Treating Patients at Risk for Rapid Osteoarthritis Progression

Abstract

The present invention relates to active compounds, particularly FGF-18 compounds, for use in the treatment of patients affected by cartilage disorders, preferably osteoarthritis (OA), particularly those at risk of rapid progression of the disorder.

Description

[Technical field]

[0001] The present invention relates to active compounds, in particular FGF-18 compounds, for use in the treatment of patients affected by cartilage disorders, preferably osteoarthritis (OA), particularly those at risk of rapid progression of the disorder. [Background technology]

[0002] Cartilage damage broadly refers to diseases characterized by the development of metabolic abnormalities in connective tissues, manifesting as pain, stiffness, and limited movement in affected body parts. These damages may be due to pathology or the result of trauma or injury. Cartilage damage specifically includes osteoarthritis (OA), cartilage injuries (including sports-related cartilage and joint damage, and surgical injuries such as microfractures). Mature cartilage has a limited ability to repair itself, especially because mature chondrocytes have little ability to proliferate and because blood vessels are absent. In addition, cartilage is poorly nitrified and has low oxygen tension.

[0003] OA is a progressive cartilage disorder that may be asymptomatic with minimal structural changes in the joint in early stages, but usually progresses to more advanced (moderate and severe) stages. The structural changes in OA are primarily characterized by progressive erosion and loss of articular cartilage, with emergence or increasing symptoms of stiffness and pain. The most common way of classifying osteoarthritis is by use of the Kellgren-Lawrence (KL) grading scale, which is described herein. Briefly, the KL grading scale defines five stages (from "0": none to "4": severe) based on radiographic analysis of the structural defects of the joint.

[0004] There are no commercially available medications that can reverse or slow cartilage damage (see Lotz, 2010). However, treatment options exist to manage clinical symptoms, which may vary depending on the severity or stage of the disease. Early stage treatments mostly include physical therapy, lifestyle changes (e.g., increased physical activity), and supportive devices. However, as osteoarthritis progresses to mild or moderate stages, clinical symptoms may worsen, necessitating the use of painkillers (e.g., nonsteroidal anti-inflammatory drugs). These are effective in relieving osteoarthritis pain and joint swelling and inflammation, but their use may be limited by gastric irritation. In severe or later stages, stronger painkillers may be useful, but surgery may still be required in some cases.

[0005] When surgery is necessary, the standard procedure is age-dependent and ranges from total joint replacement, or implantation of cartilage fragments, or bone marrow stimulation techniques (such as microfracture). Tibial or femoral osteotomy (rebalancing wear on the joint by removing bone) may help maintain an active lifestyle and postpone the need for total joint replacement. Total joint replacement can alleviate symptoms of advanced osteoarthritis, but generally requires the subject to change their lifestyle and / or activity level. Replacing damaged cartilage (especially articular cartilage) caused by injury or disease is a major challenge for physicians, and available surgical treatment procedures are not entirely predictable and are considered effective for only a limited period of time. Microfracture is a common procedure that involves invading the subchondral bone to promote cartilage colonization by stem cell-derived bone marrow. However, it has been shown that this technique does not adequately repair cartilage defects, and the new cartilage formed is primarily fibrocartilage, resulting in poor or altered function and biomechanics. In fact, fibrocartilage does not have the same durability and may not attach properly to the surrounding hyaline cartilage. For this reason, newly synthesized fibrocartilage may be more easily damaged (expected time frame: 5-10 years).

[0006] Therefore, the majority of younger subjects either do not seek surgery or are counseled to postpone surgery for as long as possible.

[0007] It is well known that disease progression is inconsistent among patients with knee OA and that multiple factors are associated with the risk of rapid progression. The rate of joint space narrowing, i.e., the rate at which cartilage thinning occurs, is one good indicator of the progression of the disease, but data must be collected over a period of time before any conclusions or predictions can be made. In clinical trials, several parameters measured at baseline, i.e., before any medication is administered, have been correlated with the risk of rapid progression of the disorder. In particular, OA defined by radiography at baseline with KL grade ≥2 has been associated with progression of the disorder (Guermazi et al., 2015). Joint space width (JSW) measured at baseline, especially medial compartment joint space width (mJSW), has been considered a strong predictor inversely correlated with the rate of progression of knee OA (Pelletier et al., 2007). Consistent with that, medial JSW value at baseline is also a strong predictor of total knee replacement. In addition, there is evidence that knee pain is not only a consequence of structural deterioration in osteoarthritis (OA) but also contributes to structural progression. Joint pain (which can be assessed by the WOMAC index) has been further identified as another strong predictor of structural progression in OA, with subjects experiencing persistent knee pain with Kellgren-Lawrence grade ≥2 indicating an increased risk of progressive OA (Wang et al., 2018).

[0008] Patients at risk for rapid progression of this cartilage damage may be forced to undergo surgery and may only find relief from pain medication for a short period of time.

[0009] Therefore, new therapeutic strategies are needed, especially for treating patients at risk of rapid progression of cartilage damage, that would limit the structural progression of this damage and ideally help manage the increasing pain associated with OA. Summary of the Invention

[0010] The present invention relates to an active compound, preferably an FGF-18 compound, for use in the treatment of a subject with cartilage damage, the subject presenting a risk of rapid progression of said cartilage damage. As more fully defined herein, a patient is considered to be at risk of rapid progression of cartilage damage when he or she presents a combination of the following two parameters: (a) significant structural defects of the joints and (b) intolerable joint pain.

[0011] The present invention further relates to a method of treating a subject having a cartilage disorder, the method comprising: a) determining whether said subject exhibits at least one significant structural defect of at least one joint, wherein said significant structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) less than 3.5 mm, preferably between 1.5 mm and 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; b) obtaining an assessment of the subject's level of joint pain, preferably, said level of joint pain is assessed based on a WOMAC pain score, a VAS pain score, an NRS score, or a KOOS score; c) i. at least one significant structural defect in at least one joint; and ii. Unbearable joint pain selecting a patient having d) administering to the selected patient an active compound, preferably an FGF-18 compound.

[0012] The invention further relates to a method of selecting subjects with cartilage disorders for inclusion in a treatment or clinical trial with an active compound based on their likelihood of being susceptible to said treatment, comprising the steps of: a) determining whether said subject exhibits at least one significant structural defect of at least one joint, wherein said significant structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) less than 3.5 mm, preferably between 1.5 mm and 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; b) obtaining an assessment of the subject's level of joint pain, preferably, said level of joint pain is assessed based on a WOMAC pain score, a VAS pain score, an NRS score, or a KOOS score; c) selecting said susceptible subjects as suitable for said treatment or clinical trial.

[0013] The present invention further relates to a method for determining a placebo effect in a clinical trial, preferably said clinical trial involving treating a cartilage disorder in a subject with an active compound, or during the treatment of a cartilage disorder with an active compound, comprising: a) determining whether said subject exhibits at least one significant structural defect of at least one joint, wherein said significant structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) less than 3.5 mm, preferably between 1.5 mm and 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; b) obtaining an assessment of the subject's level of joint pain, preferably, said level of joint pain is assessed based on a WOMAC pain score, a VAS pain score, an NRS score, or a KOOS score; c) determining the placebo effect from the results of steps a) and b).

[0014] definition

[0015] The term "active compound" as used herein means, for example, a compound selected from the group consisting of an FGF-18 compound, a BMP-2 enhancer, a BMP-7 enhancer, a GDF-5 enhancer, an FGFβ enhancer, an FGF-9 enhancer, a SOX-9 enhancer, a TGFβ inhibitor, a Wnt inhibitor, an anti-MMP-13 inhibitor, an anti-ADAMTS4 inhibitor or an anti-ADAMTS5 inhibitor, calcitonin, and any variant or fusion protein thereof.

