RU2786232C2 - Pharmaceutical composition for safe and effective treatment of knee and/or hip joint pain - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to the treatment or prevention of pain in the knee joint or the hip joint in patients suffering from osteoarthritis, which, in history, do not have adequate anesthesia or have intolerance to standard analgesic treatment. The patient is administered with a pharmaceutical composition containing 1 mg of an antibody against the nerve growth factor (hereinafter – NGF), containing a pair of amino acid sequences of a heavy chain variable region (HCVR)/light chain variable region (LCVR) of SEQ ID NOs: 2/10. The patient has Kellgren-Lawrence [K-L] assessment of ≥2 by 0-4 scale before the treatment. Administration is performed at intervals, every four or eight weeks. The composition reduces pain or improves a physical function in the patient, while the frequency of occurrence of one or more undesired phenomena in the patient is reduced compared to patients receiving higher doses of the antibody to NGF or its antigen-binding fragment.

EFFECT: inventions allow for avoidance of the risk of development of arthropathy related to the treatment with an antibody against NGF.

14 cl, 52 dwg, 1 ex

Description

FIELD OF THE INVENTION

[0001] The present invention relates to the treatment or prevention of pain in the joints, such as the knee or hip, in patients who have had a history of inadequate pain relief or intolerance to standard pain medication. More specifically, the invention relates to the administration of NGF antagonists, in particular an antibody to nerve growth factor (NGF), to reduce knee and/or hip pain in a patient in need thereof.

PRIOR ART

[0002] Many patients with acute and chronic pain do not receive adequate pain relief despite the wide range of currently available pain medications, either because the drugs are not effective for all patients or because their use is limited by toxicity or intolerance. Limitations in the use of currently available analgesics include adverse effects on the central nervous system, nausea and vomiting, constipation, gastrointestinal bleeding and ulceration, cardiovascular events, renal toxicity, and potential for abuse. Inadequate pain management has a profound impact on the quality of life of millions of people around the world and comes with significant costs to society, including health care costs and lost productivity.

[0003] Neurotrophins are a family of peptide growth factors that play a role in the development, differentiation, survival, and death of neuronal and non-neuronal cells (Chao, M. et.al. , (2006), ClinSci (Lond); 110:167) . For the adult human, NGF is not required as a survival factor, but acts as a neuronal sensitizing pain mediator (Pezet, S. et.al., (2006), Ann Rev Neurosci 29:507-518). Nerve growth factor activity is mediated by 2 different membrane-bound receptors: high-affinity type 1 tyrosine kinase (TrkA) receptors and low-affinity p75 neurotrophin receptors.

[0004] Administration of NGF has been shown to cause pain in both rodents (Lewin, GR, et al., (1994), Eur. J. Neurosci 6:1903-1912) and humans (McArthur, JC, et .al., (2000), Neurology 54:1080-1088), while NGF antagonists have been shown to prevent hyperalgesia and allodynia in animal models of neuropathic and chronic inflammatory pain (Ramer, MS et.al., (1999 ) Eur J Neurosci 11:837-846). People with mutations in TrkA (hereditary sensory and autonomic neuropathy IV) or NGF (hereditary sensory and autonomic neuropathy V) have been shown to lose deep pain perception (Indo, Y. et.al., (1996), Nature Genetics, 13:485 -488), Einarsdottir, E., et.al., (2004), Human Molecular Genetics 13:799-805). In addition, it is known that in the synovial fluid of patients with rheumatoid arthritis and other types of arthritis, the level of NGF is increased (Aloe, L. et . al ., (1992), Arthritis Rheum 35:351-355; Halliday, DA, (1998), Neurochem Res. 23:919-922) and that it is activated in damaged and inflamed tissues in conditions such as cystitis, prostatitis and chronic headache (Lowe, EM, et.al. , (1997), Br. J. Urol 79:572-577; Miller, LJ, et.al., (2002), Urology 59:603-608; Sarchielli, P. et.al. , (2001), Neurology 57:132-134).

[0005] There is an unmet need for pain relievers in people who have not had an adequate history of pain relief or who cannot tolerate standard pain management. Fasinumab is a fully human, high-affinity, monoclonal antibody directed against NGF (see U.S. Patent 7,988,967 and PCT Publication No. WO 2009/023540 and WHO Drug Information Vol. 26, No. 2, (2012), which are incorporated herein in their entirety by reference. ). By selectively blocking NGF, fasinumab may be effective in modulating NGF-related pain without some of the side effects of other analgesics such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs).

SUMMARY OF THE INVENTION

[0006] A pharmaceutical composition and method for treating knee and/or hip pain in a patient who does not respond to or cannot tolerate standard pain medication is described. A pharmaceutical composition and a method for reducing the risk of developing arthropathy in a subject receiving an anti-NGF antibody for the treatment of pain in the knees and/or hip joints are described. Also provided herein are methods for monitoring the safety of treatment for knee and/or hip pain, including administration of an anti-NGF antibody. In some aspects of the invention, the subject suffers from osteoarthritis of the knee and/or hip and the anti-NGF antibody is fasinumab.

[0007] In some aspects of the invention, a pharmaceutical composition is disclosed for use in the treatment of a subject suffering from pain in the knee or hip joint, when the subject does not respond to analgesic treatment or suffers from side effects from analgesic treatment. The composition includes a therapeutically effective amount of an antibody that specifically binds to nerve growth factor (NGF) or an antigen-binding fragment thereof. The composition is used in the absence of an anesthetic to relieve pain.

[0008] In another aspect of the invention, the use includes any of the above uses, wherein the antibody or antigen-binding fragment thereof that specifically binds to NGF is administered to a patient at a dose of about 1 mg to about 9 mg. The frequency of administration is approximately every 4 weeks.

[0009] In another aspect of the invention, the use includes any of the above uses, wherein the analgesic treatment comprises acetaminophen, opioids, non-steroidal anti-inflammatory drugs (NSAIDs), or a combination thereof.

[0010] A pharmaceutical composition is described for preventing arthropathy associated with treatment with an anti-nerve growth factor (NGF) antibody that specifically binds to NGF or an antigen-binding fragment thereof. In some aspects of the invention, the composition is formulated as a dose of less than 9 mg of the anti-NGF antibody or antigen-binding fragment thereof. In some aspects of the invention, the composition is formulated as a dose of less than 6 mg of anti-NGF antibody or antigen-binding fragment. In some aspects of the invention, the initial dose and one or more secondary doses of the arthropathy reducing pharmaceutical composition each contain about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg of an anti-NGF antibody or antigen-binding fragment thereof. . In some aspects of the invention, each initial dose and one or more secondary doses of the pharmaceutical composition that reduces the risk of developing arthropathy, contain about 1 mg or about 3 mg of anti-NGF antibody or antigen-binding fragment. In some aspects of the invention, arthropathy includes joint space narrowing that exceeds predetermined thresholds. In some aspects of the invention, arthropathy includes changes in bone structure evident on a plain radiograph. In some aspects of the invention, arthropathy includes changes in bone structure evident on a plain radiograph, joint space narrowing in excess of predetermined thresholds, or both in the knee joint. In some aspects of the invention, the frequency of administration of a dose of an anti-NGF antibody that reduces the risk of developing at least one type of arthropathy is approximately every 4 weeks.

[0011] In certain aspects of the invention, a subject treated with the compositions and methods described herein is diagnosed with knee and/or hip osteoarthritis.

[0012] In another aspect of the invention, the use includes any of the aforementioned uses in which the patient has a history of inadequate pain relief with standard pain management, resistance, inadequate response, or intolerance.

[0014] In another aspect of the invention, the use includes any of the above uses where the patient is unwilling to take standard pain medication or does not have access to standard pain medication. In another aspect of the invention, the use includes any of the above uses in which standard analgesic treatment is not recommended for administration to the patient due to risks to patient safety and health and/or in combination with sub-optimal efficacy. In another aspect of the invention, the use includes any of the above uses in which the standard pain medication is not recommended for administration to the patient due to a condition selected from the group including medical contraindications, hypersensitivity to the standard pain medication or excipients, use of a concomitant medication prohibited by the standard pain medication. treatment, increased risk of kidney damage, increased risk of liver damage, increased risk of gastrointestinal bleeding, increased risk of an allergic reaction, and increased risk of drug dependence.

[0015] In another aspect of the invention, the use includes any of the above uses, wherein the standard analgesic treatment is selected from the group consisting of paracetamol/acetaminophen, a non-steroidal anti-inflammatory drug (NSAID), and an opioid.

[0016] In another aspect of the invention, the use includes any of the above uses, wherein the opioid is selected from the group consisting of hydrocodone, oxycodone, percocet, morphine, meperidine, hydromorphone, fentanyl, and methadone.

[0017] In another aspect of the invention, the use includes any of the above uses, in which the antibody or antigen-binding fragment specifically binding to NGF is administered to the patient at a frequency of about every 4 weeks.

[0018] In another aspect of the invention, the use includes any of the above uses in which the antibody or antigen-binding fragment is administered subcutaneously (SC) or intravenously (IV).

[0019] In another aspect of the invention, the use includes any of the above uses, wherein the anti-NGF antibody comprises three heavy chain complementarity determining region (HCDR) sequences (HCDR1, HCDR2, HCDR3) containing SEQ ID NOS: 4, 6, and 8 , respectively, and three light chain complementarity determination (LCDR) sequences (LCDR1, LCDR2, LCDR3) containing SEQ ID NOs: 12, 14 and 16, respectively.

[0020] In another aspect of the invention, the use includes any of the above uses, wherein the antibody comprises an HCVR having the amino acid sequence of SEQ ID NO: 2.

[0021] In another aspect of the invention, the use includes any of the above uses, wherein the antibody comprises an LCVR having the amino acid sequence of SEQ ID NO: 10.

[0022] In another aspect of the invention, the use includes any of the above uses, wherein the antibody is fasinumab.

[0023] In another aspect of the invention, the use includes any of the above applications, in which the initial dose and one or more secondary doses are administered subcutaneously or intravenously.

[0024] In another aspect of the invention, the application includes any of the above applications, where one or more secondary doses of anti-NGF antibodies are administered every four weeks, every eight weeks, or every 12 weeks after the initial dose.

[0025] In another aspect of the invention, the use includes any of the above uses in which the use results in an improvement in one or more parameters associated with pain. In some aspects of the invention, the pain-related parameter is selected from the group consisting of: (a) change from baseline at week 16 on the Western Ontario and McMaster Universities Osteoarthritis Pain Scale (WOMAC); (b) change from baseline at week 16 on the physical function subscale; and (c) change from baseline at week 16 in the Global Patient Assessment (PGA).

[0026] In another aspect of the invention, the use includes any of the above uses, wherein the use results in an improvement in the daily and weekly (average of the previous week's daily scores) walking index joint pain score on a numerical rating scale (NRS; scale 0-10 ; 0=no pain; MCID: ~1 point).

[0027] In another aspect of the invention, the use includes any of the aforementioned uses in which the use results in an improvement in response rate using the Rheumatology Committee and the International Society for Osteoarthritis Research Clinical Trial Response Criteria Initiative (OMERACT-OARSI). ) (an 11-point instrument that measures pain in osteoarthritis of the knee or hip).

[0028] In another aspect of the invention, the use includes any of the aforementioned uses, in which the use results in an improvement in quality of life as assessed using the EuroQol-5 Dimension-5 Health Survey Summary Form 36 (SF-36) Outcome Utility Index scale ( EQ-5D-5L).

[0029] In another aspect of the invention, the application includes any of the above applications, where the application provides relief from pain associated with the knee or hip joint, for up to 36 weeks from the start of application.

[0030] Each of the aforementioned aspects of the invention is also disclosed and described herein as respective treatments.

[0031] In some aspects of the invention, a method is provided for monitoring the treatment of a subject suffering from pain in the knee or hip joints. The method includes administering a pharmaceutical composition containing a dose of about 9 mg of an anti-NGF antibody that specifically binds to NGF or an antigen-binding fragment thereof; observing the subject's knee or hip joint to determine if the subject has developed arthropathy; wherein, if the subject has developed arthropathy, administering to the subject a pharmaceutical composition containing a dose of less than about 9 mg of the antibody or antigen-binding fragment thereof; or, if the subject has not developed arthropathy, administering to the subject a pharmaceutical composition containing a dose of about 9 mg of the antibody or antigen-binding fragment thereof.

[0032] In some aspects of the monitoring method invention, if a subject has developed arthropathy, subsequent treatment comprises administering a pharmaceutical composition containing about 1.0 mg to about 6 mg of an anti-NGF antibody or antigen-binding fragment thereof, wherein the treatment reduces pain in the knee or hip joints and reduces arthropathy.

[0033] In some aspects of the monitoring method invention, the antibody comprises three heavy chain complementarity determining region (HCDR) sequences (HCDR1, HCDR2, HCDR3) containing SEQ ID NOs: 4, 6 and 8, respectively, and three complementarity determining region sequences light chain (LCDR) (LCDR1, LCDR2, LCDR3), containing SEQ ID NO: 12, 14 and 16, respectively.

[0034] In some aspects of the monitoring method invention, the antibody comprises an HCVR having the amino acid sequence of SEQ ID NO: 2.

[0035] In some aspects of the monitoring method invention, the antibody comprises an LCVR having the amino acid sequence of SEQ ID NO: 10.

[0036] In some aspects of the monitoring method invention, the antibody is fasinumab.

BRIEF DESCRIPTION OF THE DRAWINGS

[0037] The figure 1 shows the scheme of the study.

[0038] Figure 2 shows a schedule of events table for screening and treatment periods. WOCBP=women of childbearing potential. 1. Only for patients who have provided written informed consent for additional genomics testing. The sample should have been taken at the baseline visit, but may be taken at any visit during the course of the study. 2. Patients were trained in the use of IVRS after the initial suitability of the patients was confirmed during the screening period. Patients used the IVRS to report on the NRS daily index joint pain score while walking and daily acetaminophen use up to and including week 20 of the visit. 3. Study drug administration was the last procedure at each administration visit and was performed after all laboratory samples had been collected and all assessments and study procedures had been completed. Patients were observed in the clinic within 1 hour after administration of the study drug. 4. Acetaminophen use was confirmed by pill count. 5. The NRS score for index joint pain on walking was recorded in the electronic case report form (eCRF) at the site at the pre-randomization visit and by the patient every day (approximately 6:00 pm) using the IVRS from the pre-randomization period until 20th week. 6. At the screening visit, the WOMAC pain subscale was assessed for both knees and both hips. 7. Patients were provided with an activity monitor (actigraph) during the pre-visit and were trained in its use. Patients wore the monitor for 7 days before each clinic visit, from the day of the pre-randomization visit until week 20. Patients brought the monitor with them to each clinic visit for the clinic staff to download the information. 8. If the pulse was less than 45 beats per minute, an ECG was done with a rhythm strip to confirm the heart rate and rhythm. 9. In addition to the planned imaging, radiographs should have been considered for increased joint pain despite analgesic treatment, which, in the opinion of the investigator, did not correspond to the normal progression of OA and lasted at least 2 weeks (or less at the discretion of the investigator). 10. In addition to the planned MRI, MRI should be considered for increased joint pain despite treatment with analgesics, which the Investigator judged to be inconsistent with the normal progression of OA, lasted at least 2 weeks (or less, at the discretion of the Investigator), and where the x-ray showed no results. 11. After the patient otherwise met the study eligibility criteria assessed during the screening period, an MRI of the index joint, contralateral joint, and any other knee or hip joint with baseline KL ≥3 was performed prior to pre-evaluation. prior to the pre-randomization visit. In cases where the contralateral joint had previously undergone TJR surgery, MRI was not required. Confirmation that the image was accepted and validated without requesting a central reviewer must be obtained by the site prior to the pre-randomization visit. Confirmation of the absence of any exceptional MRI results must be obtained from the central reader before the patient can be randomized. 12. In the event that a patient needs to undergo TJR surgery during the study, the patient will complete an early withdrawal visit and the procedures specified in the TJR follow-up schedule. The early termination visit should be completed prior to TJR surgery, if at all possible. 13. In the event of a positive urine pregnancy test, a serum pregnancy test should have been obtained. If the serum pregnancy test was negative, the patient continued to participate in the study. If the serum pregnancy test was positive, the patient was discontinued study drug and asked to return to the clinic for all remaining study visits as scheduled. 14. The test should only be performed if it is necessary to assess postmenopausal status in patients under the age of 59 years. 15. The second morning urine should be collected after an overnight fast. This was done either at home prior to the visit or at the research center on the day of the visit. 16. Early termination of participation in the study: Imaging studies (X-rays of the knees, hips and shoulders, and MRI) were repeated only if more than 30 days had passed since the last joint imaging. If ≤30 days had elapsed since the completion of the imaging evaluation, the imaging evaluation was performed at the discretion of the investigator.

