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US20170368150A1 - Methods of treating pulmonary sarcoidosis - Google Patents

Methods of treating pulmonary sarcoidosis Download PDF

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US20170368150A1
US20170368150A1 US15/508,191 US201515508191A US2017368150A1 US 20170368150 A1 US20170368150 A1 US 20170368150A1 US 201515508191 A US201515508191 A US 201515508191A US 2017368150 A1 US2017368150 A1 US 2017368150A1
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patient
dnase
pulmonary sarcoidosis
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sarcoidosis
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Barry Burns
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Gotham Biopharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/21—Endodeoxyribonucleases producing 5'-phosphomonoesters (3.1.21)
    • C12Y301/21001—Deoxyribonuclease I (3.1.21.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention is directed to methods for treating pulmonary sarcoidosis comprising the administration of mucolytic agents.
  • the methods comprise administering a therapeutically effective amount of DNase I to a patient having pulmonary sarcoidosis.
  • DNase I is an endonuclease found in mammals and other eukaryotes that cleaves phosphodiester linkages in DNA. It acts on single-stranded DNA, double-stranded DNA, and chromatin to reduce the size of DNA strands and yield 5′-phosphate-terminated polynucleotides with a free hydroxyl group. Human DNase I and certain variants are disclosed in U.S. Pat. Nos. 5,279,823; 6,348,343; and 6,391,607.
  • Cystic fibrosis is a disease caused by mutations in a specific cellular chloride channel regulator, the cystic fibrosis transmembrane conductance regulator protein (CFTR). It is the most common autosomal recessive disease in Caucasians.
  • the mutations prevent normal passage of Cl ⁇ ions through the chloride channel lumen of the airway epithelial cell membranes, resulting in a relative impermeability to chloride ions in the epithelial cells of the lungs and a depleted airway surface liquid volume.
  • Sarcoidosis is a disease involving granulomas (abnormal collections of inflammatory cells), often present as nodules, which can form in various organs, including the skin, heart, liver, lungs, nervous system, and gastrointestinal tract.
  • the granulomas are characterized by the accumulation of neutrophils, monocytes, macrophages, and activated T cells, as well as the production of elevated levels of inflammatory mediators such as tumor necrosis factor- ⁇ (TNF- ⁇ ) interferon- ⁇ , and interleukin-2.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • sarcoidosis The cause of sarcoidosis is unknown, but there is speculation that it is triggered by an immune reaction to some infectious or environmental antigen that continues after exposure to the antigen ceases.
  • the lung is the most commonly involved organ in over 90% of cases. Most patients do not exhibit symptoms and are unaware that they have sarcoidosis. Half of all asymptomatic sarcoidosis patients are diagnosed after routine chest x-ray. The most common presenting symptoms are cough and dyspnea. The most common diagnostic clinical signs are: i) dyspnea, ii) cough, iii) skin rash, iv) inflammation of the eyes, v) weight loss, vi) fatigue, vii) fever, and viii) night sweats.
  • sarcoidosis Due to the non-specific nature of granulomas, sarcoidosis is generally diagnosed by excluding other diseases such as malignancies and infections.
  • the lung in sarcoidosis typically displays the characteristic bilateral hilar lymphadenopathy on chest x-ray.
  • Reversible stages of sarcoidosis (Scadding Radiographic Stages I and II), characterized by nodular reticular infiltrates and “ground-glass” appearance of lung parenchyma on chest x-ray, may not require treatment.
  • Irreversible sarcoidosis (Stages III and IV), characterized by pulmonary cysts, diffuse parenchymal lung disease, honey comb lung structure (due to consolidation of alveoli) and bronchiectasis, has poor long-term prognosis and a high incidence of pulmonary exacerbations/relapses.
  • Computerized tomography (“CT”) findings for Stages III and IV include bronchiolar nodules (bronchovascular and subpleural), thickened interlobular septae, pulmonary architectural distortion and conglomerate masses.