[0016] The term "FGF-18 compound" or "FGF-18" as used herein refers to a protein that maintains at least one biological activity of the wild-type human FGF-18 protein (e.g., increases osteoblast activity (see WO98 / 1664) or increases chondrogenesis (see WO2008 / 023063)). FGF-18 can be in its naturally occurring mature form (SEQ ID NO:1) (corresponding to the amino acid sequence of SEQ ID NO:1 from residue 28 (Glu) to residue 207 (Ala)), or in its truncated form (such as sprifermin) (as shown in SEQ ID NO:2; having amino acid residues 2-170 of SEQ ID NO:2 corresponding to amino acid residues 28-196 of SEQ ID NO:1). The term "FGF-18 compound" also includes variants or mutants of the naturally occurring mature or truncated form of FGF-18, as well as fusion proteins (such as those disclosed in the EP17192467.3 patent family) that contain a (bio)active FGF-18 moiety coupled to a heterologous protein or compound. In such fusion proteins, the FGF-18 portion can be the native mature or truncated form of FGF-18, or a variant or mutant thereof.

[0017] The term "calcitonin" as used herein refers to salmon type calcitonin, a 32 amino acid peptide (SEQ ID NO:3) that has been demonstrated to have protective activity for both bone and cartilage.

[0018] The term "BMP-2" as used herein refers to a protein that promotes matrix synthesis to promote cartilage repair and plays a pivotal role in the differentiation of osteoprogenitor cells into osteoblasts, thus promoting bone and cartilage formation (Deng et al., 2018). The full-length native form of human BMP-2 is represented by SEQ ID NO: 4. One recombinant form of the BMP-2 protein is known as dibothermin alpha. The term "BMP-2" also includes variants thereof, or fusion proteins that contain a BMP-2 portion.

[0019] The term "BMP-7" as used herein refers to a protein known for its osteogenic properties and has been shown to have a potent anabolic effect on cartilage by promoting the synthesis of cartilage matrix components and increasing the synthesis of proteoglycans and collagen (Deng et al., 2018). The full-length native form of human BMP7 is represented by SEQ ID NO:5. One recombinant form of the BMP-2 protein is known as eptotermin alpha. The term also includes variants thereof, or fusion proteins containing a BMP-7 portion.

[0020] The term "GDF-5", also known as LAP-4 or radtermin, is used herein to refer to a protein that has, among other things, a stimulatory effect on matrix synthesis in human articular chondrocytes cultured in vitro from both healthy subjects and OA patients (Parrish et al., 2017). The full-length native form of human GDF-5 is represented by SEQ ID NO: 6. The term also includes variants thereof, or fusion proteins that include a GDF-5 portion.

[0021] The term "FGFβ" or "FGF-2" as used herein refers to a protein known for cartilage repair. It has also been shown to promote chondrocyte proliferation in immature rabbits (Ameye and Young, 2006). The full-length native form of human FGF-2 is represented by SEQ ID NO: 7. One recombinant form of the FGFβ protein is known as trafermin. The term also includes variants thereof or fusion proteins that contain an FGFβ portion.

[0022] The term "FGF-9" as used herein refers to a protein known to slow the deterioration of articular cartilage in OA subjects while having a rather negative effect on osteophyte formation (Zhou et al., 2016). The full-length native form of human FGF-9 is represented by SEQ ID NO: 8. The term also includes variants thereof or fusion proteins that include an FGF-9 portion.

[0023] The term "TGF-β" as used herein refers to TGF-beta, a protein belonging to the TGF-beta family that plays a crucial role in cartilage maintenance. TGF-β has been shown to be an enhancer of cartilage (Wang, 2014). The term also includes variants thereof, or fusion proteins that contain a TGF-β portion.

[0024] The term "SOX-9" enhancer is intended herein to mean a compound that enhances the production of SOX9. Indeed, SOX9 is a transcription factor that has been shown to be essential for the formation of cartilage extracellular matrix (ECM).

[0025] The term "Wnt inhibitor" is intended herein to mean a compound that interferes with the WNT pathway.

[0026] The term "anti-MMP13 inhibitor" is intended herein to mean a compound that inhibits the activity of matrix metalloproteinase 13 (MMP13), which is one of the important collagen type II degrading enzymes.

[0027] The term "anti-ADAMTS4 inhibitor or anti-ADAMTS5 inhibitor" is intended herein to mean a compound that inhibits the enzymatic activity of a disintegrin and metalloproteinase having thrombospondin motifs 4 or 5 (ADAMTS4 or ADAMTS5).

[0028] The term "SD" refers to standard deviation and is associated with the normal variation of any validation assay / system.

[0029] The term "cartilage disorder" as used herein includes disorders resulting from injury resulting from damage (such as traumatic injury, chondrosis, or arthritis). Non-limiting examples of cartilage disorders that may be treated by administering the compounds described herein include arthritis (such as osteoarthritis), cartilage damage, fractures that affect articular cartilage, or surgical procedures that affect articular cartilage (such as microfractures). Cartilage or joint degenerative diseases / disorders (chondrocalcinosis, polychondritis, relapsing polychondritis, ankylosing spondylitis, or costochondritis) are also included in this term. The International Society for Cartilage Regeneration has proposed an arthroscopic evaluation system for assessing the severity of cartilage defects. Grade 0: (normal) healthy cartilage; Grade 1: the cartilage has soft spots or blisters; Grade 2: small tears are visible in the cartilage; Grade 3: the lesion has deep tears (more than 50% of the cartilage layer); and Grade 4: tears in the cartilage exposing the underlying (subchondral) bone (see, for example, page 13 at www.cartilage.org / _files / contentmanagement / ICRS_evaluation.pdf).

[0030] The term "osteoarthritis" is intended herein to mean the most common form of arthritis. The term "osteoarthritis" encompasses both primary and secondary osteoarthritis (see, for example, The Merck Manual, 17th Edition, p. 449). The most common way to classify / grade osteoarthritis is to use the Kellgren-Lawrence X-ray grading scale (see table below). Osteoarthritis can result from the destruction of cartilage. Pieces of cartilage can break off, causing pain and swelling in the joints between the bones. Over time, the cartilage can wear away completely, causing the bones to rub against each other. Osteoarthritis can affect any joint, but it usually involves the hands and weight-bearing joints (hips, knees, legs, spine). In a preferred example, the osteoarthritis can be knee osteoarthritis or hip osteoarthritis. Osteoarthritis is one of the preferred cartilage disorders that can be treated by administering the compounds according to the present invention.

[0031] The Kellgren-Lawrence (KL) radiographic grading scale for osteoarthritis is described below.

[0032] [Table 1]

[0033] Grades 1 and 2 can be considered less severe forms of the disease, whereas grades 3 and 4 can be considered more severe forms of the disease.

[0034] The term "cartilage damage" as used herein refers to cartilage damage or cartilage injury, which in particular leads to further accidents or surgery (e.g. microfracture surgery).The term "cartilage damage" includes cartilage or osteochondral fractures, meniscus injuries, and the term microfracture.Also considered in this definition are sports-related injuries or sports-related wear and tear of joint tissue.

[0035] The term "joint space width (JSW)" as used herein means joint space width measured by x-ray using a standardized technique (such as a fixed flexion protocol as disclosed in Hunter et al., 2009). X-ray JSW measurement is a recognized endpoint accepted by the European Medicines Agency and the United States Food and Drug Administration for use in efficacy studies in OA. The term "medial joint space width (mJSW)" as used herein means joint space width measured by x-ray at the medial compartment of a joint, particularly the knee. The term "lateral joint space width (lJSW)" as used herein means joint space width measured by x-ray at the lateral compartment of a joint, particularly the knee. The term "minimal joint space width (miniJSW)" as used herein means the minimum joint space width measured by x-ray at the medial or lateral compartment of a joint, particularly the knee.