[0039] The figure 3 shows the schedule table of events for the subsequent period. 1. Use of acetaminophen is confirmed by tablet count. 2. The patient's NRS assessment of pain in the index joint while walking by the patient was recorded every day (at about 18:00) using IVRS during the 20th week. 3. Patients wore the monitor for 7 days before each clinic visit up to week 20. Patients brought the monitor to the clinic at week 20 for the clinic staff to download the information. 4. If the pulse was less than 45 beats per minute, an ECG was done with a rhythm strip to confirm the heart rate and rhythm. 5. Only the joint was examined. 6. Questionnaires were filled out by the patient on the spot during a visit to the clinic; for telephone visits, the sites documented information during telephone calls. 7. In addition to routine imaging, radiographs should have been considered for an increase in joint pain despite analgesic treatment that, in the investigator's opinion, did not correspond to the normal progression of OA and lasted at least 2 weeks (or less at the discretion of the investigator). 8. An MRI of the index joint, contralateral joint, and any other knee or hip joint with baseline KL ≥3 was performed. In cases where the contralateral joint had previously undergone TJR surgery, MRI was not required. 9. In the event that a patient had TJR surgery during the study, the patient completed the early termination visit and the procedures indicated in the TJR follow-up schedule. The early termination visit should be completed before the TJR operation, if at all possible. 10. Early termination of participation in the study: Imaging studies (x-rays of the knees, hips and shoulders, and MRI) were repeated only if more than 30 days had passed since the last joint imaging. If ≤30 days had elapsed since the completion of the imaging evaluation, the imaging evaluation was performed at the discretion of the investigator.

[0040] Figure 4 is a chart of events to follow in the event of total joint replacement surgery and follow-up. 1. Any patient undergoing TJR surgery during the study was asked to return to the clinic 4 and 20 weeks after the date of surgery for safety evaluation. Relevant information related to the operation was collected during the 4 week visit, including the placement of the prosthesis and the healing of the surgical wound. The 20-week postoperative visit included assessment of OA progression (including repeat radiographs of the knees, hips, and shoulders) and collection of any information on joint pain or AE (including TJR) that may have occurred since the last clinic visit. 2. Formal post-operative assessment of total hip replacement was performed by completing the Knee Society Assessment Scale for Knee Replacement Results or the Harris Hip Assessment Questionnaire for Hip Replacement Results. Full details of these assessments are provided in the study reference guide. 3. MRI was performed for the index joint, contralateral joint, and any knee or hip joint that had a baseline KL score of ≥3. In cases where the contralateral joint had previously undergone TJR surgery, MRI was not required.

[0041] Figure 5 provides a summary of the distribution of clinical study participants (complete set of analyses). SAF = safety assay set that includes all randomized subjects who received any study drug per day. 1. FAS=full assay set that includes all randomized subjects.

[0042] Figure 6 shows a summary of protocol deviations (complete set of analyses). IVR=Interactive Voice Response.

[0043] Figure 7 shows a summary of protocol deviations leading to exclusion from the protocol suite (full set of analyses). IVR=interactive voice response; PPS=per protocol suite.

[0044] Figure 8 is a summary of study populations. FAS=Full set of analyses; SAF=safety analysis kit; PPS=per protocol suite.

[0045] Figure 9 shows a summary of baseline demographics (complete analysis set). BMI=body mass index.

[0046] Figure 10 is a table of medical history and preferred terms reported by ≥10% of patients in any treatment group (complete set of analyses). Note: The data in this table was a truncated selection from the original table. The MedDRA coding dictionary (version 18.0) has been applied. A subject who reported 2 or more medical records with the same preferred term is counted only once for that term. A subject who reported 2 or more case histories with different preferred terms within the same system organ class is counted only once in that system organ class.

[0047] Figure 11 provides a summary of treatment compliance (safety analysis kit).

[0048] Figure 12 summarizes the change in WOMAC pain score from baseline up to week 16 (full set of analyses). N=number of subjects in the complete analysis set and n=number of subjects in the specified category. SD=standard deviation, Min=minimum and Max=maximum. LS mean=least squares mean, SE=standard error of the mean LS and CI=confidence interval. Analyzes are based on the MMRM model with baseline randomization rates, baseline, treatment, visit, and interaction with treatment factor effect by visit.

[0049] Figure 13 shows change in WOMAC pain subscale score at visit from baseline to week 16: least squares mean (+/-SE) (full set of analyses).

[0050] Figure 14 shows change from baseline to week 36 in WOMAC pain subscale score at visit: baseline mean (+/-SE) (full set of analyses).

[0051] Figure 15 shows change from baseline in WOMAC Physical Function Subscale score at visit: least squares mean (+/-SE) (full set of analyses).

[0052] Figure 16 shows the change from baseline in WOMAC Physical Function Subscale score at visit: Mean (+/-SE) (full set of analyses).

[0053] Figure 17 provides a summary of the change from baseline i score on the patient's overall score up to week 16 (score range: 1 to 5) (complete set of analyses). N=number of subjects in the complete analysis set, and n=number of subjects in the specified category. SD=standard deviation, Min=minimum and Max=maximum. LS mean=least squares mean, SE=standard error of the mean LS, and CI=confidence interval. Analyzes are based on the MMRM model with baseline randomization rates, baseline, treatment, visit, and interaction with treatment factor effect by visit.

[0054] Figure 18 shows, compared to baseline, the patient's overall score at visit up to week 16: least squares mean (+/-SE) (full set of analyses).

[0055] Figure 19 shows, compared to baseline, the patient's overall visit score: Mean (+/-SE) (complete set of analyses).

[0056] Figure 20 shows the percentage of patients who used rescue medications (full set of tests). [1] The hazard ratio is facinumab versus placebo. CI=confidence interval calculated using the normal approximation. [2] P-values were obtained using the Cochran-Mantel-Haenszel (CMH) test, stratified by baseline, Kellgren-Lawrence categories (2-3 vs. 4), and index joint (knee versus hip).

[0057] Figure 21 shows the duration of study drug exposure (safety assay kit). [1] The date of the last dose is the date of the first dose+28.

[0058] Figure 22 shows the duration of observation (safety analysis set). [1] Date of last visit (including follow-up visit for TJR) - date of first dose+1.

[0059] Figure 23 provides an overview of side effects resulting from treatment during the treatment period (safety analysis kit). TEAE: treatment-related adverse events. [1] Refers to subjects who permanently discontinued study drug (from the AE group of analyses).

[0060] Figure 24 shows an overview of adverse events during the follow-up period (safety analysis set). AE: side effects.

[0061] Figure 25 provides a summary of treatment-related adverse events reported in 3% of patients in any treatment group during the treatment period by system organ class and preferred timing (safety analysis set). The MedDRA coding dictionary (version 18.0) has been applied. TEAE: Adverse events resulting from treatment. An entity reporting 2 or more TEAEs with the same preferred term is only counted once during this time period. A subject reporting 2 or more TEAEs with different preferred terms in the same system organ class is counted only once in that system organ class.

[0062] Figure 26 is a summary of adverse events reported in 3% of patients in any treatment group during the preferred time follow-up (safety analysis set). AE=Adverse Event using the MedDRA coding dictionary (version 18.0). A subject reporting 2 or more AEs with the same preferred term is only counted once during this time limit. A subject who reported 2 or more AEs with different preferred terms within the same system organ class is counted only once in that system organ class.

[0063] Figure 27 provides a summary of treatment-related adverse events reported in 2% of patients during the treatment period, broken down by systemic organ class and preferred terms (safety analysis set). The MedDRA coding dictionary (version 18.0) has been applied. TEAE: Adverse events resulting from treatment. An entity reporting 2 or more TEAEs with the same preferred term is only counted once during this time period. A subject reporting 2 or more TEAEs with different preferred terms within the same system organ class is counted only once in that system organ class.

[0064] Figure 28 provides a summary of treatment-related adverse events reported in 2% of patients during the follow-up period, disaggregated by systemic organ class and preferred timing (safety analysis set). The MedDRA coding dictionary (version 18.0) has been applied. AE: Adverse event. A subject reporting 2 or more AEs with the same preferred term is only counted once during this time limit. A subject that reported 2 or more AEs with different preferred terms within the same system organ class is counted only once in that system organ class.

[0065] Figure 29 provides a summary of serious treatment-related adverse events reported during the treatment period by system organ class and preferred terms (safety analysis set). The MedDRA coding dictionary (version 18.0) has been applied. TEAE: Adverse events resulting from treatment. An entity reporting 2 or more TEAEs with the same preferred term is only counted once during this time period. A subject reporting 2 or more TEAEs with different preferred terms in the same system organ class is counted only once in that system organ class.

[0066] Figure 30 provides a summary of adverse events reported during the follow-up period by system organ class and preferred terms (safety analysis set). The MedDRA coding dictionary (version 18.0) has been applied. An entity reporting 2 or more TEAEs with the same preferred term is only counted once during this time period. A subject reporting 2 or more TEAEs with different preferred terms in the same system organ class is counted only once in that system organ class.

[0067] Figure 31 provides a summary of treatment-related adverse events leading to study drug discontinuation by system organ class and preferred timing (safety analysis set). The MedDRA coding dictionary (version 18.0) has been applied. TEAE: Adverse events resulting from treatment. An entity reporting 2 or more TEAEs with the same preferred term is only counted once during this time period. A subject reporting 2 or more TEAEs with different preferred terms in the same system organ class is counted only once in that system organ class.

[0068] Figure 32 is a summary of treatment-related adverse events of particular interest found during the preferred treatment period (safety analysis set). AESI=Adverse Event of Special Interest. The MedDRA coding dictionary (version 18.0) has been applied. TEAE: Adverse events resulting from treatment. An entity reporting 2 or more TEAEs with the same preferred term is only counted once during this time period. A subject reporting 2 or more TEAEs with different preferred terms in the same system organ class is counted only once in that system organ class.

[0069] Figure 33 shows a summary of adverse events of particular interest found during the follow-up period by preferred time frame (safety analysis set). AESI=Adverse Event of Special Interest. The MedDRA coding dictionary (version 18.0) has been applied. A subject reporting 2 or more AEs with the same preferred term is counted only once during this period. A subject reporting 2 or more AEs with different preferred terms in the same systemic organ class is counted only once in that systemic organ class. † In 2 patients, bilateral rapidly progressive osteoarthritis was reported as a single event.

У 2 субъектов двусторонний быстро прогрессирующий остеоартрит был зарегистрирован как одно событие.[0070] Figure 34 shows a summary of all adverse events of particular interest, broken down by preferred timing during treatment and follow-up period (safety analysis set). AESI=Adverse Event of Special Interest. The MedDRA coding dictionary (version 18.0) has been applied. A subject reporting 2 or more AEs with the same preferred term is only counted once during this period. A subject reporting 2 or more AEs with different preferred terms in the same systemic organ class is counted only once in that systemic organ class.

In 2 subjects, bilateral rapidly progressive osteoarthritis was recorded as a single event.

[0071] Figure 35 is a summary of arthropathy confirmation data (safety analysis set). RPOA-1: Rapidly progressive OA type 1; RPOA-2: Rapidly progressive OA type 2; SIF: subchondral osteoporotic fracture with PT stress fracture. a Established at 36 weeks of imaging.

[0072] Figure 36 is a summary of total joint replacement during the treatment and follow-up period (safety analysis set). TJR=Total Joint Replacement.

[0073] Figure 37 is a summary of alkaline phosphatase over time (safety assay set).

[0074] Figure 38 shows change in alkaline phosphatase (U/L) from baseline at visit: mean (+/-SE) (safety assay set).

[0075] Figure 39 provides a summary of effective fasinumab concentrations by clinical study day and treatment group after multiple subcutaneous injections of fasinumab. N=number of patients; SD=standard deviation; Q=quartile; PRE=pre-dose; Q4W=Once every 4 weeks; SC=subcutaneous.

[0076] Figure 40 shows mean (+/-SD) effective concentrations of fasinumab versus week after multiple subcutaneous injections of fasinumab. Concentrations below the LLOQ (horizontal dotted line=0.0780 mg/l) are taken as 0. Placebo patients are excluded.

[0077] Figure 41 shows mean (+/-SD) logarithmically scaled effective concentrations of fasinumab versus week after multiple subcutaneous injections of fasinumab. Concentrations below the LLOQ (horizontal dotted line=0.0780 mg/L) are calculated as LLOQ/2=0.0390 mg/L. Placebo patients are excluded.

[0078] Figure 42 shows patient demographics and baseline characteristics. BMI, body mass index; SD, standard deviation.

[0079] Figure 43 shows the change in WOMAC pain subscale score from baseline up to week 16. ^a Analyzes are based on the repeated measures approach of the mixed effect model. CI, confidence interval; LS, least squares; SD, standard deviation; SE, standard error; WOMAC, Osteoarthritis Assessment by the Universities of Western Ontario and McMaster.

[0080] Figure 44 shows treatment-related adverse events during the treatment and follow-up period reported in 2% of patients by systemic organ class. The MedDRA coding dictionary (version 18.0) was applied to the preferred system organ class term. A patient reporting ≥2 TEAE at the same preferred time frame was counted only once during that time frame. A patient reporting ≥2 TEAE with different preferred terms within the same system organ class was counted only once in that system organ class. AE, adverse event; TEAE, an adverse event that occurred after treatment.

[0081] Figure 45 shows arthropathies and total number of joint replacements. During combined periods of treatment and follow-up. In 2 patients, bilateral rapidly progressive OA was reported as 1 event.

[0082] Figure 46 shows a summary of the distribution of clinical study participants. 82 patients received ≥1 dose of placebo. ^b 337 patients received ≥1 dose of fasinumab.

[0083] Figure 47 shows the change from baseline in WOMAC subscale pain (A) and physical function (B) scores at visit, as well as the change from baseline in WOMAC subscale pain scores in patients who present with ( C) and there is no exacerbation of pain (D) when the previously used analgesic is cancelled. SE, standard error; WOMAC, Osteoarthritis Assessment by the Universities of Western Ontario and McMaster.

[0084] Figure 48 shows the change in WOMAC Physical Function Subscale score from baseline up to week 16. The analysis is based on the repeated measures approach of the mixed effects model. CI, confidence interval; LS, least squares; SD, standard deviation; SE, standard error; WOMAC, Osteoarthritis Assessment by the Universities of Western Ontario and McMaster.

[0085] Figure 49 shows the change in utility index scores EQ-5D-5L from baseline up to week 16. ^a Analyzes are based on the repeated measures approach of the mixed effects model. The EQ-5D-5L utility index scores were calculated using a set of United Kingdom time trade-off values. CI, confidence interval; EQ-5D-5L, EuroQoL-5 Dimension-5 level scale; LS, least squares; SD, standard deviation; SE, standard error.

[0086] Figure 50 shows change from baseline in WOMAC pain subscale score to week 16 based on age (A), gender (B), race (C), KL score (D), index joint (E) , weight (F) and BMI (G). BMI, body mass index; LS, least squares; SE, standard error; WOMAC, Osteoarthritis Assessment by the Universities of Western Ontario and McMaster.