  • symptomatic treatment usually consists of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or aspirin; however, approximately one third of all patients develop a progressive form of chronic sarcoidosis that requires treatment.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • the first-line therapy for all such chronic sarcoidosis patients is oral steroids (e.g., prednisone or prednisolone) which have significant adverse side effects (susceptibility to infection, osteoporosis and rib fractures from coughing, diabetes, mental confusion, fluid retention, fatigue, etc.) and are not usable for chronic or long term therapy because of these adverse drug responses.
  • corticosteroids slow or reverse the course of the disease, but many patients may become refractory to steroids or do not respond at all. Those patients may experience frequent and severe respiratory infections associated with episodes of excessive coughing to dislodge and expel inspissated secretions and cell debris, including granulomas shed into the bronchial lumen.
  • corticosteroid non-responders with severe symptoms and no treatment options other cytotoxic agents such as azathioprine, methotrexate, mycophenolic acid, and leflunomide may be tried. Of these, methotrexate is most widely used and is considered a first-line treatment in neurosarcoidosis, often in conjunction with corticosteroids.
  • cytotoxic agents do not have benefits that outweigh their increased morbidity from cytotoxicity.
  • the only definitive treatment for end-stage disease is lung transplantation and such patients with pulmonary sarcoidosis represent approximately 30% of all lung transplants conducted in the New York Presbyterian, Thoracic Surgery Lung Transplant Service (J.R. Sonnet, personal communication).
  • sarcoidosis Some success in treating sarcoidosis with immunosuppressants has been observed.
  • the rationale for such treatment is that the granulomas involved in sarcoidosis are caused by collections of immune system cells, particularly airway neutrophils and circulating T-cells.
  • Infliximab a monoclonal antibody that antagonizes the action of TNF- ⁇ , has been used to treat pulmonary sarcoidosis in clinical trials, with some success.
  • Etanercept another TNF- ⁇ antagonist
  • the anti-TNF- ⁇ monoclonal antibody golimumab also failed to show any benefit in persons with pulmonary sarcoidosis.
  • Adalimumab (yet another anti-TNF- ⁇ monoclonal antibody) induced a beneficial response in about half of sarcoidosis patients. See Baughman, et al., 2013, European Respiratory Journal 41:1424-1438.
  • the anticancer drug cetuximab (colorectal cancer) is ineffective if the KRAS protein in the tumor has a specific mutation (Van Cutsem et al., 2009, N. Engl. J. Med. 360(14):1408-1417) and the US FDA has relabeled the drug to require genetic profiling before use.
  • Many other drugs have variations in effectiveness in certain patient strata that led to FDA relabeling (e.g., warfarin, carbamazepine, clopidogrel) (Flockhart et al., 2009, Clin. Pharmacol. Ther. 86(1):109-113; Topol, 2010, Sci. Transl. Med. 2(44):44cm22).
  • sequential designs with lengthy data collection processes are especially useful for rare, unique diseases (Everitt & Pickler, 2004, Statistical Aspects of The Design of Clinical Trials.
  • Described herein are methods of treating pulmonary sarcoidosis comprising administering to a patient in need thereof a therapeutically effective amount of a mucolytic agent.
  • the mucolytic agent is DNase I, e.g., recombinant human DNase I (rhDNase I).
  • the rhDNase I is the rhDNase I that is the active ingredient of PULMOZYME®.
  • the mucolytic agent is selected from the group consisting of: sodium 2-sulfanylethanesulfonate (mesna, marketed in the U.S. as UROMITEXAN®), disodium 2,2′disulfanediyldiethanesulfonate (dimesna), and combinations thereof.
  • the methods comprise administering DNase I and an additional mucolytic agent.
  • the additional mucolytic agent is selected from the group consisting of mesna, dimesna, N-acetylcysteine, and combinations thereof.
  • mesna, dimesna, and N-acetylcysteine are free-radical scavengers. Pulmonary cellular antioxidant defense is significantly reduced with increased tissue levels of destructive free radicals in the inflammatory response to pulmonary sarcoidosis (Boots, et al., 2009, Resp. Med., 103:364).