[0036] The term "thin cartilage" refers to cartilage with a JSW of 3.5 mm or less.

[0037] The term "thick cartilage" refers to cartilage with a JSW greater than 3.5 mm.

[0038] The term "progression of cartilage damage" as used herein refers to the increase in structural defects of the cartilage and / or joint affected by cartilage damage, particularly joint space narrowing (JSN), and the appearance or increase in clinical symptoms (such as pain, disability, and joint stiffness) as a result of the progression of cartilage damage over time.With regard to OA, the progression of this damage can be observed and evaluated, for example, using the KL rating scale defined above.

[0039] The expression "at risk of further structural and symptomatic progression of cartilage damage" is also used herein in the context of a subject to be treated as "at risk of rapid progression of cartilage damage", meaning the tendency of said subject to show rapid progression of cartilage damage as a result of the natural progression of this damage over time without treatment. These expressions therefore exclude structural progression of cartilage damage that may be due to trauma or injury that is not the result of cartilage damage.

[0040] The terms "subject" or "patient" refer to both human and non-human animals. The term non-human includes mammals, such as rodents (including mice), rabbits, cats, dogs, horses, cows, sheep, primates, etc.

[0041] The expression "significant structural defect of the joint" means herein a structural defect of the joint, such as a significant minimum joint space width (miniJSW) or a significant KL grade, in particular a minimum joint space width (miniJSW) of less than 3.5 mm, preferably between 1.5 mm and 3.5 mm, a KL grade of 2 to 4, preferably a KL grade of 3. More preferred, a preferred significant structural defect of the joint is a minimum joint space width (miniJSW) of 1.5 mm to 3.5 mm.

[0042] The expression "unbearable joint pain" herein means that joint pain is at a significant level.Pain level can be evaluated using methods commonly used in the field, especially in the context of clinical trials of OA patients.Non-limiting examples of such methods include patient-reported outcome measures, such as NRS score, VAS pain score, KOOS score, and WOMAC pain score, as defined below.

[0043] In the context of the present invention, a WOMAC pain score of 35 or more, preferably 40 or more, indicates intolerable joint pain.

[0044] In the context of the present invention, a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale) indicates intolerable joint pain (Williamson et al., 2005).

[0045] In the context of the present invention, an NRS score of 4 or greater (on a scale of 0 to 11) indicates intolerable joint pain (Williamson et al., 2005).

[0046] In the context of the present invention, a KOOS score of 40 or greater (on a scale of 0-100) indicates intolerable joint pain (Roos et al., 2003).

[0047] "WOMAC index" refers herein to the WOMAC® 3.1 index ("WOMAC" means the 3.1 version of the "Western Ontario-McMaster University Osteoarthritis Index"). This index is a self-administered questionnaire that evaluates three dimensions of pain in knee and hip osteoarthritis: pain, disability, and joint stiffness. It consists of a questionnaire that includes 24 items (5 items for pain, 2 items for stiffness, and 17 items for physical function) when applied to the evaluation of pain and dysfunction associated with cartilage damage (see Bellamy et al., 1988; Wolfe, 1999). It is a well-known instrument that is widely used, especially in the evaluation of the severity of OA. The latest version of this instrument (WOMAC® 3.1) is available in over 100 language forms, and can therefore be easily applied to any subject, regardless of his native language.

[0048] "WOMAC total score" or "WOMAC score" herein refers to the sum of scores obtained by one particular patient who completed the WOMAC index questionnaire ("WOMAC" stands for "Western Ontario-McMaster University Osteoarthritis Index"), which measures pain based on five items (WOMAC pain score), function based on two items (WOMAC function score), and stiffness based on 17 items (WOMAC stiffness score). Each item is scored based on the response (none = 0 points, mild = 1 point, moderate = 2 points, severe = 3 points, extreme = 4 points). The WOMAC total score corresponds to the sum of the scores obtained on the 24 items. The WOMAC pain score corresponds to the sum of the scores obtained on the five items related to pain, which is sometimes then normalized to a 0-100 scale (i.e., the WOMAC pain score is multiplied by 5). Preferably, in the context of the present invention, the indicated WOMAC pain score corresponds to the WOMAC pain score normalized to a scale of 0 to 100 points. The WOMAC function score corresponds to the sum of the scores obtained in the two items related to function, optionally subsequently normalized to a scale of 0 to 100 points (i.e. multiplied by 100 / 8). Preferably, in the context of the present invention, the indicated WOMAC function score corresponds to the WOMAC pain score normalized to a scale of 0 to 100 points. The WOMAC stiffness score corresponds to the sum of the scores obtained in the 17 items related to function, optionally subsequently normalized to a scale of 0 to 100 points (i.e. multiplied by 100 / 68). Preferably, in the context of the present invention, the indicated WOMAC stiffness score corresponds to the WOMAC stiffness score normalized to a scale of 0 to 100 points.

[0049] By "visual analog scale for pain (VAS pain)" herein is meant a self-administered questionnaire well known in the art and discussed in detail by Hawker et al.

[0050] By "Numerical Rating Scale for Pain (NRS Pain)" herein is meant a self-administered questionnaire that is well known in the art and discussed in detail by Hawker et al.

[0051] "Knee Injury and Osteoarthritis Outcome Score (KOOS)" as used herein refers to a self-administered questionnaire that includes five separately scored subscales: pain, other symptoms, function in daily living (ADL), function in sports and recreation (Sport / Rec), and knee-related quality of life (QOL). Preferably, this expression refers to the use of questionnaires available in different languages, as described in Roos et al., 1998; Roos et al., 2003; Collins et al., 2016.

[0052] The term "cartilage thinning" as used herein means a decrease in cartilage volume and / or thickness as a consequence of progression of cartilage damage over time without treatment. In the context of the present invention, cartilage thinning can be assessed by utilizing magnetic resonance imaging (MRI) measurements to measure cartilage thickness at different time points, including the outer cartilage volume (also called LFTC), inner cartilage volume (also called MFTC), total cartilage volume (also called LFTC+MFTC), and new overall average cartilage thickness.

[0053] The phrase "limiting cartilage thinning associated with cartilage damage" with respect to the therapeutic effect of an FGF-18 compound means that cartilage thinning over time upon treatment of a subject with the compound is reduced compared to the cartilage thinning that would or would likely occur over time without treatment, which can be assessed, for example, based on the results of a clinical trial.

[0054] The phrase "preventing cartilage thinning associated with cartilage damage," when describing the therapeutic effect of an FGF-18 compound, means that cartilage thinning over time upon treatment of a subject with the compound is inhibited compared to the thickness of the subject's cartilage prior to the treatment.

[0055] The expression "clinical symptoms associated with cartilage damage" means herein clinical symptoms (pain, disability, and joint stiffness) that are the result of cartilage damage. Clinical symptoms associated with the progression of cartilage damage and clinical symptoms associated with the progression of cartilage damage can be evaluated using the WOMC index as defined herein.

[0056] Pain can be assessed by the WOMAC pain score, with a WOMAC pain score of 20 or greater indicating moderate to severe pain, whereas a WOMAC pain score of 35 or greater indicates intolerable pain (Goggins et al., 2005). Similarly, disability and joint stiffness can be assessed by the WOMAC function score and WOMAC stiffness score, respectively.

[0057] The expression "clinical symptoms associated with the progression of cartilage damage over time" refers to symptoms that occur over time as a result of the natural progression of cartilage damage without treatment, including increasing pain, increasing disability, and increasing joint stiffness. An increase in WOMAC index over time indicates an increase in clinical symptoms. In particular, an increase in the subject's WOMAC pain score over time indicates an increase in pain. Similarly, an increase in WOMAC function score and WOMAC stiffness score over time indicates an increase in disability and joint stiffness, respectively.

