US20140148473A1 - Use of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl)piperidine-2,6-dione in treatment of immune-related and inflammatory diseases - Google Patents

Use of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl)piperidine-2,6-dione in treatment of immune-related and inflammatory diseases Download PDF

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US20140148473A1
US20140148473A1 US13/984,833 US201213984833A US2014148473A1 US 20140148473 A1 US20140148473 A1 US 20140148473A1 US 201213984833 A US201213984833 A US 201213984833A US 2014148473 A1 US2014148473 A1 US 2014148473A1
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patient
scleroderma
skin
compound
effective amount
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Anita Gandhi
Peter H. Schafer
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Celgene Corp
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Definitions

  • kits for treating, preventing, and/or managing diseases associated with lymphocytic activity including activity of B cells and/or T cells, e.g., immune-related diseases or inflammatory diseases, comprising administering Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, racemic mixture, co-crystal, clathrate, or polymorph thereof, where Compound I is 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.
  • Pharmaceutical compositions and dosing regimens for such treatment, prevention, and/or management are also provided herein.
  • Inflammatory and immune-related diseases modulated by lymphocytic activity including activity of B cells and/or T cells, such as lupus, scleroderma, Sjögren syndrome, ANCA-induced vasculitis, anti-phospholipid syndrome and myasthenia gravis, continue to be important medical problems.
  • Lupus or lupus erythematosus is a collection of autoimmune disorders that can cause chronic inflammation in various parts of the body, especially the skin, joints, blood, and kidneys.
  • the body's immune system normally makes proteins called antibodies to protect the body against viruses, bacteria, and other foreign materials (i.e., antigens).
  • an autoimmune disorder such as lupus
  • the immune system loses its ability to tell the difference between antigens and its own cells and tissues and can make antibodies directed against its own cells and tissues to form immune complexes. These immune complexes can build up in the tissues and cause inflammation, injury to tissues and/or pain.
  • lupus The three most common types include systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE) and drug-induced lupus. More detailed descriptions of lupus or lupus erythematosus can be found in Wallace, 2000 , The Lupus Book: A Guide for Patients and Their Families , Oxford University Press, Revised and Expanded Edition, which is incorporated by reference herein in its entirety.
  • SLE systemic lupus erythematosus
  • CLE cutaneous lupus erythematosus
  • drug-induced lupus More detailed descriptions of lupus or lupus erythematosus can be found in Wallace, 2000 , The Lupus Book: A Guide for Patients and Their Families , Oxford University Press, Revised and Expanded Edition, which is incorporated by reference herein in its entirety.
  • Scleroderma is a rare disease with a stable incidence of approximately 19 cases per 1 million persons. The exact cause of scleroderma is unknown. Abnormalities involve autoimmunity and alteration of endothelial cell and fibroblast function.
  • Systemic scleroderma usually begins with skin thickening, usually of the fingers, accompanied by Raynaud's phenomenon. Raynaud's disease typically precedes further manifestations of systemic scleroderma. Early in the disease the affected skin may be puffy and soft. The usual location of greatest skin thickening and hardening is the face, hands and fingers. Sclerodactyly is frequently present. Tendon friction rubs are often palpable on exam and can be painful.
  • Gastrointestinal dismotility is a feature, often manifested by heartburn, or by diarrhea with malabsorption or pseudo-obstruction. New onset hypertension or renal insufficiency are manifestations of the associated vascular injury. Heart failure or arrhythmia are also possible due to cardiac fibrosis. (Hachulla E, Launay D, Diagnosis and classification of systemic sclerosis , Clin Rev Allergy Immunol 2010; 40(2):78-83).
  • scleroderma and in particular of systemic sclerosis are inappropriate excessive collagen synthesis and deposition, endothelial dysfunction, spasm, collapse and obliteration by fibrosis.
  • an important clinical parameter is skin thickening proximal to the metacarpophalangeal joints.
  • Raynaud's phenomenon is a frequent, almost universal component of scleroderma. It is diagnosed by color changes of the skin upon cold exposure. Ischemia and skin thickening are symptoms of Raynaud's disease.
  • prophylactic or therapeutic drugs that can be used to treat or prevent immune-related and inflammatory diseases, including lupus, scleroderma, Sjögren syndrome, ANCA-induced vasculitis, anti-phospholipid syndrome and myasthenia gravis.
  • kits for treating, managing, ameliorating and/or preventing diseases, disorders and/or conditions associated with immune-related and inflammatory diseases comprising administering a therapeutically effective amount of a compound of formula I
  • the compound is 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.
  • the disease is selected from lupus, scleroderma, Sjögren syndrome, ANCA-induced vasculitis, anti-phospholipid syndrome and myasthenia gravis.
  • kits for modulating comprising contacting B cell and/or T cell with an effective amount of Compound I.
  • compositions, single unit dosage forms, and kits suitable for use in treating, preventing, ameliorating and/or managing diseases, disorders and/or conditions associated immune-related and inflammatory diseases which comprise Compound I, optionally in combination with one or more other therapeutic agents.
  • Compound I is administered in combination with one or more therapeutic agents, i.e., pharmaceutical agents that are modulators of lymphocytic activity, including activity of B cells and/or T cells activity.
  • therapeutic agents i.e., pharmaceutical agents that are modulators of lymphocytic activity, including activity of B cells and/or T cells activity.
  • the combinations encompass simultaneous as well as sequential administration.
  • FIG. 1 illustrates the effect of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione on cytokine and chemokine production in anti-CD3-stimulated human T cells, expressed as absolute amount produced.
  • FIG. 2 illustrates the effect of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione on cytokine and chemokine production in anti-CD3-stimulated human T cells, expressed as percentage of control.
  • FIG. 3 illustrates inhibition of production of cytokine and chemokine production in lipopolysaccharide-stimulated peripheral blood mononuclear cells by 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.
  • FIG. 4 illustrates enhancement of production of cytokine and chemokine production in lipopolysaccharide-stimulated peripheral blood mononuclear cells by 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.
  • FIG. 5 illustrates enhancement of NK cell IFN-gamma production in response to immobilized IgG and IL-2, expressed as absolute amount produced, for 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.
  • FIG. 6 illustrates enhancement of NK cell IFN-gamma production in response to immobilized IgG and IL-2, expressed as percentage of amount of IFN-gamma produced in the presence of 1 ⁇ m pomalidomide, for 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.
  • FIG. 7 illustrates the effect of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione on NK-cell mediated ADCC against Rituximab coated lymphoma cells.
  • FIG. 8 illustrates hematoxylin and eosin stained skin section photomicrographs showing dermal thickness of lesional skin in the bleomycin dermal fibrosis mouse model (prevention of inflammation driven fibrosis).
  • FIG. 9 illustrates hematoxylin and eosin stained skin section photomicrographs showing dermal thickness of lesional skin in the bleomycin dermal fibrosis mouse model (regression of established fibrosis).
  • treat refers to alleviating or reducing the severity of a disease or a symptom associated with the disease or condition being treated.
  • prevent As used herein, “prevent”, “prevention” and other forms of the word include the inhibition of onset or progression of a disease or disorder or a symptom of the particular disease or disorder. In some embodiments, subjects with familial history of cancer are candidates for preventive regimens. Generally, in the context of cancer, the term “preventing” refers to administration of the drug prior to the onset of signs or symptoms of a cancer, particularly in subjects at risk of cancer.
  • the term “managing” encompasses preventing the recurrence of the particular disease or disorder in a subject who had suffered from it, lengthening the time a subject who had suffered from the disease or disorder remains in remission, reducing mortality rates of the subjects, and/or maintaining a reduction in severity or avoidance of a symptom associated with the disease or condition being managed.
  • subject means an animal, typically a mammal, including a human being.
  • patient means a human subject.
  • the terms “therapeutically effective amount” and “effective amount” of a compound refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention and/or management of a disease, to delay or minimize one or more symptoms associated with the disease or disorder to be treated.
  • the terms “therapeutically effective amount” and “effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder or enhances the therapeutic efficacy of another therapeutic agent.
  • prophylactically effective amount of a compound is an amount sufficient to prevent a disease or condition, or one or more symptoms associated with the disease or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease.
  • prophylactically effective amount can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • the term “pharmaceutically acceptable salt” includes, but is not limited to, a salt of an acidic group that can be present in the compounds provided herein. Under certain acidic conditions, the compound can form a wide variety of salts with various inorganic and organic acids.
  • acids that can be used to prepare pharmaceutically acceptable salts of such basic compounds are those that form salts comprising pharmacologically acceptable anions including, but not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, bromide, iodide, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate (mesylate), methylsulfate, muscate, napsylate, nitrate, pantothenate, phosphate/diphosphate,
  • hydrate means a compound provided herein or a salt thereof, further including a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • the hydrates can be crystalline or non-crystalline.
