The invention provides a method of alleviating a granuloma annulare or a sarcoid disease by administering to a patient having the disease, a therapeutically effective amount of an LFA-1 antagonist.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention provides a method of alleviating granuloma annulare conditions or sarcoid disease comprising administering to a patient having the disease, a therapeutically effective amount of an LFA-1 antagonist. The methods of the invention have the benefit of achieving rapid improvement and resolution of the disease and reduced side effects that are associated with conventional therapy for the disease. For example, conventional therapy with cyclosporine carries the risk of renal dysfunction and diarrhea may be a side effect with clofazimine treatment. The present method is effective to resolve the granuloma annulare within 2 months of initiation of therapy with the LFA-1 antagonist.

The granuloma annulare can be localized, disseminated (generalized; DGA), subcutaneous, or perforating type. In a specific embodiment, the granuloma annulare is disseminated granuloma annulare (DGA, also referred to as GGA).

In any of the methods of the present invention, in certain embodiments, the LFA-1 antagonist is an anti-LFA-antibody or an anti-ICAM 1 antibody. In one embodiment, the LFA-1 antagonist is an anti-CD11a antibody. In one embodiment, the anti-CD11a antibody is efalizumab.

In the present methods of alleviation, to minimize side effects, in particular infusion reactions on initial dosing, the patient can be administered the antagonist compound or antibody at an initial conditioning dose before the therapeutic dose, wherein the conditioning dose is lower than the therapeutic dose. Where the LFA-1 antagonist is efalizumab, the antibody can be administered at a dosage of between 0.3 mg/kg to 4 mg/kg. In one embodiment, the efalizumab antibody is administered at 1 mg/kg weekly. In another embodiment, efalizumab is administered at 2 mg/kg weekly. Where the LFA-1 antagonist used is efalizumab, in one embodiment, the patient is administered a conditioning dose of efalizumab at 0.7 mg/kg. In a further embodiment, the antibody is administered at an initial conditioning dose of 0.7 mg/kg during the first week followed by a dose of 1 mg/kg weekly for at least 4 weeks. In separate embodiments, the patient is administered the weekly therapeutic dose of 1 mg/kg or 2 mg/kg for 8 weeks, 11 weeks, or 24 weeks

In any of the embodiments of the present methods of alleviating the disease, in a preferred embodiment, the LFA-1 antagonist is administered subcutaneously. In another embodiment the LFA-1 antagonist is administered intravenously.

In any of the embodiments of the method of alleviating granuloma annulare and sarcoid, the LFA-1 antagonist can be administered in conjunction with another therapy, a second therapeutic agent or an immunosuppressive agent. The second therapeutic agent is selected from the group consisting of cyclosporine, isotretinoin, etretinate, topical and systemic corticosteroids, fumaric acid esters, psoralens plus ultraviolet A (PUVA), potassium iodide, pentoxifylline, topical vitamin E, hydroxychloroquine, dapsone, niacinamide, low-dose chlorambucil, clofazimine, and a 5-lipoxygenase inhibitor plus vitamin E. In one embodiment, the second therapeutic agent is clofazimine or cyclosporine. Another second therapeutic agent is an immunoadhesin, in particular, Enbrel.RTM. or Amevive.RTM..

The second therapeutic agent and the LFA-1 antagonist can be administered consecutively, sequentially, or a combination of both, in either order.

Yet another aspect of the method of the invention is to alleviate granuloma annulare or sarcoid in a patient suffering from a relapse of the disease or a patient who is non-responsive to other therapy used to treat the disease.

In one embodiment, patient having the disease is experiencing an inadequate response or is non-responsive to cyclosporine or clofazimine treatment.