[0058] The terms "limiting clinical symptoms associated with cartilage damage" and "limiting clinical symptoms associated with the progression of cartilage damage over time" with respect to the therapeutic effect of an FGF-18 compound mean that the clinical symptoms as defined above in a subject treated with the compound are reduced over time compared to the clinical symptoms without treatment.

[0059] The term "SD" refers to standard deviation and is associated with the normal variation of any validation assay / system.

[0060] The term "placebo" as used herein means a compound or composition devoid of any therapeutic activity.

[0061] The term "placebo effect" is to be understood herein as a change in structural defects or clinical symptoms due to administration of a placebo compared to baseline, i.e. compared to structural defects or clinical symptoms in the absence of any administration. The term "weak placebo effect" means a response intensity that is equivalent or only slightly changed (less than 20%) compared to the response intensity at baseline. The term "strong placebo effect" is to be understood herein as a change of more than 20% from baseline. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] The surprising findings of the present invention are based on different studies aimed at identifying potential subgroups related to different responses to treatment. The parameters used in these studies consisted of imaging techniques and patient-reported outcome measures (e.g. WOMAC score). JSW measurements were used as imaging markers of structural defects of the joint. The relationship between patient-reported outcome measures and / or imaging markers (e.g. JSW, clinical symptom changes) and clinical symptom variations was evaluated. The reason for this type of analysis was to identify combinations of markers that may predict 1) placebo response and / or 2) clinical outcome (especially with regard to cartilage repair and symptom improvement) for subjects treated with active compounds (e.g. FGF-18 compounds, BMP-2 enhancers, BMP-7 enhancers, GDF-5 enhancers, FGFβ enhancers, FGF-9 enhancers, SOX-9 enhancers, TGFβ inhibitors, Wnt inhibitors, anti-MMP-13 inhibitors, anti-ADAMTS4 inhibitors or anti-ADAMTS5 inhibitors, calcitonin and any variants or fusion proteins thereof). In particular, it was surprisingly found that a combination of structural defects and pain levels could be used to predict placebo effect (see experimental section and Figures 2 and 3).

[0063] The present invention is based on the finding that among a wide variety of subjects affected by OA (particularly knee OA), those at risk of further progression of the structure and symptoms of cartilage damage, i.e. at risk of rapid progression of cartilage damage, respond particularly well to treatment with active compounds (particularly FGF-18 compounds).

[0064] As defined in more detail herein, a patient is considered to be at risk for rapid progression of cartilage damage when the patient exhibits a combination of the following two parameters: (a) significant structural defects of the joint, and (b) intolerable joint pain.

[0065] Fibroblast growth factor 18 (FGF-18) is a member of the FGF family of proteins and is closely related to FGF-8 and FGF-17. FGF-18 has been shown to be a proliferation agent for chondrocytes and osteoblasts (Ellsworth et al., 2002; Shimoaka et al., 2002; Gigout et al., 2017). FGF-18 has been proposed for the treatment of cartilage disorders (e.g. osteoarthritis and cartilage damage) either alone (WO2008 / 023063) or in combination with hyaluronic acid (WO2004 / 032849).

[0066] Sprifermin is a truncated form of human FGF-18 and is being investigated in clinical trials for treating both osteoarthritis and cartilage damage (see, e.g., NCT01033994, NCT00911469, and NCT01066871). The current dosing regimen for Sprifermin is once a week for three weeks (one treatment cycle), and the drug is administered via intra-articular injection. This treatment cycle can be repeated. This dosing regimen is described in WO2008 / 023063.

[0067] Interestingly, in subgroups of subjects at risk for rapid progression of osteoarthritis (also referred to herein as at-risk subgroups, at-risk subjects, or at-risk patients), treatment with FGF-18 compounds has been shown to limit, or even inhibit, the progression of cartilage thinning and limit the clinical symptoms (particularly pain) associated with said cartilage damage.

[0068] Interestingly, even 18 months after the last administration of therapeutic agent, patients from the at-risk subgroup treated with FGF-18 show improvement in clinical symptoms (especially pain) compared to the time of the last injection. In other words, even after the end of treatment, the clinical outcome of the at-risk subgroup of subjects treated with FGF-18 compounds continues to improve. In contrast, during the same period, the at-risk subgroup of subjects treated with placebo shows worsening or increasing clinical symptoms (especially pain). This suggests that FGF-18 compounds significantly improve clinical outcomes in at-risk subjects. Overall, the therapeutic effect obtained with FGF-18 compounds in the at-risk subgroup of subjects defined herein seems to clarify a special clinical situation that has not been investigated before.

[0069] The present invention relates to active compounds for use in a subject with a cartilage disorder, the subject exhibiting a risk of rapid progression of said cartilage disorder.

[0070] In the context of the present invention, the active compound is selected from the group consisting of an FGF-18 compound, a BMP-2 enhancer, a BMP-7 enhancer, a GDF-5 enhancer, an FGFβ enhancer, an FGF-9 enhancer, a SOX-9 enhancer, a TGFβ inhibitor, a Wnt inhibitor, an anti-MMP-13 inhibitor, an anti-ADAMTS4 inhibitor or an anti-ADAMTS5 inhibitor, calcitonin and any variant or fusion protein thereof.

[0071] Preferably, the active compound is an FGF-18 compound as defined herein.

[0072] In the context of the present invention, a subject is considered to be at risk for rapid progression of cartilage damage if said subject exhibits a significant difference between the following two parameters: (a) Significant structural defects of the joint; (b) A combination of intolerable joint pain It is time to show that.

[0073] In the context of the present invention, preferred significant structural defects of the joint are selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm, preferably between 1.5 mm and 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3. More preferably, preferred significant structural defects of the joint are a minimum joint space width (miniJSW) of 1.5 mm to 3.5 mm.

[0074] In the context of the present invention, preferred intolerable joint pain is selected from the group consisting of joint pain corresponding to a WOMAC joint pain score of at least 35, preferably at least 40, joint pain corresponding to a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale), joint pain corresponding to an NRS score of 4 or more (on a scale of 0 to 11), and joint pain corresponding to a KOOS score of 40 or more (on a scale of 0 to 100).

[0075] Preferably, a subject is considered to be at risk of rapid progression of said cartilage damage if said subject: (a) A significant structural defect of the joint selected from the group consisting of a minimum joint space width (miniJSW) less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; (b) joint pain corresponding to a WOMAC joint pain score of at least 35, preferably at least 40 It is time to show that.

[0076] More preferably, a subject is considered to be at risk for rapid progression of said cartilage damage if said subject: (a) minimum joint space width (miniJSW) less than 3.5 mm, preferably 1.5 mm to 3.5 mm; (b) joint pain corresponding to a WOMAC joint pain score of at least 35, preferably at least 40 It is time to show that.

[0077] Even more preferably, a subject is considered to be at risk of rapid progression of said cartilage damage if said subject: (a) Minimum joint space width (miniJSW) is 1.5 mm to 3.5 mm. (b) joint pain corresponding to a WOMAC joint pain score of at least 40 points It is time to show that.

[0078] In one preferred embodiment, the present invention relates to an FGF-18 compound for use in treating a subject with a cartilage disorder, the subject comprising: (a) Minimum joint space width (miniJSW) is 1.5 mm to 3.5 mm. (b) joint pain corresponding to a WOMAC joint pain score of at least 40 points This shows that.

[0079] The present invention further relates to a method of treating a subject having a cartilage disorder, the method comprising: a) determining whether said subject exhibits at least one significant structural defect of at least one joint, wherein said significant structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) less than 3.5 mm, preferably between 1.5 mm and 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; b) obtaining an assessment of the subject's level of joint pain, preferably, said level of joint pain is assessed based on a WOMAC pain score, a VAS pain score, an NRS score, or a KOOS score; c) i. at least one significant structural defect in at least one joint; and ii. Unbearable joint pain selecting a patient having d) administering to the selected patient an active compound, preferably an FGF-18 compound.

