111111111111111111111111111111111111111111111111111111111111111111111111111
`US009616111B2
`
`c12) United States Patent
`Ruddy et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,616,111 B2
`Apr. 11, 2017
`
`(54) C1-INH COMPOSITIONS AND METHODS
`FOR THE PREVENTION AND TREATMENT
`OF DISORDERS ASSOCIATED WITH C1
`ESTERASE INHIBITOR DEFICIENCY
`
`(71) Applicant: Shire ViroPharma Incorporated,
`Lexington, MA (US)
`
`(72)
`
`Inventors: Stephen Ruddy, Exton, PA (US);
`Mark Cornell Manning, Johnstown,
`CO (US); Ryan Erik Holcomb, Fort
`Collins, CO (US)
`
`(73) Assignee: Shire ViroPharma Incorporated,
`Lexington, MA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 14/855,168
`
`(22) Filed:
`
`Sep. 15, 2015
`
`(65)
`
`Prior Publication Data
`
`US 2016/0015795 Al
`
`Jan. 21, 2016
`
`Related U.S. Application Data
`
`application
`of
`(63) Continuation
`PCT/US2014/030309, filed on Mar. 17, 2014.
`
`No.
`
`(60) Provisional application No. 61/791,399, filed on Mar.
`15, 2013.
`
`(51)
`
`(52)
`
`(58)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2017.01)
`(2006.01)
`
`Int. Cl.
`A61K 38100
`A61P 7100
`A61K 38155
`C07K 14181
`A61K 38157
`A61K 9100
`A61K 47102
`A61K 47112
`A61K 47118
`A61K 47122
`U.S. Cl.
`CPC ............ A61K 38157 (2013.01); A61K 910019
`(2013.01); A61K 38100 (2013.01); A61K 47102
`(2013.01); A61K 47112 (2013.01); A61K 47118
`(2013.01); A61K 471183 (2013.01); A61K
`47122 (2013.01)
`
`Field of Classification Search
`CPC .. A61K 38/1725; A61K 38/57; C07K 14/472;
`C07K 14/81
`See application file for complete search history.
`
`(56)
`
`References Cited
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`
`wo
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`W0-92/06203 A1
`wo
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`W0-92/22320 A1
`wo
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`W0-95/06479 A1
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`(Continued)
`
`OTHER PUBLICATIONS
`
`Anonymous "ViroPharma and Halozyme Therapeutics Announce
`Initiation of Phase 2b Dose Ranging Combination Study for Sub(cid:173)
`cutaneous Administration of Cinryze (R) (C1 esterase inhibitor
`[human]) With Hyaluronidase (rHuPH20)" Press release, published
`Dec. 19, 2012.*
`Jiang et a!. "Subcutaneous infusion of human C 1 inhibitor in swine"
`Clinical Immunology 136:323-328. Published Jun. 8, 2010.*
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`published Sep. 4, 2008. *
`Mahmood I "Clinical Pharmacology Review" Published Dec. 4,
`2007.*
`
`(Continued)
`
`Primary Examiner- Christina Bradley
`Assistant Examiner- Zachary J Miknis
`(74) Attorney, Agent, or Firm- Proskauer Rose LLP;
`Fangli Chen; Julio J. Mendez
`
`(57)
`
`ABSTRACT
`
`Compositions and methods for the treatment and/or preven(cid:173)
`tion of disorders associated with Cl esterase inhibitor defi(cid:173)
`ciency are disclosed.
`
`18 Claims, 2 Drawing Sheets
`
`CSL EXHIBIT 1000
`CSL v. Shire
`
`Page 1 of 13
`
`

