Patent Application
20060160737
1. Field of the Invention
The invention relates to methods of using interleukin-1 (IL-1) antagonists to treat polymyalgia rheumatica and giant cell arteritis.
2. Description of Related Art
Polymyalgia rheumatica (PMR) was first described in 1888 and named in 1957. It was later described as an arthritic rheumatism in giant cell arteritis (GCA), suggesting the coexistence of the two related conditions (Hazleman (2003) in Rheumatology 3rd Ed., Hochberg et al. eds., Elsevier Ltd., pp. 1623-33). GCA is the most common systemic vasculitis in Western countries, with the highest incidence in Scandinavia and in people of Scandinavian descent. Incidence rate of PMR and GCA are three times greater in women. Polymyalgia rheumatica (PMR) occurs in the same population as GCA. Approximately 40% of people with GCA have PMR, and 10-40% of those with PMR may be biopsy-positive for GCA (Weyand and Goronzy (2003b) N Engl J Med 349,160-169 and Harmin (1972) Acta Med Scand Suppl).
In a first aspect, the invention features a method of treating, inhibiting, or ameliorating polymyalgia rheumatica (PMR), comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. An IL-1 antagonist is a compound capable of blocking or inhibiting the biological action of IL-1, including fusion proteins capable of trapping IL-1, such as an IL-1 “trap”. In a preferred embodiment, the IL-1 trap is an IL-1-specific fusion protein comprising two IL-1 receptor components and a multimerizing component, for example, an IL-1 trap described in U.S. Pat. No. 6,927,044, herein specifically incorporated by reference in its entirety. An IL-1 trap fusion protein comprises an IL-1 binding portion of the extracellular domain of human IL-1 RAcP, an IL-1 binding portion of the extracellular domain of human IL-1 RI, and a multimerizing component. In a specific embodiment, the IL-1 trap is the fusion protein shown in SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26. A preferred IL-1 trap is shown in SEQ ID NO:10. The invention encompasses the use of an IL-1 trap substantially identical to the protein of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, that is, a protein having at least 95% identity, at least 97% identity, at least 98% identity to the protein of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 and capable of binding and inhibiting IL-1. Further, in specific embodiments, the IL-1 antagonist is a modified IL-1 trap comprising one or more receptor components and one or more immunoglobulin-derived components specific for IL-1 and/or an IL-1 receptor. In another embodiment, the IL-1 antagonist is a modified IL-1 trap comprising one or more immunoglobulin-derived components specific for IL-1 and/or an IL-1 receptor.
The subject being treated is most preferably a human diagnosed as suffering from polymyalgia rheumatica. In a more specific embodiment, the subject is a patient suffering from relapsing polymyalgia rheumatica or newly diagnosed polymyalgia rheumatica with the first initiation of glucocorticoid treatment. More specifically, the subject is a human adult or child diagnosed with polymyalgia rheumatica.
In a second aspect, the invention features a method of treating, inhibiting, or ameliorating giant cell arteritis (GCA), comprising administering to a subject in need an interleukin 1 (IL-1) antagonist. The IL-1 antagonist useful in the methods of the invention is described above. The subject being treated is most preferably a human diagnosed as suffering from GCA. In a more specific embodiment, the subject is a patient suffering from newly diagnosed GCA with the first initiation of glucocorticoid treatment. More specifically, the subject is a human adult or child diagnosed with GCA.
The method of the invention includes administration of the IL-1 antagonist by any means known to the art, for example, subcutaneous, intramuscular, intranasal, intraarterial, intravenous, topical, transdermal administration or oral routes of administration. Preferably, administration is by subcutaneous or intravenous injection or intravenous infusion.