[0080] In the context of the present invention, a WOMAC pain score of 35 or more, preferably 40 or more, indicates intolerable joint pain.

[0081] In the context of the present invention, a VAS pain score of 4 or greater (on a numerical scale) or 40 or greater (on a 100 mm scale) indicates intolerable joint pain.

[0082] In the context of the present invention, an NRS score of 4 or greater (on a scale of 0 to 11) indicates intolerable joint pain.

[0083] In the context of the present invention, a KOOS score (on a scale of 0 to 100) of 40 or greater indicates intolerable joint pain.

[0084] Preferably, the present invention relates to a method of treating a subject with a cartilage disorder, the method comprising: a) determining whether said subject exhibits at least one significant structural defect in at least one joint, wherein said significant structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) less than 3.5 mm, preferably between 1.5 mm and 3.5 mm; b) obtaining an assessment of the subject's level of joint pain, preferably wherein the level of joint pain is assessed based on the WOMAC pain score; c) i. at least one significant structural defect in at least one joint; and ii. Unbearable joint pain selecting a patient having d) administering to the selected patient an active compound, preferably an FGF-18 compound.

[0085] Preferably, in the context of the present invention, the active compound (preferably an FGF-18 compound) for use or in the therapeutic method as defined above limits or prevents the progression of cartilage thinning associated with said cartilage damage. Preferably, in the context of the present invention, the active compound (preferably an FGF-18 compound) for use or in the therapeutic method as defined above limits or prevents clinical symptoms associated with said cartilage damage. Preferably, the clinical symptoms are selected from the list consisting of pain, impaired movement, and joint stiffness associated with said cartilage damage. More preferably, the clinical symptoms are pain associated with said cartilage damage. In a preferred embodiment, the clinical symptoms are selected from the list consisting of increasing pain, impaired movement, and joint stiffness associated with the progression of said cartilage damage. More preferably, the clinical symptoms are increasing pain associated with the progression of said cartilage damage. Preferably, in the context of the present invention, the active compound (preferably an FGF-18 compound) for use or in the therapeutic method as defined above limits or prevents the progression of cartilage thinning in a subject and the clinical symptoms associated with said cartilage damage.

[0086] In another aspect, the present invention relates to an active compound, preferably an FGF-18 compound, for use in preventing or treating a clinical symptom associated with cartilage damage in a subject with said cartilage damage, the subject being at risk of rapid progression of said cartilage damage. In a preferred embodiment, the clinical symptom is selected from the list consisting of pain, impaired movement, and joint stiffness associated with said cartilage damage. More preferably, the clinical symptom is pain associated with said cartilage damage. In a preferred embodiment, the clinical symptom is selected from the list consisting of increasing pain, impaired movement, and joint stiffness associated with the progression of said cartilage damage. More preferably, the clinical symptom is increasing pain associated with the progression of said cartilage damage.

[0087] In the context of the present invention, the preferred cartilage disorder is selected from osteoarthritis, cartilage trauma, fractures affecting articular cartilage, or surgical procedures (e.g. microfractures) affecting articular cartilage. Advantageously, the cartilage disorder is osteoarthritis, preferably knee or hip osteoarthritis.

[0088] Preferably, the FGF-18 compound is selected from the group consisting of a naturally occurring form of FGF-18 (SEQ ID NO:1), a mature form of naturally occurring FGF-18 (corresponding to the amino acid sequence from residue 28 (Glu) to residue 207 (Ala) of SEQ ID NO:1), a truncated form of FGF-18 (as shown in SEQ ID NO:2; having amino acid residues 2-170 of SEQ ID NO:2 corresponding to amino acid residues 28-196 of SEQ ID NO:1) (such as sprifermin) (also referred to herein as FGF-18(170 amino acids)). More preferably, the FGF-18 compound of the present invention is selected from the group consisting of a) a polypeptide comprising or consisting of a human FGF-18 mature form comprising residues 28-207-25 of SEQ ID NO:1, or b) a polypeptide comprising or consisting of FGF-18(170 amino acids) (SEQ ID NO:2).

[0089] Preferably, the FGF-18 compound is administered intra-articularly.

[0090] The FGF-18 compound should be administered in an effective dose and according to an appropriate dosing regimen, which can be tailored to the subject by the physician, taking into account, for example, sex, age, KL grade, or other parameters specific to the subject.

[0091] In a preferred embodiment, the FGF-18 compound is administered at a dose of 1-100 μg, or preferably 1-60 micrograms (μg), or preferably 3-50 μg, or preferably 5-40 μg, or preferably 10-30 μg per intra-articular administration of the FGF-18 compound. In a preferred embodiment, the treatment comprises administering the FGF-18 compound at a dose of about 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 μg per intra-articular administration. Preferred doses include 5, 10, 15, 20, 25, and 30 μg per intra-articular administration of the FGF-18 compound.

[0092] In yet another preferred embodiment, the FGF-18 compound is administered at a dose of 50-200 mcg / kg, preferably 80-120 mcg / kg, per intravenous administration of the FGF-18 compound. In a preferred embodiment, the treatment comprises administering the FGF-18 compound at a dose of 80, 90, 100, 110, or 120 mcg / kg per intravenous administration.

[0093] Preferably, the FGF-18 compound is administered according to a dosing regimen comprising at least one treatment cycle of at least two administrations, said two administrations being separated by 4, 5, 6, 7, 8, 9, or 10 days, preferably 7 days. Preferably, the dosing regimen comprises at least two treatment cycles of at least two administrations, said treatment cycles being separated by about 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, preferably 6 months.

[0094] In a preferred embodiment, the FGF-18 compound is administered intra-articularly at a dose of 100 μg per injection, once per week for 3 weeks, in a regimen comprising at least two treatment cycles, said treatment cycles being separated by about 10-14 months, preferably 12 months. In a further preferred embodiment, the FGF-18 compound is administered intra-articularly at a dose of 100 μg per injection, once per week for 3 weeks, in a regimen comprising at least four treatment cycles, said treatment cycles being separated by about 4-8 months, preferably 6 months.

[0095] The FGF-18 compound can be formulated as a pharmaceutical composition, i.e., with a 20 pharmaceutically acceptable carrier, excipient, etc. The definition of "pharmaceutically acceptable" is meant to encompass any carrier, excipient, etc. that does not interfere with the effectiveness of the biological activity of the active ingredient and is not toxic to the patient to whom it is administered. For example, for parenteral administration, the active protein can be formulated in a unit dosage form for injection in a vehicle (such as saline, dextrose solution, serum albumin, and Ringer's solution). Formulations for intra-articular application will meet most of the conditions that also apply to other injectable formulations; that is, these formulations must be sterile and compatible with the physiological conditions at the site of application (e.g., knee joint, synovial fluid). The excipients used for intra-articular injections can also be present in other injectable formulations, e.g., for intramuscular or subcutaneous application. Such formulations of FGF-18 compounds, including at least one further carrier, excipient, etc. that are 20 pharmaceutically acceptable, are also referred to herein as "FGF-18 compositions" or "FGF-18 formulations." The above-mentioned "FGF-18 compositions" or "FGF-18 formulations" are also useful in the context of the present specification.

[0096] The invention further relates to a method of selecting subjects with a cartilage disorder for inclusion in a treatment or clinical trial with an active compound based on the likelihood that they will be sensitive to said treatment, comprising: a) determining whether said subject exhibits at least one significant structural defect of at least one joint, wherein said significant structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) less than 3.5 mm, preferably between 1.5 mm and 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; b) obtaining an assessment of the subject's level of joint pain, preferably, said level of joint pain is assessed based on a WOMAC pain score, a VAS pain score, an NRS score, or a KOOS score; c) selecting said susceptible patients as suitable for said treatment or clinical trial.

