weeks, a 53% to 72% reduction from baseline stiffness was observed in the steroid pretreated cohort across all dose levels, and a 33% to 53% reduction from baseline stiffness was observed in the not pretreated cohort across all dose levels. At 156 weeks, the LSM improvement from baseline for WOMAC-B score for the steroid pretreated cohort was 3.3 to 4.1 points (38% to 76% reduction from baseline stiffness).

[0075] FIGs. 3A and 3B show the LSM change from baseline in KOOS activities of daily living scores across 3 doses in the not pretreated and steroid pretreated cohorts through week 156. At 104 weeks, the LSM improvement from baseline for KOOS activities of daily living scores was 26.6 to 36.2 of 100 points for the steroid pretreated cohort across doses and 22.3 to 31.8 of 100 points for the not pretreated cohort across doses. At 156 weeks, the LSM improvement from baseline for KOOS activities of daily living scores was 26.1 to 27.5 of 100 points for the steroid pretreated cohort across doses. For each of FIGs. 3A and 3B, the sample sizes from top to bottom correspond to the low-dose, mid-dose and high-dose groups, respectively.

[0076] FIGs. 4A and 4B show the LSM change from base line for WOMAC-A pain across K / L grade 2, 3, and 4 in the not pretreated and steroid pretreated cohorts through week 104. Participants in the not pretreated cohort with K / L grade 2 had the largest LSM reduction from baseline in WOMAC-A pain (4.7 points), but participants with K / L grade 3 or 4 also had reductions from baseline (3.0 and 2.6, respectively). Participants in the steroid pretreated cohort with K / L grade 2 had the largest LSM reduction from baseline in WOMAC-A pain (5.5 points), but participants with K / L grade 3 or 4 also had reductions (3.8 and 3.5, respectively).

[0077] FIGs. 5A and 5B show the LSM change from base line for WOMAC-B stiffness across K / L grade 2, 3, and 4 in the not pretreated and steroid pretreated cohorts through week 104.

[0078] FIGs. 6A and 6B shows the LSM change from baseline in KOOS activities of daily living scores across K / L grade 2, 3, and 4 in the not pretreated and steroid pretreated cohorts through week 104. For each of FIGs. 4A, 4B, 5A, 5B, 6A and 6B, the sample sizes from top to bottom correspond to Grade 4, Grade 3 and Grade 2 groups in terms of severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale, respectively.

[0079] A single IA injection of PCRX-201 in the index knee had an acceptable safety profile with improvements in pain, function, and stiffness sustained through 156 weeks, indicating long-term clinical efficacy. The sustained improvements in WOMAC pain and stiffness scores at 156 weeks suggest that lower doses of PCRX-201 may be sufficient to provide efficacy. Additionally, no procedure- or treatment-related serious adverse events (AEs) were reported. Dose-related index knee effusion was the most commonly reported AE and occurred less frequently in the steroid pretreated cohort (36% of participants) than the not pretreated cohort (63% of participants). At all doses and across both cohorts, pain and function benefits were observed, with the greatest improvements occurring in the steroid pretreated cohort.Example 2

[0080] In this example, a phase 2, two-part, randomized, double -blind, active-controlled study to assess the safety and tolerability of PCRX-201 in subjects with painful osteoarthritis of the knee is summarized here. The purpose of this phase 2 study is to assess safety and tolerability of 2 doses of a single intra-articular (IA) knee injection of PCRX-201 (Dose A [1.4 x 1010genome copies (GC)] or Dose B [1.4 x 1011GC]) with steroid pretreatment versus IA saline (placebo) with steroid pretreatment in subjects with osteoarthritis of the knee (OAK). This study is also intended to address the following objectives: (1) to characterize the systemic biodistribution of PCRX-201 following a single IA knee injection in subjects with OAK; (2) to characterize immunogenicity of PCRX-201 following a single IA knee injection in subjects with OAK; (3) to assess efficacy of 2 dose levels of a single IA knee injection of PCRX-201 Dose A or Dose B in subjects with OAK; (4) to compare the clinical safety and tolerability between drug products from 2 manufacturing processes in Part A versus Part B; and (5) to compare the clinical efficacy between drug products from 2 manufacturing processes in Part A versus Part B.Study Design