In specific embodiments of the therapeutic method of the invention, the subject is treated with a combination of an IL-1 trap and a second therapeutic agent. The second therapeutic agent may be a second IL-1 antagonist, such as, for example, anakinra (KINERET®), Amgen), a recombinant, nonglycosylated form of the human IL-1 receptor antagonist (IL1Ra), or an anti-IL-18 drug such as IL-18BP or a derivative, an IL-18-binding fusion protein, anti-IL-18, anti-IL-18R1, or anti-IL-18Racp. Other co-therapies include low dose (colchicine) aspirin or other NSAIDs, steroids such as prednisone and prednisolone, methotrexate, low dose cyclosporine A, TNF inhibitors such as ENBREL® (Amgen), or HUMIRA® (Abbott), other inflammatory inhibitors such as inhibitors of caspase-1, p38, IKK1/2, CTLA-4Ig, anti-IL-6 or anti-IL6Ra, etc.
In a third aspect, the invention features a therapeutic method of treating polymyalgia rheumatica (PMR) and/or giant cell arteritis (GCA), comprising administering a pharmaceutical composition comprising an IL-1 antagonist and a pharmaceutically acceptable carrier. The invention may also be used to treat other vasculitities such as Wegeners's granulomatosis, Churg-strauss, PAN and Takyasu's disease.
Other objects and advantages will become apparent from a review of the ensuing detailed description.
Before the present methods are described, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus for example, a reference to “a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety.
Polymyalgia Rheumatica (PMR) and Giant Cell Arteritis (GCA)
The classification division between PMR and GCA may be arbitrary as many physicians consider the two syndromes as part of one disease spectrum. The conditions may present independently or may occur in the same subject, either together or individually at the same or at different times. Both PMR and GCA affect elderly people and are rarely seen in people less than 50 years (mean age approximately 74 years). Constitutional symptoms of low-grade fever, fatigue, weight loss and depression are frequently reported. PMR is characterized by symptoms of systemic inflammation, with muscle pain and stiffness in the neck, shoulders and hips. The symptoms are usually bilateral. The prognosis for people diagnosed with PMR is generally relatively good compared with GCA. Over a period of one to three years, PMR may be self-limiting in the majority of people. However, in some subjects, treatment may be required for more than five years or indefinitely. During the period of treatment, relapses are common and the requirement for prolonged glucocorticoid (GCS) therapy has led to a high frequency of treatment side-effects, which include increased susceptibility to infections, diabetes, osteoporosis and gastrointestinal bleeding. The most significant morbidities associated with GCA are reduced blood flow to the eye and optic nerve, ischemic optic neuropathy leading to visual loss, large vessel stenoses leading to increased risk of stroke, extremity claudication and aortic aneurysm formation, which can lead to rupture, dissection and sudden death.
By definition, PMR does not include features of vascular inflammation and injury, while GCA is characterized by infiltrates of T lymphocytes, dendritic cells and macrophages in the walls of medium to large-sized arteries. Infiltrating cells produce IL-1, IL-2, IL-6, IL-8, IFNγ, TNFα, and a variety of chemokines, oxidative products, MMPs, and growth factors. The result is vascular and systemic inflammation followed by myointimal proliferation that can lead to luminal occlusion and subsequent tissue ischemia. In the aorta, the results of GCA are more often aneurysm formation, which can lead to dissection, rupture and sudden death.
There is evidence that IL-1 plays a role as an inflammatory mediator in the pathogenesis of PMR and GCA both systemically and at the local level, e.g., enthesis, joint, and in the vasculature. Blockade of IL-1 is expected to produce symptomatic relief and possibly reverse of an inflammatory cascade and induce disease remission.
Definitions
By the term “blocker”, “inhibitor”, or “antagonist” is meant a substance that retards or prevents a chemical or physiological reaction or response. Common blockers or inhibitors include but are not limited to antisense molecules, antibodies, antagonists and their derivatives. More specifically, an example of an IL-1 blocker or inhibitor is an IL-1 antagonist including, but not limited to, IL-1 trap, which binds and inhibits the biological activity of IL-1.
By the term “therapeutically effective dose” is meant a dose that produces the desired effect for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).
By the term “substantially identical” is meant a protein sequence having at least 95% identity to an amino acid sequence selected from the group consisting of the amino acid sequences SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26, and capable of binding IL-1 and inhibiting the biological activity of IL-1.