[0097] Preferably, according to the method, a) A significant structural defect selected from the group consisting of a minimum joint space width (miniJSW) less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; b) intolerable joint pain selected from the group consisting of joint pain corresponding to a WOMAC joint pain score of at least 35, preferably at least 40, joint pain corresponding to a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale), joint pain corresponding to an NRS score of 4 or more (on a scale of 0 to 11), and joint pain corresponding to a KOOS score of 40 or more (on a scale of 0 to 100). The presence of indicates that the subject will be susceptible to said treatment.

[0098] The present invention further relates to a method for determining a placebo effect in a clinical trial, preferably said clinical trial involving treating a cartilage disorder in a subject with an active compound, or during the treatment of a cartilage disorder with an active compound, comprising: a) determining whether said subject exhibits at least one significant structural defect of at least one joint, wherein said significant structural defect is preferably selected from the group consisting of a minimum joint space width (miniJSW) less than 3.5 mm, preferably between 1.5 mm and 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; b) obtaining an assessment of the subject's level of joint pain, preferably, said level of joint pain is assessed based on a WOMAC pain score, a VAS pain score, an NRS score, or a KOOS score; c) determining the placebo effect from the results of steps a) and b).

[0099] Preferably, according to the method, a) A significant structural defect selected from the group consisting of a minimum joint space width (miniJSW) less than 3.5 mm, preferably 1.5 mm to 3.5 mm, and a KL grade of 2 to 4, preferably a KL grade of 3; b) intolerable joint pain selected from the group consisting of joint pain corresponding to a WOMAC joint pain score of at least 35, preferably at least 40, joint pain corresponding to a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale), joint pain corresponding to an NRS score of 4 or more (on a scale of 0 to 11), and joint pain corresponding to a KOOS score of 40 or more (on a scale of 0 to 100). The presence of predicts a smaller placebo effect.

[0100] More preferably, according to the method, a minimum JSW of more than 3.5 mm and a WOMAC pain score of less than 35, preferably less than 40, predicts a strong placebo effect. Conversely, a minimum JSW of 3.5 mm or less and a WOMAC pain score of less than 35, preferably less than 40, predicts no placebo effect or a weak placebo effect. [Brief description of the drawings]

[0101] [Figure 1] FIG. 1: Scheme of the dosing regimen utilized for FGF-18 compounds in the prospective study.

[0102] [Diagram 2] Figure 2: Mean differences observed in WOMAC pain scores between patients treated with sprifermin and those treated with placebo in different subgroups at 2 and 3 years in the prospective study.

[0103] [Diagram 3] Figure 3: Change in WOMAC total score between patients treated with sprifermin and patients treated with placebo in different subgroups at 3 years of the prospective study.

[0104] [Figure 4] Figure 4: Changes in MRI total cartilage thickness (tCT) over time during (26, 52, 78, 104 and 156 weeks) and after treatment (156 weeks) in subjects treated with different dosing schedules of FGF-18 compounds and placebo in the entire prospective study (A) and in patients at risk for rapid OA progression (B). A: Changes in MRI total cartilage thickness over time in the entire prospective study. B: Changes in MRI total cartilage thickness over time in subjects with a total knee minimum joint space width (shown as mJSW in the figure) of 1.5-3.5 mm and a WOMAC pain score of 40-90 (N=171).

[0105] [Diagram 5] Figure 5: Changes over time during (26, 52, 78, 104 and 156 weeks) and after (156 weeks) treatment in the WOMAC total score for pain and function assessment in subjects treated with different dosing regimens of FGF-18 compounds and placebo in the entire prospective study (A) and in specific patient subgroups (B). A: WOMAC total score in the entire prospective study. B: WOMAC total score in subjects with a total knee minimum joint space width (shown as mJSW in the figure) between 1.5 and 3.5 mm and a WOMAC pain score between 40 and 90.

[0106] [Figure 6] Figure 6: Treatment with FGF-18 compounds has a significant and increasing effect on pain and function in subjects at risk during treatment. Mean differences observed in subjects' WOMAC total score after treatment with FGF-18 compounds (FGF-18 compounds: 100 μg × 4 regimen) compared to placebo in the entire prospective study (ITT, meaning intention to treat) and in the subgroups of subjects with a WOMAC pain score of 40 or more (independently of other criteria), with a minimum > 3.5 mm (independently of other criteria), with a total knee minimum joint space width (shown as mJSW in the figures) between 1.5 and 3.5 mm and a WOMAC pain score between 40 and 90 points.

[0107] [Figure 7] Figure 7: The effect of treatment with FGF-18 compounds on pain and function in at-risk subjects is maintained for at least 1 year after the end of treatment (1 year after the last injection cycle). Mean differences observed in subjects' WOMAC total scores 1 year after the end of treatment with FGF-18 compounds (FGF-18 compounds: 100 μg × 4 regimen) compared to placebo (1 year after the last dose of FGF-18 compounds) in the entire prospective study (ITT, meaning intention to treat) and in the subgroups of subjects with a WOMAC pain score of 40 or more (independently of other criteria), a total knee minimum joint space width (shown as mJSW in the figures) of > 3.5 mm (independently of other criteria), and a total knee minimum joint space width (shown as mJSW in the figures) of 1.5-3.5 mm and a WOMAC pain score of 40-90 points.

[0108] Array description:

[0109] SEQ ID NO: 1: Amino acid sequence of native human FGF-18.

[0110] SEQ ID NO: 2: Amino acid sequence of recombinant truncated FGF-18 (trFGF-18).

[0111] SEQ ID NO: 3: Amino acid sequence of salmon calcitonin.

[0112] SEQ ID NO: 4: Amino acid sequence of human BMP-2.

[0113] SEQ ID NO: 5: Amino acid sequence of human BMP-7.

[0114] SEQ ID NO: 6: Amino acid sequence of human GDF-5.

[0115] SEQ ID NO: 7: Amino acid sequence of human FGFβ.

[0116] SEQ ID NO: 8: Amino acid sequence of human FGF-9. EXAMPLES

[0117] statistical methods

[0118] Repeated measures analysis of variance (ANOVA, using PROC MIXED in SAS) on absolute change from baseline was used to assess the effect of treatment on the primary endpoint across varying doses (factors included baseline value, treatment group, time, and country, with treatment by time point as an interaction). Primary effect analyses consisted of examining the linear dose relationship and overall treatment effect at 2 years. The level of significance was set at 5% two-sided for both tests. Pairwise comparisons (sprifermin vs placebo and between sprifermin dose and treatment group) were performed within the context of this modelling framework. For each pairwise comparison, the difference between treatments is presented along with the corresponding 95% confidence interval (CI) and p-value. The same ANOVA model used for the primary endpoint was used to evaluate treatment effects at each time point and over time for continuous secondary endpoints, including MRI endpoints, WOMAC endpoints (total score, pain score, function score, and stiffness score), and radiographic endpoints. Logistic regression was used to compare treatment effects for binary efficacy endpoints, including OMERACT-OARSI response rate. Point estimates for each pairwise comparison are presented, along with corresponding 95% CI and p-values.

[0119] Pain and function assessment

[0120] The WOMAC is a validated instrument used to assess symptom change in clinical OA studies. This clinical score was developed in 1981 and is considered a valid instrument by both clinical investigators and regulatory agencies. The WOMAC has been widely used in clinical studies in hip and knee OA and has been extensively validated.

[0121] Subjects had to self-answer all 24 questions (i.e., 5 for pain, 2 for stiffness, and 17 for physical function assessment) using the 11-box NRS rating (categories 0 to 10) with reference to the past 48 hours for Example 1, and the 100 mm VAS (visual analog scale; each question is scored from 0 to 100) with reference to the past 24 hours for Example 2. Different forms of the questionnaire exist for the left and right knees. To reduce confounding of WOMAC responses with symptoms of the contralateral knee, subjects used the WOMAC questionnaire specific to the targeted knee.

