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`APPLICATION
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`61/387,636
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`FILING or
`371(c) DATE
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`09/29/2010
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`GRP ART
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`30623
`MINTZ, LEVIN, COHN, FERRIS, GLOVSKY AND POPEO, P.C
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`FORMULATIONS OF GUANYLATE CYCLASE C AGONISTS AND METHODS OF USE
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`FORMULATIONS OF GUANYLATE CYCLASE C AGONISTS AND METHODS OF USE
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`SIGNATURE
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`TeLeprone 212-935-3000
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`REGISTRATION NO. 55,382
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`0005
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`

`Electronically Filed
`Date of Deposit: September 29, 2010
`
`Attny Ref: 40737-509P02US
`
`FORMULATIONS OF GUANYLATE CYCLASE C AGONISTS AND
`
`METHODS OF USE
`
`RELATED APPLICATIONS
`
`[01]
`
`This application claims the benefit of priority to U.S. Provisional Application No.
`
`61/383,156 filed on September 15, 2010, the contents of which is incorporated by reference in its
`
`entirety
`
`FIELD OF THE INVENTION
`
`[02]
`
`The present invention relates to low-dose formulations of guanylate cyclase C
`
`peptide agonists useful for the treatment and prevention of various diseases and disorders.
`
`BACKGROUND OF THE INVENTION
`
`[03]
`
`Guanylate cyclase C is a transmembrane form of guanylate cyclase that is
`
`expressed on various cells, including gastrointestinal epithelial cells (reviewed in Vaandrager
`
`2002 Mol. Cell. Biochem. 230:73-83). It was originally discovered as the intestinal receptor for
`
`the heat-stable toxin (ST) peptides secreted by enteric bacteria and which cause diarrhea. The
`
`ST peptides share a similar primary amino acid stracture with two peptides isolated from
`
`intestinal mucosa and urine, guanviin and uroguanylin (Curie, et al, Proc. Nar'l Acad. Sci. USA
`
`8§9:947-951 (1992), Hamra, ef af., Proc. Nat'l Acad. Sci. USA 90:.10464-10468 (1993); Forte, 1.
`
`Reg. Pept. 81:25-39 (1999); Schulz, er al, Cell 63:941-948 (1990); Guba, ef al,
`
`Gastroemterology 1111538-1568 (1996); Joo, et al, Am. J. Physiol. 274:G633-G644 (1998),
`
`[04]
`
`In the intestines, guanylin and uroguanylin act as regulators of fluid and
`
`electrolyte balance. In response to high oral salt intake, these peptides are released into the
`
`intestinal lumen where they bind to guanylate cyclase C localized on the luminal membrane of
`
`enterocytes (simple columnar epithelial cells of the small intestines and colon). The binding of
`
`the guanylin peptides to guanylate cyclase C induces electrolyte and water excretion into the
`
`SO31207v
`
`0006
`
`

