FIELD OF THE INVENTION

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

BACKGROUND

Many patients with acute and chronic pain do not receive adequate pain relief despite the wide variety of analgesic medications that are currently available, either because the medications are not effective in all patients, or because their use is limited by toxicity or intolerability. The limitations of currently available analgesic therapies include adverse central nervous system effects, nausea and vomiting, constipation, gastrointestinal bleeding and ulceration, cardiovascular events, renal toxicity, and potential for abuse. Inadequate pain relief has a profound impact on the quality of life for millions of people worldwide with an associated substantial cost to society, including healthcare cost and loss of productivity.

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). In the adult, NGF is not required as a survival factor but acts as a pain mediator that sensitizes neurons (Pezet, S. et.al., (2006), Ann Rev Neurosci 29:507-518). Nerve growth factor activity is mediated through 2 different membrane-bound receptors, the high-affinity tyrosine kinase type 1 (TrkA) and the low-affinity p75 neurotrophin receptors.

Administration of NGF has been shown to provoke pain in both rodents (Lewin, G. R., et.al., (1994), Eur. J. Neurosci 6:1903-1912) and humans (McArthur, J. C., 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, M. S. et.al., (1999) Eur J Neurosci 11:837-846). Humans with mutations in TrkA (hereditary sensory and autonomic neuropathy IV) or NGF (hereditary sensory and autonomic neuropathy V) have been identified with a loss of 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, NGF is known to be elevated in the synovial fluid of patients with rheumatoid arthritis and other types of arthritis (Aloe, L. et.al., (1992), Arthritis Rheum 35:351-355; Halliday, D. A., (1998), Neurochem Res. 23:919-922), and to be up-regulated in injured and inflamed tissues in conditions such as cystitis, prostatitis, and chronic headache (Lowe, E. M., et.al., (1997), Br. J. Urol. 79:572-577; Miller, L. J., et.al., (2002), Urology 59:603-608; Sarchielli, P. et.al., (2001), Neurology 57:132-134).

There is an unmet need for agents that alleviate pain in individuals who have a history of inadequate pain relief, or who are intolerant to standard analgesic therapy. Fasinumab is a fully-human high-affinity monoclonal antibody directed against NGF (see U.S. Pat. No. 7,988,967 and PCT Publication No. WO 2009/023540 and WHO Drug Information Vol. 26, No. 2, (2012), which are all hereby incorporated by reference in their entirety). By selectively blocking NGF, fasinumab has the potential to be effective in modulating NGF-associated pain without some of the adverse side effects of other analgesic medications, such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs).

BRIEF SUMMARY OF THE INVENTION

A pharmaceutical composition and a method for treating knee and/or hip pain in a patient non-responsive or intolerant to standard analgesic therapy are disclosed. A pharmaceutical composition and a method for reducing risk for developing an arthropathy in a subject receiving an anti-NGF antibody for treatment of knee and/or hip pain are disclosed. Also provided herein are methods for monitoring safety of a treatment of knee and/or hip pain involving administration of an anti-NGF antibody. In certain aspects, the subject has osteoarthritis of the knee and/or hip and the anti-NGF antibody is fasinumab.

In certain aspects, a pharmaceutical composition for use in treatment of a subject having pain in the knee joint or the hip joint, where the subject is non-responsive to analgesic treatment or suffers from side-effects from analgesic treatment is disclosed. The composition comprises a therapeutically effective amount of an antibody that binds specifically to nerve growth factor (NGF) or an antigen binding fragment thereof. The composition is used in the absence of an analgesic treatment to relieve pain.

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

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

A pharmaceutical composition for avoidance of an arthropathy associated with treatment with an anti-nerve growth factor (NGF) antibody that binds specifically to NGF or an antigen binding fragment thereof is disclosed. In certain aspects, the composition is formulated as a dose of less than 9 mg of the anti-NGF antibody or the antigen binding fragment thereof. In certain aspects, the composition is formulated as a dose of less than 6 mg of the anti-NGF antibody or the antigen binding fragment thereof. In certain aspects, the initial dose and the one or more secondary doses of the pharmaceutical composition that reduces risk of development of an arthropathy each comprise about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg of the anti-NGF antibody or the antigen binding fragment thereof. In certain aspects, the initial dose and the one or more secondary doses of the pharmaceutical composition that reduces risk of development of an arthropathy each comprise about 1 mg or about 3 mg of the anti-NGF antibody or the antigen binding fragment thereof. In certain aspects, the arthropathy includes joint space narrowing exceeding pre-specified thresholds. In certain aspects, the arthropathy includes changes in bone structure evident on plain film. In certain aspects, the arthropathy includes changes in bone structure evident on plain film, joint space narrowing exceeding pre-specified thresholds, or both, in a knee joint. In certain aspects, the arthropathy includes changes in bone structure evident on plain film, joint space narrowing exceeding pre-specified thresholds, or both, in a hip joint. In certain aspects, the frequency of administration of a dose of the anti-NGF antibody that reduces risk of developing at least one arthropathy is about every 4 weeks.