[0122] To administer the questionnaire, the instructions for the WOMAC 3.1 index in both Examples 1 and 2 were followed.

[0123] Another instrument for assessing pain and function is the KOOS (Knee Injury and Osteoarthritis Outcome Score; Collins et al., 2016 ).

[0124] X-ray evaluation of JSW

[0125] Changes in JSW measured by X-rays are a recognized endpoint accepted by the European Medicines Agency and the United States Food and Drug Administration for use in efficacy studies in OA. JSW was measured using standardized techniques. X-rays were also used to assess the KL grade.

[0126] qMRI assessment

[0127] The primary endpoint for the DBPC treatment phase was the change from baseline in total femoro-tibial cartilage thickness, assessed at 2 years in the mITT. Total femoro-tibial cartilage thickness was calculated in two ways: 1. Average cartilage thickness (total volume divided by total surface area) 2. Total cartilage thickness (sum of cartilage thickness in the medial and lateral compartments).

[0128] Repeated measures analysis of variance (ANOVA) on absolute change from baseline was used to assess the effect of treatment on the primary endpoint across varying doses (with treatment group, time point, and (pooled) country as fixed factors, baseline value as covariate, and treatment by time point as interaction). Repeated measures over time were accounted for by the use of an "unstructured" covariate pattern.

[0129] Pairwise comparisons of absolute change from baseline in cartilage thickness (treatment with compound vs placebo) were performed within the context of the modelling framework described above. For each pairwise comparison, the difference between treatments and the corresponding 95% confidence intervals (CIs) and p-values ​​are presented. For all time point combinations (i.e. baseline values, treatment, time point, treatment by time point interaction, country) and for all time points, p-values ​​(corresponding to fixed effects type 3 tests) of all covariates in the original "overall" model are reported. Overall and for each time point, estimated coefficients, p-values ​​and 95% CIs are presented for (i) the dose relationship (linear trend) and (ii) each pairwise comparison between dose levels and placebo.

[0130] To assess the robustness of the primary results, we used the PP analysis set to repeat tests for linear dose relationships and overall treatment effects. For the mITT analysis set, we performed nonparametric analyses of ordered data for cartilage thickness in all femoro-tibial joints as an alternative to the primary analysis. Data were ordered by magnitude of absolute change from baseline over 2 years during the DBPC treatment phase using rank transformation.

[0131] Example 1: Clinical effects on total cartilage thickness and pain and function in subjects treated with FGF-18 as measured by MRI and WOMAC total score

[0132] The FGF-18 compound used as a therapeutic agent in this example is Sprifermin (as defined in the "Definitions" section). Two strengths of Sprifermin were provided for the study: 30 μg and 100 μg. Sprifermin was provided as a white, sterile, lyophilized powder in 3 ml glass vials. Each vial contained 31.5 μg or 105 μg of Sprifermin active agent, and these amounts included a 5% surplus, allowing for the extraction of 30 μg or 100 μg of Sprifermin active agent, respectively, after reconstitution with 0.9% w / v sodium chloride injection (referred to herein as "saline solution"). The formulation excipients were sodium phosphate buffer (pH 7.2), sodium hydroxide, O-phosphonic acid, sucrose, and poloxamer 188. The volume administered for all treatment groups was 2 ml.

[0133] This study was based on a prospective study (see study EMR700692-006).

[0134] The study enrolled adult subjects of either sex with primary femoro-tibial OA according to American College of Rheumatology (ACR) clinical and radiographic criteria, Kellgren-Lawrence grade (KLG) 2 or 3, and a total knee joint space width (JSW) of 2.5 mm or greater. Subjects had to have had pain in the target knee most days and / or had to have had symptoms of knee pain treated with paracetamol (acetaminophen) (a systemic nonsteroidal anti-inflammatory drug (NSAID), which includes COX inhibitors (COXibs)) or tramadol most days in the previous month, and had at least 5 half-lives of withdrawal from the following analgesics: acetaminophen (topical or oral systemic NSAID), COXibs, opioids, and / or tramadol. At screening and baseline, subjects had to have both 1) a history of pain due to OA in the target knee for at least 6 months and 2) a pain score of 4–9 in the target knee in response to question 1 of the Western Ontario–McMaster Universities Osteoarthritis Index (WOMAC) Pain Index ("How much pain have you had [in the target knee over the past 48 hours] when walking on a flat surface?"). Women of childbearing potential had to be using contraceptives with a failure rate of less than 1% per year through the study institution.

[0135] Major exclusion criteria included femoro-tibial malalignment of the target knee >5°, clinical signs of inflammation (i.e., redness) in the target knee, intra-articular administration of corticosteroids or hyaluronic acid in either knee within 6 months prior to screening, any plans for knee surgery (affecting the target knee or the contralateral knee) within the next 2 years, existing comorbidities or treatments deemed incompatible with study participation, contraindications to MRI scanning (including inability to fit into the scanner or knee coil), pregnancy or breastfeeding, participation in another clinical trial within the past 30 days, and incapacity or limited legal capacity.

[0136] Written informed consent had to be obtained prior to any study-related activity.

[0137] Five groups of patients were studied: Arm 1 (four cycles of placebo; henceforth referred to as placebo or PBO): 108 subjects. Group 2 (2 cycles of sprifermin 30 μg / injection alternating with 2 cycles of placebo; henceforth referred to as sprifermin / placebo 30 μg × 2): 110 subjects. Group 3 (4 cycles of Sprifermin 30 μg / injection; henceforth referred to as Sprifermin 30 μg × 4): 111 subjects. Group 4 (2 cycles of sprifermin 100 μg / injection alternating with 2 cycles of placebo; henceforth referred to as sprifermin / placebo 100 μg × 2): 110 subjects. Group 5 (4 cycles of Sprifermin 100 μg / injection; henceforth referred to as Sprifermin 100 μg × 4): 110 subjects.

[0138] In this prospective study, patients received four cycles of treatment (each consisting of three intra-articular injections given once a week for three consecutive weeks) at six-month intervals (see Figure 1). All injections were intra-articular (given into the joint).

[0139] The primary efficacy endpoint was change from baseline in cartilage thickness within the total femoro-tibial joint as assessed by MRI at 104 weeks (2 years).

[0140] Exploratory endpoints included response to treatment or disease progression (response assessed by MRI and / or WOMAC index questionnaire).

[0141] Effect of sprifermin on WOMAC pain in different subpopulations based on differences in baseline parameters of patients included in the study

[0142] As is evident from Figure 2, subjects treated with sprifermin and subgrouped based on differences in measurements at baseline responded differently with respect to symptoms as judged by the WOMAC pain measure. In all figures, mJSW means minimum joint space width across the knee.

[0143] Effect of sprifermin on WOMAC pain in different JSW-based subsets of patients included in the study:

[0144] As is evident from Figure 3, subjects treated with Sprifermin and subgrouped based on different measurements responded differently regarding symptoms as judged by the WOMAC pain measurements. Patients with a larger minimum JSW responded more favorably to placebo, whereas patients with a minimum JSW between 1.5±2 SD mm and 3.5±2 SD mm experienced positive pain relief as indicated by reduced WOMAC pain scores. The at-risk subgroup (first row) preferred Sprifermin and was given the largest mean effect. In all figures, mJSW means minimum joint space width across the knee.

[0145] The effect of placebo and sprifermin on cartilage thickness in the entire population of patients included in the study As can be seen in FIG. 4A, subjects treated with placebo experienced loss of cartilage thickness during the first 18 months of the study when the placebo was being injected and 18 months after the last injection (in contrast, subjects treated with sprifermin injections (sprifermin 100 μg×4) experienced an increase in cartilage thickness during the treatment period). Although these subjects experience a decrease in cartilage thickness after the last injection of the sprifermin compound, cartilage loss remains significantly less in FGF-18 treated subjects compared to placebo treated subjects (0.05 mm, p-value 0.025) over the entire duration of the study, indicating limited cartilage thinning in all subjects treated with FGF-18.