[0081] The study consists of two parts, Part A and Part B, which use PCRX-201 from two different manufacturing processes. A total of 135 eligible subjects, male and female, ages 45to 80 years old, with painful OA of the index knee will be enrolled. A maximum of 45 subjects is planned for Part A (15 per dose group) and 90 subjects for Part B (30 per dose group) of this study. Subjects arc randomly assigned to a treatment dose group, stratified by Kcllgrcn-Lawrcncc (K-L) Grade, in both parts of the study. All eligible subjects will be pretreated with the same dose of methylprednisolone acetate (40 mg) on Day 1 immediately before treatment with PCRX-201 or placebo. Before injection, the intended injection site will be assessed for skin integrity and condition. It should be confirmed that the index knee is free of any signs of local or joint infection; the index knee will be examined for tenderness, heat / redness, swelling, effusion that may be indicative of localized inflammation or infection, and Baker’s cyst. The primary evaluation period will encompass Baseline / Day 1 through Week 52. Subjects will attend 14 outpatient visits, and complete study questionnaires on their own at Weeks 28, 32, 42, and 46 (for a total of 15 outpatient visits including Screening with reminder phone calls for the Week 28, 32, 42, and 46 questionnaires as needed). The long-term follow-up period will begin at Week 53 and will encompass 4 phone call visits from the site at Weeks 78, 130, 182, and 234 as well as 4 annual outpatient visits at Weeks 104, 156, 208, and 260 (a total of 4 phone visits and 4 outpatient visits). The final long-term follow-up visit will occur at Week 260 (± 4 weeks). Therefore, each subject may participate in the study for up to a maximum of 269 weeks (approximately 1,883 days) (a total of 23 visits with reminder phone calls as needed).Treatment Arms

[0082] Treatment arms include the following:1 mL methylprednisolone acetate (40 mg / mL) administered as an IA knee injection followed by 5 mL PCRX-201 2.8 x 109GC / mL administered as an IA knee injection.1 mL methylprednisolone acetate (40 mg / mL) administered as an IA knee injection followed by 5 mL PCRX-201 2.8 x 1010GC / mL administered as an IA knee injection.1 mL methylprednisolone acetate (40 mg / mL) administered as an IA knee injection followed by 5 mL sterile saline administered as an IA knee injection.Inclusion Criteria

[0083] Subjects are eligible to be included in the study only if all of the following criteria apply:1. Subjects must provide written consent to participate in the study.2. Subjects must be willing and able to comply with the study procedures and visit schedule and able to follow verbal and written instructions.3. Subjects must be male or female and 45 to 80 years old, inclusive, at Screening.4. Subjects must exhibit symptoms associated with OA of the index knee for >12 months before Screening (subject self-reporting is acceptable).5. Subjects must have index knee pain for >15 days over the last month before Screening (subject self-reporting is acceptable).6. Subjects must have failed 2 or more therapies: Restricted physical activity as per Osteoarthritis Research Society International (OARSI) core level recommendation, e.g., “structured land-based exercise” (this may include physical therapy), and failure of an additional type of conservative therapy for OA of the index knee, e.g., nonselective NSAIDs or COX-2 inhibitors, in the past 12 months.7. Subjects must have a body mass index (BMI) <40 kg / m2at Screening.8. Subjects must have an index knee examination indicating the index knee and the intended injection site area are free of any signs of local or joint infection at Baseline.9. Subjects must have an index knee Average Daily Knee Pain (NRS) between >5.0 and <9.0 at Screening and Baseline.10. Sexually active subjects of child-bearing potential (SOCBP) and partners of SOCBP must agree to use effective birth control while in the study.11. Subjects must have active synovitis in the index knee as determined by ultrasound Doppler.12. Subjects must exhibit American College of Rheumatology Criteria (clinical and radiological) for OA (Altman et al, 1986) as follows:a. Knee painb. At least 1 of the following:i. Age >50 yearsii. Morning stiffness <30 minutesiii. Crepitus on knee motionc. Osteophytes13. Subjects must have K-L Grade 2, 3, or 4 in the index knee based on X-rays performed during Screening and confirmed by trained radiographers at a central facility before enrollment:• Grade 2: Definite osteophytes and possible narrowing of joint space. • Grade 3: Moderate multiple osteophytes, definite narrowing of joint space, some sclerosis, and possible deformity of bone ends.• Grade 4: Large osteophytes, marked narrowing, severe sclerosis, and definite deformity of bone ends.14. Subjects need to show the presence of moderate or severe synovitis based on 11 -point synovitis score using contrast-enhanced MRI:a. Moderate synovitis: Score of 9 to 12.b. Severe synovitis: Score >13.Exclusion Criteria