Also provided by the invention is an article of manufacture comprising a container containing an efalizumab composition, and a package insert indicating that the composition can be used to treat disseminated granuloma annulare.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Granuloma annulare encompasses an uncommon benign group of granulomatous diseases that include localized, disseminated (generalized), subcutaneous, and perforating types. Approximately 10% to 15% of patients have disseminated granuloma annulare (DGA), which occurs primarily in adults and is characterized by multiple discrete or confluent papules with either an annular or nonannular configuration. DGA occurs predominantly on the trunk and proximal extremities, and patients with DGA may present with hundreds of lesions. In approximately one third of cases, patients report symptoms of pruritus or burning sensations. Histologically, DGA typically is characterized by areas of collagen alteration and elastic fiber degeneration in the middle and upper dermis surrounded by palisading inflammatory cells; the epidermis appears normal. The inflammatory infiltrates in DGA are primarily composed of a mixture of histiocytes (macrophages) and lymphocytes.

Compositions and Methods of the Invention

According to one embodiment, the LFA-1 antagonist is an immunoadhesin, e.g., Amevive.RTM. (Biogen, Boston, Mass.)

In the methods of treatment of the present invention, the LFA-1 antagonist can be administered chronically or intermittently.

The patient can be treated with the LFA-1 antagonists in conjunction with one or more therapeutic agents. Second therapeutic agents useful in the treatment of granuloma annulare include the following: cyclosporine, isotretinoin, etretinate, topical and systemic corticosteroids, fumaric acid esters, psoralens plus ultraviolet A (PUVA), potassium iodide, pentoxifylline, topical vitamin E, hydroxychloroquine, dapsone, niacinamide, low-dose chlorambucil, clofazimine, and a 5-lipoxygenase inhibitor plus vitamin E.

"Immunosuppressive agent" as used herein refers to substances that act to suppress or mask the immune system of a patient. Such agents would include substances that suppress cytokine production, down regulate or suppress self-antigen expression, or mask the MHC antigens. Examples of such agents include steroids such as glucocorticosteroids, e.g., prednisone, methylprednisolone, and dexamethasone; 2-amino-6-aryl-5-substituted pyrimidines (see U.S. Pat. No. 4,665,077), azathioprine (or cyclophosphamide, if there is an adverse reaction to azathioprine); bromocryptine; glutaraldehyde (which masks the MHC antigens, as described in U.S. Pat. No. 4,120,649); anti-idiotypic antibodies for MHC antigens and MHC fragments; cyclosporin A; cytokine or cytokine receptor antagonists including anti-interferon-.gamma., -.beta., or -.alpha. antibodies; anti-tumor necrosis factor-.alpha. antibodies; anti-tumor necrosis factor-.beta. antibodies; anti-interleukin-2 antibodies and anti-IL-2 receptor antibodies; anti-L3T4 antibodies; heterologous anti-lymphocyte globulin; pan-T antibodies, preferably anti-CD3 or anti-CD4/CD4a antibodies; soluble peptide containing a LFA-3 binding domain (WO 90/08187 published Jul. 26, 1990); streptokinase; TGF-.beta.; streptodomase; RNA or DNA from the host; FK506; RS-61443; deoxyspergualin; rapamycin; T-cell receptor (U.S. Pat. No. 5,114,721); T-cell receptor fragments (Offner et al., Science 251:430-432 (1991); WO 90/11294; and WO 91/01133); and T cell receptor antibodies (EP 340,109) such as T10B9. The immunosuppressive agents herein may overlap with the second therapeutic agent.

Dosing

For the methods of the invention, the antagonists and antibodies of the invention will be administered at a dosage that is efficacious for the treatment of the granuloma annulare or sarcoid disease while minimizing toxicity and side effects.

The LFA-1 antibodies can be administered to the patient in a dosage range of about 1 mg/kg to 20 mg/kg. In different embodiments, the dosage range is 1-15 mg/kg, 1-10 mg/kg, 2-10 mg/kg, 3-10 mg/kg. Efalizumab antibody can be administered at a dosage range of from 0.3 mg/kg to 4 mg/kg, at least once a week for at least 4 weeks.

Doses of efalizumab of up to 4 mg/kg/wk SC for 10 weeks following a conditioning (0.7 mg/kg) first dose have been administered without an observed increase in acute toxicity.

In one embodiment, efalizumab is administered to the patient subcutaneously as an initial conditioning dose of 0.7 mg/kg followed by 11 weekly SC (subcutaneous) doses of 1 mg/kg/wk. The initial lower conditioning dose is optional; the patient can receive instead 12 weekly doses at 1 mg/kg/wk.