  • solvate means a solvate formed from the association of one or more solvent molecules to compound provided herein.
  • solvate includes hydrates (e.g., monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
  • the solvates can be crystalline or non-crystalline.
  • stereoisomer encompasses all enantiomerically/stereomerically pure and enantiomerically/stereomerically enriched compounds provided herein.
  • stereomerically pure or “enantiomerically pure” means that a compound comprises one stereoisomer and is substantially free of its counter stereoisomer or enantiomer.
  • a compound is stereomerically or enantiomerically pure when the compound contains 80%, 90%, or 95% or more of one stereoisomer and 20%, 10%, or 5% or less of the counter stereoisomer.
  • a compound provided herein is considered optically active or stereomerically/enantiomerically pure (i.e., substantially the R-form or substantially the S-form) with respect to a chiral center when the compound is about 80% ee (enantiomeric excess) or greater, preferably, equal to or greater than 90% ee with respect to a particular chiral center, and more preferably 95% ee with respect to a particular chiral center.
  • co-administration and “in combination with” include the administration of two or more therapeutic agents (for example, Compound I or a composition provided herein and another modulator of lymphocytic activity, including activity of B cells and/or T cells activity or other active agent) either simultaneously, concurrently or sequentially with no specific time limits.
  • Compound I and at least one other agent are present in the cell or in the subject's body at the same time or exert their biological or therapeutic effect at the same time.
  • the therapeutic agent(s) are in the same composition or unit dosage form. In another embodiment, the therapeutic agent(s) are in separate compositions or unit dosage forms.
  • a “B cell” is a lymphocyte that matures within the bone marrow, and includes a naive B cell, memory B cell, or effector B cell (plasma cells).
  • the B cell herein may be a normal or non-malignant B cell.
  • a “T cell” is a lymphocyte that matures in thymus, and includes a helper T cell, a memory T cell, and a cytotoxic T cell.
  • all survival refers to the time from randomization until death from any cause, and is measured in the intent-to-treat population. Overall survival can be evaluated in randomized controlled studies.
  • object response rate refers to the proportion of patients with reduced predefined scleroderma symptoms at the end of a predefined period of time. Response duration is usually measured from the time of initial response until documented scleroderma progression.
  • time to progression means the time from randomization until objective scleroderma progression. In certain embodiments, time to progression does not include deaths.
  • progression-free survival means the time from randomization until objective scleroderma progression or death.
  • time-to-treatment failure means any endpoint(s) measuring time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death.
  • memory means a measure of the number of deaths in a given population.
  • respiratory mortality means patients who die from acute hypoxemia or other specific respiratory deterioration resulting in death such as need for mechanical ventilation leading to death, respiratory arrest, or any other event in a subject deemed to be respiratory in nature.
  • respiratory hospitalization means those hospitalized for deterioration in pulmonary status as documented by patient hospital admission notes or other medical opinion.
  • modified Rodnan skin score means a validated numerical scoring system to assess dermal skin thickness.
  • skin thickness means hard or indurated skin that can be evaluated using a variety of techniques including durometer and mRSS
  • skin induration means skin that is hardened, red, inflamed, thickened or tender.
  • skin quality of life index means an evaluation of quality or life related to the skin symptoms for a patient having scleroderma.
  • pulmonary function means any measurement of forced expiratory flow, forced vital capacity, FEV 25-75%, lung volumes or vital capacity.
  • carbon monoxide diffusing capacity means an assessment of the uptake of carbon monoxide across the alveolar-capillary membrane. It can be a proxy for the measurement of the lungs ability to transfer oxygen from the lungs to the blood stream.
  • Mahler Dyspnea index means an instrument that provides clinical measurement of shortness of breath.
  • Saint George's Respiratory Questionnaire score means an instrument that measures quality of life in patients with pulmonary disease.
  • UCLA scleroderma clinical trial consortium gastrointestinal tract score means a questionnaire administered to patients having scleroderma to evaluate gastrointestinal symptoms associated with scleroderma (systemic sclerosis).
  • flow-mediated dilatation means any measurement of vascular endothelial function in a patient having scleroderma.
  • ix minute walk distance means any evaluation of the distance a patient having scleroderma can walk within 6 minutes or any standardized procedure to evaluate ability to walk for a fixed period of time or distance.
  • pomalidomide refers to the following compound:
  • Compound I for use in the methods provided herein, including the combination therapy, and in compositions provided herein is a compound of formula:
  • the compound is 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione.
  • Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, racemic mixture, co-crystal, clathrate, or polymorph thereof can be prepared by methods known to one of skill in the art, for example, according to the procedure described in U.S. Pat. No. 7,635,700 and U.S. Provisional App. No. 61/451,806.
  • the compound of Formula I is a solid. In certain embodiments, the compound of Formula I is hydrated. In certain embodiments, the compound of Formula I is solvated. In certain embodiments, the compound of Formula I is anhydrous. In certain embodiments, the compound of Formula I is nonhygroscopic.
  • the solid compound of Formula I is amorphous. In certain embodiments, the solid compound of Formula I is crystalline. In certain embodiments, the solid compound of Formula I is in a crystalline form described in U.S. Provisional Pat. App. No. 61/451,806, filed Mar. 11, 2011, which is incorporated herein by reference in its entirety.
  • the solid forms of the compound of Formula I can be prepared according to the methods described in the disclosure of U.S. Provisional Pat. App. No. 61/451,806.
  • the solid forms can be also prepared according to other methods apparent to those of skill in the art.
  • the compound of Formula I is a hydrochloride salt of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
  • the hydrochloride salt is a solid.
  • the hydrochloride salt is anhydrous.
  • the hydrochloride salt is nonhygroscopic.
  • the hydrochloride salt is amorphous.
  • the hydrochloride salt is crystalline.
  • the hydrochloride salt is in crystalline Form A.
  • hydrochloride salt of the compound of Formula I and solid forms thereof can be prepared according to the methods described in the disclosure of U.S. Provisional Pat. App. No. 61/451,806.
  • the hydrochloride salt the solid forms thereof can be also prepared according to other methods apparent to those of skill in the art.
  • the compound of Formula I provided herein contains one chiral center, and can exist as a mixture of enantiomers, e.g., a racemic mixture.
  • This disclosure encompasses the use of stereomerically pure forms of such a compound, as well as the use of mixtures of those forms.
  • mixtures comprising equal or unequal amounts of the enantiomers of the compound of Formula I provided herein may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents.
  • the disease is selected from lupus, scleroderma, Sjögren syndrome, ANCA-induced vasculitis, anti-phospholipid syndrome and myasthenia gravis. In certain embodiments, the disease is lupus or scleroderma.
  • the sensitivity of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof can be studied in various in vivo and in vitro assays, including animal models known to one of skill in the art for immune-related and inflammatory diseases, including, but not limited to MRL/MpJ-Fas1pr/J mouse model of systemic lupus erythematosus, NZBWF1/J mouse model of systemic lupus erythematosus, bleomycin-induced skin fibrosis model, and murine tight skin-1 (Tsk-1) mouse model.
  • provided herein are methods of treating, preventing, and/or managing scleroderma or a symptom thereof, comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to a patient having scleroderma.
  • provided herein are methods of preventing scleroderma or a symptom thereof, comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to a patient at risk of having scleroderma.
  • the scleroderma is localized, systemic, limited or diffuse scleroderma.
  • the systemic scleroderma comprises CREST syndrome (Calcinosis, Raynaud's syndrome, esophagaeal dysfunction or dysmotility, sclerodactyl), telangiectasia). Scleroderma is also known as systemic sclerosis or progressive systemic sclerosis. In certain embodiments, provided herein are methods of treating or preventing Raynaud's disease or syndrome.
  • systemic sclerosis comprises scleroderma lung disease, scleroderma renal crisis, cardiac manifestations, muscular weakness (including fatigue or limited CREST), gastrointestinal dysmotility and spasm, and abnormalities in the central, peripheral and autonomic nervous system (including carpal tunnel syndrome followed by trigeminal neuralgia). It also includes general disability, including depression, and impact on quality of life.
  • limited scleroderma is limited to the hands, the face, neck, or combinations thereof.
  • diffuse scleroderma comprises skin tightening and also occurs above the wrists (or elbows).
  • the diffuse systemic sclerosis is sine scleroderma, comprising internal organ fibrosis, but no skin tightening; or familial progressive systemic sclerosis.
  • scleroderma is not associated with wasting, such as disease-related wasting.