The term “identity” or “homology” is construed to mean the percentage of amino acid residues in the candidate sequence that are identical with the residue of a corresponding sequence to which it is compared, after aligning the sequences and introducing gaps, if necessary to achieve the maximum percent identity for the entire sequence, and not considering any conservative substitutions as part of the sequence identity. Neither N- or C-terminal extensions nor insertions will be construed as reducing identity or homology. Methods and computer programs for the alignment are well known in the art. Sequence identity may be measured using sequence analysis software (e.g., Sequence Analysis Software Package, Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Ave., Madison, Wis. 53705). This software matches similar sequences by assigning degrees of homology to various substitutions, deletions, and other modifications.
IL-1 Trap Antagonists
Interleukin-1 (IL-1) traps are multimers of fusion proteins containing IL-1 receptor components and a multimerizing component capable of interacting with the multimerizing component present in another fusion protein to form a higher order structure, such as a dimer. Cytokine traps are a novel extension of the receptor-Fc fusion concept in that they include two distinct receptor components that bind a single cytokine, resulting in the generation of antagonists with dramatically increased affinity over that offered by single component reagents. In fact, the cytokine traps that are described herein are among the most potent cytokine blockers ever described. Briefly, the cytokine traps called IL-1 traps are comprised of the extracellular domain of human IL-1R Type I (IL-1 RI) or Type II (IL-1 RII) followed by the extracellular domain of human IL-1 Accessory protein (IL-1AcP), followed by a multimerizing component. In a preferred embodiment, the multimerizing component is an immunoglobulin-derived domain, such as, for example, the Fc region of human IgG, including part of the hinge region, the CH2 and CH3 domains. An immunoglobulin-derived domain may be selected from any of the major classes of immunoglobulins, including IgA, IgD, IgE, IgG and IgM, and any subclass or isotype, e.g. IgG1, IgG2, IgG3 and IgG4; IgA-1 and IgA-2. Alternatively, the IL-1 traps are comprised of the extracellular domain of human IL-1AcP, followed by the extracellular domain of human IL-1 RI or IL-1 RII, followed by a multimerizing component. For a more detailed description of the IL-1 traps, see WO 00/18932, which publication is herein specifically incorporated by reference in its entirety. Preferred IL-1 traps have the amino acid sequence shown in SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26, or a substantially identical protein at least 95% identity to a sequence of SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, or 26, and capable of binding and inhibiting IL1.
In specific embodiments, the IL-1 antagonist comprises an antibody fragment capable of binding IL-1α, IL-1β, IL-1R1 and/or IL-1 RAcp, or a fragment thereof. The preferred embodiment would be an antagonist of IL-1β. One embodiment of an IL-1 antagonist comprising one or more antibody fragments, for example, single chain Fv (scFv), is described in U.S. Pat. No. 6,472,179, which publication is herein specifically incorporated by reference in its entirety. In all of the IL-1 antagonist embodiments comprising one or more antibody-derived components specific for IL-1 or an IL-1 receptor, the components may be arranged in a variety of configurations, e.g., a IL-1 receptor component(s)-scFv(s)-multimerizing component; IL-1 receptor component(s)-multimerizing component-scFv(s); scFv(s)-IL-1 receptor component(s)-multimerizing component, ScFv-ScFv-Fc, etc., so long as the molecule or multimer is capable of inhibiting the biological activity of IL-1.
Treatment Population
There is an unmet clinical need for the treatment of PMR and GCA due to the long term side effects of prolonged use of glucocorticoids. Accordingly, the treatment population are subjects diagnosed with PMR and/or GCA which may include newly diagnosed subjects with PMR and/or GCA where the invention is given as a co-therapy with the first initiation of glucocorticoids. More particularly, subjects suffering from relapsing PMR are candidates for treatment with the methods of the invention. Subjects previously unable to be tapered off prednisone without relapse are candidates and included in the population for treatment.
Methods of Administration
The invention provides methods of treatment comprising administering to a subject an effective amount of an agent of the invention. In a preferred aspect, the agent is substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects).