[0084] Subjects arc excluded from the study if any of the following criteria apply:1. Subjects have any current or prior diagnosis of autoimmune connective tissue disorders, secondary OA conditions, benign synovial tumors, gout / pseudogout, reactive arthritis, RA, psoriatic arthritis, ankylosing spondylitis, or arthritis associated with inflammatory bowel disease.2. Subjects have any active systemic or local infection, including infection of the index knee.3. Subjects are unable to undergo MRI with contrast due to presence of ocular foreign body, neurological or vascular stent with unknown safety profile, surgical hardware, a cardiac pacemaker not compatible with MRI equipment, foreign body in the index knee, or inability to receive contrast agent based on previous allergy or estimated glomerular filtration rate (eGFR) <60 mL / min / 1.73 m2.4. Subjects with X-ray or MRI exclusionary events such as subchondral insufficiency fracture, osteonecrosis, stress or pathologic fracture or bone contusion, inflammatory disease other than OA, bone marrow infiltration, borderline or malignant bone tumor, soft tissue tumor, severe malalignment (>10 degrees varus or valgus), posterior root tear of the lateral or medial meniscus, Paget disease, large cystic lesions exceeding half of the femoral condyle or tibial plateau which may constitute a risk of articular bone collapse, or other similar events judged by the Investigator as exclusionary.5. Subjects have an unstable index knee joint (e.g., tom anterior cruciate ligament) within 12 months of Screening.6. Subjects have used any approved or investigational IA drug / biologic in index knee within 6 months of Screening (e.g., hyaluronic acid, platelet rich plasma, stem cells, prolotherapy, and amniotic fluid injection).7. Subjects are receiving or have received any gene therapy treatment (e.g., IL- IRa) in the past 3 years.8. Subjects have used IA steroids <3 months before screening.9. Subjects have a history of chronic diseases (e.g., asthma, chronic obstructive pulmonary disease [COPD], autoimmune diseases, etc.) that would require oral, intravenous (IV), intramuscular (IM), intranasal steroid treatments within 12 months after dosing. Occasional topical steroid creams and intranasal (nondaily use <1 month) are allowed; ophthalmic drops are acceptable.10. Subjects will require or plan to have cold or radiofrequency nerve ablation, arthroscopic or open surgery of the index knee, or any other major surgery within 12 months of dosing.11. Subjects who are pregnant or nursing or plan to become pregnant within 12 months after dosing.12. Subjects whose partner is planning to conceive within 12 months after dosing.13. Subjects with loss of skin integrity over the index knee where the injection would take place.14. Subjects with evidence of positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Hepatitis B virus (HBV) immune subjects (i.e., hepatitis B surface antigen [HBsAg]-negative and hepatitis B antibody-positive) may, however, be included.Note: Subjects who are negative for HBsAg, but positive for HBcAb, the participant would be considered eligible if the absence of HBV DNA is confirmed by HBV DNA polymerase chain reaction reflex testing performed in the central laboratory.15. Subjects with chronic hepatitis C virus (HCV) (i.e., positive HCV antibody [HCVAb] and HCV RNA).Note: Subjects who are HCVAb-positive without evidence of HCV RNA may be considered eligible (spontaneous viral clearance or previously treated and cured [defined as no evidence of HCV RNA at least 12 weeks before baseline]).16. Subjects with laboratory evidence of infection with human immunodeficiency virus (HIV).17. Subjects with current uncontrolled hypertension >Stage II per American Heart Association (AHA).18. Subjects with type II diabetes mellitus with hemoglobin Ale (HbAlc) >7% at Screening.19. Subjects who have received glucagon-like peptide 1 agonist medications within 12 months of Screening or are planning to be on one within 12 months after dosing.20. Subjects with active or history of malignancy within the last 5 years, except resected basal cell carcinoma, squamous cell carcinoma of the skin, or effectively managed cervical carcinoma in situ.21. Subjects with active pharmacologic treatment for depression, including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), nonselective serotonin reuptake inhibitors (NSRIs), and tricyclics, if dose / regimen has not been stable for > 3 months before Screening.22. Subjects with active substance use disorder (drugs or alcohol) or history of substance use disorder within the past 12 months.23. Subjects currently on opioid medication or have a history of opioid medication use (e.g., oxycodone, hydrocodone, codeine, morphine, etc.) or other illicit drug use within 1 month of Screening.24. Subjects with any systemic or local, acute, or chronic (including for preventive use) bacterial or viral infection requiring IV antibiotics or antivirals within 4 weeks of Screening or oral antibiotics or antivirals within 2 weeks of Screening.25. Subjects with current or a history of tuberculosis, systemic fungal, or opportunistic infections per medical history.26. Subjects unwilling or unable to use or comply with an electronic Patient-Reported Outcome (cPRO) system.27. Subjects with bilateral OAK and average pain in the contralateral knee >4 (0 to 10 NRS scale).28. Subjects with a clinically relevant level of pain catastrophizing defined as Pain Catastrophizing Scale score >30 at Screening.29. Subjects with prior total or partial knee arthroplasty procedures in the index knee.30. Subjects with an international normalized ratio (INR) >1.5; activated partial thromboplastin time (aPTT) >1.5 upper limit of normal (ULN).31. Subjects with alanine aminotransferase or aspartate aminotransferase >1.5; alkaline phosphatase >1.5; total bilirubin level >1.5 ULN (exception: subjects with Gilbert syndrome may be allowed).32. Subjects with absolute neutrophil count (ANC) <1000 to 500 / mm3; <1.0 to 0.5 x 109 / L (except due to benign ethnic neutropenia).33. Subjects with a known allergy or sensitivity to acetaminophen.34. Subjects with a known allergy or sensitivity to corticosteroids or unwillingness to receive IA corticosteroids as pretreatment or to manage index knee effusions, or subject has contraindication to IA corticosteroid administration.35. Subjects with known allergy or sensitivity to gadolinium contrast.36. Subjects currently taking coumadin or have been taken coumadin for >3 weeks prior to Baseline.37. Subjects with any other clinically significant acute or chronic pain condition that, in the judgment of the Investigator and in consultation with the Medical Monitor (MM) and / or Sponsor, would or could compromise (or convey increased risk of) subject safety, limit the subject’s ability to complete the study, and / or compromise the objectives of the study.38. Subjects with any other clinically significant acute or chronic medical conditions (e.g., autoimmune disorder; asthma; bleeding disorder; other major hematological conditions, cardiac, renal, metabolic, gastrointestinal, neurologic, or psychiatric disease) that, in the judgment of the Investigator and in consultation with the MM, would preclude the use of the study drug or IA corticosteroids or that could compromise (or convey increased risk of) subject safety, limit the subject’s ability to complete the study, and / or compromise the objectives of the study.Injection Administration Procedure