  • scleroderma e.g., gradual hardening, thickening, and tightening of the skin (e.g., in extremities, such as hands, face, and feet); (ii) skin discoloration; (iii) numbness of extremities; (iv) shiny skin; (v) small white lumps under the surface of the skin that erupt into a chalky white fluid; (vi) Raynaud's esophagaeal dysfunction (pain, numbness, and/or color changes in the hands caused by spasm of the blood vessels upon exposure to cold or emotional stress); (vii) telangiectasia (red spots on, e.g., the hands, palms, forearms, face, and lips); (viii) pain and/or stiffness of the joints; (ix) swelling of the hands and feet; (x) itching of the skin; (xi) stiffening and curl
  • Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof enhances Th1 immune response, and suppresses Th2 immune response, which may result in anti-fibrotic effects in the skin.
  • the skin thickness is reduced by about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70% about 80%, about 90% or more.
  • compositions for achieving one or more clinical endpoints associated with scleroderma comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to a patient in need thereof.
  • modified Rodnan skin score of a patient having scleroderma comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to the patient.
  • the improvement in modified Rodnan skin score is 5, 10, 15 or 20 points or more.
  • the skin thickness is reduced by about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70% about 80%, about 90% or more.
  • compositions for improving or reducing skin induration of a patient having scleroderma comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to the patient.
  • compositions for improving the dermatology quality of life index of a patient having scleroderma comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to the patient.
  • compositions for improving the pulmonary function of a patient having scleroderma comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to the patient.
  • the carbon monoxide diffusing capacity of a patient is improved by an improvement in the diffusing capacity of the lung for carbon monoxide (D L co) of about 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70% about 80%, about 90% or more.
  • D L co carbon monoxide
  • Mahler Dyspnea index of a patient having scleroderma
  • methods for improving the Mahler Dyspnea index of a patient having scleroderma comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to the patient.
  • the improvement in Mahler Dyspnea index is 4, 5, 6, 7, 8, 9 or 10 points or more.
  • kits for improving the Saint George's Respiratory Questionnaire score of a patient having scleroderma comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to the patient.
  • the improvement in Saint George's Respiratory Questionnaire score is 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 points or more.
  • compositions for treating or preventing digital ulcer of a patient or patient population having scleroderma comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to the patient.
  • the improvement in the six minute walk distance is about 200 meters, about 250 meters, about 300 meters, about 350 meters, about 400 meters or more.
  • provided herein are methods of treating, preventing, and/or managing lupus erythematosus or a symptom thereof, comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to a patient having lupus erythematosus.
  • provided herein are methods of preventing lupus erythematosus or a symptom thereof, comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to a patient at risk of having lupus erythematosus.
  • provided herein are methods for treating, preventing, and/or managing systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE) or drug-induced lupus.
  • SLE systemic lupus erythematosus
  • CLE cutaneous lupus erythematosus
  • drug-induced lupus drug-induced lupus.
  • Systemic lupus erythematosus is interchangeably used herein with SLE and lupus and refers to all manifestations of the disease as known in the art (including remissions and flares).
  • SLE abnormal hyperactivity of B lymphocytes and massive abnormal production of immunoglobulin gamma (IgG) auto-antibodies play a key role. This pathological process results in sequestration and destruction of Ig-coated cells, fixation and cleaving of complement proteins, and release of chemotaxins, vasoactive peptides and destructive enzymes into tissues (Hahn B H. Systemic Lupus Erythematosus.
  • Symptoms of SLE vary from person to person, and may come and go. In most patients, the symptoms include joint pain and swelling. Frequently affected joints are the fingers, hands, wrists, and knees. Some patients develop arthritis. Other common symptoms include: chest pain when taking a deep breath, fatigue, fever with no other cause, general discomfort, uneasiness, or ill feeling (malaise), hair loss, mouth sores, swollen lymph nodes, sensitivity to sunlight, skin rash—a “butterfly” rash over the cheeks and bridge of the nose affects about half of people with SLE, in some patients, the rash gets worse in sunlight, and the rash may also be widespread.
  • Brain and nervous system headaches, numbness, tingling, seizures, vision problems, personality changes,
  • Heart abnormal heart rhythms (arrhythmias),
  • Lung coughing up blood and difficulty breathing
  • Skin patchy skin color, fingers that change color when cold (Raynaud's phenomenon).
  • discoid lupus Some patients only have skin symptoms. This is called discoid lupus.
  • severe SLE refers to an SLE condition where the patient has one or more severe or life-threatening symptoms (such as hemolytic anemia, extensive heart or lung involvement, kidney disease, or central nervous system involvement).
  • compositions for achieving one or more clinical endpoints associated with SLE comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to a patient in need thereof.
  • Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof acts as an inhibitor of primary human memory CD19+ B-cell differentiation to the plasmablast stage.
  • Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof blocks cells at a premature stage thereby decreasing the numbers of plasmablasts that are capable of producing high levels of immunoglobulin.
  • a functional consequence of this effect is reduced immunoglobulin G (IgG) and immunoglobulin M (IgM) production in these differentiation cultures.
  • Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof inhibits of the ability of primary human memory CD19+ B-cells to differentiate to the plasmablast stage. In certain embodiments, Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof has no significant effect on mature CD138+ plasma cells in short term cultures.
  • Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof inhibits B cell differentiation factors including interferon regulatory factor 4 (IRF4), lymphocyte-induced maturation protein (BLIMP), X-box-protein-1 (XBP-1) and B cell lymphoma 6 (Bcl6).
  • IRF4 interferon regulatory factor 4
  • BLIMP lymphocyte-induced maturation protein
  • XBP-1 X-box-protein-1
  • Bcl6 B cell lymphoma 6
  • a method of treating an individual having a disease or disorder, wherein the disease or disorder is caused by, or is associated with, an inappropriate or undesirable immune response, e.g., a disease, disorder or condition that can be treated beneficially by immunosuppression comprising administering to the individual Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof.
  • said immune-related disease is one or more of selected from Sjögren syndrome, ANCA-induced vasculitis, anti-phospholipid syndrome, myasthenia gravis, Addison's disease, alopecia greata, ankylosing spondylitis, antiphospholipid antibody syndrome, antiphospholipid syndrome (primary or secondary), asthma, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative disease, autoimmune thrombocytopenic purpura, Balo disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, cicatrical pemphigoid (e.g., mucous membrane pemphigoid), cold agglutinin disease, degos disease, dermatitis hepatiformis, essential mixed cryoglobulinemia, Goodpasture's syndrome
  • the dose of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof to be administered to a patient is rather widely variable and can be subject to the judgment of a health-care practitioner. Doses of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof vary depending on factors such as: specific indication to be treated, prevented, or managed; age and condition of a patient; and amount of second active agent used, if any.
  • Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof can be administered one to four or more times a day in a dose of about 0.005 mg/kg of a patient's body weight to about 10 mg/kg of a patient's body weight in a patient, but the above dosage may be properly varied depending on the age, body weight and medical condition of the patient and the type of administration.
  • the dose is about 0.01 mg/kg of a patient's body weight to about 5 mg/kg of a patient's body weight, about 0.05 mg/kg of a patient's body weight to about 1 mg/kg of a patient's body weight, about 0.1 mg/kg of a patient's body weight to about 0.75 mg/kg of a patient's body weight or about 0.25 mg/kg of a patient's body weight to about 0.5 mg/kg of a patient's body weight.
  • one dose is given per day.
  • the amount of Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
  • application of a topical concentration provides intracellular exposures or concentrations of about 0.01-10 ⁇ M.
  • Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof is used in an amount of from about 0.1 mg to about 1000 mg per day, and can be adjusted in a conventional fashion (e.g., the same amount administered each day of the treatment, prevention or management period), in cycles (e.g., one week on, one week off), or in an amount that increases or decreases over the course of treatment, prevention, or management.
  • the dose can be from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10 mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg to about 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about 30 mg, or from about 1 mg to about 20 mg.
  • Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof can be combined with other pharmacologically active compounds (“second active agents”) in methods and compositions provided herein. Certain combinations may work synergistically in the treatment of particular types diseases or disorders, and conditions and symptoms associated with such diseases or disorders. Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof can also work to alleviate adverse effects associated with certain second active agents, and vice versa.
  • Second active ingredients or agents can be used in the methods and compositions provided herein.
  • Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).
  • the method of treatment provided herein comprises the administration of a second therapeutic agent, wherein the second therapeutic agent is an anti-inflammatory drug, e.g., a steroidal anti-inflammatory drug, or a non-steroidal anti-inflammatory drug (NSAID), acetaminophen, naproxen, ibuprofen, acetylsalicylic acid, and the like.