  • rhDNase I such as PULMOZYME
  • the rhDNase I may be administered before, after, or concomitantly with the additional mucolytic agent.
  • the rhDNase I is administered before or after the additional mucolytic agent.
  • rhDNase I is administered by nebulization and and mesna or dimesna is administered intravenously.
  • mesna or dimesna act as free-radical scavengers.
  • the methods treat a patient who has acute pulmonary sarcoidosis (patient diagnosed with sarcoidosis for ⁇ 2 years). In certain embodiments, the methods treat a patient who has chronic pulmonary sarcoidosis (patient diagnosed with sarcoidosis for ⁇ 2 years). In certain embodiments, the methods safely treat a patient with chronic pulmonary sarcoidosis for periods in excess of 12 years.
  • Treatment with a rhDNase I such as PULMOZYME® could be long-term (over 12 years) without progression of, or with minimal progression of, the disease or recurring pulmonary exacerbations.
  • a key question relating to use of a rhDNAse I such as PULMOZYME® in pulmonary sarcoidosis patients is: “Is long-term use tolerated by the patient and does the clinical condition deteriorate as with untreated or steroid refractory disease?”
  • PULMOZYME® breaks the cycle of bronchial damage, impaired mucus clearance, recurrent inflammation and more damage—leading to pulmonary fibrosis and/or hemoptysis and death in the most seriously afflicted pulmonary sarcoid patients.
  • the methods described herein may improve the health of pulmonary sarcoidosis patients by decreasing the need for other medications (e.g., corticosteroids), reducing coughing, decreasing the number and severity of bacterial infections, improving the oxygen saturation of the patient's blood, and/or allowing for greater physical activity (e.g., improving exercise tolerance).
  • other medications e.g., corticosteroids
  • reducing coughing decreasing the number and severity of bacterial infections
  • improving the oxygen saturation of the patient's blood and/or allowing for greater physical activity (e.g., improving exercise tolerance).
  • a method of treating pulmonary sarcoidosis comprising administering to a patient in need thereof a therapeutically effective amount of a mucolytic agent.
  • Other embodiments include:
  • mucolytic agent selected from the group consisting of: sodium 2-sulfanylethanesulfonate, disodium 2,2′-disulfanediyldiethanesulfonate, and combinations thereof.
  • the method of embodiment 4 comprising administering an additional mucolytic agent selected from the group consisting of: sodium 2-sulfanylethanesulfonate; disodium 2,2′-disulfanediyldiethanesulfonate; N-acetylcysteine to the patient; and combinations thereof.
  • an additional mucolytic agent selected from the group consisting of: sodium 2-sulfanylethanesulfonate; disodium 2,2′-disulfanediyldiethanesulfonate; N-acetylcysteine to the patient; and combinations thereof.
  • FIG. 1 shows the nucleotide (SEQ ID NO. 1) and deduced amino acid (SEQ ID NO. 2) sequences of human DNase I as reported in Shak et al., 1990, Proc. Natl. Acad. Sci. USA 87:9188-9192. Nucleotides are numbered at left. Amino acids are numbered above the line starting at Leu+1 of the mature enzyme sequence and preceded by a 22-amino-acid putative signal sequence (underlined). The four cysteine residues are printed in boldface. Two potential N-linked glycosylation sites are indicated by lines above the amino acid sequence.
  • FIG. 2 shows the amino acid sequence of native human DNase I (SEQ ID NO. 3) as reported in U.S. Pat. No. 6,348,343.
  • FIG. 3 shows the clinical timeline for the treatment of the patient in Example 1.
  • DNA hydrolytic activity refers to the enzymatic activity of native human DNase I or a variant of human DNase I to cleave DNA to yield 5′-phosphorylated oligonucleotide end products.
  • Mucolytic agent refers to an agent used to dissolve mucus in order to help loosen and clear the mucus from the airways of the lung.
  • Patient refers to a human patient.
  • rhDNase I refers to recombinant human DNase I, i.e., human DNase I that is obtained by expressing a DNA construct encoding human DNase I in certain host cells such as Chinese hamster ovary (CHO) cells.