[0085] IA injections will be administered by the assigned unblinded injector, who has significant experience in the administration of I A injections and has been trained on study administration procedures. The injector may choose the position of the knee (e.g., extended or flexed), the approach for the injection (e.g., anterior, medial, or lateral), and the use of topical or local numbing agent (including subcutaneous lidocaine 1%) based on standard of care.

[0086] The injector will use a 21 -gauge needle or larger for injection and aspiration of fluid. The same needle used for synovial fluid aspiration may also be used for IA injection of corticosteroid and the study medication, thereby allowing for a single injection with syringe replacement. The index knee will be aspirated in all cases before administration of study drug and synovial fluid, if present, will be collected for biomarkers. If IA effusion is detected using ultrasound guidance, the injector will withdraw to near dryness before injection. Following attempted synovial fluid aspiration, 1 mL of methylprednisolone acetate suspension (40 mg / mL) is injected (Syringe 1). After administration of Syringe 1, a I mL 0.9% normal saline flush is performed to flush any remaining suspension contents from the needle. Syringe 2, containing blinded study drug (5 mL), will then be administered. Following administration of study drug, a second flush of normal saline (1 to 2 mL) will be performed to ensure all study drug was administered. After the final saline flush, 10 mL of room air will be administered. All injections should be performed under ultrasound guidance and without any change of the needle position.Studv Endpoints

[0087] The primary endpoint of each study part (Part A and Part B) is the incidence (number and percent) treatment emergent adverse events (TEAEs), adverse events of special interest (AESIs), and serious adverse events (SAEs) following a single IA knee injection of PCRX-201 at Dose A or Dose B with steroid pretreatment in subjects with OAK through Week 52. No formal statistical tests will be conducted to compare the incidence of safety endpoints between treatment groups. Safety data will be summarized descriptively by dose group, study part, and overall, including but not limited to, the number of subjects experiencing each of TEAEs, AESIs, and SAEs, and the number of TEAE, AESI, and SAE events reported by system organ class and preferred term.

[0088] The secondary and exploratory endpoints include (1) real-time quantitative polymerase chain reaction (qPCR) measurement profile in plasma of PCRX-201 Dose A and Dose B from postdose through Week 8; (2) real-time qPCR measurement profile of skin swab samples from Baseline through Week 4; (3) assessment of the levels of adenovirus type 5 neutralizing antibodies (anti-Ad5 NAbs), high-sensitivity C reactive protein (hs-CRP), and biomarkers of inflammation (e.g., interleukin [IL]-1, cytokines [tumor necrosis factor alpha (TNFa), IL-ip, IL-6, IL-10], and chemokines [IL-8]) at Baseline, Week 4, Week 12, and Week 52; (4) absolute change in average daily pain score in the index knee (0-10 Numerical Rating Scale [NRS]) for PCRX-201 Dose A and Dose B versus placebo at Weeks 38 and 52; (5) absolute change from Baseline on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score for PCRX-201 Dose A and Dose B versus placebo at Weeks 38 and 52; (6) absolute change from Baseline on the WOMAC stiffness score for PCRX-201 Dose A and Dose B versus placebo at Weeks 38 and 52; (7) absolute change from Baseline on the WOMAC physical function score for PCRX-201 Dose A and Dose B versus placebo at Weeks 38 and 52; (8) absolute change from Baseline on the Knee Injury and Osteoarthritis Outcome Score (KOOS) function / daily living score for PCRX-201 Dose A and Dose B versus placebo at Weeks 38 and 52; (9) incidence (number and percent) of TEAEs, AESIs, and SAEs in Part A versus Part B from Week 1 through Week 52; (10) absolute change in average daily pain score in the index knee (0-10 NRS) for PCRX-201 in Part A versus Part B at Weeks 38 and 52; (11) absolute change from Baseline on the WOMAC pain score for PCRX-201 in Part A versus Part B at Weeks 38 and 52; (12) absolute change from Baseline on the WOMAC stiffness score for PCRX-201 in Part A versus Part B at Weeks 38 and 52; (13) absolute change from Baseline on the WOMAC physical function score for PCRX-201 in Part A versus Part B at Weeks 38 and 52; (14) absolute change from Baseline on the KOOS function / daily living score for PCRX-201 in Part A versus Part B at Weeks 38 and 52; (15) change in synovitis score from Baseline (synovitis improvement by magnetic resonance imaging([MRI)with or without contrast) for PCRX-201 Dose A and Dose B versus placebo at Week 52; (16) bone changes by B-Score via MRI from Baseline for PCRX-201 Dose A and Dose B versus placebo at Week 52; (17) joint space change by X-ray from Baseline for PCRX-201 Dose A and Dose B versus placebo at Week 52; (18) absolute change from Baseline on the KOOS symptoms, stiffness, pain, function / sports and recreation, and knee-related quality-of-life (QoL) scores for PCRX-201 Dose A and Dose B versus placebo at Week 52; (19) absolute change from Baseline in European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L) for PCRX-201 Dose A and Dose B versus placebo at Week 52; and (20) absolute change from Baseline in the Subject Satisfaction questionnaire for PCRX-201 Dose A and Dose B versus placebo at Week 52.