In treating disease, the LFA-1 antagonists of the invention can be administered to the patient chronically or intermittently, as determined by the physician of skill in the disease.

A patient administered a drug by intravenous infusion or subcutaneously may experience adverse events such as fever, chills, burning sensation, asthenia and headache. To alleviate or minimize such adverse events, the patient may receive an initial conditioning dose(s) of the antibody followed by a therapeutic dose. The conditioning dose(s) will be lower than the therapeutic dose to condition the patient to tolerate higher dosages.

"Initial" dosing means dosing that is not the last dosing administered in the treatment. The initial dosing need not be a single dose, but it is not the last dose. "Subsequent" dosing is dosing that follows the initial dosing and includes the last dose administered for the treatment.

Route of Administration

The antagonists and antibodies as well as second therapeutic agents and immunosuppressive agents used in the methods of the invention are administered to a human patient in accord with methods known to medical practitioners, such as by intravenous administration, e.g., as a bolus or by continuous infusion over a period of time, by subcutaneous, topically, intramuscular, intra-arterial, intrapulmonary, intra-articular, intrasynovial, intrathecal, intralesional, or inhalation routes (e.g., intranasal), generally by subcutaneous, intravenous or topical administration.

The LFA-1 antagonist, the second therapeutic agent and immunosuppressive agent can be provided systemically or topically. In one embodiment, the LFA-1 antagonist is administered topically.

Pharmaceutical Formulations

Therapeutic formulations of the antagonists and antibodies used in accordance with the present invention are prepared for storage by mixing the compound or antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as olyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN.TM., PLURONICS.TM. or polyethylene glycol (PEG).

The LFA-1 antagonists useful in the methods of the present invention can be provided in an extended release formulation.

The term "extended-release" or "sustained-release" formulations in the broadest possible sense means a formulation of an active LFA-1 antagonist compound resulting in the release or activation of the compound for a sustained or extended period of time or at least for a period of time which is longer than if the compound was made available in vivo in the native or unformulated state. Optionally, the extended-release formulation occurs at a constant rate and/or results in sustained and/or continuous concentration of the active polypeptide. Suitable extended release formulations may comprise microencapsulation, semi-permeable matrices of solid hydrophobic polymers, biogradable polymers, biodegradable hydrogels, suspensions or emulsions (e.g., oil-in-water or water-in-oil). Optionally, the extended-release formulation comprises poly-lactic-co-glycolic acid (PLGA) and can be prepared as described in Lewis, "Controlled Release of Bioactive Agents form Lactide/Glycolide polymer," in Biodegradable Polymers as Drug Delivery Systems, M. Chasin & R. Langeer, Ed. (Marcel Dekker, New York), pp. 1-41. Optionally, the extended-release formulation is stable and the activity of the LFA-1 antagonist does not appreciably diminish with storage over time. More specifically, such stability can be enhanced through the presence of a stabilizing agent such as a water-soluble polyvalent metal salt.

Articles of Manufacture and Kits

Another embodiment of the invention is an article of manufacture containing materials useful for the treatment of granuloma annulare or sarcoid disease. The article of manufacture comprises at least one container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, etc. The containers may be formed from a variety of materials such as glass or plastic. At least one container holds a composition which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Two therapeutic compositions may be provided in the article of manufacture. At least one active agent in the first composition is a CD11a binding antibody of the invention. The second or second and third compositions may be held in one or more separate containers. The label or package insert indicates that the composition is used for treating granuloma annulare, DGA or sarcoid. The label or package insert will further comprise instructions for administering the compositions to the patient. Package insert refers to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. Additionally, the article of manufacture may further comprise a container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

In a specific embodiment, the container contains an efalizumab composition, and the package insert indicates that the composition can be used to treat disseminated granuloma annulare (DGA).
 

Claim 1 of 20 Claims

1. A method of alleviating a disseminated granuloma annulare comprising administering to a patient having the disease, a therapeutically effective amount of an LFA-1 antagonist wherein the LFA-1 antagonists is an anti-CD11a antibody.

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