Various delivery systems are known and can be used to administer an agent of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432), construction of a nucleic acid as part of a retroviral or other vector, etc. Methods of introduction can be enteral or parenteral and include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compounds may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.
In a specific embodiment, it may be desirable to administer the pharmaceutical compositions of the invention locally to the area in need of treatment; this may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., by injection, by means of a catheter, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, fibers, commercial skin substitutes or angioplasty balloons or stents.
In another embodiment, the active agent can be delivered in a vesicle, in particular a liposome (see Langer (1990) Science 249:1527-1533). In yet another embodiment, the active agent can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer (1990) supra). In another embodiment, polymeric materials can be used (see Howard et al. (1989) J. Neurosurg. 71:105). In another embodiment where the active agent of the invention is a nucleic acid encoding a protein, the nucleic acid can be administered in vivo to promote expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see, for example, U.S. Pat. No. 4,980,286), or by direct injection, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus (see e.g., Joliot et al. 1991, Proc. Natl. Acad. Sci. USA 88:1864-1868), etc. Alternatively, a nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination.
Combination Therapies
In numerous embodiments, the IL-1 antagonists of the present invention may be administered in combination with one or more additional compounds or therapies. Combination therapy may be simultaneous or sequential. The IL-1 traps of the invention may be combined with, for example, TNF-inhibiting agents such as etanercept (ENBREL®, Amgen), infliximab (REMICADE®, Centocor), HUMIRA® (Abbott), thalidomide, glucocorticoids, anakinra (KINARET®, Amgen), colchicine, methotrexate, cyclosporine A, chlorambucil, cyclophosphamide, other inflammatory inhibitors such as inhibitors of caspase-1, p38, IKK1/2, CTLA-4Ig, anti-IL-6 or anti-IL6Ra, and sulfasalazine.
Pharmaceutical Compositions
The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of an active agent, and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.
In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
The active agents of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
The amount of the active agent of the invention which will be effective in the treatment of delayed-type hypersensitivity can be determined by standard clinical techniques based on the present description. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the condition, and should be decided according to the judgment of the practitioner and each subject's circumstances. However, suitable dosage ranges for intravenous administration are generally about 100 to 2000 mg of active compound or 1-30 mg/kg of body weight. Suitable doses for subcutaneous injection may be 100-320 mg or about 1-5 mg/kg.
For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Initial dosages can also be estimated from in vivo data, e.g., animal models, using techniques that are well known in the art. One having ordinary skill in the art could readily optimize administration to humans based on animal data.
Dosage amount and interval may be adjusted individually to provide plasma levels of the compounds that are sufficient to maintain therapeutic effect. In cases of local administration or selective uptake, the effective local concentration of the compounds may not be related to plasma concentration. One having skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.
The amount of compound administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. The therapy may be repeated intermittently while symptoms are detectable or even when they are not detectable. The therapy may be provided alone or in combination with other drugs.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.
The following example is put forth so as to provide those of ordinary skill 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 regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
The IL-1 trap is expected to be well tolerated in subjects with relapsing PMR, based on a descriptive comparison of adverse events reported from subjects receiving active study drug compared with subjects receiving placebo. It is expected that treatment with IL-1 trap will result in a greater proportion of subjects who do not experience disease flares, requiring less to no glucocorticoid therapy in this population of subjects with PMR.
Endpoints. The primary endpoint is the percent change from baseline to week 2 in the hs-CRP.2. Secondary endpoints include: (1) Achievement of a reduction of 50% or more in hs-CRP from Baseline to Week 2; (2) achievement of lack of disease activity at Week 2; (3) change in Subject's Global Assessment from Baseline to Week 2; (4) changes in ESR, fibrinogen and SAA from Baseline to Week 2. Exploratory endpoints include: (1) Achievement of not requiring glucocorticoids for at least 12 consecutive weeks during the Open-Label extension; (2) Number of relapses during the Open-Label extension; changes in selected biomarker profiles from Baseline to Week 2; changes in individual clinical parameters from Baseline to Week 2.