[0089] It is observed that a single IA injection of PCRX-201 of both Dose A and Dose B in the index knee have an acceptable safety profile with improvements in pain, physical function, and stiffness sustained through 52, 104, 156, 208 and 260 weeks, indicating long-term clinical efficacy, as compared to steroid pretreatment with (placebo) with steroid pretreatment in subjects with K / L scale 2, 3 or 4. The sustained improvements in WOMAC pain, stiffness and physical function scores suggest that lower dose (Dose A) of PCRX-201 may be sufficient to provide efficacy. Additionally, no procedure- or treatment-related serious adverse events (AEs) are reported.

Claims

WHAT IS CLAIMED IS:

1. A method of treating knee osteoarthritis pain in a subject in need thereof, comprising:identifying and / or selecting a subject, or selecting a subject identified as, having at least grade 2 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale; andadministering a pharmaceutical composition comprising at least about 1 X 109genome copies (GC) of enekinragene inzadenovec to the subject by a single intra-articular injection to an osteoarthritic knee of the subject;wherein the method improves one or more measurements of knee osteoarthritis pain selected from the group consisting of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, WOMAC stiffness score, WOMAC physical functional score, and Knee Injury and Osteoarthritis Outcome Score (KOOS).

2. A method of improving one or more measurements of knee osteoarthritis pain in a subject having grade 2, 3 or 4 severity of knee osteoarthritis, comprising:identifying and / or selecting a subject, or selecting a subject identified as, having grade 2, 3 or 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale and optionally also synovitis; andadministering a pharmaceutical composition comprising at least about 1 x 109genome copies (GC) of enekinragene inzadenovec by a single intra-articular injection to an osteoarthritic knee of the subject;wherein the knee osteoarthritis pain measurements are selected from the group consisting of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (scale 0 to 10), WOMAC stiffness score (scale 0 to 10), WOMAC physical functional score (scale 0 to 68), and Knee Injury and Osteoarthritis Outcome Score (KOOS) (scale 0 to 100), and wherein the method reduces the WOMAC pain score of the osteoarthritic knee by at least 1 to 8 points in the subject, the method reduces the WOMAC stiffness score of the osteoarthritic knee by at least 1 to 8 points in the subject, the method reduces the WOMAC physical function score of the osteoarthritic knee by at least 1 to 68 points, and / or the method increases the KOOS score of the osteoarthritic knee by at least 1 to 100 points.

3. The method of claim 1 or 2, comprising identifying and / or selecting a subject, or selecting a subject identified as, having grade 2 severity of knee osteoarthritis based on the K / L scale.

4. The method of claim 1 or 2, comprising identifying and / or selecting a subject, or selecting a subject identified as, having grade 3 severity of knee osteoarthritis based on the K / L scale.

5. The method of claim 1 or 2, comprising identifying and / or selecting a subject, or selecting a subject identified as, having grade 4 severity of knee osteoarthritis based on the K / L scale.

6. The method of claim 1 or 2, comprising identifying and / or excluding a subject having grade 4 severity of knee osteoarthritis based on the K / L scale.

7. The method of any one of claims 1 to 6, wherein the pharmaceutical composition comprises about IO10GC to about 1012GC of enekinragene inzadenovec.