[0087] Figure 51 shows the change from baseline in walking pain on a numerical rating scale during the treatment period. Mean LS values were based on a repeated measures approach of a mixed effects model with baseline levels of randomization including baseline, treatment, visit, and treatment factor effect by visit. LS, least squares; SE, standard error.

[0088] Figure 52 summarizes changes from baseline up to week 16 in WOMAC physical function subscale scores (full set of analyses). N=number of subjects in the complete analysis set and n=number of subjects in the specified category. SD=Standard Deviation, Min=Minimum and Max=Maximum. LS mean=least squares mean, SE=standard error of the mean LS and CI=confidence interval. Analyzes are based on the MMRM model with baseline randomization rates, baseline, treatment, visit, and treatment factor effect by visit.

DETAILED DESCRIPTION

[0089] In anticipation of the description of the present invention, it should be noted that this invention is not limited to the specific described methods and experimental conditions, since such methods and conditions may vary. It should also be understood that the terminology used herein is only intended to describe specific embodiments and is not intended to be limiting, as the scope of the present invention will only be limited by the appended claims.

[0090] Unless otherwise indicated, all technical and scientific terms used in this document have the same meanings that are commonly understood by specialists in the field to which this invention relates. The term "about" as used herein, when used in relation to a particular numerical value given, means that the value may differ from the stated value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (eg, 99.1, 99.2, 99.3, 99.4, etc.). As used herein, the terms "treat", "treatment" and the like mean to alleviate symptoms, eliminate the causation of symptoms on a temporary or permanent basis, or prevent or slow the onset of symptoms of the named disorder or condition.

[0091] While any methods and materials similar or equivalent to those described herein may be used in the practice of the present invention, preferred methods and materials are described below. All patents, applications, and non-patent publications referenced herein are incorporated herein by reference in their entirety.

Methods for the treatment of pain in the knees and / or hip joints in selected groups of patients

[0092] The present invention includes methods and compositions for the treatment of patients with moderate to severe knee and/or hip pain who have a history of intolerance or inadequate pain relief from standard therapies, including paracetamol/acetaminophen, oral NSAIDs, and opioid therapy. This subset of patients is a group of patients with unmet medical needs who may benefit from treatment with an NGF antagonist such as fasinumab, which may be effective and may provide a better safety profile than other standard therapies.

[0093] As described herein, the phrase "moderate to severe pain in the knee and/or hip" refers to moderate to severe pain in the index joint, defined as the Western Ontario and McMaster Universities Osteoarthritis Subscale Pain Score (WOMAC ), component ≥4. In some cases, moderate to severe knee and/or hip pain may be due to osteoarthritis. Thus, a subject with moderate to severe pain in the knees and/or hips could be diagnosed with osteoarthritis of the knees and/or hips) based on the criteria for OA of the American College of Rheumatology with radiological confirmation (Kellgren-Lawrence [K-L] score ≥ 2 on a scale of 0 to 4).

[0094] The Kellgren-Lawrence [K-L] scoring system uses plain radiographs and provides the following scores: grade 0, no radiographic evidence of osteoarthritis; grade 1, possible joint space narrowing (normal joint space is at least 2 mm in the superior acetabulum) and osteophyte formation; grade 2, pronounced osteophyte formation with possible narrowing of the joint space; grade 3, multiple osteophytes, severe joint space narrowing, sclerosis, and possible bone deformity; Grade 4, large osteophytes, marked narrowing of the joint space, severe sclerosis, and obvious bone deformity.

[0095] In some embodiments, a patient may be selected for treatment as described herein based on a clinical diagnosis of osteoarthritis (OA) of the knee and/or hip.

[0096] In some embodiments, the subject has a history of regular pain medication such as NSAIDs, COX-2 inhibitors, opioids, acetaminophen, or combinations thereof.

[0097] According to some embodiments, the patient has a history of insufficient analgesia or intolerance to analgesics used to treat pain, as defined by: intolerance or insufficient analgesia of paracetamol and intolerance or insufficient analgesia of at least one oral NSAID and intolerance or insufficient analgesia of at least single opioid, unwillingness to take opioid therapy, or lack of access to opioid therapy.

[0098] The present invention includes methods that include administering to a subject in need thereof a therapeutic composition comprising an NGF antagonist. In the context of the present description, the expression "in need of this subject" means a person who has pain in the knees and/or hip joints. In some embodiments, "subject in need thereof" refers to a patient diagnosed with hip OA, knee OA, or both. In some embodiments, a "subject in need thereof" refers to a patient suffering from knee and/or hip pain who has not had a history of adequate pain relief with standard pain management (e.g., there was no significant reduction in pain after standard pain medication on average 4 days a week for 4 weeks) or intolerance to standard pain medication. In some embodiments, the methods of the present invention may be used to treat patients with knee and/or hip OA with a Kellgren-Lawrence [K-L] score of ≥2 on a scale of 0 to 4 and/or moderate to severe index joint pain , defined as ≥4 points on the WOMAC pain subscale.

[0099] In the context of the present invention, a "subject in need thereof" may also include, for example, subjects who, prior to treatment, demonstrated (or exhibited) one or more parameters associated with pain that improved after treatment with an anti-NGF antibody of the present invention. .

[00100] In some aspects of the invention, treatment comprises administering the pharmaceutical composition described herein at a dose that includes about 1 mg to about 9 mg of an anti-NGF antibody or antigen-binding fragment thereof. As shown in the Examples section of this application, doses of 1 mg, 3 mg, 6 mg, and 9 mg provided a reduction in knee pain in a subject suffering from moderate to severe knee pain and a reduction in hip pain in a subject suffering from moderate to severe pain in the hip joint, and the subject did not respond to or tolerated standard pain management.

[00101] In some aspects of the invention, the improvement demonstrated by the treatment described herein includes improvement from baseline up to week 16 on the WOMAC pain subscale (composite score of 5 questions related to joint pain when walking, using stairs, being able to rest in bed, sitting or lying down and standing) (Bellamy N. WOMAC Osteoarthritis Index: A User's Guide. London, Ontario, Canada: Victoria Hospital; 1995).

[00102] In some aspects of the invention, the improvement demonstrated by the treatment described herein includes improvement from baseline to week 16 on the WOMAC subscale (0 to 68 scale; arithmetically converted to a 0 to 10 scale).

[00103] In some aspects of the invention, the improvement demonstrated by the treatment described herein includes improvement from baseline up to week 16 on the Global Patient Assessment (PGA) scale (one question on a scale of 1 to 5, with the worst score being the highest score) (Strand V, Kellman A. Curr Rheumatol Rep 2004: 6:20-30).

[00104] In some aspects of the invention, the improvement demonstrated by the treatment described herein includes an improvement in the daily and weekly (average of daily scores for the previous week) index joint pain score when walking on a numerical rating scale (NRS; scale 0-10; 0 = no pain; MCID: ~1 point) (Salaffi F, et al. Eur J Pain 2004;8:283-91).

[00105] In some aspects of the invention, the improvement demonstrated by the treatment described herein includes an improvement in the rate of response to treatment using the responder score on the Outcome Evaluation Committee for Rheumatology and the International Standing Committee for Osteoarthritis Research. (an 11-item instrument that measures osteoarthritis pain in the knees or hips) (Pham T, et al., J Rheumatol 2003; 30:1648-54).

[00106] In some aspects of the invention, the improvement demonstrated by the treatment described herein includes an improvement in quality of life, assessed using the Brief Health Questionnaire Form 36 (SF-36) (Ware JE Jr, Sherbourne CD. Med Care 1992; 30 :473-83) and the EuroQol-5 Dimension-5 Level (EQ-5D-5L) utility index scale (van Reenen M, Janssen B. EQ-5D-5L User Guide. Version 2.1. Rotterdam, The Netherlands: European Quality of Life Research Foundation; April 2015).

[00107] In one aspect, after administration of the pharmaceutical composition described herein, the patient experiences improvement in one or more of the following: (a) Western Ontario and McMaster Universities Osteoarthritis Pain Scale (WOMAC); (b) WOMAC physical function subscale scores; and (c) Global Patient Assessment (PGA) score.

[00108] In one embodiment of the invention, the patient after administration of a pharmaceutical composition containing fasinumab, there is an improvement in one or more parameters associated with pain, selected from the group consisting of: a) a change in average daily pain intensity compared to baseline by 16 a week assessed on the Numerical Rating Scale (NRS) scale; b) change from baseline at week 16 in the total score on the Roland Morris Questionnaire (RMDQ); c) change from baseline at week 16 in the Global Patient Assessment (PGA) pain score; d) change in mean daily pain intensity on the NRS scale at 2, 4, 8 and 12 weeks compared to baseline; e) change from baseline at week 16 in the percentage of patients responding to treatment, as defined by a 30% reduction and a 50% reduction for (i) mean daily NRS pain intensity; (ii) total RMDQ score; and (iii) PGA pain scores; f) change from baseline at week 16 in Medical Outcomes Study (MOP) sleep subscale scores; g) change from baseline at week 16 in the Brief Health Survey (SF-36) subscale scores; h) EQ-5D-5L change from baseline at week 16; and i) change from baseline at week 16 in the percentage of patients taking emergency pain medications.

[00109] The degree of pain is assessed using standard methods known to those skilled in the art. For example, using methods including those described herein, such as scoring on the Numerical Pain Rating Scale (NRS); Roland Morris Disability Questionnaire (RMDQ) total score; or Global Patient Assessment (PGA) pain score (see Mannion, AF, et al. Nature Clinical Practice Rheumatology (2007) 3: 610-618.

[00110] Various tools have been developed to assess pain intensity (how much a person is in pain) and pain impact (how much a person is suffering). Three methods are traditionally used to measure pain intensity: visual analogue scales (VAS), verbal rating scales (VRS), and numerical rating scales (NRS). See Von Korff M et al. (2000), Spine 25: 3140-3151; Zanoli G et al. (2000), Spine 25: 3178-3185; Haefeli M and Elfering A (2006), Eur Spine J 15 (Suppl 1): S17-S24; McGuire DB (1999), Instruments for Health-Care Research 528-561 (Eds Frank-Stromborg M and Olsen S) Boston: Jones and Bartlett; Ogon M et al. (1996), Pain 64: 425-428; Hagg O et al. (2003), Eur Spine J 12: 12-20; Jensen MP et al. (1986), Pain 27: 117-126).

[00111] The Visual Analogue Scale (VAS) consists of a line, typically 100 mm long, the ends of which are labeled extreme ("no pain" and "pain as bad as possible"); the rest of the line is empty. The patient is asked to mark the line indicating the intensity of the pain (currently, in the last week, or in the last 2 weeks, etc.). The distance between this mark and the starting point is measured to obtain the patient's score. Sometimes descriptive terms such as "mild", "moderate" and "severe" or numbers are given along the scale for guidance, with "moderate" falling in the middle range of the scale, and then the scale is referred to as the graphic rating scale.

[00112] Verbal Rating Scales (VRS) consist of a list of adjectives that describe different levels of pain intensity. The VRS for pain assessment includes adjectives that reflect extremes (e.g., "no pain" to "pain is as bad as it gets") and enough adjectives to capture gradations in between. VRS is most often a five-point or six-point scale. The patient is asked to select from a questionnaire or verbally indicate the adjective that best describes his or her level of pain intensity. In behavior rating scales, different levels of pain are described by sentences that include behavioral parameters.

[00113] The Numeric Rating Scale (NRS) involves asking patients to rate the intensity of their pain by selecting a number on a scale from 0 to 10 (11 point scale), 0-20 (21 point scale), or 0-100. (101-point scale) by filling out a questionnaire or verbally indicating a numerical level. For example, zero (0) would mean "no pain" and one hundred (100) would mean "as much pain as possible". The patient is asked to write only one number. For example, using 0-10 NRS, a patient showing "moderate back pain" could enter a number from 4 to 6 for "moderate pain" and 7 to 10 for "severe pain". See the example table below.

Grade Pain level 0 No pain 1-3 Mild pain (drawing, irritating, little interfering with daily activities (ADL)) 4-6 Moderate pain (significantly interferes with ADL) 7-10 Severe pain (disability; inability to perform ADL)

[00114] It can also be said that the patient has moderate to severe pain in the knees and/or hips when the patient is resistant or refractory to treatment with standard analgesics such as acetaminophen or NSAIDs, or any other commonly used therapeutic agent known in this areas for the treatment of pain in the knees and / or hip joints.

[00115] As noted above, the present invention includes methods for treating knee and/or hip pain in patients who have a history of inadequate pain relief or intolerance to standard pain medication, or who are resistant, unresponsive, or under-responsive to standard analgesic treatment. The term "inadequate pain relief" refers to an unacceptable level of pain relief experienced by subjects after treatment with a standard analgesic, who may find that they are unable to carry out normal daily activities due to the pain level score.

[00116] The term "intolerance to standard analgesic treatment" refers to subjects or patients who, for example, are allergic to a standard analgesic or who experience an adverse event after treatment with a standard analgesic. The term "resistant, refractory or insufficiently sensitive to standard analgesic" in the context of the present description refers to subjects or patients with pain in the knees and/or hip joints, who were treated, for example, NSAIDs, and in which NSAIDs do not have a curative effect. In some embodiments, the term refers to decreased patient compliance and/or toxicity and side effects and/or ineffectiveness of an administered analgesic in reducing, alleviating, or reducing symptoms of knee and/or hip pain. In some embodiments of the invention, the term refers to patients suffering from moderate to severe pain in the knees and/or hip joints, which are not amenable to treatment with standard analgesics. In some embodiments of the invention, patients who are "resistant, insensitive or insufficiently responsive to a standard analgesic" may not show improvement in one or more parameters associated with pain. Examples of pain-related parameters are described herein. For example, treatment with a standard analgesic may not change the NRS knee and/or hip pain score or the Roland Morris Questionnaire (RMDQ) total score. In some embodiments, the present invention includes methods for treating moderate to severe knee and/or hip pain in patients who have previously received an analgesic, e.g., for ≥1 month, and have shown no change (e.g., decrease) in one or more parameters associated with pain.

[00117] While any methods and materials similar or equivalent to those described herein may be used in the practice of the present invention, preferred methods and materials are described below. All publications mentioned in this document are incorporated herein by reference for their full description.

Ways to reduce the risk of developing arthropathy associated with the use of anti-NGF antibodies

[00118] In some aspects of the invention, the methods and compositions of the present disclosure are used to prevent arthropathy developing in a subset of patients receiving a higher dose of an anti-NGF antibody or fragment thereof for the treatment of hip and/or knee pain.

[00119] As can be seen from the data presented in the "Examples" section of the application, about 7% of patients who received anti-NGF antibody at a dose of 6 or 9 mg developed arthropathy. Thus, in certain aspects of the invention, methods and compositions for treating hip and/or knee pain may include the use of an anti-NGF antibody at a dose of less than 9 mg or a dose of less than 6 mg.

[00120] In some aspects of the invention, methods and compositions for treating hip and/or knee pain can help avoid arthropathy by using an anti-NGF antibody at a dose of less than 5 mg, such as 1 mg-4 mg, such as 1 mg or 3 mg.

[00121] In some aspects of the invention, arthropathy that can be avoided using the described compositions and methods of treatment is a confirmed arthropathy. In some aspects of the invention, arthropathy includes rapidly progressive OA. OA can be type 1, in which there is a narrowing of the joint space that exceeds predetermined thresholds. In some aspects of the invention, OA may be type 2, in which changes in bone structure are observed on a plain radiograph. Plain radiography refers to plain X-ray radiography and does not require computed tomography (CT), ultrasound, or magnetic resonance imaging (MRI). In some aspects of the invention, arthropathy avoidable by the described compositions and methods of treatment is joint space narrowing in excess of predetermined thresholds, changes in bone structure on a plain radiograph, or both.

[00122] A dose of anti-NGF antibody suitable for preventing arthropathy may be administered intravenously or subcutaneously at a frequency of every 4 weeks for up to 16 weeks.