Study Design. This is a two-week, multi-center, randomized, double-blind, placebo-controlled, parallel group study of IL-1 trap in subjects with relapsing polymyalgia rheumatica.
Subjects are randomized in a 1:1 ratio to receive 320 mg of IL-1 trap or placebo administered subcutaneously. Subjects will receive a total of three doses of study drug on Days 0, 3, and 7 during the two-week double-blind phase. Subjects will be evaluated for efficacy and safety on a regular basis with clinical observations and laboratory measurements including anti-IL-1 trap antibodies, hs-CRP and ESR. Following completion of the primary 2-week double-blind treatment phase, all subjects will be eligible to receive subcutaneous injections of IL-1 trap 320 mg every week in an Open-Label safety extension phase for an additional 24 weeks.
At the screening visit, subjects will have the study explained to them and the informed consent will be read and discussed. Any and all questions relating to the study and consent form will be answered prior to signing and prior to the initiation of study procedures. For subjects who require a PPD skin test, they are to be instructed to return to the study site or physician's office within 48 to 72 hours of having the PPD placed to have their PPD skin test read. Subjects who meet all inclusion and exclusion criteria are to be called and an appointment scheduled for the baseline visit.
Polymyalgia rheumatica: Three or more of the five criteria are required for diagnosis (Modified Bird et al. (1979) Ann. Rheum. Dis. 38:434439): (1) Age>65 years; (2) ESR≧40 mm/hr; (3) Bilateral upper arm tenderness; (4) Morning stiffness>1 hour; (5) Onset of illness within two weeks (at the time of initial diagnosis).
Disease activity or relapse is defined as: 1. ESR increase from normal to ≧30 mm in the first hour and the presence of signs or symptoms of PMR or giant cell arteritis, as listed in 2 and 3:2. New onset systemic symptoms attributable to PMR and not able to be attributed to other causes, including: significant morning stiffness; shoulder and/or hip girdle pain; other arthralgias/myalgias. Other features judged by the treating physician to be due to PMR to be confirmed by the Medical Monitor (such as fever, malaise, unintentional weight loss (greater than 10 lbs. in 1 month); 3. New onset of features of giant cell arteritis (GCA): new-onset severe or atypical headache; temporal artery tenderness; abnormal temporal artery biopsy; angiographic abnormalities compatible with large vessel vasculitis; other vascular features judged by the clinician to be compatible with GCA (e.g carotidynia, oral, masseter muscle claudication or visual loss). If signs and symptoms of GCA develop, the subject will be withdrawn from the study and treated by the Investigator with the appropriate doses of glucocorticoid for GCA.
Lack of disease activity is defined as: absence of features of disease activity for at least one week prior to visit and assessment, regardless of glucocorticoid (GCS) dose. This classification can be sub-divided in two groups: on or off GCS.
Remission is defined as: absence of features of disease activity for at least one month after withdrawal of GCS (dose=0)
Subject Eligibility. Inclusion Criteria. Subjects must meet all inclusion criteria to be eligible for enrollment in this study: (1) Diagnosis of polymyalgia rheumatica (see criteria above); (2) Age>65 years; (3) Evidence of a disease flare involving aching and/or stiffness at the shoulder or hip girdle at baseline; (4) Previously or currently treated for PMR with glucocorticoids. A prednisone dose (or prednisone equivalent) of 20 mg or less must have been stable or have been decreased within one month prior to the screening visit, and be stable between screening and baseline; (5) Negative PPD (≦5 mm induration) skin test read at 48 to 72 hours after PPD placement or a negative PPD test within two months prior to screening; (6) hs-CRP>20 mg/L and an ESR≧30 mm/hr at the screening visit; (7) A negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline visit or within a two-day window prior to the Baseline visit for women of childbearing potential, defined as: A woman who is post-menopausal for less than 2 years or not surgically sterile by bilateral tubal ligation, bilateral oophorectomy or hysterectomy). For men and women of childbearing potential, willingness to utilize adequate contraception and not become pregnant (or have their partner[s] become pregnant) during the full course of the study. The following methods of birth control are adequate contraception and must be used throughout the study and for 2 months after the last dose of study medication: condom or diaphragm plus either contraceptive sponge, foam or jelly; IUD; contraceptives (oral, transdermal patch or parenteral) for 2 or more cycles prior to screening; vasectomy; and (6) Able to read, understand, and willing to sign the informed consent form.