  • NSAID non-steroidal anti-inflammatory drug
  • acetaminophen e.g., a non-steroidal anti-inflammatory drug
  • a proton pump inhibitor e.g., omeprazole
  • the antiinflammatory agent is a corticosteroid.
  • the antiinflammatory agent is colchicine.
  • the second therapeutic agent is an immunomodulatory compound or an immunosuppressant compound such as azathioprine (ImuranTM, AzasanTM), methotrexate (RheumatrexTM, TrexallTM), penicillamine (DepenTM, CuprimineTM), cyclophosphamide (CytoxanTM), mycophenalate (CellCeptTM, MyforticTM), bosentan (Tracleer®), prednisone (DeltasoneTM, Liquid PredTM), and a PDE5 inhibitor.
  • a vasodilator such as prostacyclin (iloprost) may be administered.
  • the second therapeutic agent is an inhibitor of ActRII receptors or an activin-ActRII inhibitor
  • Inhibitors of ActRII receptors include ActRIIA inhibitors and ActRIIB inhibitors.
  • Inhibitors of ActRII receptors can be polypeptides comprising activin-binding domains of ActRII.
  • the activin-binding domain comprising polypeptides are linked to an Fc portion of an antibody (i.e., a conjugate comprising an activin-binding domain comprising polypeptide of an ActRII receptor and an Fc portion of an antibody is generated).
  • the activin-binding domain is linked to an Fc portion of an antibody via a linker, e.g., a peptide linker.
  • An exemplary activin-binding ActRIIA polypeptide fused to a human Fc domain is provided in SEQ ID NO: 1.
  • An exemplary fusion protein comprising a soluble extracellular domain of ActRIIB fused to an Fc domain is provided in SEQ ID NO: 2.
  • non-antibody proteins selected for activin or ActRIIA binding are found in WO/2002/088171, WO/2006/055689, WO/2002/032925, WO/2005/037989, US 2003/0133939, and US 2005/0238646, each of which is incorporated herein by reference in its entirety.
  • any combination of the above therapeutic agents, suitable for treatment of the diseases or symptoms thereof, can be administered.
  • Such therapeutic agents can be administered in any combination with Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof, at the same time or as a separate course of treatment.
  • Compound I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer or racemic mixtures thereof provided herein is cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest (i.e., discontinuation of the administration) for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment.
  • a compound provided herein is administered daily in a single or divided doses in a four to six week cycle with a rest period of about a week or two weeks. Cycling therapy further allows the frequency, number, and length of dosing cycles to be increased.
  • another embodiment encompasses the administration of a compound provided herein for more cycles than are typical when it is administered alone.
  • a compound provided herein is administered for a greater number of cycles than would typically cause dose-limiting toxicity in a patient to whom a second active ingredient is not also being administered.
  • a compound provided herein is administered daily and continuously for three or four weeks at a dose of from about 0.1 mg to about 500 mg per day, followed by a rest of one or two weeks.
  • the dose can be from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10 mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg to about 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about 30 mg, or from about 1 mg to about 20 mg, followed by a rest.
  • a compound provided herein and a second active ingredient are administered orally, with administration of the compound provided herein occurring 30 to 60 minutes prior to the second active ingredient, during a cycle of four to six weeks.
  • the combination of a compound provided herein and a second active ingredient is administered by intravenous infusion over about 90 minutes every cycle.
  • the number of cycles during which the combination treatment is administered to a patient will be from about one to about 24 cycles, from about two to about 16 cycles, or from about four to about three cycles.
  • compositions can be used in the preparation of individual, single unit dosage forms.
  • Pharmaceutical compositions and dosage forms provided herein comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, racemate, clathrate, or prodrug thereof.
  • Pharmaceutical compositions and dosage forms can further comprise one or more excipients.
  • compositions and dosage forms provided herein can also comprise one or more additional active ingredients.
  • additional active ingredients examples of optional second, or additional, active ingredients are disclosed above.
  • Single unit dosage forms provided herein are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal or transcutaneous administration to a patient.
  • mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
  • parenteral e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial
  • topical e.g., eye drops or other ophthalmic preparations
  • transdermal or transcutaneous administration e.g., transcutaneous administration to a patient.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous or non-aqueous liquid suspensions, oil-in-water e
  • compositions, shape, and type of dosage forms will typically vary depending on their use.
  • a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease.
  • compositions and dosage forms comprise one or more excipients.
  • Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient.
  • oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms.
  • the suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water.
  • lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
  • Lactose-free compositions can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002).
  • lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
  • anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80.
  • water and heat accelerate the decomposition of some compounds.
  • the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
  • Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are, in one embodiment, packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • compounds which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • dosage forms comprise a compound provided herein in an amount of from about 0.10 to about 500 mg. In other embodiments, dosage forms comprise a compound provided herein in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • dosage forms comprise the second active ingredient in an amount of 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg.
  • the specific amount of the second active agent will depend on the specific agent used, the diseases or disorders being treated or managed, and the amount(s) of a compound provided herein, and any optional additional active agents concurrently administered to the patient.
  • compositions that are suitable for oral administration can be provided as discrete dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing, Easton Pa. (2000).
  • Oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • oral dosage forms are tablets or capsules, in which case solid excipients are employed.
  • tablets can be coated by standard aqueous or nonaqueous techniques.
  • Such dosage forms can be prepared by any of the methods of pharmacy.
  • pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof.
  • An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions is, in one embodiment, present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Disintegrants may be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients may be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. In one embodiment, pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, or from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R.
  • lubricants may be used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • a solid oral dosage form comprises a compound provided herein, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
  • Active ingredients such as the compounds provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 each of which is
  • Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.
  • the compositions provided encompass single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled release.
  • controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non controlled counterparts.
  • the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance.
  • controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
  • Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • the drug may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)).
  • polymeric materials can be used.
  • a controlled release system can be placed in a subject at an appropriate site determined by a practitioner of skill, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled release systems are discussed in the review by Langer ( Science 249:1527-1533 (1990)).
  • the active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, ne
  • Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial.
  • administration of a parenteral dosage form bypasses patients' natural defenses against contaminants, and thus, in these embodiments, parenteral dosage forms are sterile or capable of being sterilized prior to administration to a patient.
  • parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • cyclodextrin and its derivatives can be used to increase the solubility of a compound provided herein. See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein by reference.
  • Topical and mucosal dosage forms include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th , 18 th and 20 th eds., Mack Publishing, Easton Pa. (1980, 1990 and 2000); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
  • excipients e.g., carriers and diluents
  • excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable.
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms. Examples of additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th ,18 th and 20 th eds., Mack Publishing, Easton Pa. (1980, 1990 and 2000).
  • the pH of a pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients.
  • the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
  • Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, or as a delivery-enhancing or penetration-enhancing agent.
  • salts, solvates, hydrates, prodrugs, clathrates, or stereoisomers of the active ingredients can be used to further adjust the properties of the resulting composition.
  • active ingredients provided herein are not administered to a patient at the same time or by the same route of administration.
  • kits which can simplify the administration of appropriate amounts of active ingredients.
  • kits comprises a dosage form of a compound provided herein.
  • Kits can further comprise additional active ingredients such as other anti-inflammatory, immunomodulatory or immunosuppressant compounds, or a combination thereof.
  • additional active ingredients include, but are not limited to, those disclosed herein.
  • kits can further comprise devices that are used to administer the active ingredients.
  • devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
  • Kits can further comprise cells or blood for transplantation as well as pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles such as, but not limited to, ethyl alcohol
  • Luminex Human Cytokine/Chemokine 12-Plex Kit (Millipore, Cat# MPXHCYTO-60K-12)
  • test compounds were prepared as stock solutions of 4 mM in DMSO. T cells were isolated from buffy coat by negative selection using the RosetteSep® T Cell Enrichment Cocktail according to manufacturer's procedures.
  • All 96-well plates were pre-coated with 3 ⁇ g/mL anti-human CD3 antibody in 100 ⁇ L, 1 ⁇ PBS for 4 hours at 37° C.
  • the plates were washed 3 times with RPMI-1640 Complete Media prior to the T cell assay.
  • the T cells were then plated in anti-CD3-pre-coated plates at a density of 2.5 ⁇ 10 5 cells/well in 180 ⁇ L RPMI-1640 Complete Media.
  • the cells were treated with 20 ⁇ L 10 ⁇ titrated test compound at 10, 1, 0.1, 0.01, 0.001, 0.0001, and 0.00001 ⁇ M in duplicate.
  • the final DMSO concentrations were 0.25%.
  • the plates were incubated for 48 hours at 37° C., 5% CO 2 .
  • CBA cytometric bead array
  • test compound demonstrated immunomodulatory activity in anti-CD3 stimulated primary human T cells, altering the production of several cytokines and chemokines.