[00123] In some aspects of the invention, the methods and compositions described herein can reduce the incidence of arthropathy in treated subjects by at least 50% (e.g., at least 55%, at least 60%, at least 70%) compared with the incidence of arthropathy in a subject receiving a higher dose of anti-NGF antibody, for example, in a subject receiving a dose of at least 6 mg or at least 9 mg of anti-NGF antibody.

[00124] In some aspects of the invention, the methods and compositions described herein can reduce the occurrence of rapidly progressive osteoarthritis in treated subjects by at least 50% (e.g., at least 55%, at least 60%, by at least 70%), compared with a subject receiving a higher dose of anti-NGF antibody, for example, a subject receiving a dose of at least 6 mg or at least 9 mg of anti-NGF antibody.

[00125] Subjects that may benefit from the described method and composition for reducing the risk of developing arthropathy may be the same as those described in the previous section. For example, the subject is refractory to pain medication or suffers side effects from pain medication, the subject is diagnosed with osteoarthritis of the knee and/or hip, the subject is diagnosed with moderate to severe pain in the index joint of the knee and/or hip, defined as a subscale pain score Western Ontario and McMaster Universities (WOMAC) osteoarthritis scores ≥4, subject has a Kellgren-Lawrence [K-L] score ≥2 on a scale of 0 to 4, subject has a Kellgren-Lawrence [K-L] score of 3 or 4 prior to treatment , scale from 0 to 4, and/or the subject received analgesic treatment on average 4 days per week for a 4-week period prior to initiation of anti-NGF antibody treatment.

Method for Monitoring the Safety of NGF Antagonist Treatment

[00126] As shown in the Examples section of the application, doses of about 9 mg and about 6 mg may have distinct advantages over 3 mg and 1 mg of anti-NGF antibody in the treatment of hip and/or knee pain. For example, a higher dose may result in pain relief and/or increased knee/hip function at a faster rate than lower doses. However, a small subset of patients receiving a higher dose (eg, about 9 mg of about 6 mg of fasinumab) may experience treatment-emergent side effects (TEAEs), such as arthropathy.

[00127] The method for treating hip and/or knee pain described herein combines the superior results associated with a higher dose of anti-NGF antibody with a reduced risk of treatment-related adverse events (TEAEs), such as arthropathy observed at a lower dose (eg, less than 6 mg of anti-NGF antibody).

[00128] In some aspects of the invention, the method may include administering a higher dose of anti-NGF antibody; monitoring a joint (eg, knee or hip) of the subject to determine if the subject has developed arthropathy; wherein, if the subject has developed arthropathy, administering to the subject a pharmaceutical composition containing a dose of less than about 9 mg of the antibody or antigen-binding fragment thereof; or, if the subject has not developed arthropathy, administering to the subject a pharmaceutical composition containing a dose of about 9 mg of the antibody or antigen-binding fragment thereof.

[00129] If the subject has developed arthropathy, subsequent treatment comprises administering a pharmaceutical composition containing 1.0 mg to less than about 6 mg of an anti-NGF antibody or antigen-binding fragment thereof, wherein treatment reduces knee or hip pain and reduces arthropathy .

[00130] Subjects that may benefit from the described method for monitoring the safety of anti-NGF antibody treatment may be the same as those described in the previous sections. For example, the subject is refractory to pain medication or suffers side effects from pain medication, the subject is diagnosed with osteoarthritis of the knee and/or hip, the subject is diagnosed with moderate to severe pain in the index knee and/or hip, defined as a subscale pain score University of Western Ontario and McMaster (WOMAC) osteoarthritis scores ≥4, subject has a Kellgren-Lawrence [K-L] score ≥2 on a scale of 0 to 4, prior to treatment subject has a Kellgren-Lawrence [K-L] score of 3 to 4 on a scale of 0 to 4, and/or the subject received analgesic treatment on average 4 days per week for a 4 week period prior to initiation of anti-NGF antibody treatment.

[00131] Arthropathy can be the same as described in the previous section. Monitoring for the presence of arthropathy may include x-rays of the hip and/or knee. In some aspects of the invention, the development of arthropathy in other locations, such as the shoulders, fingers and toes, can be assessed. Evaluation for arthropathy may also include a CT scan, MRI, or ultrasound of joints such as the hip, knee, shoulder, fingers, and/or toes.

[00132] In some aspects of the invention, arthropathy can be controlled after administration of a dose of anti-NGF, but before administration of a secondary dose. For example, the presence of arthropathy can be monitored 2 weeks, 3 weeks, or 4 weeks after anti-NGF antibody administration. If arthropathy is found, the secondary dose may be reduced from the previous dose.

[00133] In some aspects of the invention, after administration of a lower dose, the subject can again be observed for evidence of arthropathy. If the arthropathy improved about 4 weeks after taking a lower dose, the next dose can be increased, and so on.

[00134] In some aspects of the invention, the method may include administering a dose of 9 mg of anti-NGF antibody; monitoring a subject's joint (eg, knee or hip) to determine if the subject has developed arthropathy; wherein, if the subject has developed arthropathy, administering to the subject a pharmaceutical composition containing a dose of less than about 9 mg of the antibody or antigen-binding fragment thereof; or, if the subject has not developed arthropathy, administering to the subject a pharmaceutical composition containing a dose of about 9 mg of the antibody or antigen-binding fragment thereof.

[00135] In some aspects of the invention, the method may include administering a dose of 6 mg of anti-NGF antibody; observing the subject's joint (knee or hip) to determine if the subject has developed arthropathy; wherein, if the subject has developed arthropathy, administering to the subject a pharmaceutical composition containing a dose of less than about 6 mg of the antibody or antigen-binding fragment thereof; or, if the subject has not developed arthropathy, administering to the subject a pharmaceutical composition containing a dose of about 6 mg of the antibody or antigen-binding fragment thereof.

[00136] In some aspects of the invention, if the subject has developed arthropathy, one or more secondary doses may be 1 mg until the arthropathy decreases or becomes undetectable. If arthropathy is not detected, the subsequent dose may be the same as the initial dose. If the arthropathy has improved, a subsequent dose may be 3 mg until the arthropathy becomes undetectable. If arthropathy is not detected, the subsequent dose may be the same as the initial dose.

Ways to Improve Pain-Related Parameters: Measurements of Therapeutic Efficacy

[00137] The present invention includes methods for improving one or more pain-related parameters in a subject in need thereof, the methods comprising administering to the subject a pharmaceutical composition comprising an NGF antagonist, such as an anti-NGF antibody of the invention, or an antigen-binding fragment thereof.

[00138] Examples of "pain-related parameters" include: (a) Western Ontario and McMaster Universities Osteoarthritis Pain Scale (WOMAC); (b) physical function subscale scores; and (c) a General Patient Assessment (PGA) numeric knee and/or hip pain scale (NRS); (d) Roland Morris Disability Questionnaire (RMDQ) scores; (e) Medical Outcomes Study (MOP) sleepiness subscale score; (f) Brief Health Survey (SF-36) subscale scores; (g) EQ-5D-5L; and (h) the percentage of patients who are taking emergency medications for knee and/or hip pain.

[00139] "Improvement in a pain-related parameter" means a significant change from baseline in one or more of the following: (a) change in average daily knee and/or hip pain intensity in Numerical Rating Scale (NRS) scores ; (b) the change from baseline at week 16 in the total score of the Roland Morris Disability Questionnaire; (c) change from baseline at week 16 in the Patient Global Assessment (PGA) score for knee and/or hip pain; or (d) change from baseline at weeks 2, 4, 8 and 12 in the mean daily NRS knee and/or hip pain score. In addition, "improvement in a pain-related parameter" means a change from baseline in one or more of the following: (e) a change from baseline at week 16 in the percentage of patients responding to treatment, as defined by a 30% and 50% for (i) mean daily NRS knee and/or hip pain score; (ii) total RMDQ score; and (iii) PGA knee and/or hip pain assessment; or (f) a change from baseline at week 16 in Medical Outcomes Study sleepiness subscale scores; or (g) change from baseline at week 16 on the Brief Health Assessment subscale (SF-36); or (h) change from baseline at week 16 on EQ-5D-5L; or i) change from baseline at week 16 in the percentage of patients taking rescue medications for knee and/or hip pain.

[00140] As used herein, the term "baseline" in relation to a pain-related parameter means the numerical value of a pain-related parameter for a subject before or during administration of a pharmaceutical composition of the present invention.

[00141] To determine whether a parameter associated with pain has "improved", the parameter is quantified at baseline and at one or more time points after administration of the pharmaceutical composition of the present invention. For example, a pain-related parameter can be measured at various time points after fasinumab administration, such as day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 12, day 18, day 22, day 36, day 50, day 57, day 64, day 78, day 85, day 92, day 106, day 113, day 120; or at the end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16 or longer after initial treatment with a pharmaceutical composition of the present invention. The difference between the parameter value at a particular point in time after the start of treatment and the parameter value at baseline is used to determine whether there has been an "improvement" (eg, decrease) in the parameter associated with pain.

[00142] Western Ontario and McMaster Universities Osteoarthritis Subscale Pain Score (WOMAC) : The WOMAC Subscale Pain Score is a composite index of 5 questions related to joint pain when walking, using stairs, at rest in bed, sitting, or lying, standing, and described by Bellamy N. WOMAC Osteoarthritis Index: A Userʼs Guide. London, Ontario, Canada: Victoria Hospital; 1995. Individual WOMAC questions are scored on a scale of 0 to 10. The scores for each of the 5 questions are averaged.

[00143] WOMAC Physical Function Subscale Score: The WOMAC Physical Function Subscale Score defines 17 functional limitation items (scale 0 to 68; arithmetically converted to a scale of 0 to 10). Physical functioning questions cover activities of daily living such as using stairs, getting up from a sitting or lying position, standing, bending over, walking, getting in and out of a car, shopping, putting on or taking off socks, lying in bed, getting in and out of the bath , sitting and performing heavy and light household chores.

[00144] Numerical Knee and/or Hip Pain Intensity Rating Scale: The Knee and/or Hip Pain Intensity Numeric Rating Scale (NRS) involves asking patients to rate their pain intensity by selecting a number on a scale from 0 to 10 (11- point scale), 0-20 (21-point scale) or 0-100 (101-point scale) by filling out a questionnaire or verbally indicating a numerical level. For example: “Please write on the line below the number from 0 to 100 that best describes your pain. Zero (0) would mean "no pain" and one hundred (100) would mean "as much pain as possible. Please write only one number. To enter the corresponding number, an empty field or line is provided. A slight variation on the NRS is the box scale, where each number (e.g., 0-10) is written in a box, and patients are asked, "If zero (0) means 'no pain' and ten (10) means 'pain so bad, as far as possible”, what is your level of pain on a scale from 0 to 10? Put an "X" to indicate this number." In some embodiments of the present invention, administration of an NGF antagonist to a patient results in a decrease in NRS score. For example, the present invention includes therapeutic methods that result in a reduction from baseline in the NRS score of at least about 10%, 20%, 30%, 40%, 50%, or more by 2, 4, 8, 12, and 16 a week or later after administration of an NGF antagonist (eg, after administration of about 1 mg, about 2 mg, about 6 mg, or 9 mg of an anti-NGF antibody or antigen-binding fragment thereof).

[00145] The Roland Morris Disability Questionnaire : The RMDQ is a widely used self-assessment of health status for knee and/or hip pain (Roland MO, Morris RW, Spine 1983; 8: 141-144). It measures pain and function using 24 items that describe the limitations of daily life that may be caused by knee and/or hip pain. The RMDQ score is the total number of items tested, that is, from a minimum of 0 to a maximum of 24. The Roland-Morris Disability Questionnaire is compiled by selecting statements from the Disease Impact Profile (SIP), which is a 136-item measure of health status covering a range of aspects of daily life relating to physical and mental functions. The scale consists of 24 yes/no items specific to physical function for a specific assessment of disability from knee and/or hip pain. Physical functions considered include walking, bending over, sitting, lying down, dressing, sleeping, grooming, and activities of daily living. Patients are asked if the statements apply to them on that day (that is, in the last 24 hours). The scale gives one point for each subject. The RDQ score can be obtained by adding up the number of items tested. The final score ranges from 0 (no disability) to 24 (severe disability). According to some embodiments of the present invention, administration of an NGF antagonist to a patient results in a decrease in RMDQ. For example, the present invention includes therapeutic methods that result in a decrease from baseline in the RMDQ score of at least about 2-5 points for a moderate improvement and more than 5 points, which is considered a significant or significant improvement of 2, 4, 8 , 12 and 16 weeks or later after the administration of the NGF antagonist (for example, after administration of about 6 mg or 9 mg of anti-NGF antibody or antigen-binding fragment).

[00146] Patient Overall Assessment of Knee and/or Hip Pain: The PGA of knee and/or hip pain is the patient's assessment of the current disease state on a 5-point Likert scale (1=very good; 2=good; 3=fair ; 4=bad; 5=very bad). In some embodiments of the present invention, administering an NGF antagonist to a patient results in a reduction in the PGA score for knee and/or hip pain. For example, the present invention includes therapeutic methods that result in a lower than baseline PGA score in knee and/or hip pain scores of at least 1 point, or 2 points, or 3 points, or more by 2, 4, 8, 12, and 16 weeks or later after administration of the NGF antagonist (eg, after administration of about 6 mg or 9 mg of anti-NGF antibody or antigen-binding fragment thereof).

[00147] Brief Health Assessment Questionnaire (36) : The SF-36 is a self-assessment of general health. It assesses 8 areas of health: physical functioning, role functioning limitations due to physical condition, bodily pain, general perception of health, vitality, social functioning, role functioning limitations due to emotional state, and mental health. It gives a scoring scale for each of these 8 health areas and 2 physical and mental health summaries: a physical component summary and a mental component summary. Each scale is directly converted to a scale from 0 to 100, provided that each question has an equal weight. The lower the score, the greater the disability. The higher the score, the less disability, that is, a zero score corresponds to the maximum disability, and 100 points to the absence of disability. In some embodiments of the present invention, administration of an NGF antagonist to a patient results in an increase in SF-36. For example, the present invention includes therapeutic methods that result in an increase from baseline in SF-36 by at least about 10%, 20%, 30%, 40%, 50%, or more by 2, 4, 8, 12 and 16 weeks or later after administration of the NGF antagonist (eg, after administration of about 6 mg or 9 mg of an anti-NGF antibody or antigen-binding fragment thereof).

[00148] The Sleep Measures Medical Outcomes Study: The MOS Sleep Study is a 12-question self-guided sleep habit survey (Hays RD, Stewart AL (1992). Sleep measures. In AL Stewart & JE Ware (eds.), Measuring functioning and well-being: The Medical Outcomes Study approach (pp235-259), Durham, NC: Duke University Press). In accordance with some embodiments of the present invention, administration of an NGF antagonist to a patient results in an improvement in MOS sleep study results compared to baseline. For example, the present invention includes therapeutic methods that result in a change from baseline in an MOS sleep study at or after weeks 2, 4, 8, 12, and 16 after administration of an NGF antagonist (e.g., after administration of about 6 mg or 9 mg of an anti -NGF antibody or antigen-binding fragment).

[00149] EQ-5D-5L: The EQ-5D-5L questionnaire is a standardized health measure developed by the EuroQol Group as a simple health analysis tool for clinical and economic evaluation. EQ-5D-5L as an indicator of health-related quality of life, defines health in terms of 5 dimensions: movement in space, self-care, daily activities, pain/discomfort, anxiety/depression. Each dimension has 3 ordinal severity levels: "no problems" (1), "some problems" (2), "severe problems" (3). General health is defined as a 5-digit number. The health status defined by the 5-dimensional classification can be converted into corresponding index scores that quantify health status, where -0.594 means "severe problems" and 1 means "no problem". In some embodiments of the present invention, administration of an NGF antagonist to a patient results in an improvement in EQ-5D-5L from baseline. For example, the present invention includes therapeutic methods that result in a change from baseline in EQ-5D-5L levels at or after 2, 4, 8, 12, and 16 weeks after administration of an NGF antagonist (for example, after administration of about 6 mg or 9 mg anti-NGF antibody or antigen-binding fragment).