Exclusion Criteria. Any of the following will exclude the subject from the study: (1) Prior treatment with Tumor Necrosis Factor (TNF) inhibitors, Interleukin-1 inhibitors, or any other biologic agents for the treatment of inflammatory diseases including investigational agents (2) Treatment with the following DMARDs prior to the Baseline visit: within 8 weeks: methotrexate, sulfasalazine, hydroxychloroquine, gold, or penicillamine; treatment within 6 months: with azathioprine, cyclophosphamide, leflunomide or cyclosporine; (3) any intra-articular, IM or IV dose of glucocorticoids within 2 months prior to the Screening visit; (4) severe respiratory disease, including but not limited to, severe bronchiectasis, chronic obstructive pulmonary disease, bullous lung disease, uncontrolled asthma, or pulmonary fibrosis; (5) general systemic inflammatory condition other than PMR, including but not limited to giant cell arteritis, rheumatoid arthritis, systemic lupus erythematosus, or myositis; (6) history of fibromyalgia or chronic fatigue syndrome (7) subjects with synovitis; (8) active infection: acute or chronic, requiring antibiotics including tuberculosis; (9) known HIV antibody, hepatitis B surface antigen and/or hepatitis C antibody test positive; (10) history of malignancy other than a successfully treated non-metastatic cutaneous squamous or basal cell carcinoma and/or localized carcinoma in-situ of the cervix within five years prior to baseline; (7) female subjects who are pregnant, planning to become pregnant during the course of the study, or breast-feeding; (8) receipt of a live (attenuated) vaccine within three months prior to screening or during the course of the study; (9) hemoglobin<9.0 mg/dL, hemoglobin A1C≧9.0%, WBC<3.0×103/mm3, platelet count<100×103/mm3, serum creatinine>1.5×ULN, AST/ALT>2×ULN, alkaline phosphatase>2×ULN at screening visit; (10) participation in an investigational drug or device trial within 30 days prior to Screening; and (11) history of unstable ischemic heart disease or stroke within 1 year of screening, active congestive heart disease, or any other condition which, in the opinion of the Investigator, would render the subject inappropriate for this study.
Concomitant Medications. Analgesics such as acetaminophen, codeine, oxycodone and/or propoxyphene, or combinations of these analgesics are permitted for pain as required. The dose of all analgesics should remain stable during the 2-week blinded portion of the study. Subjects may receive prednisone (or equivalent) for the treatment of their PMR provided that the dose has been stable for at least 4 weeks prior to or has been decreased in the 4 weeks prior to the Screening visit and the dose does not exceed 20 mg/day. The prednisone dose must remain unchanged during the double blind phase. Subjects may receive NSAIDs (including ibuprofen and naproxen) for the treatment of their PMR provided that the dose has been stable for at least 4 weeks prior to the Baseline visit (Visit 2). The NSAID dose must remain unchanged during the course of the study. The following drugs are not allowed during the study: leflunomide, methotrexate, sulfasalazine, hydroxychloroquine, cyclosporine, azathioprine, cyclophosphamide, gold and potent opioid-containing analgesics including; morphine, fentanyl, methadone, meperidine, high potency agents containing pentazocine, oxymorphone, and hydromorphone. In addition, long-acting oxycodone containing agents are excluded (e.g., OxyContin). Intra-articular, IM or IV doses of glucocorticoids must not be administered throughout the duration of the study. Methotrexate, other DMARDS, and other investigational drugs are prohibited during the double-blind and open-label phases of the study. Live (attenuated) vaccines must not be administered during the course of the study.
Subject Enrollment. Approximately 12 study sites will screen to enroll 40 evaluable subjects (20 subjects per randomized arm).