  • a variant of human DNase I refers to a polypeptide that comprises an amino acid sequence that is different from that of native human DNase I but still retains at least 90% amino acid sequence identity with native human DNase I.
  • “Therapeutically effective amount,” as used herein, refers to an amount of mucolytic agent that provides a therapeutic benefit in the treatment or management of pulmonary sarcoidosis, e.g., by delaying or minimizing one or more symptoms associated with pulmonary sarcoidosis, or by enhancing the therapeutic benefit provided by another therapeutic agent for pulmonary sarcoidosis.
  • the form of rhDNase I used in the methods described herein is that found in PULMOZYME®, which contains a highly purified aqueous solution of rhDNase I obtained from Chinese hamster ovary (CHO) cells genetically engineered to express native human DNase I.
  • the rhDNase I in PULMOZYME® is a glycoprotein containing 260 amino acids with a molecular weight of 37,000 daltons. The primary amino acid sequence of this protein is identical to that of native human DNase I. Its generic name is dornase alfa.
  • PULMOZYME® is administered to pulmonary sarcoidosis patients in the same general manner (e.g., dosage, method of administration) that it is administered to cystic fibrosis patients.
  • the form of rhDNase I used in the methods described herein is a biosimilar of PULMOZYME®.
  • FIG. 1A of Shak shows the DNA and amino acid sequences of native human DNase I and is reproduced herein as FIG. 1 of this application.
  • rhDNase I found in PULMOZYME®
  • the methods described herein may be practiced by administering a different rhDNase I.
  • U.S. Pat. No. 5,279,823 describes a deamidated rhDNase I that may be used.
  • U.S. Pat. No. 6,348,343 describes rhDNase I variants having slightly different amino acid sequences from that found in native human DNase I that may be used in the methods for treating pulmonary sarcoidosis described herein. For example, described are the following:
  • variants of human DNase I comprising at least one amino acid substitution at the following positions corresponding to the sequence of native human DNase I: His44, Leu45, Val48, Gly49, Leu52, Asp53, Asn56, His64, Tyr65, Val66, Val67, Ser68, Glu69, Ser94, Tyr96 or Ala 114, wherein said variants have DNA hydrolytic activity;
  • variants of human DNase I having amino acid sequences that are at least 99% identical to SEQ ID NO: 3, wherein said variants have DNA hydrolytic activity;
  • variants of human DNase I having amino acid sequences that are at least 95% identical to SEQ ID NO: 3, wherein said variants have DNA hydrolytic activity;
  • variants of human DNase I having amino acid sequences that are at least 90% identical to SEQ ID NO: 3, wherein said variants have DNA hydrolytic activity;
  • variants of human DNase I having amino acid sequences that differ from SEQ ID NO: 3 by only one amino acid substitution, wherein said variants have DNA hydrolytic activity;
  • variants of a human DNase I comprising at least one amino acid substitution selected from the group consisting of: E13A, E13H, E13R, E13W, E13Y, H44A, H44D, H44Y, H44W, H44C, H44Q, H44N, H44E, L45C, L45K, L45R, V48C, V48K, V48R, G49C, G491, G49K, G49R, G49Y, L52C, L52K, L52M, L52N, L52R, D53A, D53K, D53R, D53Y, D53C, D53L, D53M, N56C, N56F, N56K, N56R, N56W, D58T, H64N, Y65A, Y65R, Y65W, Y65C, Y65K, Y65M, Y65S, Y65N, Y65E, Y65P, V
  • variants of a human DNase I comprising at least one amino acid substitution selected from the group consisting of: E13A, E13H, E13R, E13W, E13Y, H44A, G49R, D53R, D53K, D53Y, D53A, D53C, N56R, Y65A, Y65R, Y65W, V67E, E69K, E69R A114G and A114H; and
  • variants of a human DNase I comprising at least one amino acid substitution selected from the group consisting of: H44A:D53R:Y65A, H44A:Y65A:E69R, D53R:Y65A, D53R:E69R, S94N:Y96T, V67N:E69T, Y65N:V67T and H64N:V66T.