  • Baseline levels of cytokines and chemokines produced by stimulated human T cells incubated with vehicle are presented in Table 1 below.
  • the test compound enhanced IL-2, IL-3, IL-5, IL-10, IL-13, GM-CSF, IFN- ⁇ , RANTES, and TNF- ⁇ production in stimulated human T cells.
  • the enhancement of production by the test compound was largely concentration-dependent for most of the cytokines and chemokines, except for IL-10 and IL-5.
  • the test compound enhanced IL-10 production at lower concentrations but inhibited enhancement of IL-10 production at higher concentrations.
  • the test compound increased IL-5 production 3- and 4-fold at 0.01 and 0.1 ⁇ M, respectively, showing less enhancement at both lower and higher concentrations.
  • FIGS. 1 and 2 The effect of the test compound on cytokine and chemokine production in anti-CD3-stimulated human T cells, expressed as absolute amount produced and as percentage of vehicle control cells are provided in FIGS. 1 and 2 , respectively.
  • the dashed line denotes the level equivalent to double the baseline production (EC 200 ) in FIG. 2 .
  • Luminex Technology was used to determine the inhibitory (enhancement) concentration, IC 50 for the compound for the simultaneous profiling of pro-inflammatory cytokines/chemokines and IL-10 (anti-inflammatory cytokine) from LPS-stimulated healthy human donor PBMCs.
  • GM-CSF Granulocyte Macrophage Colony Stimulating Factor IL
  • Interleukin LPS lipopolysaccharide MCP-1 monocyte chemotactic protein-1
  • MDC Macrophage-derived chemokine
  • MIP-1 ⁇ Macrophage inflammatory protein-1alpha MIP-1 ⁇ Macrophage inflammatory protein-1beta PBMC
  • Buffy coat from healthy donors was obtained from Blood Center of New Jersey (East Orange, N.J.). Lipopolysaccharide (strain) (Cat# L-1887) was purchased from Sigma. Milliplex kits with antibody bound beads for Luminex xMAP Technology was purchased from Millipore (Billerica, Mass.) and combined into multiplex format prior to assay.
  • strain Lipopolysaccharide
  • Milliplex kits with antibody bound beads for Luminex xMAP Technology was purchased from Millipore (Billerica, Mass.) and combined into multiplex format prior to assay.
  • 50 ml human buffy coat was aliquoted 25 ml each into two 50 ml conical tubes and 25 ml sterile HBSS was added to each conical tube. The tubes were gently mixed by inverting. Fifteen ml of room temperature Ficoll-Paque Plus (GE Healthcare (location); cat#17-1440-02) was aliquoted into four 50 ml conical tubes. Then 25 ml of the Buffy coat/HBSS mixture was layered gently and slowly on top of the Ficoll. The samples were centrifuged at 450 rpm for 35 minutes. The top layered containing plasma was pipetted off and discarded. The interface containing mononuclear cells was transferred into two 50 ml conical tubes.
  • Ficoll-Paque Plus GE Healthcare (location); cat#17-1440-02
  • Both conical tubes were filled to total volume of 50 ml with HBSS and centrifuged at 1200 rpm for 10 minutes. The cells were washed again in HBSS and spun at 1000 rpm for 10 minutes. Cell pellet was resuspended with 20 ml RPMI complete medium (RPMI/5% human sera/1 ⁇ pen/strep/glut) and counted.
  • cytokines were analyzed for cytokines in multiplex format according to the manufacturer's instructions (Millipore, Billerica, Ma 01821) using a Luminex IS100 instrument.
  • IL-12 and GM-CSF analyses were done in a two-plex format using neat supernatants while all other cytokines were done in a multiplex format using supernatants diluted 1:20.
  • Data analysis was performed using Upstate Beadview software.
  • IC 50 s were calculated using non-linear regression, sigmoidal dose-response, constraining the top to 100% and bottom to 0%, allowing variable slope.
  • the EC 50 s were based on the upper constraint of the sigmoidal curves equaling 246.9%, representing the average IL-10 enhancement produced by pomalidomide (control) at 10 ⁇ M and the lower constraint to 100%.
  • the IC 50 were performed using GraphPad Prism v5.00.
  • the data values represent the mean ⁇ SEM (standard error of the mean) of n (number of experiments in duplicate).
  • test compound has varied potencies for the inhibitions of the multiple cytokines examined, e.g., 11-6, IL-8, IL- ⁇ , GM-CSF, MDC, MIP-1 ⁇ , MIP-1 ⁇ , and TNF- ⁇ , in general. Also, the test compound enhanced production of IL-10, MCP-1, and RANTES with various potencies as provided in Table 3 and FIG. 4 .
  • the capacity of the test compound to enhance human NK cell function in response to IgG/Rituximab was studied.
  • the immunomodulatory activity of the test compound was compared in two assays of natural killer (NK) cell functions (1) IgG- and IL-2-induced interferon-gamma (IFN- ⁇ ) production and (2) killing activity, as measured in an in vitro ADCC (antibody-dependent cellular cytotoxity) model.
  • NK natural killer
  • RPMI-1640 Medium supplemented with 10% FBS (fetal bovine serum), 100 units/mL penicillin,
  • RPMI-1640 Medium (without phenol red) supplemented with 10% FBS, 100 units/mL penicillin,
  • ABS-DLBCL Activated B cell-like—diffuse large B cell lymphoma
  • GEB-DLBCL Germinal center B-cell-like—diffuse large B cell lymphoma
  • WSU-DLCL2 (Celgene Signal, CA)
  • BL Burkitt's lymphoma
  • Raji ATCC, VA
  • NK cells from healthy donors were isolated from buffy coat blood by negative selection using the RosetteSep NK cell enrichment cocktail (Stem Cell Technologies, Vancouver, BC) prior to Ficoll-Hypaque (Fisher Scientific Co LLC, PA) density gradient centrifugation following the manufacturers' instructions.
  • CD56+ NK cells were isolated to ⁇ 85% purity, as determined by flow cytometry (BD Biosciences, CA).
  • EC 50 is the concentration of the test compound providing half-maximal IFN- ⁇ production, with maximal production defined as the amount of IFN- ⁇ produced in the presence of 1 ⁇ M pomalidomide.
  • EC 50 values were calculated using non-linear regression, sigmoidaldose-response constraining the top to 100% and bottom to 0% allowing for a variable slope. EC 50 for the test compound was 0.0015 ⁇ M.
  • test compound enhanced NK cell IFN- ⁇ production in a dose dependent manner in response to immobilized IgG and IL-2 stimulation.
  • Results are provided in FIG. 5 (expressed as pg/mL of IFN- ⁇ produced), respectively.
  • FIG. 6 provides results expressed as a percentage of increased IFN- ⁇ produced relative to the IFN- ⁇ produced in the presence of pomalidomide at 1 ⁇ M for the test compound. Each value plotted in FIGS. 5 and 6 represents the mean of 12-14 determinations ⁇ SEM.
  • Purified NK cells (5 ⁇ 104) were seeded in 96-well U-bottom plates in 100 ⁇ L of RPMI-1640 medium without phenol (Invitrogen)+2% human AB+ serum (Gemini Bio Products, CA) and treated with 10 ng/mL rhIL-2 and rituximab (5 ⁇ g/mL) plus different concentrations of the test compound at 0.01 to 10 ⁇ M for 48 hours.
  • Various lymphoma cell lines (GCB-DLBCL: WSU-DLCL2 and Farage; Follicular lymphoma:DoHH2; ABC-DLBCL: Riva; Burkitt's lymphoma [BL]: Raji) were treated with 5 ⁇ g/mL rituximab for 30 minutes at 37° C. Unbound rituximab was washed off, target cells (5 ⁇ 103/100 ⁇ L/well) were added to the pretreated effector cells (NK cells) at a 10:1 ratio, and the two were co-incubated for 4 hours at 37° C. Control conditions consisted of NK cells plus tumor cells treated with (1) medium alone, (2) rituximab only, or (3) IL-2 alone.
  • NK cell cytotoxicity against tumor cells was analyzed using a standard lactate dehydrogenease (LDH) release assay to measure ADCC (CytoTox 96 Non-Radioactive Cytoxicity Assay, Promega, WI).
  • LDH lactate dehydrogenease
  • Spontaneous release by target cells alone was ⁇ 15% of the maximum release, as determined with target cells lysed in 1% Triton X-100.
  • the experimental release was corrected by subtraction of the spontaneous release of effector cells at the corresponding dilution. The percentage of specific lysis was calculated according to the formula:
  • Percentage specific lysis 100 ⁇ (experimental ⁇ effector spontaneous ⁇ target spontaneous)/(target maximum ⁇ target spontaneous).