8. The method of any one of claims 1 to 7, wherein the pharmaceutical composition comprises about 1.4 X IO10or about 1.4 X 1011GC of enekinragene inzadenovec.

9. The method of any one of claims 1 to 8, wherein the pharmaceutical composition for single intra-articular injection is about 5 mL.

10. The method of any one of claims 1 to 9, further comprising identifying and / or selecting a subject, or selecting a subject identified as, having synovitis.

11. The method of claim 10, comprising identifying and / or selecting a subject, or selecting a subject identified as, having synovitis graded at a score of 9 or higher based on an 11 -point synovitis scoring method using contrast-enhanced MRI.

12. The method of any one of claims 1 to 11, further comprising aspirating synovial fluid prior to administering the pharmaceutical composition.

13. The method of any one of claims 1 to 12, further comprising administering a corticosteroid to the subject by intra-articular injection immediately, or less than 120, 90, 60, 45, 30, 15, 10 or 5 minutes, prior to administering the pharmaceutical composition.

14. The method of claim 13, wherein the corticosteroid is in the form of a suspension of about 1 mL.

15. The method of any one of claims 1 to 12, wherein the pharmaceutical composition further comprises a corticosteroid.

16. The method of any one of claims 13 to 15, wherein the corticosteroid comprises about 40 mg of methylprednisolone acetate.

17. The method of any one of claims 1 to 16, further comprising determining or receiving information on the subject’s baseline WOMAC pain score prior to the treatment.

18. The method of any one of claims 1 to 17, wherein the method reduces the subject’s WOMAC pain score by 1, 2, 3, 4, 5 or 6 points or at least 1, 2, 3, 4, 5 or 6 points, or a range defined by any of the two preceding values, from the subject’s baseline WOMAC pain score,wherein the subject’s WOMAC pain score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment.

19. The method of any one of claims 1 to 18, wherein the method reduces the subject’s WOMAC pain score by about, or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, or a range defined by any of the two preceding values, from the subject’s baseline WOMAC pain score, wherein the subject’s WOMAC pain score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment.

20. The method of claim 18 or 19, wherein the subject’s WOMAC pain score is measured after, or after at least, about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks.

21. The method of any one of claims 1 to 20, further comprising determining or receiving information on the subject’s baseline WOMAC stiffness score prior to the treatment.

22. The method of any one of claims 1 to 21, wherein the method reduces the subject’s WOMAC stiffness score by 1, 2, 3, 4, 5 or 6 points or at least 1, 2, 3, 4, 5 or 6 points from the subject’s baseline WOMAC stiffness score, or a range defined by any of the two preceding values, and wherein the subject’s WOMAC stiffness score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment.

23. The method of any one of claims 1 to 22, wherein the method reduces the subject’s WOMAC stiffness score by about, or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, or a range defined by any of the two preceding values, from the subject’s baseline WOMAC stiffness score, and wherein the subject’s WOMAC stiffness score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment.

24. The method of claim 22 or 23, wherein the subject’s WOMAC stiffness score is measured after about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks of treatment.

25. The method of any one of claims 1 to 24, further comprising determining or receiving information on the subject's baseline WOMAC physical function score prior to the treatment.

26. The method of any one of claims 1 to 25, wherein the method reduces the subject’s WOMAC physical function score by 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 or 34 points, or at least 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 or 34 points, or a range defined by any of the two preceding values, optionally 10-34, 12-32, 14-30, 8-34, 6-34, 16-32, 18-30, 20-28 or 22-26 points, from the subject’s baseline WOMAC physical function score, and wherein the subject’s WOMAC physical function score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment.

27. The method of any one of claims 1 to 26, wherein the method reduces the subject’s WOMAC physical function score by about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by anyof the two preceding values, from the subject’s baseline WOMAC physical function score, and wherein the subject’s WOMAC physical function score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment.

28. The method of claim 26 or 27, wherein the subject's WOMAC physical function score is measured after about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks of treatment.

29. The method of any one of claims 1 to 28, further comprising determining or receiving information on the subject’s baseline KOOS prior to the treatment, wherein the KOOS score comprises five subscales selected from the group consisting of activities of daily living (ADL) function score, symptom score, pain score, sports and recreation function score, and quality of life (QoL) function score.

30. The method of claim 29, wherein the method increases the subject’s KOOS ADL function score by or at least by 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60 points, or a range defined by any of the two preceding values, optionally 10-60, 12-58, 14-56, 8-60, 6-60, 16-46, 18-44, 20-42, 22-40, 24-38, or 26-36 points from the subject’s baseline KOOS ADL function score, wherein the subject’s KOOS ADL function score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment.

31. The method of method of claim 29 or 30, wherein the method increases the subject’s KOOS ADL function score by about, or at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%, or a range defined by any of the two preceding values, from the subject’s baseline KOOS ADL function score and wherein the subject’s KOOS ADL function score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment.