  • U.S. Pat. No. 6,391,607 also describes rhDNase I variants having slightly different amino acid sequences from that found in native human DNase I that may be used in the methods for treating pulmonary sarcoidosis described herein.
  • human DNase I variants comprising amino acid sequences having at least 90% identity with the amino acid sequence of native human DNase I (SEQ ID NO: 3) and a substitution at one or more amino acid residues corresponding to Gln9, Thr14, Asn74, Ser75, and Thr205 of native human DNase I.
  • rhDNase I may be produced recombinantly in Chinese hamster ovary (CHO) cells by growing CHO cells that have been transfected with a suitable expression vector encoding human DNase I in a suitable medium and purifying the rhDNase I by conventional means, e.g., by tangential flow filtration and column chromatography.
  • rhDNase I may be produced using other suitable recombinant host cells, as is well known in the art.
  • nebulizer/compressor systems include the following:
  • a dose of about 2.5 mg once daily may be used.
  • a dose of about 2.5 mg twice daily may be used.
  • Other doses that may be used include about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, or about 5.0 mg, either once or twice per day.
  • Doses of 0.5 mg to 5.0 mg, 1.0 mg to 4.0 mg, or 1.5 mg to 3.5 mg, either once or twice per day, may also be used.
  • the mucolytic agent is delivered by inhalation to the patient 1, 2, 3, 4, 5, 6, or 7 times per week for a certain time period.
  • the time period is about 1 week, about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, about 9 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, or about 12 years.
  • compositions comprising a therapeutically effective amount of rhDNase I and a pharmaceutically acceptable carrier or excipient may be administered to patients in need of treatment for pulmonary sarcoidosis according to the methods described herein.
  • a buffered or unbuffered aqueous solution of DNase I e.g., an isotonic salt solution such as 150 mM sodium chloride containing 1.0 mM calcium chloride at pH 7, may be a suitable pharmaceutical composition.
  • rhDNase I is administered as a sterile, aqueous solution containing 1.0 mg/mL dornase alfa, 0.15 mg/mL calcium chloride dehydrate, and 8.77 mg/mL sodium chloride with no preservative.
  • the nominal pH of the solution is 6.3.
  • the rhDNase I is supplied in single-use ampoules that deliver 2.5 mL of this solution through a nebulizer.
  • the methods comprise administering a mucolytic agent and an oral corticosteroid, e.g., prednisone or prednisolone, to a patient in need of treatment for pulmonary sarcoidosis.
  • the methods comprise administering a mucolytic agent and a bronchodilator to a patient in need of treatment for pulmonary sarcoidosis.
  • the methods comprise administering a mucolytic agent and an antibiotic to a patient with pulmonary sarcoidosis.
  • the mucolytic agent may be DNase I and the antibiotic may be selected from the group consisting of TOBREX®, TOBI®, tobramycin, AKTOB®, BETHKIS®, TOBI® Podhaler, PROVENTIL®, VENTOLIN®, albuterol, ZITHROMAX®, azithromycin, Azasite, Cotazym, CREON®, ZENPEP®, Pancreaze, PERTZYE®, ULTRESA®, VIOKASE®, Nebcin, and combinations thereof.
  • the antibiotic may be administered by inhalation, e.g., using a nebulizer.
  • the antibiotic may be administered together with, or separately from, the mucolytic agent.
  • the mucolytic agent is administered with non-pharmaceutical therapies typically used to treat pulmonary sarcoidosis (e.g., chest physical therapy and/or postural drainage).
  • non-pharmaceutical therapies typically used to treat pulmonary sarcoidosis (e.g., chest physical therapy and/or postural drainage).