  • test compound induced dose-dependent NK cell-mediated ADCC in all cell lines. Three experiments were conducted for each cell line and samples from each of three donors were tested in each experiment. Data are presented in FIG. 8 , as mean of 9 determinations ⁇ SEM.
  • Buffy coat from healthy donors were obtained from Blood Center of New Jersey.
  • SLE Lupus PBMC samples were obtained from Conversant Bio (Huntsville, Ala. 35806).
  • ITEM Source Iscoves Modified Dulbecco medium Invitrogen Fetal Bovine Serum Lonza Human Insulin Sigma Human Transferrin Sigma penicillin/streptomycin Lonza Recombinant Human IL-2 R & D Systems Recombinant Human IL-6 R & D Systems Recombinant Human IL-10 R & D Systems Recombinant Human IL-15 R & D Systems CD40 Ligand/TNFSF5/histidine-tagged R & D Systems polyHistidine mouse IgG1 antibody R & D Systems ODN 2006- Human TLR9 ligand Invivogen Human Interferon ALPHA A PB interferon source
  • Fifty ml human buffy coat was aliquoted 25 ml each into two 50 ml conical tubes and 25 ml sterile HBSS was added to each conical tube. The tubes were gently mixed by inverting. Fifteen ml of room temperature Ficoll-Paque Plus (GE Healthcare; cat#17-1440-02) was aliquoted into four 50 ml conical tubes. Then 25 ml of the Buffy coat/HBSS mixture was layered gently and slowly on top of the Ficoll. The samples were centrifuged at 450 rpm for 35 minutes. The top layered containing plasma was pipetted off and discarded. The interface containing mononuclear cells was transferred into two 50 ml conical tubes.
  • Ficoll-Paque Plus GE Healthcare; cat#17-1440-02
  • Both conical tubes were filled to total volume of 50 ml with HBSS and centrifuged at 1200 rpm for 10 minutes. The cells were washed again in HBSS and spun at 1000 rpm for 10 minutes. Cell pellet was resuspended with 20 mL of B cell media (Iscoves+10% PFBS, 1% P/S, and 5 ⁇ g/mL human insulin) and counted on the cell counter.
  • B cell media Iscoves+10% PFBS, 1% P/S, and 5 ⁇ g/mL human insulin
  • PBMCs Purified PBMCs were counted and aliquoted at 2 ⁇ 10 8 cells per tube. The cells were centrifuged at 1200 rpm for 5 minutes and then supernatants were discarded. The cells were resuspended in 4 mL of Robosep Buffer (Stemcell Technologies catalog #20104) and transferred to a 14 mL polystyrene round bottom tube (BD catalog #352057) and mixed well. Then 200 ⁇ L of EasySep Human B cell enrichment cocktail was added (StemCell Technologies catalog #19054). Samples were vortexed and incubated at room temperature for 10 minutes.
  • Step 1 B cell Activation—day 0 through day 4: Prepare fresh B cell cocktail by adding 50 ⁇ g/mL of human transferrin to B cell media. (Iscoves+10% PFBS, 1% P/S, and 5 ⁇ g/mL human insulin). Filter required volume of media needed for experiment through a 0.22 ⁇ M filter.
  • B cell differentiation cocktail (final concentration): recombinant human IL-2 (20 U/mL), IL-10 (50 ng/mL), IL-15 (10 ng/mL), CD40 Ligand/TNFSF5/histidine-tagged (50 ng/mL), polyHistidine mouse IgG1 antibody (5 ⁇ g/mL), and ODN 2006-Human TLR9 ligand (10 ⁇ g/mL) to cells.
  • IL-2 20 U/mL
  • IL-10 50 ng/mL
  • IL-15 10 ng/mL
  • CD40 Ligand/TNFSF5/histidine-tagged 50 ng/mL
  • polyHistidine mouse IgG1 antibody 5 ⁇ g/mL
  • ODN 2006-Human TLR9 ligand 10 ⁇ g/mL
  • Step 2 Plasmablast Generation—day 4 through day 7: Cells were harvested and counted on the cell counter; an aliquot was removed for flow analysis, the remaining cells were washed with PBS.
  • Prepare fresh B cell cocktail by adding 1 ⁇ g/ml of human transferrin to B cell media. (Iscoves+10% PFBS, 1% P/S, and 5 ⁇ g/mL human insulin). Filter required volume of media needed for experiment through a 0.22 filter.
  • Add B cell differentiation cocktail final concentration: recombinant human IL-2 (20 U/mL), IL-10 (50 ng/mL), IL-15 (10 ng/mL), IL-6 (50 ng/mL) to cells.
  • test compounds was weighed and dissolved in sterile 100% DMSO (dimethyl sulfoxide; Research Organics, Cleveland, Ohio) to create 40 mM stock solution. Dilutions of the 40 mM stock were used in the assay to obtain final test compound concentrations based on experimental design.
  • DMSO dimethyl sulfoxide
  • RNA ribonucleic acid
  • Qiacube RNA extraction instrument Qiagen, Valencia, Calif.
  • QIAGEN RNeasy mini spin-column kits Purified RNA was reverse transcribed into cDNA with thermal cycler [MJ Research; Inc., St. Bruno, Quebec, Canada) using a reverse-transcriptase kit (Applied Biosystems).
  • the gene expression assay was carried out using 7500 RT-PCR system (Applied Biosystems) in triplicate.
  • a glyceraldehyde 3-phosphate dehydrogenase gene expression assay control was run for each sample and used as a normalization control. For each gene, samples within each experiment were normalized to 0.1% DMSO treatment only for that particular time point.
  • Differentiated B cells were harvested, counted, and aliquoted at about 1 ⁇ 10 6 cells or less per 4 mL tube. The cells were washed 1 ⁇ with stain buffer. Next, the cells then were blocked with 10% human serum/PBS for 20-30 minutes. Following blocking, the cells were centrifuged for 5 minutes at 1200 rpm and supernatants discarded. In the 100 ⁇ L of remaining buffer, 20 ⁇ L of various BD Pharmigen flow antibodies were added according to experimental design. The cells were stained for 20-30 minutes at 4° C. Then the cells were washed 2 ⁇ with stain buffer and supernatants discarded. Next, 500 ⁇ l, of stain buffer or PBS was added to the tubes.
  • B cells (see section 4.3.3) were stained with 0.4% trypan blue and live cells counted using the Countess automated cell counter (Invitrogen) in duplicate samples.
  • IC 50 values were calculated using non-linear regression, sigmoidal-dose response constraining the top to 100% and bottom to 0% allowing for a variable slope.
  • the results for test compounds in the Ig assays were expressed as the percentage inhibition relative to control DMSO values.
  • the potency for inhibition of normal and SLE PBMC production of IgG and IgM for the test compound is as follows:
  • DBA/2 mice were used in this study. Eight animals were used per treatment group in the study.
  • mice were kept in the animal house under standard conditions with food and water ad libidum.
  • CMC carboxymethyl cellulose
  • Tween 80 0.5% carboxymethyl cellulose
  • test compound powder was weighed out and suspended fresh daily in the vehicle 0.5% CMC/0.25% Tween 80, to avoid drug hydrolysis in the aqueous medium.
  • the compound was suspended, not dissolved, in this vehicle.
  • the formulation was homogenized with a Teflon pestle and mortar (Potter-Elvehjem tissue grinder) using a motorized Eberbach tissue homogenizer.
  • the daily drug stock concentration used in these studies was 3 mg/ml.
  • Bleomycin was obtained from the pharmacy of the University of Er Weg-Nuremberg and freshly prepared once a week. Skin fibrosis was induced in 6-week-old DBA mice by local intracutaneous injections of 100 ⁇ l of bleomycin dissolved in 0.9% NaCl, at a concentration of 0.5 mg/ml, every other day in defined areas of 1.5 cm2 on the upper back.
  • the mouse model of bleomycin induced dermal fibrosis is widely used to evaluate anti-fibrotic therapeutics.
  • a localized dermal fibrosis is induced by intradermal injections with bleomycin every other day for 3 weeks.
  • This model resembles early, inflammatory stages of SSc.
  • treatment was initiated simultaneously with the first bleomycin injection.
  • the treatments were divided into following groups:
  • mice were pre-challenged with bleomycin to induce a robust skin fibrosis.
  • One group received treatment with the test compound, while challenge with bleomycin was ongoing for additional three weeks. The outcome of this group was compared to mice challenged with bleomycin for six weeks (prevention of further progression) and to mice challenged with bleomycin for three weeks followed by NaCl for additional three weeks (induction of regression).