32. The method of claim 29, wherein the method increases the subject’s KOOS symptom score by or at least by 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, or 50, points, or a range defined by any of the two preceding values, optionally 10-50, 12-48, 14-46, 8-50, 6-50, 14-34, 16-36, 18-40, or 20-36 points from the subject’s baseline KOOS symptom score, wherein the subject’s KOOS symptom score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment.

33. The method of claim 29, wherein the method increases the subject’s KOOS pain score by or at least by 6, 8, 10. 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, or 60 points, or a range defined by any of the two preceding values, optionally 10-60, 12-48, 14-46, 16-44, 18-42, 20-42, 22-40, 24-38, or 26-36 points from the subject’s baseline KOOS pain score, wherein the subject’s KOOS pain score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment.

34. The method of claim 29, wherein the method increases the subject’s KOOS sports and recreation function score by or at least by 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60 or 61 points, or a range defined by any of the two preceding values, optionally 10-60, 12-58, 14-56, 8-60, 6-60, 16-46, 18-44, 20-42, 22-40, 24-38, or 26-36 points, from the subject’s baseline KOOS sports and recreation function score, wherein the subject’s KOOS sports and recreation function score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment.

35. The method of claim 29, wherein the method increases the subject’s KOOS QoL score by or at least by 6, 8, 10, 12, 14, 16.

18. 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60 or 61 points, or a range defined by any of the two preceding values, optionally 10-60, 12-58, 14-56, 16-46, 18-44, 20-50, 22-48, 20-42, 22-40, 24-38, or 26-36 points, from the subject’s baseline KOOS QoL score, wherein the subject’s KOOS QoL score is measured at, or at least, about 12, 16, 20, 24, 38 or 52 weeks after the treatment.

36. The method of any one of claims 29 to 35, wherein the subject’s KOOS score is measured after about 52 weeks, 104 weeks, 156 weeks, 208 weeks, or 260 weeks of treatment.

37. The method of any one of claims 1 to 36, wherein the method reduces the level of one or more inflammatory biomarkers selected from the group consisting of high-sensitivity C-reactive protein (hs-CRP), TNFa, IL-1, IL-ip, IL-6, IL-8 and IL-10.

38. The method of any one of claims 1 to 37, wherein the method improves the one or more measurements of knee osteoarthritis pain regardless of the subject’s preexisting baseline anti-Ad5 neutralizing antibody (NAb) level prior to the treatment.

39. The method of any one of claims 10 to 38, wherein the method reduces the synovitis score of the subject.

40. The method of any one of claims 10 to 39, wherein the method excludes subject who does not have synovitis.

41. The method of any one of claims 1 to 40, wherein the pharmaceutical composition provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% reduction, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC pain scores change from baseline of a group of at least 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 2 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale.

42. The method of any one of claims 1 to 40, wherein the pharmaceutical composition provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values,optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC pain scores change from baseline of a group of at least 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 3 severity of knee osteoarthritis based on the Kcllgrcn-Lawrcncc (K / L) scale.

43. The method of any one of claims 1 to 40, wherein the pharmaceutical composition provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC pain scores change from baseline of a group of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale.

44. The method of any one of claims 1 to 43, wherein the pharmaceutical composition provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC stiffness scores change from baseline of a group of at least 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 2 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale.

45. The method of any one of claims 1 to 43, wherein the pharmaceutical composition provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC stiffness scores change from baseline of a group of at least 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 3 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale.

46. The method of any one of claims 1 to 43, wherein the pharmaceutical composition provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC stiffness scores change from baseline of a group of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale.

47. The method of any one of claims 1 to 46, wherein the pharmaceutical composition provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values,optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC physical function scores change from baseline of a group of about or at least about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 2 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale.

48. The method of any one of claims 1 to 46, wherein the pharmaceutical composition provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC physical function scores change from baseline of a group of about or at least about 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 3 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale.

49. The method of any one of claims 1 to 46, wherein the pharmaceutical composition provides about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC physical function scores change from baseline of a group of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale.

50. The method of any one of claims 1 to 49, wherein the pharmaceutical composition provides about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, or 200%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 30%-80%, 50%-90%, 100%-150%, 150%-200%, or 100%-200%, increase in the KOOS scores change from baseline of a group of at least 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 2 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale.

51. The method of any one of claims 1 to 49, wherein the pharmaceutical composition provides about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, or 200%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, 50%-90%, 100%-150%, 150%-200%, or 100%-200%, increase in the KOOS scores change from baseline of a group of at least 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 3 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale.

52. The method of any one of claims 1 to 49, wherein the pharmaceutical composition provides about or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, or 200%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, 50%-90%, 100%- 150%, 150%-200%, or 100%-200%, increasein the KOOS scores change from baseline of a group of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects having grade 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale.