  • a patient (middle aged female, African ancestry) had a history of debilitating chronic pulmonary sarcoidosis with multiple pulmonary exacerbations requiring antibiotic therapy yearly. Constant coughing resulted in fractured ribs and abdominal hernias. At times, the patient was bedridden, dyspneic, and could not climb stairs or walk more than 10 feet. Steroids had been prescribed by pulmonary specialists; however the side effects of steroid therapy (diabetes, weight gain, memory loss, mental confusion, crippling joint pain) were intolerable. The patient's pulmonary sarcoidosis was deemed ultimately refractory to steroid therapy, which was discontinued, leaving essentially no therapeutic options for this patient.
  • PULMOZYME® was prescribed to the patient by a licensed medical practitioner to initiate treatment.
  • the patient responded to PULMOZYME® treatment as follows:
  • Pulmonary exacerbations no in more than 10 years of treatment;
  • the extended clinical timeline described above allowed for a distinction between remission and stabilization of the disease to be made.
  • One way to distinguish patients that are in remission from those that have had their disease stabilized and are being maintained in a quasi-steady state by the therapeutic intervention is to observe treatment over a suitably long interval (perhaps equivalent to the interval leading to ARF and death) and periodically discontinue therapy to observe whether the disease symptoms worsen or remain unchanged, thereby indicating true remission of disease. This was done on an annual basis for the patient described above for the typical “survival window” (8-14 years for patients with progressive, chronic disease).
  • the clinical timeline for treatment of the patient described above with PULMOZYME® is represented diagrammatically in FIG. 3 during pretreatment and for the entire treatment interval.
  • the patient voluntarily discontinued therapy with PULMOZYME® for 2-week intervals every year during the treatment period to determine whether regression of disease has occurred or if continued therapy with PULMOZYME® is necessary.
  • the patient's pulmonary disease symptoms (dyspnea, inspissated secretions, etc.) worsened, but were resolved upon resumption of PULMOZYME® therapy (2.5 mg qd 4 ⁇ weekly).
  • pulmonary disease symptoms dispnea, inspissated secretions, etc.
  • PULMOZYME® therapy 2.5 mg qd 4 ⁇ weekly.
  • the patient's routine chest x-rays have shown improvement during treatment, with evidence of scarring that has not progressed to more severe disease.
  • the only temporary coughing episodes noted during PULMOZYME® therapy have been associated with periodic bronchial irritation due to mucus plugs and/or expectoration of shed granulomas, none of which were severe enough to result in abdominal hernia pain or rib fractures.
  • the patient's sarcoid skin involvement is unchanged and the patient's diet has been unrestricted.
  • the patient is currently in a good state of health, enjoying a markedly improved quality of life, but must continue therapy with PULMOZYME® for the foreseeable future on the maintenance schedule of 2.5 mg qd, 4 ⁇ -5 ⁇ weekly.
  • the overarching goal was to determine the optimal individualized treatment using objective, results-driven criteria evolved over the course of therapy.
  • this patient has helped to provide key insights into identifying how individual outcomes might be improved within the larger heterogeneous at-risk population by establishing individual treatment stratifications based on specific clinical risk profiles and the stage and spectrum of disease. Furthermore, as a part of the individualized therapy, annual no-treatment (“washout”) intervals with the index patient were utilized over time to periodically evaluate the continued benefits of long-term therapy.
  • washout annual no-treatment
  • washout periods (annual 2-week “no-treatment” intervals) were invariably associated with return of disease symptoms, indicating that the index chronic pulmonary sarcoidosis patient may be analogous to the CF patient requiring quasi-daily therapy; furthermore, the patient's subjective experience confirmed the utility of treatments and adverse drug responses (ADRs) were not observed over the entire treatment interval reported herein.
  • ADRs adverse drug responses
  • PULMOZYME® is clearly validated as a safe and effective life-long treatment regimen based upon the study length and the index patient's subjective and objective responses. It should be noted that the patient was monitored daily during washout intervals to avoid compromising patient safety—an approach analogous to the placebo arm of a RCT. In addition, the patient was instructed to immediately resume treatment if her physical condition (dyspnea, excessive coughing, discolored mucus, etc.) deteriorated. Typically, these disease symptoms began to recur between week 1 and week 2, prior to the end of the 2 week washout interval.

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