Study Drug Dosage. Based on a Phase I IL-1 trap study in healthy volunteers, the dose selected for this study is 320 mg, administered as two 2.0 mL subcutaneous injections. During the two week double blind portion, subjects will be randomly allocated to receive IL-1 trap or placebo on Days 0, 3, and 7. Subjects randomized to receive placebo will receive injections of diluent only. During the open label phase, beginning at Week 2, subjects will receive 320 mg IL-1 trap weekly for an additional 24 weeks.
Dose Preparation and Administration. Reconstituted IL-1 trap or placebo is prepared and administered by study staff in the clinic, physician's office, visiting nurse (Day 3 only) or research center. Subjects will self-administer IL-1 trap during the open label phase of the study.
Study Procedures. This study involves a total of 13 clinic visits. At the baseline visit, Day 0, subjects receive two 2.0 mL subcutaneous injections of 320 mg IL-1 trap or placebo, followed by additional doses of study medication on Days 3 and 7. Beginning at week 2 (end of Double Blind phase) the open-label phase begins, where all subjects will be eligible to receive 320 mg IL-1 trap, administered subcutaneously every week for an additional 24 weeks. Standard safety laboratory evaluations will be collected at designated intervals and sent to a central laboratory. C-reactive protein and erythrocyte sedimentation rate and fibrinogen will be measured at each clinic visit; CRP and fibrinogen samples will be sent to the central lab, ESR will be measured at the study site.
Evaluation of Serum Cytokines. Serum levels of IL-1β, IL-1ra, TNF-alpha, IL-2, IL-8, IL-12, IL-18, IL-6 and IFN gamma will be collected at screening, baseline, week 2 (Double Blind), weeks 4, 10, 18, 26 (Open-label), and at follow-up.
Glucocorticoid Guidelines. The glucocorticoid dose must remain unchanged until at least one week after the second dose in the open label phase (Visit 6, Week 4).
Schedule of Study Visits: Screening Visit (Visit 1; Day −21 to day −3): The informed consent must be signed before any study procedures are conducted; Informed consent; Medical history—to include all co-morbidities; physical examination; vital signs; weight; chest x-ray; ECG; serum pregnancy test (for women of childbearing potential); hematology panel; chemistry panel; urinalysis; serum biomarkers, PPD skin test or negative PPD within prior two months; blood for RNA, CRP, ESR, fibrinogen; concomitant medications; clinical assessments of disease activity [Physician's Global Assessment (11 point Likert like scale); Subject's Global Assessment (11 point Likert like scale); Subject's Pain (11 point Likert like scale); duration of morning stiffness (MST)]; serum for storage.
Study Visits: Baseline. Day 0, Visit 2: Physical examination; vital signs; weight; urine pregnancy test (for women of childbearing potential); hematology panel; chemistry panel; urinalysis; CRP. ESR, Fibrinogen; SAA; RF, ANA, ferritin; serum biomarkers; concomitant medications; adverse events; pharmacokinetic draw (baseline level); blood for RNA: pharmacogenetic draw (if consent obtained); anti-IL-1 trap antibody; serum for storage; Physician's Global Assessment (11 point Likert like scale); Subject's Global Assessment (11 point Likert like scale); Subject's Pain (11 point Likert like scale); duration of morning stiffness (MST); administer study drug.
Visit 3: Vital signs; concomitant medications; adverse events; administer IL-1 trap.
Week 1, Double Blind Visit 4: Vital signs; CRP, ESR, fibrinogen; pharmacokinetic draw; Physician's Global Assessment (11 point Likert like scale); Subject's Global Assessment (11 point Likert like scale); Subject's Pain (11 point Likert like scale); duration of morning stiffness (MST); adverse events; administer study drug.
Week 2, Double Blind, Visit 5±1 day (Start of Open label extension): Physical examination; vital signs; weight; hematology panel; chemistry panel; urinalysis; CRP, ESR, fibrinogen; ferritin, SAA; serum biomarkers; serum for storage, concomitant medications; adverse events; pharmacokinetic draw; Physician's Global Assessment VAS; Subject's Global Assessment (VAS); Subject's Pain VAS; duration of morning stiffness (MST); administer first dose of open label drug.