53. A method of treating knee osteoarthritis pain in a subject in need thereof, comprising:identifying and / or selecting a subject, or selecting a subject identified as, having grade 2 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale optionally also have synovitis; andadministering a pharmaceutical composition comprising at least about 1 x 109genome copies (GC) of enekinragene inzadenovec to the subject by a single intra-articular injection to the subject’s;wherein the pharmaceutical composition further comprises a corticosteroid, or the subject is pretreated with a corticosteroid prior to or immediately prior to the administering of the pharmaceutical composition; andwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC pain scores change from baselines of a group of about, or at least about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects, and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, in the WOMAC stiffness scores change from baselines of a group of about, or at least about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or arange defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, in the WOMAC physical function scores change from baselines of a group of about, or at least about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provides about or at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, or 200%, or a range defined by any two preceding values, optionally 10%-90%, 10%-50%, 30%-80%, 50%-90%, 100%-150%, 150%-200%, 100%-200%, 150%-300%, 150%-250%, 200%-300%, or 250%-300%, increase in the KOOS scores change from baselines of a group of about, or at least about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects.

54. A method of treating knee osteoarthritis pain in a subject in need thereof, comprising:identifying and / or selecting a subject, or selecting a subject identified as, having grade 3 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale and optionally also have synovitis; andadministering a pharmaceutical composition comprising at least about 1 X 109genome copies (GC) of enekinragene inzadenovec to the subject by a single intra-articular injection to the subject;wherein the pharmaceutical composition further comprises a corticosteroid, or the subject is pretreated with a corticosteroid prior to or immediately prior to the administering of the pharmaceutical composition; andwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC pain scores change from baselines of a group of about, or at least about 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects, and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC stiffness scores change from baselines of a group of about, or at least about 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or50%-90%, reduction in the WOMAC physical function scores change from baselines of a group of about, or at least about 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provides about or at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, or 200%, or a range defined by any two preceding values, optionally 10%-90%, 10%-50%, 30%-80%, 50%-90%, 100%-150%, 150%-200%, 100%-200%, 150%-300%, 150%-250%, 200%-300%, or 250%-300%, increase in the KOOS scores change from baselines of a group of about, or at least about 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects.

55. A method of treating knee osteoarthritis pain in a subject in need thereof, comprising:identifying and / or selecting a subject, or selecting a subject identified as, having grade 4 severity of knee osteoarthritis based on the Kellgren-Lawrence (K / L) scale optionally also have synovitis; andadministering a pharmaceutical composition comprising at least about 1 X 109genome copies (GC) of enekinragene inzadenovec to the subject by a single intra-articular injection to the subject;wherein the pharmaceutical composition further comprises a corticosteroid, or the subject is pretreated with a corticosteroid prior to or immediately prior to the administering of the pharmaceutical composition; andwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC pain scores change from baselines of a group of about, or at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects, and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or 50%-90%, reduction in the WOMAC stiffness scores change from baselines of a group of about, or at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provide about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or a range defined by any two of the preceding values, optionally 10%-90%, 10%-50%, 20%-70%, 40%-60%, 30%-80%, or50%-90%, reduction in the WOMAC physical function scores change from baselines of a group of about, or at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects; and / orwherein the enekinragene inzadenovec and the corticosteroid treatment provides about or at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250% or 300% or a range defined by any two preceding values, optionally 10%-90%, 10%-50%, 30%-80%, 50%-90%, 100%-150%, 150%-200%, 100%-200%. 150%-300%, 150%-250%, 200%-300%, or 250%-300% increase in the KOOS scores change from baselines of a group about, or at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 subjects.

56. The method of any one of claims 53 to 55, wherein the corticosteroid comprises about 40 mg of methylprednisolone acetate.

57. The method of claim 56, wherein the corticosteroid is in a second pharmaceutical composition in the form of a liquid or suspension.

58. The method of claim 56, wherein the corticosteroid is in the same pharmaceutical composition as the enekinragene inzadenovec.

59. The method of any one of claims 41 to 58, wherein the WOMAC pain scores, the WOMAC stiffness scores, the WOMAC physical function scores, or the KOOS scores are measured at, or at least, about 12 weeks, 18 weeks, 24 weeks, 30 weeks, 36 weeks, 42 weeks, 49 weeks, 52 weeks, 78 weeks, 104 weeks, 130 weeks, 156 weeks, 182 weeks, 208 weeks, 234 weeks, or 260 weeks, or a range defined by any two of the preceding values, optionally 52-260 weeks, 52-156 weeks, 52-104 weeks, or 104-208 weeks, after the treatment.

60. The method of any one of claims 1 to 59, wherein the WOMAC pain scores, WOMAC stiffness scores, WOMAC physical function scores, and / or the WOMAC stiffness scores, or KOOS scores are measured as least squares mean (LSM) scores.

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