[00150] Additional details of various methods for assessing pain, resistance or intolerance to analgesics, and the like are described in US20180147280, which is incorporated herein by reference in its entirety.

NGF antagonists

[00151] As detailed above, the present invention includes methods that include administering to a subject in need thereof a therapeutic composition comprising an NGF antagonist. As used herein, "NGF antagonist" means any agent that binds to or interacts with NGF and inhibits the normal biological function of NGF when NGF is expressed in a cell in vitro or in vivo . Non-limiting examples of NGF antagonist categories include small molecule NGF antagonists, anti-NGF aptamers, peptide-based NGF antagonists (e.g., "peptibody" molecules), and antibodies or antigen-binding antibody fragments that specifically bind human NGF.

[00152] The terms "NGF", "hNGF" and the like, as used herein, are intended to refer to nerve growth factor, and in particular human nerve growth factor, the amino acid sequence of which is shown as SEQ ID NO: 18, and which is encoded by the sequence nucleic acid shown as SEQ ID NO: 17. Unless specifically indicated as belonging to a non-human species, the term "NGF" as used herein should be understood to mean human NGF.

[00153] The term "antibody" as used herein is intended to refer to immunoglobulin molecules containing four polypeptide chains, two heavy (H) chains, and two light (L) chains linked together by disulfide bonds, as well as their multimers ( e.g. IgM). Each heavy chain includes a heavy chain variable region (abbreviated herein as HCVR or V _H ) and a heavy chain constant region. The heavy chain constant region includes three domains: C _H 1, C _H 2 and C _H 3. Each light chain includes a light chain variable region (abbreviated as LCVR or V _L ) and a light chain constant region. The light chain constant region includes one domain (C _L 1). The V _H and V _L regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), interspersed with regions that are more conserved, called framework regions (FRs). Each V _H and V _L consists of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments, the FR of the anti-NGF antibody (or antigen-binding portion thereof) may be identical to human germline sequences, or may be naturally or artificially modified. Amino acid consensus sequence can be determined based on the analysis of two or more CDRs.

[00154] The term "antibody" as used herein also includes antigen-binding fragments of complete antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically produced, synthetic, or engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody can be generated, for example, from complete antibody molecules using any suitable standard techniques such as proteolytic cleavage or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding the variable and optionally constant domains of the antibody. Such DNA is known and/or readily available, for example from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. DNA can be sequenced and processed chemically or using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or remove amino acids, and so on.

[00155] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(abʼ)2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single chain Fv molecules (scFv); (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic an antibody hypervariable region (eg, a distinguished complementarity determining region (CDR) such as a CDR3 peptide) or a limited FR3-CDR3-FR4 peptide. Other engineered molecules such as domain specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR grafted antibodies, diabodies, tribodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, divalent nanobodies, etc.) , small modular immunopharmaceuticals (SMIPs), and shark IgNAR variable domains are also encompassed by the expression "antigen binding fragment" as used herein.

[00156] An antigen binding fragment of an antibody typically contains at least one variable domain. The variable domain can be of any size or any amino acid composition, and typically contains at least one CDR that is adjacent to or in-frame with one or more framework sequences. In antigen-binding fragments having a V _H domain associated with a V _L domain, the V _H and V _L domains may be arranged relative to each other in any suitable order. For example, the variable region may be dimeric and contain V _H -V _H , V _H -V _L or V _L -V _L dimers. Alternatively, the antigen-binding fragment of an antibody may comprise a V _H or V _L monomeric domain.

[00157] In some embodiments, an antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting typical configurations of variable and constant domains that can be found in the antigen-binding fragment of the antibody of the present invention include: (i) V _{H -CH} 1; (ii) V _H -C _H 2; (iii) V _H -C _H 3; (iv) V _H -C _H 1 -C _H 2; (v) V _H -C _H 1 -C _H 2 -C _H 3; (vi) V _H -C _H 2 -C _H 3; (vii) V _H -C _L ; (viii) V _L -C _H 1; (ix) V _{L -CH} 2; (x) V _L -C _H 3; (xi) V _L -C _H 1 -C _H 2; (xii) V _L -C _H 1 -C _H 2 -C _H 3; (xiii) V _L -C _H 2 -C _H 3 and (xiv) V _L -C _L . In any configuration of the variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may either be directly linked to each other or may be linked through a complete or partial hinge or linker region. The hinge region may be at least 2 (eg, 5, 10, 15, 20, 40, 60 or more) amino acids, resulting in a flexible or semi-flexible bond between adjacent variable and/or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present invention may comprise a homodimer or heterodimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with each other and/or with one or more V _H or V _L monomeric domains. (for example, via disulfide bond(s)).

[00158] As with full antibody molecules, antigen-binding fragments can be monospecific or multispecific (eg, bispecific). A multispecific antigen-binding fragment of an antibody typically contains at least two different variable domains, where each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in the context of an antigen-binding fragment of an antibody of the present invention using standard techniques available in the art.

[00159] The constant region of an antibody is important for the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the antibody isotype can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[00160] The term "human antibody" as used herein is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. However, human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-directed mutagenesis or in vivo somatic mutation), for example, in CDRs and, in particular, in CDR3. However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[00161] The term "human antibody" as used herein is intended to include non-naturally occurring human antibodies. The term includes antibodies that are recombinantly produced in a non-human mammal or in cells of a non-human mammal. The term is not intended to include antibodies isolated or generated from humans.

[00162] The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are produced, expressed, generated, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a cell host (described below), antibodies isolated from a recombinant combinatorial library of human antibodies (described below), antibodies isolated from an animal (e.g., mouse) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies produced, expressed, constructed or isolated by any other means that involve splicing human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies undergo in vitro mutagenesis (or, when an animal transgenic for human Ig sequences, in vivo somatic mutagenesis is used) and thus the amino acid sequences of the V _H and V _L regions of the recombinant antibody are sequences , which, although derived from and related to human germline V _H and V _L sequences, may not exist naturally in the in vivo human germline antibody repertoire.

[00163] Human antibodies can exist in two forms that are associated with hinge heterogeneity. In one form, the immunoglobulin molecule contains a stable four chain construct of approximately 150-160 kDa, in which the dimers are held together by an interchain heavy chain disulfide bond. In the second form, the dimers are not linked by interchain disulfide bonds, and a molecule of approximately 75-80 kDa is formed, consisting of covalently linked light and heavy chains (half-antibodies). These forms were extremely difficult to separate even after affine purification.

[00164] The frequency of appearance of the second form in different isotypes of intact IgG is due to, but not limited to, structural differences associated with the isotype of the hinge region of the antibody. A simple amino acid substitution at the human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels normally seen with the human IgG1 hinge. The present invention encompasses antibodies having one or more mutations in the hinge region, CH2 or CH3 region, which may be desirable, for example during production, to increase the yield of the desired antibody form.

[00165] "Isolated antibody" in the context of the present description means an antibody that has been identified and isolated and/or isolated from at least one component of its natural environment. For example, an antibody that has been isolated or removed from at least one component of an organism, or from a tissue or cell in which the antibody exists or is naturally produced, is an "isolated antibody" for the purposes of the present invention. An isolated antibody also includes an antibody in situ in a recombinant cell. Isolated antibodies are antibodies that have undergone at least one purification or isolation step. In some embodiments, the isolated antibody may be substantially free of other cellular material and/or chemicals.

[00166] The term "specifically binds" and the like means that an antibody or antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" NGF as used in the context of the present invention includes antibodies that bind NGF, or a portion thereof, with a KD of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 0.5 nM, less than 0.1 nM, less than 1.0 pM, or less than 0.5 pM, as determined by surface plasmon resonance analysis.

[00167] Anti-NGF antibodies useful for the methods of the present invention may contain one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequence, from which antibodies were obtained. Such mutations can be readily identified by comparing the amino acid sequences described herein with germline sequences available, for example, from public antibody sequence databases. The present invention includes methods comprising the use of antibodies and antigen-binding fragments thereof that are derived from any of the amino acid sequences described herein, wherein one or more amino acids in one or more framework regions and/or CDR regions are mutated to the corresponding residue(s) the germline sequence from which the antibody is derived, or the corresponding residue(s) of another human germline sequence, or up to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are collectively referred to herein as "germline mutations"). One skilled in the art, starting from the heavy and light chain variable region sequences described herein, can easily generate numerous antibodies and antigen-binding fragments that contain one or more individual germline mutations, or combinations thereof. In some embodiments, all framework and/or CDR residues in the V _H and/or V _L domains are mutated back to residues found in the original germline sequence from which the antibody originated. In other embodiments, only certain residues are mutated back to the original germline sequence, for example, only mutated residues found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only mutated residues found in CDR1, CDR2, or CDR3. In other embodiments, one or more framework and/or CDR residues are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that differs from the germline sequence from which the antibody was originally derived). In addition, the antibodies of the present invention may contain any combination of two or more germline mutations within the framework region and/or CDR regions, for example, where certain individual residues are mutated to the corresponding residue of a particular germline sequence, while some other residues, that differ from the original germline sequence are retained or mutated to the corresponding residue of a different germline sequence. Once generated, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as applicable) , reduced immunogenicity, etc. The use of antibodies and antigen-binding fragments obtained by this general method is covered by the present invention.

[00168] The present invention also includes methods comprising the use of anti-NGF antibodies containing variants of any of the HCVR, LCVR and/or CDR amino acid sequences described herein having one or more conservative substitutions. For example, the present invention includes the use of anti-NGF antibodies having the amino acid sequences HCVR, LCVR, and/or CDR, e.g., 10 or less, 8 or less, 6 or less, 4 or less, etc. conservative amino acid substitutions relative to any from the HCVR, LCVR and/or CDR amino acid sequences described herein.

[00169] The term "Surface Plasmon Resonance", as used herein, refers to an optical phenomenon that allows real-time analysis of interactions by detecting changes in protein concentrations in a biosensor array, for example, using the BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[00170] The term "KD" as used herein is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[00171] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. One antigen may have more than one epitope. Thus, different antibodies can bind to different regions of the antigen and have different biological effects. Epitopes may be conformational or linear. A conformational epitope is produced by spatially arranged amino acids from different segments of the linear polypeptide chain. A linear epitope is an epitope produced by adjacent amino acid residues in a polypeptide chain. In certain circumstances, an epitope may include portions of saccharides, phosphoryl groups, or sulfonyl groups on an antigen.

Obtaining human antibodies

[00172] Methods for producing human antibodies in transgenic mice are known in the art. Any such known methods can be used in the context of the present invention to obtain human antibodies that specifically bind to human NGF.

[00173] Using VELOCIMMUNE™ technology (see, for example, US 6596541, Regeneron Pharmaceuticals) or any other known method for producing monoclonal antibodies, high affinity anti-NGF chimeric antibodies having a human variable region and a mouse constant region are initially isolated. The VELOCIMMUNE® technology involves generating a transgenic mouse whose genome contains human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigen challenge. The DNA encoding the heavy and light chain variable regions of an antibody is isolated and operably linked to the DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing a fully human antibody.

[001744] Typically, a VELOCIMMUNE® mouse is challenged with an antigen of interest and antibody-expressing lymphatic cells (such as B cells) are isolated from the mice. Lymphatic cells can be fused with a myeloma cell line to generate immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific for the antigen of interest. DNA encoding the heavy chain and light chain variable regions can be isolated and linked to the desired isotypic heavy chain and light chain constant regions. Such an antibody protein may be produced in a cell, such as a CHO cell. Alternatively, DNA encoding antigen-specific chimeric antibodies or light and heavy chain variable domains can be isolated directly from antigen-specific lymphocytes.

[00175] Initially, high affinity chimeric antibodies having a human variable region and a mouse constant region are isolated. Antibodies are characterized and selected for desirable characteristics, including affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art. The mouse constant regions are replaced with the desired human constant region to produce a fully human antibody of the invention, eg wild-type or modified IgG1 or IgG4. Although the constant region chosen may vary depending on the particular use, the characteristics of high affinity antigen binding and target specificity are in the variable region.

[00176] Typically, antibodies that can be used in the methods of the present invention have high affinity, as described above, when measured by binding to an antigen immobilized on the solid phase or in the solution phase. The mouse constant regions are replaced with the desired human constant regions to produce fully human antibodies of the invention. Although the constant region chosen may vary depending on the particular use, the characteristics of high affinity antigen binding and target specificity are in the variable region.

[00177] Specific examples of human antibodies or antigen-binding antibody fragments that specifically bind NGF that can be used in the context of the methods of the present invention include any antibody or antigen-binding fragment that includes the three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained in heavy chain variable region (HCVR) having an amino acid sequence consisting of SEQ ID NO: 2. An antibody or antigen binding fragment may comprise three light chain CDRs (LCVR1, LCVR2, LCVR3) contained in a light chain variable region (LCVR) having an amino acid a sequence consisting of SEQ ID NO: 10. Methods and techniques for identifying CDRs in HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs in certain HCVR and/or LCVR amino acid sequences described herein. Exemplary conventions that can be used to identify CDR boundaries include, for example, the definition of Kabat, the definition of Chothia, and the definition of AbM. In general terms, Kabat's definition is based on sequence variability, Chothia's definition is based on the location of structural loop regions, and AbM's definition is a compromise between Kabat's and Chothia's approaches. See, for example, Kabat, "Sequences of Proteins of Immunological Interest", National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al. , J. Mol. Biol. 273 :927-948 (1997); and Martin et al. , Proc. Natl. Acad. sci. USA 86 :9268-9272 (1989). Generic databases are also available for identifying CDR sequences in an antibody.

[00178] In some embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) pairs of heavy and light chain variable region (HCVR/LCVR) amino acid sequences SEQ ID NO: 2/ 10.

[00179] In some embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3) having amino acid sequences consisting of SEQ ID NOs: 4/6/8/12/14 /16.

[00180] In some embodiments, the antibody or antigen-binding fragment thereof comprises HCVR/LCVR amino acid sequence pairs consisting of SEQ ID NO: 2/10.

[00181] As used herein, the term "facinumab" is used interchangeably to refer to an anti-NGF antibody. The amino acid sequences of the heavy and light chain variable regions and CDRs, as well as the nucleotide sequences of fascinumab, are described in Tables 1A and 1B, respectively. Characterization of fasinumab is described in PCT Publication No. WO 2009/023540 and WHO Drug Information Vol. 26, no. 2, (2012), which are incorporated herein by reference in their entirety. Tables 1A and 1B list the amino acids of SEQ ID NO and the nucleic acids of SEQ ID NO for the anti-NGF antibody described herein:

Table 1A AMINO ACIDS SEQ ID NO: Designation of antibodies HCVR HCDR1 HCDR2 HDDR3 LC
VR LCDR1 LCDR2 LCDR3 Fasinumab 2 4 6 eight 10 12 fourteen 16 Table 1B NUCLEIC ACIDS SEQ ID NO: Designation of antibodies HC
VR HCDR1 HCDR2 HDDR3 LC
VR LCDR1 LCDR2 LCDR3 Fasinumab one 3 five 7 nine eleven 13 fifteen

Pharmaceutical compositions

[00182] The present invention includes methods that include administering an NGF antagonist to a patient, wherein the NGF antagonist is contained in a pharmaceutical composition. Pharmaceutical compositions of the invention are formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerability, and the like. Many suitable formulations can be found in recipes known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipids (cationic or anionic) containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorbent pastes, oil in water, and water. emulsions in oil, carbovax emulsions (polyethylene glycols of various molecular weights), semi-solid gels and semi-solid mixtures containing carbovax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

[00183] The dose of an antibody administered to a patient according to the methods of the present invention may vary depending on the patient's age and size, symptoms, condition, route of administration, and the like. The dose is usually calculated based on body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. Effective dosages and modes of administration of pharmaceutical compositions containing anti-NGF antibodies can be determined empirically; for example, the progress of a patient's treatment can be monitored by periodic evaluation and the dose can be adjusted accordingly. Moreover, cross-species dosage scaling can be performed using techniques well known in the art (eg, Mordenti et al. , 1991, Pharmaceut. Res. 8 :1351). Specific examples of doses of anti-IL4R antibodies and regimens with their participation, which can be used in the context of the present invention, are described elsewhere in this document.