`

`US 9,616,111 B2
`Page 2
`
`(56)
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`3, acknowledged by European Patent Office on Jan. 19, 2017.
`
`Anonymous, Press Release by BMI Research on 5th Mar. 2012,
`"Subcutaneous Cinryze with rHuPH20 produced positive effects in
`prevention of HAO," in connection with poster titled "Safety,
`Pharmacokinetics (PK), and Pharmacodynamics (PD) of Subcuta(cid:173)
`neous (SC) Cinryze® (C 1 Esterase Inhibitor [Human]) with Recom(cid:173)
`binant Human Hyaluronidase (rHuPH20) in Subjects with Heredi(cid:173)
`tary Angioedema (HAE)".
`Anonymous, CSL R&D Briefing, Dec. 5th, 2012.
`Anonymous, ViroPharma Press release, ViroPharma Provides
`Update on Phase 2 Clinical Evaluation of Subcutaneous Cinryze®
`(Cl esterase
`inhibitor
`[human]) with Recombinant Human
`Hyaluronidase (rHuPH20), Aug. 1, 2012.
`Extract from "Ansel's Pharmaceutical Dosage Forms and Drug
`Delivery Systems"; ninth edition; 2001; Chapter 5, pp. 162-170;
`Eds. Allen Jr. et a!.
`Giatlin et al., "Formulation and Administration Techniques to
`Minimize Injection Pain and Tissue Damage Associated with
`Parenteral Products," extract from "Injectable Drug Development.
`Techniques to Reduce Pain and irritation"; 1999; Chapter 17.
`* cited by examiner
`
`Page 4 of 13
`
`

`

`U.S. Patent
`U.S. Patent
`
`Apr. 11, 2017
`Apr. 11,2017
`
`Sheet 1 of 2
`Sheet 1 of 2
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`US 9,616,111 B2
`US 9,616,111 132
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`Page 5 of 13
`
`
`
`

`

`U.S. Patent
`
`Apr. 11, 2017
`
`Sheet 2 of 2
`
`US 9,616,111 B2
`
`........ pH 7 9
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`
`Page 6 of 13
`
`