Week 4 Open Label Visit 6±2 days: Vital signs; weight; hematology panel; chemistry panel; urinalysis; CRP, ESR, fibrinogen, RF, ANA, SM; serum biomarkers, serum for storage, blood for RNA, blood for DNA if applicable, pharmacokinetic draw; concomitant medications; adverse events; Physician's Global Assessment (11 point Likert like scale); Subject's Global Assessment (11 point Likert like scale) Subject's Pain (11 point Likert like scale); duration of morning stiffness (MST); administer IL-1 trap.
Week 6 Open-label. Visit 7±2 days: Vital signs; weight; hematology panel; chemistry panel; urinalysis; CRP, ESR, fibrinogen, SM; concomitant medications; adverse events;
pharmacokinetic draw; duration of morning stiffness (MST); Physician's Global Assessment (11 point Likert like scale); Subject's Global Assessment (11 point Likert like scale); Subject's Pain (11 point Likert like scale); administer IL-1 trap.
Week 10 Open-label, Visit 8±3 days: Vital signs; weight; urine; hematology panel; chemistry panel; urinalysis; CRP, ESR, fibrinogen; SM; serum biomarkers; pharmacokinetic draw; serum for storage; concomitant medications; adverse events; Physician's Global Assessment (11 point Likert like scale); Subject's Global Assessment (VAS); Subject's Pain (11 point Likert like scale); duration of morning stiffness (MST); administer IL-1 trap.
Week 14 Open-label, Visit 9±3 days: Vital signs; weight; hematology panel; chemistry panel; urinalysis; CRP, ESR, fibrinogen; SM; concomitant medications; adverse events; pharmacokinetic draw; duration of morning stiffness (MST); Physician's Global Assessment (11 point Likert like scale); Subject's Global Assessment (11 point Likert like scale); Subject's Pain (11 point Likert like scale); administer IL-1 trap.
Week 18 Open-label, Visit 10±3 days: Vital signs; weight; hematology panel; chemistry panel; urinalysis; CRP, ESR, fibrinogen; SM; serum biomarkers; pharmacokinetic draw; anti-IL-1 trap antibody; serum for storage; concomitant medications; adverse events; Physician's Global Assessment (11 point Likert like scale); Subject's Global Assessment (11 point Likert like scale); Subject's Pain (11 point Likert like scale); duration of morning stiffness (MST); administer IL-1 trap.
Week 22 Open-label. Visit 11±3 days: Physical examination; vital signs; weight; hematology panel; chemistry panel; urinalysis; CRP, ESR, fibrinogen; SAA; concomitant medications; adverse events; pharmacokinetic draw; anti-IL-1 trap antibody; duration of morning stiffness (MST); Physician's Global Assessment (11 point Likert like scale); Subject's Global Assessment (11 point Likert like scale); Subject's Pain (11 point Likert like scale); administer IL-1 trap.
Week 26 Open-Label, Visit 12±3 days: Physical examination; vital signs; weight; chest X-ray; urine pregnancy test (for women of childbearing potential); hematology panel; chemistry panel; urinalysis; CRP, ESR, fibrinogen; SAA; RF, ANA; ferritin; blood for RNA; serum biomarkers; concomitant medications; adverse events; pharmacokinetic draw; anti-IL-1 trap antibody; serum for storage; duration of morning stiffness (MST); Physician's Global Assessment (11 point Likert like scale); Subject's Global Assessment (11 point Likert like scale); Subject's Pain (11 point Likert like scale); Termination.
Follow-Up, Visit 13: Vital signs; weight; pharmacokinetic draw; serum biomarkers; concomitant medications; adverse events; anti-IL-1 trap antibody; serum for storage.
This application claims the benefit under 35 USC § 119(e) of U.S. Provisional 60/644,048 filed 14 Jan. 2004, which application is herein specifically incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 60644048 | Jan 2005 | US |