[00184] Various delivery systems are known that can be used to administer the pharmaceutical composition of the invention, for example, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, for example, Wu et al. , 1987, J Biol Chem 262:4429-4432). Routes of administration include, without limitation, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous membranes (for example, through the oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with others. biologically active agents.

[00185] The pharmaceutical composition of the present invention may be administered subcutaneously or intravenously using a standard needle and syringe. In addition, with regard to subcutaneous delivery, a pen-type delivery device can easily find use in delivering the pharmaceutical composition of the present invention. Such a pen delivery device may be reusable or disposable. A refillable pen delivery device typically uses a replaceable cartridge containing a pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been introduced and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. There is no replaceable cartridge in the disposable delivery device in the form of a syringe pen. Rather, a disposable pen delivery device is supplied pre-filled with a pharmaceutical composition contained in a reservoir within the device. Once the reservoir is empty of the pharmaceutical composition, the entire device is discarded.

[00186] Numerous reusable pen and auto-injectors are used for subcutaneous delivery of the pharmaceutical composition of the present invention. Examples include but are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes , NJ), OPTIPEN™ OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany) to name but a few. Examples of disposable pen-type delivery devices used for subcutaneous delivery of the pharmaceutical composition of the present invention include, but are not limited to, SOLOSTAR™ pen (sanofi-aventis), FLEXPEN™ (Novo Nordisk) and KWIKPEN™ (Eli Lilly), an auto-injector SURECLICK™ (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.) and HUMIRA™ Pen (Abbott Labs, Abbott Park IL) to name just a few.

[00187] In certain situations, the pharmaceutical composition may be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). Alternatively, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed in close proximity to the target of delivery of the composition, requiring only a fraction of the systemic dose (see, for example, Goodson, 1984, Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are reviewed by Langer, 1990, Science 249:1527-1533.

[00188] Formulations for injection may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, etc. These injections can be obtained by known methods. For example, injectable formulations can be prepared, for example, by dissolving, suspending, or emulsifying an antibody or salt thereof, as described above, in a sterile aqueous or oily medium commonly used for injection. As the aqueous injection medium, for example, physiological saline, isotonic solution containing glucose and other auxiliary agents, etc. are used, which can be used in combination with a suitable solubilizing agent such as an alcohol (for example, ethanol), a polyalcohol (for example, , propylene glycol, polyethylene glycol), non-ionic surfactant [e.g. polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, e.g. sesame oil, soybean oil are used. etc., which can be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus obtained can be filled into an appropriate ampoule.

[00189] Preferably, the oral or parenteral pharmaceutical compositions described above are formulated in unit dose dosage forms appropriate to match the dosage of the active ingredients. Such unit dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[00190] Describes examples of pharmaceutical compositions containing an anti-NGF antibody that can be used in the context of the present invention. Examples of antibodies used are described in International Publication No. 7988967 and US Patent Application Publication No. 2012/0097565. In addition, useful formulations containing antibodies are described in US Patent Application Publication No. 2012/0014968. All are incorporated herein by reference.

Dosage

[00191] The amount of an NGF antagonist (eg, anti-NGF antibody) administered to a subject in accordance with the methods of the present invention is typically a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" means an amount of an NGF antagonist that results in one or more of the following: (a) an improvement in one or more parameters associated with pain (as defined elsewhere herein); and/or (b) a marked improvement in one or more symptoms or signs of pain. A "therapeutically effective amount" also includes an amount of an NGF antagonist that inhibits, prevents, reduces, or delays the progression of pain in a subject.

[00192] In the case of an anti-NGF antibody, a therapeutically effective amount may be from about 0.05 mg to about 600 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg , about 2.0 mg, about 3.0 mg, about 6.0 mg, about 9.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg. mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg or about 600 mg anti-NGF antibody. In some embodiments, about 1-10 mg of an anti-NGF antibody is administered to the subject. In some embodiments, about 1 mg, 3 mg, 6 mg, or 9 mg of an anti-NGF antibody is administered to the subject. In some instances, the anti-NGF antibody includes the CDRs described herein. In some aspects of the invention, the anti-NGF antibody is fasinumab.

[00193] The amount of NGF antagonist contained in individual doses can be expressed as milligrams of antibody per kilogram of the patient's body weight (ie, mg/kg). For example, the NGF antagonist may be administered to a patient at a dose of about 0.0001 to about 10 mg/kg of the patient's body weight. For example, the NGF antagonist may be administered to a patient at a dose of about 0.03 to about 3 mg/kg of the patient's body weight. For example, the NGF antagonist may be administered to a patient at a dose of about 0.03 to about 3 mg/kg of the patient's body weight.

Combination Therapy

[00194] The methods of the present invention, in certain embodiments, comprise administering to a subject one or more additional therapeutic agents in combination with an NGF antagonist. As used herein, the expression "in combination with" means that additional therapeutic agents are administered before, after or simultaneously with a pharmaceutical composition containing an NGF antagonist. The term "in combination with" also includes the sequential or simultaneous administration of an NGF antagonist and a second therapeutic agent.

[00195] For example, when administered "before" a pharmaceutical composition containing an NGF antagonist, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the pharmaceutical composition containing an NGF antagonist. When administered "after" the pharmaceutical composition containing the NGF antagonist, the additional therapeutic agent may be administered after about 10 minutes, after about 15 minutes, after about 30 minutes, after about 1 hour, after about 2 hours, after about 4 hours, after about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of a pharmaceutical composition containing an NGF antagonist. Administration "simultaneously" with or with a pharmaceutical composition containing an NGF antagonist means that an additional therapeutic agent is administered to a subject in a separate dosage form in the range of less than 5 minutes (before, after or simultaneously) with the administration of a pharmaceutical composition containing an NGF antagonist, or is administered to a subject in as a single combination dosage form containing both an additional therapeutic agent and an NGF antagonist.

[00196] The additional therapeutic agent may be, for example, another NGF antagonist (for example, see NGF antibodies described in US7449616 (tanezumab); US7569364; US7655232; US8088384; WO2011049758 (fulranumab)), an IL-1 antagonist (including, for example, IL-1 antagonist described in US 6927044), IL-6 antagonist, IL-6R antagonist (including, for example, anti-IL-6R antibody described in US 7582298), opioid, acetaminophen, local anesthetic, NMDA modulator, cannabinoid agonist receptor, P2X family modulator, VR1 antagonist, substance P antagonist, Nav1.7 antagonist, cytokine or cytokine receptor antagonist, antiepileptic drug, steroid, other inhibitors of inflammation such as caspase-1, p38, IKK1/2, CTLA-4Ig and corticosteroid.

Modes of administration

[00197] The present invention includes methods comprising administering to a subject a pharmaceutical composition comprising an NGF antagonist at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, one once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently as a therapeutic response is achieved. In some embodiments involving the administration of a pharmaceutical composition containing an anti-NGF antibody, such as fasinumab, once every 4 weeks, a dosage of about 1, 3, 6, or 9 mg may be used. In some embodiments involving administering a pharmaceutical composition containing an anti-NGF antibody, such as fasinumab, once every 8 weeks, a dosage of about 1, 3, 6, or 9 mg may be used. In some embodiments, comprising administering a pharmaceutical composition containing an anti-NGF antibody, such as fasinumab, once every 12 weeks at a dosage of about 1, 3, 6, or 9 mg.

[00198] According to some embodiments of the present invention, multiple doses of an NGF antagonist may be administered to a subject over a period of time. Methods according to this aspect of the invention include sequential administration of multiple doses of an NGF antagonist to a subject. As used herein, the term "sequential administration" means that each dose of an NGF antagonist is administered to a subject at a different point in time, such as on different days separated by a predetermined interval (eg, hours, days, weeks, or months). The present invention includes methods that consist of sequentially administering to a patient a single initial dose of an NGF antagonist, followed by one or more secondary doses of an NGF antagonist, and optionally followed by one or more tertiary doses of an NGF antagonist.

[00199] The terms "initial dose", "secondary doses" and "tertiary doses" refer to the time sequence of administration of the NGF antagonist. Thus, "starting dose" is the dose that is administered at the start of a treatment regimen (also referred to as "initial dose"); "secondary doses" are doses that are administered after the initial dose; and "tertiary doses" are doses that are administered after secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of NGF antagonist, but may generally differ from each other in terms of frequency of administration. However, in some embodiments of the invention, the amount of NGF antagonist contained in the initial, secondary and/or tertiary doses differ from each other (for example, increases or decreases depending on the circumstances) during the course of treatment. In some embodiments, one or more (eg, 1, 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses" followed by doses that are administered less frequently (eg, "maintenance doses"). For example, an NGF antagonist may be administered to a patient suffering from low back pain at a loading dose equivalent to 2 times the maintenance dose. Accordingly, if the maintenance dose is 3 mg, the loading dose will be 6 mg. If the maintenance dose is 6 mg, the loading dose is 12 mg. If the maintenance dose is 9 mg, the loading dose is 18 mg. Accordingly, it is contemplated that a loading dose of about 6 mg, 12 mg, or 18 mg followed by one, two, or more maintenance doses of about 3 mg, 6 mg, or 9 mg, respectively, may be sufficient to achieve a change from baseline of at least at least one pain parameter as specified herein.

[00200] In one example embodiment of the present invention, each secondary and/or tertiary dose is administered from 1 to 16 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7 , 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½, 15, 15½, 16 or more) weeks after the immediately preceding dose. I In one exemplary embodiment of the present invention, each secondary and/or tertiary dose is administered every 4, 8 or 12 weeks after the immediately preceding dose. The phrase "immediately preceding dose" as used herein means, in a multi-dose sequence, the dose of the NGF antagonist that is administered to the patient prior to the next dose in the sequence without intermediate doses.

[00201] Methods according to this aspect of the invention may include administering any number of secondary and/or tertiary doses of an NGF antagonist to a patient. For example, in some embodiments of the invention, only a single secondary dose is administered to the patient. In other embodiments, two or more (eg, 2, 3, 4, 5, 6, 7, 8 or more) secondary doses are administered. Similarly, in some embodiments of the invention, only a single tertiary dose is administered to the patient. In other embodiments, two or more (eg, 2, 3, 4, 5, 6, 7, 8 or more) tertiary doses are administered to the patient.

[00202] In embodiments of the invention involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to a patient 1-2 weeks after the immediately preceding dose, or 4-8 weeks after the immediately preceding dose. Similarly, in embodiments of the invention involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to a patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency with which secondary and/or tertiary doses are administered to a patient may vary during the course of treatment. The frequency of administration can also be adjusted by the physician during the course of treatment, depending on the needs of the individual patient after clinical examination.

[00203] The present invention includes methods comprising sequentially administering an NGF antagonist and a second therapeutic agent to a patient for the treatment of osteoarthritis pain. In some embodiments, the present methods include administering one or more doses of an NGF antagonist followed by one or more doses of a second therapeutic agent. For example, one or more doses of an NGF antagonist from about 1 mg to about 20 mg may be administered, followed by one or more doses of a second therapeutic agent (e.g., acetaminophen , opioid, or any other therapeutic agent as described elsewhere herein). In some embodiments, the NGF antagonist is administered at one or more doses resulting in improvement in one or more pain-related parameters, followed by administration of a second therapeutic agent to prevent recurrence of at least one osteoarthritis pain symptom. Alternative embodiments of the invention relate to the simultaneous administration of an NGF antagonist and a second therapeutic agent. For example, one or more doses of the NGF antagonist are administered, and the second therapeutic agent is administered in a separate dose at the same or different frequency relative to the NGF antagonist. In some embodiments, the second therapeutic agent is administered before, after, or simultaneously with the NGF antagonist.

EXAMPLES

[00204] The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention and are not intended to limit the scope of what the inventors consider their invention. Efforts have been made to ensure the accuracy of the numbers used (eg quantities, temperatures, etc.), but some experimental errors and deviations should be taken into account. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

Example 1

PATIENTS AND METHODS

[00205] Patients. Eligible patients were 40-80 years of age; had a diagnosis of knee and/or hip OA (designated as the most symptomatic index joint at the screening visit) based on the criteria for OA of the American College of Rheumatology with radiological confirmation (Kellgren-Lawrence [KL] score ≥2 on a scale of 0 to 4) ; and demonstrated moderate to severe index joint pain, defined as Western Ontario and McMaster Universities Osteoarthritis Pain Subscale (WOMAC) pain subscale score ≥4, both at screening with conventional pain medication and at randomization 7 days after pain medication was stopped. Patients must have had a history of inadequate analgesia or intolerance to acetaminophen and ≥1 oral NSAIDs, as well as a history of inadequate analgesia, intolerance to, or reluctance to use opioids. Patients also had to have a history of regular use of analgesics for pain in OA (average 4 days per week for 4 weeks before screening). Patients were excluded if they had a history of other joint disease, index joint injury within 30 days prior to screening, active fibromyalgia or another condition with moderate to severe pain, or a body mass index of 39.

[00206] Study design. This double-blind, placebo-controlled, phase IIb/III study was conducted at 61 institutions in the United States. Patients were randomized (1:1:1:1:1) to receive fasinumab 1 mg, 3 mg, 6 mg, or 9 mg, or placebo administered subcutaneously every 4 weeks for a total of 4 doses over a 16-week treatment period (Figure one). To ensure that treatment was balanced by joint and OA severity, randomization was stratified by joint index (knee or hip) and KL scores (2–3 vs. 4). After the treatment period, the patients were followed up for an additional 20 weeks, resulting in a study period of 36 weeks. Efficacy and safety were evaluated at each study visit up to week 36. Additional safety data was obtained through a telephone survey at 24 and 32 weeks.

[00207] Patients were required to stop using analgesics at the pre-visit, 7 days prior to randomization. Pain scores and global scores were obtained before and after discontinuation of the previous pain medication. Although these scores were required to meet a pain threshold (≥4 points on a 10-point scale), there were no requirements for pain exacerbation.

[00208] Beginning with the pre-randomization period (at the time of withdrawal of previous pain medication) and continuing until week 20, patients were allowed to take the pain medication provided during the study as a backup therapy (1-2 325 mg acetaminophen tablets every 4-6 hours, as needed). needed for intolerable pain, maximum 8 tablets or 2600 mg per day) and discontinued ≥48 hours before the start of each study visit for 16 weeks. Patients could only receive opioids after the completion of the week 16 visit, if deemed necessary by the investigator. Patients were not allowed to use any NSAIDs (oral or topical, with the exception of aspirin ≤100 mg/day for cardioprophylaxis) until ≥16 weeks after the last dose of study drug (week 28).

[00209] An independent data monitoring committee periodically reviewed all open data and, if necessary, made recommendations to the clinical research client working with anonymized data regarding the conduct of the study. This study was conducted in accordance with ethical principles originating in the Declaration of Helsinki and consistent with the recommendations of the International Council for the Harmonization of Good Clinical Practice and applicable regulatory requirements. Informed consent was obtained from each patient prior to inclusion in the study.

[00210] Efficiency Endpoints . The primary efficacy endpoint was change from baseline to week 16 on the WOMAC pain subscale (composite score of 5 questions related to joint pain while walking, using stairs, at rest in bed, sitting or lying down and standing) (Bellamy N. London, Ontario, Canada: Victoria Hospital; 1995). Individual WOMAC questions were scored on a scale of 0 to 10. The scores for each of the 5 questions were averaged. Treatment groups assessed median placebo-adjusted improvements with facinumab on the WOMAC pain subscale (Bellamy N. London, Ontario, Canada: Victoria Hospital; 1995).