`

`US 9,616,111 B2
`
`2
`FIG. 2 provides a graph of the effect of protein concen(cid:173)
`tration on viscosity for initial spin concentration samples.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`1
`Cl-INH COMPOSITIONS AND METHODS
`FOR THE PREVENTION AND TREATMENT
`OF DISORDERS ASSOCIATED WITH Cl
`ESTERASE INHIBITOR DEFICIENCY
`
`This application is a continuation of PCT/US2014/
`030309, filed Mar. 17, 2014, which claims priority to U.S.
`Provisional Patent Application No. 61/791,399, filed Mar.
`15, 2013, the disclosure of which is hereby incorporated by
`reference.
`The instant application contains a Sequence Listing which
`has been submitted electronically in ASCII format and is
`hereby incorporated by reference in its entirety. Said ASCII
`copy, created on Sep. 14, 2015, is named 2006685-
`1184_SL.txt and is 4,606 bytes in size.
`
`FIELD OF THE INVENTION
`
`10
`
`The present invention relates to the field of therapeutic
`agents and methods of use thereof. Specifically, the instant
`invention provides compositions and methods for the treat- 20
`ment and/or prevention of disorders associated with C1
`esterase inhibitor deficiency.
`
`BACKGROUND OF THE INVENTION
`
`The restoration of active C1 esterase inhibitor levels in
`patients having a disorder associated with deficient or
`reduced levels of active C1 esterase inhibitor (e.g., HAE) is
`an effective measure for treating such disorders. Currently,
`C1 esterase inhibitor (such as Cinryze® (ViroPharma, Inc.;
`Exton, Pa.)) is administered to a patient intravenously by a
`medical professional. Herein, formulations of a C1 esterase
`inhibitor (such as Cinryze®) are provided which are also
`15 effective for subcutaneous (SC) administration. Surpris(cid:173)
`ingly, the subcutaneous administration of the C1 esterase
`inhibitor is sufficient to maintain the blood levels of the C1
`esterase inhibitor. The SC administration of a C1 esterase
`inhibitor fulfills an urm1et medical need due to the limita-
`tions of intravenous administration in HAE patients.
`In accordance with the instant invention, compositions
`and methods for inhibiting (e.g., reducing or slowing),
`treating, and/or preventing a disorder associated with C1
`esterase inhibitor deficiency in a subject are provided. In a
`particular embodiment, the methods comprise administering
`(e.g., subcutaneously or intravenously) to a subject in need
`thereof at least one C1 esterase inhibitor. In a particular
`embodiment, the C1 esterase inhibitor is administered sub(cid:173)
`cutaneously after an initial administration of the C1 esterase
`inhibitor intravenously.
`C1 esterase inhibitors are also known as C1 inhibitors (C1
`INH). C1 esterase inhibitors are inhibitors of complement
`C1 and belong to the superfamily of serine proteinase
`inhibitors. Human C1 esterase inhibitor is a protein of 500
`amino acids, including a 22 amino acid signal sequence
`(Carteret a!. (1988) Eur. J. Biochem., 173: 163). In plasma,
`the C1 esterase inhibitor is a heavily glycosylated glyco(cid:173)
`protein of approximately 76 kDa (Perkins et a!. (1990) J.
`Mol. Bioi., 214:751). The activity of a C1 esterase inhibitor
`may be assayed by known methods (see, e.g., Drouet eta!.
`(1988) Clin. Chim. Acta., 174:121-30). In a particular
`embodiment, the C1 esterase inhibitor is human. An amino
`acid sequence of human C1 esterase inhibitor is provided in
`GenBankAccession No. CAA30314 (see also GeneiD: 710,
`which also provides nucleotide sequences of the C1 esterase
`inhibitor) and FIG. 1. A C1 esterase inhibitor for use in the
`methods of the instant invention may have an amino acid
`sequence that has at least 65, 70, 75, 80, 85, 90, 95, 98, 99,
`or 100% identity with the amino acid sequence of FIG. 1.
`The C1 esterase inhibitor may be isolated or purified from
`plasma (e.g., human plasma) or recombinantly produced.
`When purified from plasma, the C1 esterase inhibitor may be
`nanofiltered and pasteurized. In a particular embodiment, the
`plasma-derived C1 esterase inhibitor is Cinryze®. In a
`55 particular embodiment, the C1 esterase inhibitor is present
`in the compositions of the instant invention at high concen(cid:173)
`tration. Indeed, compositions comprising very high levels of
`C1 esterase inhibitor have been determined to be surpris(cid:173)
`ingly stable and active. In a particular embodiment, the C1
`60 esterase inhibitor is present at about 250 U/ml to about 1000
`U/ml, about 400 U/ml to about 600 U/ml, or about 500 U/ml.
`In a particular embodiment, the compositions of the
`instant invention do not contain citrate or citric acid. The
`compositions lacking citrate and citric acid are particularly
`65 useful for the subcutaneous administration of the C1 esterase
`inhibitor as citrate/citric acid can cause an injection site
`reaction. In a particular embodiment, the buffer of the instant
`
`25
`
`30
`
`Several publications and patent documents are cited
`throughout the specification in order to describe the state of
`the art to which this invention pertains. Full citations of
`these references can be found throughout the specification.
`Each of these citations is incorporated herein by reference as
`though set forth in full.
`Hereditary angioedema (HAE) is a rare, life-threatening,
`genetic disorder caused by a deficiency of the C1 esterase
`inhibitor (see generally www.haei.org and www.haea.org).
`At least 6,500 people in the United States and at least 10,000
`people in Europe have HAE. HAE patients experience 35
`recurrent,
`unpredictable,
`debilitating,
`life-threatening
`attacks of inflammation and submucosa/subcutaneous swell(cid:173)
`ing. The inflmation is typically of the larynx, abdomen,
`face, extremities, and urogenital tract. This genetic disorder
`is a result of a defect in the gene controlling the synthesis of 40
`the C1 esterase inhibitor. Accordingly, restoring the levels of
`active C1 esterase inhibitor in these patients to or near
`normal levels is an effective measure for treating HAE. Still,
`new and improved methods of treating and preventing
`disorders associated with a deficiency of the C1 esterase 45
`inhibitor, such as HAE, are desired.
`
`SUMMARY OF THE INVENTION
`
`In accordance with the instant invention, methods for 50
`inhibiting, treating, and/or preventing a disorder associated
`with a deficiency in C1 esterase inhibitor in a subject are
`provided. In a particular embodiment, the method comprises
`administering a composition comprising at least one C1
`esterase inhibitor.
`In accordance with the instant invention, therapeutic
`compositions are also provided. In a particular embodiment,
`the composition comprises at least one C1 esterase inhibitor
`and, optionally, at least one pharmaceutically acceptable
`carrier for delivery (e.g. intravenous or subcutaneous deliv(cid:173)
`ery). Kits comprising a composition comprising at least one
`C1 esterase inhibitor are also provided herein.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 provides an amino acid sequence of human C1
`esterase inhibitor.
`
`Page 7 of 13
`
`

`

`US 9,616,111 B2
`
`3
`composJtwns is sodium phosphate (e.g., about 5 mM to
`about 50 mM sodium phosphate, about 10 mM to about 30
`mM sodium phosphate, or about 20 mM sodium phosphate).
`In a particular embodiment (e.g., for intravenous adminis(cid:173)
`tration), the buffer of the instant compositions comprises a
`carbo