  • the following groups were used in the regression study:
  • Dermal thickness was determined by staining with hematoxylin and eosin and activated fibroblasts by using immunohistochemistry for alpha smooth mucle actin ( ⁇ -SMA).
  • the dermal thickness as determined by the modified Rodnan Skin Score, is currently the most common primary outcome in human clinical trials for anti-fibrotic agents in SSc. Skin sections were stained with hematoxylin/eosin for better visualization of the tissue structure. Dermal thickness was analyzed with a Nikon Eclipse 80i microscope (Nikon, Badhoevedorp, The Netherlands) by measuring the maximal distance between the epidermal-dermal junction and the dermal-subcutaneous fat junction at 4 different skin sections in each mouse. The evaluation was performed by 2 independent examiners.
  • ⁇ -SMA monoclonal anti- ⁇ -SMA antibodies
  • Goat anti-rabbit antibodies labeled with horseradish peroxidase (Dako, Hamburg, Germany) were used as secondary antibodies.
  • the expression of ⁇ -SMA was visualized with 3,3′-diaminobenzidine tetrahydrochloride (Sigma-Aldrich).
  • Monoclonal mouse IgG antibodies (Calbiochem, San Diego, Calif.) were used as controls.
  • test compound significantly decreases dermal thickness of lesional skin in the bleomycin dermal fibrosis mouse model.
  • FIG. 8 Representative photomicrographs of hematoxylin and eosin stained skin sections are shown in FIG. 8 .
  • Dermal thickness was assessed by measuring the maximal distance between the epidermal-dermal junction and the dermal-subcutaneous fat junction. The line drawn between the junction points shows the relative thickness in the treatment groups.
  • ⁇ -SMA+myofibroblasts were counted in lesional skin sections.
  • the test compound at 30 mg/kg; PO, QD reduced the number of myofibroblasts by 30 ⁇ 0.23% (p ⁇ 0.0001).
  • FIG. 9 shows photomicrographs of representative hematoxylin and eosin stained skin sections. Dermal thickness was assessed by measuring the maximal distance between the epidermal-dermal junction and the dermal-subcutaneous fat junction. The line drawn between the junction points shows relative thickness in the treatment groups.

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10159675B2 (en) 2015-12-02 2018-12-25 Celgene Corporation Cycling therapy using 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione
US10973822B2 (en) 2015-07-02 2021-04-13 Celgene Corporation Combination therapy for treatment of hematological cancers and solid tumors

Families Citing this family (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5388854B2 (ja) 2006-09-26 2014-01-15 セルジーン コーポレイション ５−置換キナゾリノン誘導体、それを含む組成物、及びその使用方法
EP2436387B1 (fr) 2009-05-25 2018-07-25 Celgene Corporation Composition pharmaceutique contenant crbn et son utilisation dans le traitement des maladies du cortex cerebral.
DK2683708T3 (da) 2011-03-11 2018-01-29 Celgene Corp Faste former af 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidin-2,6-dion og farmaceutiske sammensætninger og anvendelser deraf
AU2012236655B2 (en) 2011-03-28 2016-09-22 Deuterx, Llc, 2',6'-dioxo-3'-deutero-piperdin-3-yl-isoindoline compounds
JP6016892B2 (ja) * 2011-04-29 2016-10-26 セルジーン コーポレイション セレブロンを予測因子として使用する癌及び炎症性疾患の治療方法
WO2014004990A2 (fr) 2012-06-29 2014-01-03 Celgene Corporation Procédés pour déterminer l'efficacité d'un médicament en utilisant des protéines associées au céréblon
EP2882442B1 (fr) * 2012-08-09 2021-06-09 Celgene Corporation Procédés de traitement du cancer à l'aide de 3-(4-((4-(morpholinométhyl)benzyl)oxy)-1-oxo-iso-indolin-2-yl)pipéridine-2,6-dione
US9587281B2 (en) 2012-08-14 2017-03-07 Celgene Corporation Cereblon isoforms and their use as biomarkers for therapeutic treatment
US9682952B2 (en) 2012-09-04 2017-06-20 Celgene Corporation Isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl) piperidine-2-6-dione and methods of preparation thereof
BR112015005243A2 (pt) * 2012-09-10 2017-07-04 Celgene Corp métodos para o tratamento de câncer de mama localmente avançado
CA2935495C (fr) * 2013-01-14 2021-04-20 Deuterx, Llc Derives de 3-(5-substitute-4-oxoquinazolin-3(4h)-yl)-3-deutero-piperidine-2,6-dione
EP2968334A4 (fr) 2013-03-14 2016-08-03 Deuterx Llc Dérivés de 3-(oxoquinazolin-3(4h)-yl-4 substitué)-3-deutéro-pipéridine-2,6-dione et des compositions les comprenant et des procédés les utilisant
CA2909625C (fr) * 2013-04-17 2021-06-01 Signal Pharmaceuticals, Llc Polytherapie comprenant un inhibiteur de kinase tor et un compose de quinazolinone substitue en 5 pour le traitement du cancer
CN105392499B (zh) * 2013-04-17 2018-07-24 西格诺药品有限公司 用于治疗癌症的包含tor激酶抑制剂和胞苷类似物的组合疗法
SI2991976T1 (sl) * 2013-05-01 2017-11-30 Celgene Corporation Sintheza 3-(5-amino-2-metil-4-oksokvinazolin-3(4H)-il)piperidin-2,6- diona
TW201534305A (zh) * 2013-05-03 2015-09-16 Celgene Corp 使用組合療法治療癌症之方法
WO2015077058A2 (fr) 2013-11-08 2015-05-28 The Broad Institute, Inc. Compositions et méthodes permettant de sélectionner un traitement pour la néoplasie des lymphocytes b
EA201691144A1 (ru) * 2013-12-06 2016-11-30 Селджин Корпорейшн Способы определения эффективности лекарственного средства для лечения диффузной крупноклеточной b-клеточной лимфомы, множественной миеломы и злокачественных новообразований миелоидного ростка
AR099385A1 (es) * 2014-01-15 2016-07-20 Celgene Corp Formulaciones de 3-(5-amino-2-metil-4-oxo-4h-quinazolin-3-il)-piperidina-2,6-diona
ES2843973T3 (es) 2014-06-27 2021-07-21 Celgene Corp Composiciones y métodos para inducir cambios conformacionales en cereblon y otras ubiquitina ligasas E3
CN107073122A (zh) * 2014-07-11 2017-08-18 细胞基因公司 恶性肿瘤的联合治疗
HUE061382T2 (hu) 2014-08-22 2023-06-28 Celgene Corp Eljárás myeloma multiplex kezelésére immunomoduláló vegyületekkel, antestekkel kombinálva
MX2017005163A (es) 2014-11-17 2018-01-18 Arno Therapeutics Inc Composiciones de liberación prolongada de onapristona y métodos.