[00211] Secondary efficacy endpoints were changed from baseline to week 16 on the WOMAC physical function subscale (scale 0 to 68; arithmetically converted to a scale of 0 to 10; Bellamy N. London, Ontario, Canada: Victoria Hospital; 1995) and the Global Patient Assessment (PGA) scale (one question on a scale of 1 to 5, with the worst score being the highest score (Strand V, Kellman A. Curr Rheumatol Rep 2004: 6:20-30).

[00212] Research efficacy endpoints included daily and weekly (average of daily scores from the previous week) gait index joint pain score on a numerical rating scale (NRS; scale 0-10; 0=no pain; MCID: ~1 point) ( Salaffi F, et al Eur J Pain 2004;8:283-91); percentage of patients responding at week 16 on the WOMAC subscale of pain and physical function (defined as a decrease of ≥30% and ≥50%); response rate using the Outcome Score for the Rheumatology Committee and the International Standing Committee on Clinical Trials Response Criteria Initiative (OMERACT-OARSI) (an 11-item instrument that measures pain in osteoarthritis of the knee or hip) (Pham T, et al. J Rheumatol 2003;30:1648-54); and quality of life was assessed using the Short Form 36 (SF-36) Medical Examination (Ware JE Jr, et al. Med Care 1992;30:473-83) and the EuroQol-5 Dimension-5 Level (EQ-5D-5L) scale utility index (van Reenen M, et al. Rotterdam, The Netherlands: European Quality of Life Research Foundation; April 2015). An additional exploratory analysis was performed to assess response to fasinumab according to the presence or absence of pain exacerbation after discontinuation of prior analgesic treatment, as defined by thresholds for change in pain scores from pre-randomization to randomization of -1, -1.5, and -2 on a 10-point scale. WOMAC pain subscale.

[00213] Security endpoints. Safety was assessed by evaluation of treatment-related adverse events (AEAEs), adverse events of special interest (confirmed arthropathy and sympathetic nervous system dysfunction), and laboratory tests of hematological and biochemical analyzes.

[00214] Given that an increased risk of joint side effects has been reported in clinical studies with anti-NGF antibodies (Miller RE, et al. Clin Exp Rheumatol 2017;35 Suppl 107:85-7; Kumar V, Mahal BA. J Pain Res 2012;5:279-87; and Hochberg M.C. Osteoarthritis Cartilage 2015:23 Suppl 1;S18-21), confirmed arthropathy, an umbrella term for rapidly progressive OA (type 1: joint space narrowing exceeding predetermined thresholds, and type 2: changes in bone structure on plain radiograph), subchondral insufficiency fracture and primary osteonecrosis was assessed by an independent, anonymized panel of 3 radiologists. Joint safety was monitored in all subjects with plain radiographs of the shoulders, hips, and knees at screening, at the end of the treatment period (week 16), and at the end of the study (week 36). Imaging was also performed at any time during the study to detect increasing joint pain, which the investigator judged to be inconsistent with the patient's normal pain due to OA. Magnetic resonance imaging (MRI) was performed at baseline at the index and contralateral joints, and at any joint with a K-L score at baseline ≥3. Additional MRIs were performed if follow-up radiographs showed important interval changes.

[00215] Subjects were also monitored for sympathetic nervous system dysfunction using predefined criteria that included an autonomic dysfunction questionnaire and thresholds for changes in blood pressure or heart rate on positional provocation (Strand V, Kellman A. Curr Rheumatol Rep 2004: 6: 20-30).

[00216] Statistical analysis. It was estimated that 375 patients would need to be randomized for a balanced allocation to 5 treatment groups based on treatment effect assumptions to minimize type 1 error to 0.05, a statistical power of 85%, and a detectable difference for the primary endpoint of 1.1 (active vs. placebo). A combination of the Hochberg procedure (Hochberg MC, et al. Arthritis Rheumatol 2016; 68 (2): 382-391) and the access control method was used to address the issue of multiplicity in treatment groups by applying the Hochberg method to test first the 6-mg and 9-mg doses at alpha 0.05. Only if both tests exceed this threshold will testing of the 3 mg and 1 mg doses versus placebo be performed sequentially, each with a significance level of 0.05. If 1 of the 2 highest doses does not meet the 0.05 significance level, the lower p value will be compared to the 0.025 significance level. If both doses of 6 mg and 9 mg were not statistically significantly better than placebo (threshold 0.05), further testing according to the predefined hierarchy was not allowed.

[00217] Efficacy variables were analyzed using a repeated measures mixed effects model (MMRM) approach. The model included randomization strata (KL score of 2 or 3 versus 4) and index joint, baseline score, treatment, and treatment factor effect by visit. Least squares (LS) means for change from baseline to week 16, as well as mean LS differences between fasinumab and placebo doses with respective standard errors (SE), P values, and 95% confidence intervals (CI), were provided by MMRM .

RESULTS

[00218] A summary of the distribution of participants in a clinical study. A total of 1214 patients were examined, 421 were randomized to receive fasinumab (n=338) or placebo (n=83; figure 1). Of the 421 randomized patients, 419 patients received ≥1 dose of study drug (1 patient each randomized to placebo and 1 patient each to placebo and facinumab 9 mg, which were discontinued prior to study drug administration). A total of 342 patients completed the entire 36-week study period (facinumab: n=294; 87%; placebo: n=67; 81%).

[00219] Demographic and baseline characteristics of patients. The demographic and baseline characteristics of patients in the treatment groups were generally balanced (Figure 42). The majority of patients (66%) had a KL score of 3 or 4 for the hip or knee. The majority of index joints (88%) were knee joints .

[00220]Efficiency . All four doses of fasinumab showed a significantly greater reduction from baseline at week 16 on the WOMAC Pain Subscale than placebo. The mean difference in LS versus placebo for the treatment groups ranged from -0.78 to -1.40, exceeding the published MCID (individual patient: 0.67-0.75 points), with the greatest difference observed at the 9 mg dose ( figure 43). The reduction in pain subscale scores was evident by week 2 for fasinumab doses and was maintained throughout the 16 week treatment period (Figure 47(A)). During the follow-up period (after week 16), pain scores returned to baseline, although not completely, for each dose of fasinumab. To assess the robustness of this treatment approach, a per-protocol analysis was performed that yielded similar results (data not shown). The reduction in pain subscale scores was evident by week 2 for fasinumab doses and was maintained throughout the 16 week treatment period (Figure 47(A)). During the follow-up period (after week 16), pain scores returned to baseline, although not completely, for each dose of fasinumab. To assess the robustness of this treatment approach, a per-protocol analysis was performed that yielded similar results (data not shown).

[00221] In addition, all 4 doses of fasinumab at week 16 showed a statistically significant and clinically significant decrease from baseline on the WOMAC physical function subscale compared to placebo, with an incomplete return to baseline, paralleling the changes noted for the pain subscale WOMAC (figure 47 (B); figure 48). For all doses, fasinumab was also associated with a greater numerical reduction from baseline at week 16 in PGA scores than placebo, reaching statistical significance for the 1 mg and 9 mg doses (30% improvement; P-values: 0.0132 and 0.008, respectively) . PGA scores returned to baseline in the subsequent period.

[00222] Fasinumab resulted in clinical benefit for most of the study endpoints, although these analyzes were not specifically designed for comparison. A statistically significant and clinically significant reduction in NRS walking pain was noted by week 2 and was maintained throughout the 16 week treatment period at fasinumab doses (FIG. 51).

[00223] In a respondent analysis, significant treatment effects, defined as an improvement of ≥30% from baseline, were seen in more patients treated with any of the 4 doses of fasinumab than in patients treated with placebo on the WOMAC pain subscale (63 .5-73.8% vs. 47% for placebo) and WOMAC physical function subscale scores (61.2-71.4% vs. 44.6% for placebo). Similar results were demonstrated for ≥50% improvement from baseline, reaching statistical significance for all 4 doses at week 16. In a respondent analysis based on the OMERACT-OARSI responder index, a greater proportion of patients who received any of the 4 doses of fasinumab showed clinically significant responses to treatment compared with those who received placebo (72.9%, 72.6%, 63, 5% and 78.6% for the 1 mg, 3 mg, 6 mg, and 9 mg doses, respectively, compared with 51.8% for placebo; P < 0.01 for all but the 6 mg dose).

[00224] WOMAC pain subscale scores were also assessed in patients with or without pain exacerbation after analgesic drug withdrawal prior to randomization. By dose of fasinumab, patients with pain exacerbation had worse baseline mean pain scores compared with patients without exacerbation. The proportion of patients randomized to facinumab who experienced a prior pain exacerbation (score ≥1 on a scale of 0 to 10) was approximately 25% across all doses. Placebo-adjusted improvements in mean pain scores at week 16 with facinumab ranged from -1.12 to -1.81 in patients with pain exacerbation (Figure 47 (C)) and from -0.87 to -1.14 in patients without exacerbation (Figure 47(D)). Patients with pain exacerbation compared with patients without pain exacerbation randomized to placebo showed a greater degree of improvement (-3.68 vs -2.19). Similar trends were noted when using higher pain thresholds, but were based on fewer observations. Stronger treatment effects were observed in patients with higher baseline pain scores or who experienced greater worsening after discontinuation of previous pain medication.

[00225] The results of the SF-36 Medical Assessment Tool showed an improvement in quality of life for all 4 doses of fasinumab compared to placebo on scales of pain and functionality, including bodily pain and physical functioning (data not shown). However, consistent improvements on other scales (i.e., general health, social functioning, role emotional, mental health, vitality, and mental component) were not observed. An improvement in quality of life was also demonstrated using the EQ-5D-5L utility index (Figure 49).

[00226] Security. The mean (SD) duration of treatment was similar in the placebo (101 (26)) and pooled fasinumab (105 (20)) groups. The mean duration of follow-up (SD) was similar (219 (75) days, placebo vs. 236 (54) days, fasinumab). The safety analysis set included 419 patients, 82 of whom received placebo and 337 received facinumab.

[00227] During the 16-week treatment period, the incidence of treatment-related adverse events arising from treatment (TEAE) was 17% in the fasinumab group and 10% in the placebo group (Figure 44). Nervous system and musculoskeletal symptoms were more common in patients treated with fasinumab than in the placebo group (7% versus 4% and 3% versus 2%, respectively). The fasinumab combination group, compared to the placebo group, had a slightly higher incidence of paresthesia (2% versus 0%) and a similar incidence of hypesthesia (1% each) and arthralgia (1% each). In all treatment groups, the majority of adverse events were mild to moderate in severity. The incidence of serious TEAE during the treatment period was low, but slightly higher in the placebo group than in the fasinumab combination group (2% vs. 1%). There was no apparent dose response to fasinumab in patients with severe TEAE. A small proportion of patients discontinued therapy due to TEAE during the treatment period in both the fasinumab and placebo groups (4% [n=14] and 1% [n=1]). No group demonstrated an identifiable or predominant reason for discontinuation, which included musculoskeletal/connective tissue disorders (2% and 1%), nervous system (paresthesia: 1% and 0%; hypoesthesia: 1% and 0%), and also skin and subcutaneous tissue (1% and 0%) in the combined fasinumab and placebo groups, respectively.

[00228] During the 20-week follow-up period, the incidence of TEAE was higher in the facinumab combination group than in the placebo group (8% vs. 4%; Figure 44), as was the incidence of serious TEAE (6% vs. 5%). The incidence of serious TEAE during the follow-up period was higher in those randomized to the 9 mg dose (8%) than to the 1 mg (6%), 3 mg (4%), or 6 mg (6%) doses.

[00229] Arthropathies were found in 23 (5%) patients overall, affecting 25 joints, in 7% and 1% of patients in the combined fasinumab and placebo groups, respectively (Figure 45). Arthropathy consisted of rapidly progressive OA in 5% of patients in the fasinumab group (in most cases it was joint space narrowing without evidence of bone structure change) and in none of the patients in the placebo group and subchondral insufficiency fracture occurring in 2% and 1% of patients in the respective groups. Primary osteonecrosis was not observed. An increase in the number of arthropathies was observed over the course of the study with fasinumab dose and time.

[00230] Of the identified arthropathies in a retrospective analysis, destructive arthropathy, classified as new bone fragmentation, destruction or fracture during the study period, near or complete joint surface collapse, and subluxation/displacement, all features inconsistent with expected radiological findings in conventional OA were assessed . Destructive arthropathy was observed in two patients (<1% of 338 subjects treated with fasinumab): one (1) in the 6 mg treatment groups and one (1) in the 9 mg treatment groups.

[00231] Overall, 16 (4%) patients underwent 18 total joint replacements, which occurred in 4% of patients in the fasinumab group and 2% of patients in the placebo group (Figure 45). There was no apparent dose dependence of fasinumab for total joint replacement.

[00232] There were no signs of sympathetic nervous system dysfunction. Regular monitoring of laboratory tests did not reveal significant changes, with the exception of alkaline phosphatase (ALP), which increased depending on time and dose during the study, but remained within the normal range. At follow-up, mean ALP values decreased by week 36, although they did not return to baseline. There were no deaths during the study.

DISCUSSION

[00233] In this phase IIb/III study in patients with moderate to severe OA, fasinumab was superior to placebo in reducing pain and improving physical function. Patients treated with fasinumab, compared with patients treated with placebo, demonstrated a statistically significant and clinically significant reduction in WOMAC pain subscale scores. Placebo-adjusted mean improvements in WOMAC pain subscale scores ranged from 0.78 to 1.40 points, exceeding the MCID (Bellamy N. London, Ontario, Canada: Victoria Hospital; 1995). Analysis of responders for pain reduction thresholds of ≥30% and ≥50% on the WOMAC subscale confirmed that a significantly higher proportion of patients treated with fasinumab achieved a threshold improvement in pain compared with patients treated with placebo. Improvements in WOMAC Physical Function Subscale scores were also statistically significant and clinically significant with fasinumab compared with placebo. In addition, marked relief of walking pain was achieved within 7 days of initiation of all 4 doses of fasinumab therapy as evidenced by NRS scores (Salaffi F, et al. Eur J Pain 2004;8:283-91).

[00234] Fasinumab reduced pain as demonstrated by the WOMAC pain subscale score and the NRS pain score. WOMAC's physical function also showed improvements, as did PGA, indicating a reduction in the impact of the disease. Efficacy was observed at all doses evaluated with no apparent relationship between the 1, 3 and 6 mg doses. A dose of 9 mg showed the greatest therapeutic effect. The effective concentrations of fasinumab increased with increasing dose approximately in proportion to the dose from 3 mg to 9 mg. Although similar efficacy was achieved at the lowest dose, an efficacy analysis performed at the 1 mg dose revealed a slower onset of action combined with the lowest serum concentrations. Adverse events in this trial were consistent with those previously reported for fasinumab and the anti-NGF class of compounds. The most common AEs affected the musculoskeletal and nervous systems, with frequent events including arthralgia, paresthesia, and hypoesthesia. These events rarely resulted in patients discontinuing study medication and were generally rated as mild or moderate in severity. Arthropathy-related events were more common in the fasinumab groups in a dose-dependent manner. Patients randomized to the 9 mg dose group had more articular arthropathies compared to other active groups. Of the 25 confirmed cases of arthropathy in 23 patients, 1 occurred in a patient receiving placebo. The frequency of joint replacement surgery in the placebo and fasinumab treatment groups was generally similar; unlike cases of arthropathy, there was no apparent relationship between dose and rate of joint replacement, although the number of cases was small (2 to 4 per treatment group).