[0146] Effect of placebo and sprifermin on cartilage thickness in subjects at risk (minimum JSW 1.5-3.5 mm and WOMAC pain score 40-90):

[0147] As is evident from Figure 4B and expected, patients at risk and treated with placebo alone experience increased cartilage loss compared to placebo in the entire study population (mean change in cartilage thickness compared to baseline at 156 weeks in this group is 0.07 mm, see Figure 1A). In contrast, subjects at risk and treated with Sprifermin injections (Sprifermin 100 μg × 4) experience limited loss of cartilage thickness during the treatment period (mean change in cartilage thickness compared to baseline at 156 weeks in this group is 0.03 mm). Thus, despite the tendency of subjects at risk to progress rapidly in this disease, the benefit of Sprifermin in limiting cartilage thinning was observed in the entire population of OA subjects in this study. In all figures, mJSW means minimum joint space width across the knee.

[0148] The effect of placebo and sprifermin on WOMAC total score and pain score in the entire population of patients included in the study:

[0149] As can be seen from Figure 5A, the change in WOMAC total score was not statistically different between placebo- and sprifermin-treated subjects, either during the first 18 months while receiving injections or after the last injection. In all figures, mJSW means minimum joint space width across the knee.

[0150] Effect of sprifermin on WOMAC total score in subjects at risk (minimum JSW 1.5-3.5 mm and WOMAC pain score 40-90 points)

[0151] As can be seen from FIG. 5B, the change in WOMAC total score is statistically different in subjects treated with sprifermin (sprifermin 100 μg×4) compared to placebo or compared to placebo-treated subjects, despite the fact that the last injection was administered by the end of the study (week 156), and therefore at week 78. This improvement in clinical symptoms measured by WOMAC score in treated subjects compared to placebo was unexpected, since these subjects are characterized by intolerable pain at baseline and are expected to progress more rapidly to more severe stages. Interestingly, in treated subjects, the WOMAC total score continues to improve after the last injection (negative change in WOMAC total score), whereas placebo-treated subjects experience a relative increase in clinical symptoms during the same period (as seen by the change in WOMAC total score between weeks 78 and 156 in these subjects). This may reflect an indirect effect on sprifermin on clinical symptoms of OA, at least for this particular subgroup. In all figures, mJSW refers to the minimum joint space width across the knee.

[0152] Effect of Sprifermin on WOMAC Total Score in Subjects at Risk

[0153] As is evident from Figures 6 and 7, the magnitude of effect of sprifermin on the WOMAC total score in subjects at risk as defined herein is greater than in subjects who only exhibit a minimum JSW of 1.5-3.5 mm or a WOMAC pain score of 40 or more at baseline. This further suggests that the observed effect on clinical symptoms is particularly ameliorated in subjects at risk for progression of the disease, particularly rapidly. In all figures, the term mJSW refers to the minimum joint space width across the knee.

[0154] References 1) WO2008 / 023063 2) WO2004 / 032849 3) WO2014 / 023703 4) http: / / www.cartilage.org / _files / contentmanagement / ICRS_evaluation.pdf 5) Lotz, 2010, Arthritis research therapy, 12:211 6) Guermazi et al., 2015, Osteoarthritis Cartilage; 23(12): 2191-2198. 7) Pelletier et al., 2007, Arthritis Res Ther. 9(4):R74. 8) Wang et al., 2018, Arthritis Res Ther. 20: 250. 9) Ellsworth et al., 2002, Osteoarthritis and Cartilage, 10: 308-320 10) Shimoaka et al., 2002, J. Bio. Chem. 277(9):7493-7500 11) Gigout et al., 2017, Osteoarthritis and Cartilage, Osteoarthritis and Cartilage, 25(11):1858-1867. 12) The Merck Manual, 17th edition, page 449 13) Bellamy et al., 1988, J. Rheumatology, 15:1833-1840 14) Wolfe, 1999, Rheumatology, 38:355-361 15) Hunter et al., 2009, Curr Opin Rheumatol.;21(2):110-7. 16) Hawker et al., 2011, Arthritis Care & Research, 63(S11):S240-S252. 17) Williamson et al., 2005 , J Clin Nurs.;14(7):798-804. 18) Roos et al., 2003, Health Qual Life Outcomes;1:17. 19) Collins et al., 2016, Osteoarthritis Cartilage. 24(8):1317-29. 20) Roos et al., 1998, Scand J Med Sci Sports.;8(6):439-48.

Claims

1. 1. A pharmaceutical composition comprising an FGF-18 compound for use in treating a subject having a cartilage disorder, the subject comprising: (a) a significant structural defect of the joint, wherein said significant structural defect of the joint is selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm and a KL grade of 2-4; (b) intolerable joint pain, wherein said intolerable joint pain is selected from the group consisting of joint pain corresponding to a WOMAC joint pain score of at least 35 points, joint pain corresponding to a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale), joint pain corresponding to an NRS score of 4 or more (on a scale of 0 to 11), and joint pain corresponding to a KOOS score of 40 or more (on a scale of 0 to 100); When indicating The subject is at risk for rapid progression of the cartilage disorder, and A pharmaceutical composition, wherein said FGF-18 compound comprises a) residues 28-207 of SEQ ID NO:1 or b) SEQ ID NO:

2.

2. 1. A pharmaceutical composition comprising an FGF-18 compound for use in the prevention or treatment of clinical symptoms associated with a cartilage disorder in a subject having said cartilage disorder, said subject comprising: (a) a significant structural defect of the joint, wherein said significant structural defect of the joint is selected from the group consisting of a minimum joint space width (miniJSW) of less than 3.5 mm and a KL grade of 2-4; (b) intolerable joint pain, wherein said intolerable joint pain is selected from the group consisting of joint pain corresponding to a WOMAC joint pain score of at least 35 points, joint pain corresponding to a VAS pain score of 4 or more (on a numerical scale) or 40 or more (on a 100 mm scale), joint pain corresponding to an NRS score of 4 or more (on a scale of 0 to 11), and joint pain corresponding to a KOOS score of 40 or more (on a scale of 0 to 100); When indicating The subject is at risk for rapid progression of the cartilage disorder, and A pharmaceutical composition, wherein said FGF-18 compound comprises a) residues 28-207 of SEQ ID NO:1 or b) SEQ ID NO:

2.

3. 3. The pharmaceutical composition of claim 2, wherein said clinical symptoms are selected from the list consisting of pain, disability, and joint stiffness associated with said cartilage damage.

4. The pharmaceutical composition according to claim 3, wherein the clinical symptom is pain associated with the cartilage disorder.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the joint disorder is selected from the group consisting of osteoarthritis, cartilage damage, fractures affecting articular cartilage, and surgical procedures affecting articular cartilage.

6. The pharmaceutical composition of claim 5, wherein the joint disorder is osteoarthritis.

7. The pharmaceutical composition according to claim 6, wherein the joint disorder is knee osteoarthritis or hip osteoarthritis.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is administered intra-articularly.

9. 9. The pharmaceutical composition of any one of claims 1 to 8, wherein the pharmaceutical composition is administered according to a dosing regimen comprising at least one treatment cycle consisting of at least two administrations, the two administrations being separated by about 4, 5, 6, 7, 8, 9, or 10 days.

10. The pharmaceutical composition of claim 9, wherein the two administrations are separated by about 7 days.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the pharmaceutical composition is administered intra-articularly at a dose of 100 μg per injection, once a week for three weeks per treatment cycle in a dosing regimen comprising at least four treatment cycles, the treatment cycles being separated by about 4 to 8 months.

12. 12. The method of claim 11, wherein the four treatment cycles are separated by about six months.

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