TW201642857A (zh) * 2015-04-06 2016-12-16 西建公司 以組合療法治療肝細胞癌
US9809603B1 (en) 2015-08-18 2017-11-07 Deuterx, Llc Deuterium-enriched isoindolinonyl-piperidinonyl conjugates and oxoquinazolin-3(4H)-yl-piperidinonyl conjugates and methods of treating medical disorders using same
CN107921004A (zh) * 2015-08-27 2018-04-17 细胞基因公司 包含3‑(5‑氨基‑2‑甲基‑4‑氧代基‑4h‑喹唑啉‑3‑基)‑哌啶‑2,6‑二酮的药物组合物
US11459613B2 (en) 2015-09-11 2022-10-04 The Brigham And Women's Hospital, Inc. Methods of characterizing resistance to modulators of Cereblon
BR112018005999A2 (pt) 2015-09-25 2019-01-08 Context Biopharma Inc métodos para a produção de intermediários de onapristona
CN108883067B (zh) 2015-12-15 2021-03-09 康特斯生物制药公司 非晶奥那司酮组合物及其制备方法
US10830762B2 (en) 2015-12-28 2020-11-10 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon and other E3 ubiquitin ligases
EP3404024B1 (fr) 2016-01-14 2020-11-18 Kangpu Biopharmaceuticals, Ltd. Dérivé de quinazolinone, son procédé de préparation, composition pharmaceutique, et applications associées
AU2017232906B2 (en) * 2016-03-16 2022-03-31 H. Lee Moffitt Cancer Center & Research Institute, Inc. Small molecules against cereblon to enhance effector T cell function
US20180148471A1 (en) 2016-11-30 2018-05-31 Arno Therapeutics, Inc. Methods for onapristone synthesis dehydration and deprotection
US20180258064A1 (en) * 2017-03-07 2018-09-13 Celgene Corporation Solid forms of 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses
ES2959860T3 (es) * 2017-06-22 2024-02-28 Celgene Corp Tratamiento del carcinoma hepatocelular caracterizado por la infección por el virus de la hepatitis B
WO2019077968A1 (fr) 2017-10-18 2019-04-25 Canon Kabushiki Kaisha Contenant d'emballage et paquet
EP3774815A1 (fr) * 2018-03-30 2021-02-17 Biotheryx Inc. Composés de thiénopyrimidinone
SG11202012464WA (en) 2018-07-11 2021-01-28 H Lee Moffitt Cancer Center And Research Institute Inc Dimeric immuno-modulatory compounds against cereblon-based mechanisms
JP7323603B2 (ja) * 2018-09-07 2023-08-08 メッドシャイン ディスカバリー インコーポレイテッド 三環式縮合フラン置換ピペリジンジオン系化合物
WO2020072334A1 (fr) 2018-10-01 2020-04-09 Celgene Corporation Polythérapie pour le traitement du cancer
US20220178929A1 (en) * 2019-03-22 2022-06-09 University Of Ulsan Foundation For Industry Cooperation Biomarker cereblon for diagnosing hepatocellular carcinoma, and novel monoclonal antibody specific thereto
EP4126847A1 (fr) * 2020-03-30 2023-02-08 ENYO Pharma Dérivés de quinazolinone et leurs utilisations pour le traitement d'un cancer
WO2024040036A2 (fr) * 2022-08-16 2024-02-22 iTeos Belgium SA Antagonistes du récepteur de l'adénosine et compositions associées destinées à être utilisées dans le traitement d'une maladie associée à l'expression d'au moins un marqueur cellulaire sécrétant un anticorps

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7341995B2 (en) * 2000-12-06 2008-03-11 Laboratoires Serono Sa Use of SARP-1 for the treatment and/or prevention of scleroderma
US7635700B2 (en) * 2006-09-26 2009-12-22 Celgene Corporation 5-Substituted quinazolinone derivatives and compositions comprising and methods of using the same

Family Cites Families (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
KR890002631B1 (ko) 1984-10-04 1989-07-21 몬산토 캄파니 생물학적으로 활성인 소마토트로핀을 지속적으로 유리하는 조성물
IE58110B1 (en) 1984-10-30 1993-07-14 Elan Corp Plc Controlled release powder and process for its preparation
US5391485A (en) 1985-08-06 1995-02-21 Immunex Corporation DNAs encoding analog GM-CSF molecules displaying resistance to proteases which cleave at adjacent dibasic residues
US4810643A (en) 1985-08-23 1989-03-07 Kirin- Amgen Inc. Production of pluripotent granulocyte colony-stimulating factor
JPS63500636A (ja) 1985-08-23 1988-03-10 麒麟麦酒株式会社 多分化能性顆粒球コロニー刺激因子をコードするｄｎａ
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
IT1229203B (it) 1989-03-22 1991-07-25 Bioresearch Spa Impiego di acido 5 metiltetraidrofolico, di acido 5 formiltetraidrofolico e dei loro sali farmaceuticamente accettabili per la preparazione di composizioni farmaceutiche in forma a rilascio controllato attive nella terapia dei disturbi mentali organici e composizioni farmaceutiche relative.
PH30995A (en) 1989-07-07 1997-12-23 Novartis Inc Sustained release formulations of water soluble peptides.
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
KR0166088B1 (ko) 1990-01-23 1999-01-15 . 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5580578A (en) 1992-01-27 1996-12-03 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
TW333456B (en) 1992-12-07 1998-06-11 Takeda Pharm Ind Co Ltd A pharmaceutical composition of sustained-release preparation the invention relates to a pharmaceutical composition of sustained-release preparation which comprises a physiologically active peptide.
US5360352A (en) 1992-12-24 1994-11-01 The Whitaker Corporation Wire retainer for current mode coupler
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US6087324A (en) 1993-06-24 2000-07-11 Takeda Chemical Industries, Ltd. Sustained-release preparation
IT1270594B (it) 1994-07-07 1997-05-07 Recordati Chem Pharm Composizione farmaceutica a rilascio controllato di moguisteina in sospensione liquida
ATE268591T1 (de) 1995-06-27 2004-06-15 Takeda Chemical Industries Ltd Verfahren zur herstellung von zubereitungen mit verzögerter freisetzung
TW448055B (en) 1995-09-04 2001-08-01 Takeda Chemical Industries Ltd Method of production of sustained-release preparation
JP2909418B2 (ja) 1995-09-18 1999-06-23 株式会社資生堂 薬物の遅延放出型マイクロスフイア
US5980945A (en) 1996-01-16 1999-11-09 Societe De Conseils De Recherches Et D'applications Scientifique S.A. Sustained release drug formulations
US6264970B1 (en) 1996-06-26 2001-07-24 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6419961B1 (en) 1996-08-29 2002-07-16 Takeda Chemical Industries, Ltd. Sustained release microcapsules of a bioactive substance and a biodegradable polymer
CA2217134A1 (fr) 1996-10-09 1998-04-09 Sumitomo Pharmaceuticals Co., Ltd. Formulation a liberation-retard
ATE272394T1 (de) 1996-10-31 2004-08-15 Takeda Chemical Industries Ltd Zubereitung mit verzögerter freisetzung
DE69719367T2 (de) 1996-12-20 2003-10-16 Takeda Chemical Industries Ltd Verfahren zur herstellung einer zusammensetzung mit verzoegerter abgabe
US5891474A (en) 1997-01-29 1999-04-06 Poli Industria Chimica, S.P.A. Time-specific controlled release dosage formulations and method of preparing same
US6613358B2 (en) 1998-03-18 2003-09-02 Theodore W. Randolph Sustained-release composition including amorphous polymer
KR19990085365A (ko) 1998-05-16 1999-12-06 허영섭 지속적으로 약물 조절방출이 가능한 생분해성 고분자 미립구 및그 제조방법
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
EP2141243A3 (fr) 2000-10-16 2010-01-27 Brystol-Myers Squibb Company Supports de protéine pour mimer des anticorps et d'autres protéines de liaison
US7754208B2 (en) 2001-01-17 2010-07-13 Trubion Pharmaceuticals, Inc. Binding domain-immunoglobulin fusion proteins
US20030133939A1 (en) 2001-01-17 2003-07-17 Genecraft, Inc. Binding domain-immunoglobulin fusion proteins
US20030082630A1 (en) 2001-04-26 2003-05-01 Maxygen, Inc. Combinatorial libraries of monomer domains
US7498171B2 (en) 2002-04-12 2009-03-03 Anthrogenesis Corporation Modulation of stem and progenitor cell differentiation, assays, and uses thereof
US7968569B2 (en) 2002-05-17 2011-06-28 Celgene Corporation Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
US7393862B2 (en) 2002-05-17 2008-07-01 Celgene Corporation Method using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for treatment of certain leukemias
JP2008520207A (ja) 2004-11-16 2008-06-19 アヴィディア リサーチ インスティテュート タンパク質骨格およびその使用
US20080051379A1 (en) 2004-12-01 2008-02-28 Trustees Of Boston University Compositions and Methods for the Treatment of Peripheral B-Cell Neoplasms
GB0709092D0 (en) * 2007-05-11 2007-06-20 Borrebaeck Carl Diagnosis and method of disease
BRPI0817525A2 (pt) * 2007-09-26 2014-11-18 Celgene Corp Composto, composição farmacêutica, e, metódo de tratamento, controle ou prevenção de uma doença ou distúrbio.
MX2010006092A (es) * 2007-12-07 2010-07-05 Celgene Corp Biomarcadores para monitorear el tratamiento mediante compuestos de quinazolinona.
EP2436387B1 (fr) 2009-05-25 2018-07-25 Celgene Corporation Composition pharmaceutique contenant crbn et son utilisation dans le traitement des maladies du cortex cerebral.
JP6016892B2 (ja) * 2011-04-29 2016-10-26 セルジーン コーポレイション セレブロンを予測因子として使用する癌及び炎症性疾患の治療方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7341995B2 (en) * 2000-12-06 2008-03-11 Laboratoires Serono Sa Use of SARP-1 for the treatment and/or prevention of scleroderma
US7635700B2 (en) * 2006-09-26 2009-12-22 Celgene Corporation 5-Substituted quinazolinone derivatives and compositions comprising and methods of using the same

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10973822B2 (en) 2015-07-02 2021-04-13 Celgene Corporation Combination therapy for treatment of hematological cancers and solid tumors
US10159675B2 (en) 2015-12-02 2018-12-25 Celgene Corporation Cycling therapy using 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione

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