[00235] Patients in this study received treatment for 16 weeks. When treatment was discontinued, patients experienced more AE arthralgia and experienced an increase in WOMAC pain and physical function scores consistent with the return of signs and symptoms of OA after discontinuation of effective facinumab treatment. There was no dose-dependent pattern in post-treatment reports of AE arthralgia, and the post-treatment WOMAC pain subscale score did not return to baseline levels by week 36, suggesting that patients had no effect of recovery or worsening of underlying OA. In terms of post-treatment effects, at week 36, there were only small differences between the placebo groups and most treatment groups for the various efficacy measures studied, with a possible difference only for the 9 mg group, which returned closer to baseline.

[00236] The trend for the 9 mg dose to revert to scores that are still below baseline at study entry, but higher than placebo for some endpoints, with dose response reversal among different treatment groups, consistent with interpretation, according to in which the stronger analgesic effect of higher doses of fasinumab after discontinuation results in a greater perceived return of pain from a prolonged state of pain suppression. Because patients on the 9 mg dose experienced marked and sustained pain relief over a period of 3 to 4 months, the return of pain in these patients was more marked than in patients who had less pain relief.

[00237] This construct is supported by the fact that the placebo group appears to have adapted to the new level of chronic pain that does not change with the withdrawal of an ineffective treatment (placebo). Instead, this group seems to have "rebooted" into a new level of chronic pain.

[00238] Improvement in pain and function with fasinumab should be considered in the context of published data on analgesics. A recent meta-analysis of 17 OA trials found that acetaminophen, the first choice analgesic for OA pain, provided very moderate pain relief with a mean improvement of about 0.4 points from baseline of 6 points on the 10-point WOMAC scale (Machado GC, et al. BMJ 2015;35 (Machado GC, et al. BMJ 2015;350:h1225) In another analysis (Stam W, et al. Open Rheumatol J 2012;6:6-20), the effect size of acetaminophen compared to placebo (-0.09) was significantly lower than any of the studied NSAIDs (ranging from -0.39 to -0.49 for naproxen, ibuprofen and diclofenac).The effect size of celecoxib, the only selective inhibitor of cyclooxygenase (COX) - 2 available in the US was generally less than non-specific NSAIDs (-0.11 to -0.34 depending on dosage) A comprehensive meta-analysis comparing opioids with NSAIDs in 6 studies in OA showed no significant difference in pain relief between these analgesics (Smith SR, et al. Osteoarthritis Cartilage 2016;24:962-72). A more recent review arrived at similar conclusions (Berthelot JM, et al. Joint Bone Spine 2015;82:397-401). In our study, patients treated with fasinumab experienced an average improvement of 3.4 on the 10-point WOMAC Pain Subscale Scale (-3.49, -3.39, -3.07, and -3.81 points for 1 mg doses, 3 mg, 6 mg and 9 mg, respectively, representing an improvement of 50-58% from baseline); while placebo resulted in a change from baseline of -2.43 (38%). This resulted in an effect size of up to 0.47 facinumab doses, which was significantly larger than the effect size of acetaminophen, NSAIDs, and opioids.

[00239] In most analgesic studies in patients with OA, who experienced pain exacerbation upon discontinuation of previous pain medication, was approximately 10 points on the WOMAC pain scale 0-100 (or 1 point on a scale of 0-10). In contrast, the study design allowed for the inclusion of patients with significant pain at both screening and baseline, with no requirement for pain exacerbation after analgesic withdrawal. This allowed the study to include patients whose pain may not have been adequately treated with analgesics. Most patients in this study did not experience pain exacerbation after discontinuation of analgesics. However, in the subgroup of patients who did experience a pain exacerbation with an exacerbation score of ≥1, ≥1.5, or ≥2 points, responses to treatment tended to be higher than those who did not, consistent with a larger magnitude effect seen in OA studies using a pain exacerbation regimen (Trijau S, et al. Osteoarthritis Cartilage 2010;18:1012-8). It has been reported that pain treatment effects and functional scores in regimens without pain exacerbation may underestimate treatment effects by 37-50% (Trijau S, et al. Osteoarthritis Cartilage 2010;18:1012-8). Thus, if this underestimation is taken into account, facinumab may provide even greater pain relief than acetaminophen, NSAIDs, or opioids in patients with OA pain.

[00240] For other anti-NGF antibodies, the trial study compared tanezumab, a humanized IgG2 monoclonal anti-NGF antibody administered intravenously at a dose of 10-200 μg/kg (i.e., 0.7-14 mg for a 70 kg patient) per Days 1 and 56 with placebo (Lane NE, et al. N Engl J Med 2010;363:1521-31) using a pain exacerbation regimen. Enrollment was restricted to patients whose pain increased by ≥10 points on the WOMAC 100-point pain subscale compared to the screening value 1 week after discontinuation of prior analgesics, assessed at the time of randomization. Mean WOMAC scores at randomization ranged from 62.1 to 69 points. Improvement from baseline with tanezumab ranged from 29 points (50 µg/kg dose) to 44 points (200 µg/kg dose), with a net effect of 12.8-27.3 compared to placebo. The results of a subsequent phase III study with tanezumab at doses of 2.5 to 10 mg every 8 weeks, also using an exacerbation regimen, showed slightly lower treatment effects (Brown MT, et al. J Pain 2012;13:790-8) .

[00241] Fasinumab was generally well tolerated. Although the incidence of TEAE was higher with fasinumab than with placebo, there were few discontinuations due to TEAE. There was a moderate increase in alkaline phosphatase, probably of bone origin, which was not associated with arthropathy and was largely reversible after discontinuation of fasinumab. The increase in alkaline phosphatase may reflect the overall stimulatory effect of facinumab on bone synthesis, or may be due to pain relief resulting in increased physical activity (not quantified in this study), which may stimulate bone formation and bone mass (Kerr D, et al J Bone Miner Res 1996;11:218-225, Heinonen A, et al Lancet 1996;348:1343-7). Nervous and musculoskeletal disorders were more common in patients treated with fasinumab than with placebo, similar to rates previously reported for tanezumab (Hochberg MC. Osteoarthritis Cartilage 2015:23 Suppl 1;S18-21), may be due to NGF inhibition although several patients discontinued treatment due to changes in peripheral sensations and there were no cases meeting the criteria for sympathetic nerve dysfunction.

[00242] The study provided previously unavailable opportunities to assess dose-dependent co-changes in the setting of an NGF inhibitor clinical trial. Fasinumab was associated with a dose-dependent higher rate of reported arthropathies than placebo, most notably at the 6 and 9 mg doses. A slight increase in the rate of recognized arthropathies dominated by joint space narrowing (RPOA-1) was observed with lower doses of fasinumab compared with the rate observed in the placebo group. Higher rates of all recognized arthropathies, including RPOA-2 and DA, were observed at the two highest doses studied. Because, to our knowledge, this is the only study to date that includes routine, prospective, intensive radiological assessment of the joints using both plain films and MRI, the incidence of these adverse events with facinumab cannot be compared with previous analgesic trials. Despite intensive co-monitoring of both symptomatic and asymptomatic patients, rates of destructive arthropathy reported in our fasinumab study were modest (2 of 338 subjects randomized to active treatment with the two highest doses of 6 and 9 mg). These rates were lower than those reported in studies with tanezumab, in which this type of joint event was only observed retrospectively after referral for joint replacement (Schnitzer TJ, Marks JA. Osteoarthritis Cartilage 2015;23 Suppl 1:S8- 17).

[00243] In conclusion, in this phase IIb/III study of 400 patients, the NGF inhibitor fasinumab demonstrated an unprecedented degree of pain relief in patients with moderate to severe pain from OA, even in patients who did not experience benefit from previously used analgesics, the patient group , previously excluded from most other studies of analgesics for osteoarthritis, representing an important unmet medical need. Intensive laboratory and radiological monitoring of patients during the study indicated that fasinumab was well tolerated by the majority of patients, with a dose-dependent increase in joint abnormalities notable at the highest two doses studied. The results presented in this guideline are doses of facinumab that may provide the greatest benefit versus risk in current and future clinical trials of fasinumab in OA and other pain conditions.

[00244] The results are also important in confirming that the patients included in the study were significantly suffering from chronic pain that returned after fasinumab was discontinued. The results also provide further support for the relationship between fasinumab dose and degree of pain relief during the first 16 weeks of the study (most evident at the extremes of the dose range, in the 1 and 9 mg treatment groups), given the reappearance of pain in the order of dose response following treatment withdrawal. In this study, doses of 1 mg every 4 weeks and 3 mg every 4 weeks showed the best benefit/risk ratio. These doses have shown efficacy with a better safety profile compared to higher doses.

[00245] Positive results from a phase 3 placebo-controlled study using an anti-NGF antibody described herein are presented. The particular active ingredient used is an anti-NGF antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region (HCVR)/light chain variable region (LCVR) amino acid sequence pair of SEQ ID NO: 2/10. However, the basic methods can be applied to the class of anti-NGF drugs.

[00246] The results are long-term trials in patients with chronic pain due to osteoarthritis of the hip or knee. Primary efficacy analysis at 16 weeks for patients treated with antibodies indicates that they experienced less pain and significantly improved functional ability from baseline compared to patients treated with placebo, which were the second primary end points of the study.

[00247] The study identified doses that maximize efficacy while significantly reducing known safety risks with anti-NGF class drugs. The results show the possibility of using anti-NGF antibodies as an additional choice in the treatment of pain, in contrast to steroidal anti-inflammatory drugs or opioids.

[00248] The study included 646 patients who were treated with the same antibody at different dosing intervals, with both groups treated with 1 mg of NGF antibody and one group treated every four weeks, the other group treated every 8 weeks and both groups compared with placebo. The results demonstrate consistent efficacy in reducing pain while reducing known safety risks.

Important Findings from the Phase 3 Efficacy Study

placebo
(n=214) Fasinumab 1 mg every 8 weeks
(n=215) Fasinumab 1 mg every 4 weeks
(n=217) Change in pain at week 16 from baseline (mean LS)* -1.56 -2.25
(p=0.0019) -2.78
(p<0.0001) Change in physical function at week 16 from baseline (mean LS)** 1.37 2.10
(p=0.0011) 2.57
(p<0.0001)

[00249] * Universities of Western Ontario and McMaster's (WOMAC) Osteoarthritis Pain Subscale Score (score range: 0-10); ** WOMAC physical function subscale score (score range: 0-10)

[00250] The overall incidence of adverse events (AEs), including serious AEs and joint replacement, was similar between the fasinumab 1 mg (every 4 weeks or 8 weeks) and placebo groups. The fasinumab program includes robust radiographic monitoring of potential identified arthropathies, the first of which occurs at week 24. This was implemented for early detection of potential identified arthropathies in which their clinical consequences are likely to be less. At the time of the primary efficacy data cut-off, approximately 80% of patients completed their visit at week 24. The placebo-adjusted cumulative estimate of any type of established arthropathy was less than 1.5% at both weeks 16 and 24. In addition, the vast majority of arthropathies identified were isolated joint space narrowing, termed RPOA-1 (rapidly progressive OA type 1). To date, no cases of osteonecrosis have been identified in this study.

[00251] The foregoing merely illustrates the principles of the invention. It should be understood that those skilled in the art will be able to develop various devices which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. In addition, all examples and conventions provided herein are primarily intended to assist the reader in understanding the principles of the invention and the concepts introduced by the inventors into the development of the art, and should be construed as not limiting such specifically listed examples and conditions.

[00252] Moreover, all statements herein that set forth principles, aspects, and embodiments of the invention, as well as specific examples thereof, are intended to cover both its structural and functional equivalents. Further, such equivalents are intended to include both currently known equivalents and future developed equivalents, ie any elements developed that perform the same function, regardless of structure. Therefore, the scope of the present invention is not intended to be limited by the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention is embodied in the appended claims.

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<---

Claims (29)

1. The use of a pharmaceutical composition for the treatment of a subject suffering from pain in the knee or hip joint, where the subject does not respond to pain medication or suffers from side effects of pain medication or the subject has a history of taking opioids, where the composition contains: 1 mg of an antibody against nerve growth factor (NGF) that specifically binds to NGF, or an antigen-binding fragment thereof; where the anti-NGF antibody or antigennegative fragment contains HCVR having the amino acid sequence of SEQ ID NO: 2, and LCVR having the amino acid sequence of SEQ ID NO: 10; and whereby the pharmaceutical composition reduces the subject's knee or hip pain. 2. Use according to claim 1, wherein the analgesic treatment is selected from the group consisting of acetaminophen, opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and combinations thereof. 3. Use according to claim 1 for preventing arthropathy associated with treatment with an anti-nerve growth factor (NGF) antibody that specifically binds to NGF, or an antigen-binding fragment thereof. 4. The use of claim 3, wherein the arthropathy includes joint space narrowing in excess of predetermined thresholds. 5. Use according to claim 3, wherein the arthropathy includes changes in bone structure evident on a plain radiograph. 6. Use according to claim 3, wherein the pharmaceutical composition is formulated for subcutaneous administration. 7. The use of any one of claims 1 to 6 wherein the subject is diagnosed with moderate to severe pain in the index joint of the knee and/or hip, defined as ≥4 points on the Western Ontario and McMaster Universities Osteoarthritis Pain Subscale (WOMAC). ). 8. Use according to any one of claims 1-6, wherein the subject has a Kellgren-Lawrence [K-L] score of ≥2 on a scale of 0 to 4 prior to treatment. 9. Use according to any one of claims 1 to 8, wherein the pharmaceutical composition is administered to the patient at a frequency of about every 4 weeks (Q4W) or every 8 weeks (Q8W). 10. Use according to any one of claims 1 to 9, characterized in that the antibody is fasinumab. 11. A method for reducing pain or improving physical function of a knee or hip joint in a patient suffering from osteoarthritis, the method avoiding the risk of developing arthropathy associated with treatment with an anti-nerve growth factor (NGF) antibody that specifically binds to NGF, or an antigen-binding fragment thereof , where the method includes: diagnosing a patient as not responding to pain medication or suffering from side effects of pain medication, or as having a history of taking opioids; and administering to a patient a pharmaceutical composition comprising 1 mg of an anti-nerve growth factor (NGF) antibody that specifically binds to NGF, or an antigen-binding fragment thereof, at intervals of every eight weeks; wherein the pharmaceutical composition reduces pain or improves physical function in the patient, and wherein the incidence of one or more adverse events in the patient is reduced compared to patients receiving higher doses of the anti-NGF antibody or antigen-binding fragment thereof; where the anti-NGF antibody or antigennegative fragment contains a pair of amino acid sequences of the variable region of the heavy chain (HCVR)/variable region of the light chain (LCVR) of SEQ ID NOs: 2/10; and the patient has a Kellgren-Lawrence [K-L] score of ≥2 on a scale of 0-4 prior to treatment. 12. The method of claim 11, wherein the patient has a Kellgren-Lawrence [K-L] score of 3 or 4 on a scale of 0 to 4. 13. A method for reducing pain or improving physical function of a knee or hip joint in a patient suffering from osteoarthritis, the method avoiding the risk of developing arthropathy associated with treatment with an anti-nerve growth factor (NGF) antibody that specifically binds to NGF, or an antigen-binding fragment thereof , where the method includes: diagnosing a patient as not responding to pain medication or suffering from side effects of pain medication, or as having a history of taking opioids; and administering to a patient a pharmaceutical composition comprising 1 mg of an anti-nerve growth factor (NGF) antibody that specifically binds to NGF, or an antigen-binding fragment thereof, at intervals of every four weeks; wherein the pharmaceutical composition reduces pain or improves physical function in the patient, and wherein the incidence of one or more adverse events in the patient is reduced compared to patients receiving higher doses of anti-NGF antibody; where the anti-NGF antibody or antigennegative fragment contains a pair of amino acid sequences of the variable region of the heavy chain (HCVR)/variable region of the light chain (LCVR) of SEQ ID NOs: 2/10; and the patient has a Kellgren-Lawrence [K-L] score of ≥2 on a scale of 0-4 prior to treatment. 14. The method of claim 13, wherein the patient has a Kellgren-Lawrence [K-L] score of 3 or 4 on a scale of 0 to 4.

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