In certain aspects of the invention, the subject being treated with the compositions and methods disclosed herein is diagnosed with osteoarthritis of the knee and/or the hip.

In another aspect of the invention the use includes any of the above uses wherein a patient which exhibits a history of inadequate pain relief from, or is resistant, inadequately responsive, or intolerant to standard analgesic therapy.

In another aspect of the invention the use includes any of the above uses wherein a patient is unwilling to take standard analgesic therapy or does not have access to standard analgesic therapy.

In another aspect of the invention the use includes any of the above uses wherein a situation wherein standard analgesic therapy is inadvisable for administration to the patient due to safety and health risks to the patient and/or coupled with suboptimal efficacy. In another aspect of the invention the use includes any of the above uses wherein a situation wherein the standard analgesic therapy is inadvisable for administration to the patient due to a condition selected from the group consisting of medical contraindications, hypersensitivity to standard analgesic therapy, or excipients, use of a concomitant medication prohibited with standard analgesic therapy, 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 developing drug dependence.

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

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.

In another aspect of the invention the use includes any of the above uses wherein the antibody or antigen-binding fragment thereof that binds specifically to NGF is administered to the patient at a frequency of about every 4 weeks.

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

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) comprising SEQ ID NOs: 4, 6 and 8, respectively, and three light chain complementarity determining (LCDR) sequences (LCDR1, LCDR2, LCDR3) comprising SEQ ID NOs: 12, 14 and 16, respectively.

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.

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.

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

In another aspect of the invention the use includes any of the above uses wherein the initial dose and the one or more secondary doses are administered either subcutaneously or intravenously.

In another aspect of the invention the use includes any of the above uses wherein the one or more secondary doses of the anti-NGF antibody are administered every four weeks, every eight weeks, or every 12 weeks after the initial dose.

In another aspect of the invention the use includes any of the above uses wherein the use results in improvement in one or more pain-associated parameters. In certain aspects, the pain-associated parameter is selected from the group consisting of: (a) a change from baseline at week 16 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score; (b) a change from baseline at week 16 in the physical function subscale scores; and (c) a change from baseline at week 16 in the Patient Global Assessment (PGA).

In another aspect of the invention the use includes any of the above uses wherein the use results in an improvement in daily and weekly (average of daily scores over the preceding week) walking index joint pain score on the Numeric Rating Scale (NRS; scale 0-10; 0=no pain; MCID: ˜1 point).

In another aspect of the invention the use includes any of the above uses wherein the use results in an improvement in the rate of response using the Outcome Measures for Rheumatology Committee and Osteoarthritis Research Society International Standing Committee for Clinical Trials Response Criteria Initiative (OMERACT-OARSI) responder index (an 11-item tool that measures knee or hip osteoarthritis pain).

In another aspect of the invention the use includes any of the above uses wherein the use results in an improvement in quality of life assessed using the short form-36 (SF-36) health survey and EuroQol-5 Dimension-5 Level (EQ-5D-5L) scale utility index score.

In another aspect of the invention the use includes any of the above uses wherein the use provides a relief from pain associated with knee or hip joint for a period of up to 36 weeks from the start of the use.

Each of the above aspects of the invention are also disclosed and described herein as corresponding methods of treatment.

In certain aspects, a method for monitoring treatment of a subject having pain in the knee joint or the hip joint is provided. The method includes administering a pharmaceutical composition comprising a dose of about 9 mg of an anti-NGF antibody that specifically binds to NGF or an antigen binding fragment thereof; monitoring a knee joint or a hip joint of the subject to determine whether the subject has developed an arthropathy; wherein if the subject has developed arthropathy, administering a pharmaceutical composition comprising a dose of less than about 9 mg of the antibody or the antigen binding fragment thereof to the subject; or wherein if the subject has not developed arthropathy, administering a pharmaceutical composition comprising a dose of about 9 mg of the antibody or the antigen binding fragment thereof to the subject.

In certain aspects of the method of monitoring, if the subject has developed arthropathy, the subsequent treatment comprises administering a pharmaceutical composition comprising about 1.0 mg to about less than 6 mg of the anti-NGF antibody or an antigen binding fragment thereof, wherein the treatment reduces pain in the knee joint or the hip joint and reduces arthropathy.

In certain aspects of the method of monitoring, the antibody comprises three heavy chain complementarity determining region (HCDR) sequences (HCDR1, HCDR2, HCDR3) comprising SEQ ID NOs: 4, 6 and 8, respectively, and three light chain complementarity determining (LCDR) sequences (LCDR1, LCDR2, LCDR3) comprising SEQ ID NOs: 12, 14 and 16, respectively.

In certain aspects of the method of monitoring, the antibody comprises an HCVR having the amino acid sequence of SEQ ID NO:2.

In certain aspects of the method of monitoring, the antibody comprises an LCVR having the amino acid sequence of SEQ ID NO: 10.

In certain aspects of the method of monitoring, the antibody is fasinumab.