`

`intestinal lumen via a complex intracellular signaling cascade that is initiated by an increase in
`
`cyclic guanosine monophosphate (cGMP).
`
`[05]
`
`The ¢GMP-mediated signaling that is initiated by the guanyiin peptides is critical
`
`for the normal functioning of the gut. Any abnormality in this process could lead to
`
`gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel
`
`diseases. Inflammatory bowel disease 1s a general name given to a group of disorders that cause
`
`the intestines to become inflamed, characterized by red and swollen tissue. Examples include
`
`ulcerative colitis and Crohn's disease. Crohn's disease is a serious inflammatory disease that
`
`predominantly affects the leur and colon, but can alse occur 1a other sections of the
`
`gastrointestinal tract. Ulcerative colitis is exclusively an inflammatory disease of the colon, the
`
`large intestine. Unlike Crohn's disease, in which all layers of the intestine are involved, and in
`
`which there can be normal healthy bowel in between patches of diseased bowel, ulcerative colitis
`
`affects only the innermost lining (mucosa) of the colon in a continuous manner. Depending on
`
`which portion of the gastrointestinal iract 1s invelved, Crohn's disease may be referred to as
`
`ileitis, regional enteritis, colitis, ete. Crohn's disease and ulcerative colitis differ from spastic
`
`colon or writable bowel syndrome, which are motility disorders of the gastrointestinal tract.
`
`Gastrointestinal inflammation can be a chronic condition. It is estimated that as many as
`
`1,000,000 Americans are afflicted with inflammatory bowel disease, with male and female
`
`patients appearing to be equally affected. Most cases are diagnosed before age 30, but the
`
`disease can occur in the sixth, seventh, and later decades of life.
`
`[06]
`
`IBS and chronic idiopathic constipation are pathological conditions that can cause
`
`a great deal of intestinal discomfort and distress but unlike the inflammatory bowel diseases, IBS
`
`does not cause the serious inflammation or changes in bowel tissue and it is not thought to
`
`increase the risk of colorectal cancer. In the past, inflammatory bowel disease, celiac disease and
`
`IBS were regarded as completely separate disorders. Now, with the description of inflammation,
`
`albeit low~grade, in IBS, and of symptom overlap between IBS and celiac disease, this
`
`contention has come under question. Acute bactenal gastroenteritis 1s the strongest risk factor
`
`identified to date for the subsequent development of postinfective irritable bowel syndrome.
`
`Clinical risk factors include prolonged acute illness and the absence of vomiting. A genetically
`
`determined susceptibility to inflammatory stimuli may also be a risk factor for irritable bowel
`
`3
`
`0007
`
`

`

`syndrome. The underlying pathophysiology indicates increased intestinal permeability and low
`
`grade inflammation, as well as altered motility and visceral sensitivity. Serotonin {5-
`
`hydrox viryptamine {S-HT}} 1s a kev modulator of gut function and is known to play a major role
`
`in pathophysiology of IBS. The activity of 5-HT 1s regulated by cGMP.
`
`[07]
`
`While the precise causes of IBS and inflammatory bowel diseases (IBD) are not
`
`known, a disruption in the process of continual renewal of the gastrointestinal mucosa may
`
`contribute to disease pathology in IBD and aggravate IBS. The renewal process of the
`
`gastrointestinal lining is an efficient and dynamic process involving the continual proliferation
`
`and replenishment of unwanted damaged cells. Proliferation rates of cells lining the
`
`gastrointestinal mucosa are very high. second only to the hematopoietic system. Gastrointestinal
`
`homeostasis depends on both the proliferation and programmed cellular death (apoptosis) of
`
`epithelial cells lining the gut mucosa. Cells are continually lost [rom the vilius into the lumen of
`
`the gut and are replenished at a substantially equal rate by the proliferation of cells in the crypts,
`
`followed by their upward movement to the villus. The rates of cell proliferation and apoptosis in
`
`the gut epithelium can be increased or decreased in a variety of circumstances, e.g, in response
`
`to physiclogical stimuli such as aging, inflammatory signals, hormones, peptides, growth factors,
`
`chemicals and dietary habits. In addition, an enhanced proliferation rate is frequently associated
`
`with a reduction in turnover time and an expansion of the proliferative zone. The proliferation
`
`index is much higher in pathological states such as ulcerative colitis and other gastrointestinal
`
`disorders. Intestinal hyperplasia is a major promoter of gastrointestinal inflammation. Apoptosis
`
`and cell proliferation together regulate cell number and determine the proliferation index.
`
`Reduced rates of apoptosis are often associated with abnormal growth, inflammation, and
`
`neoplastic transformation. Thus, both increased proliferation and/or reduced cell death may
`
`increase the proliferation index of intestinal tissue, which may in turn lead to gastrointestinal
`
`inflammatory diseases.
`
`[08]
`
`In addition to a role for uroguanylin and guanylin as modulators of intestinal fluid
`
`and ion secretion, these peptides may also be involved in the continual renewal of
`
`gastrointestinal mucosa by maintaining the balance between proliferation and apoptosis. For
`
`example, uroguanylin and guanylin peptides appear to promote apoptosis by controlling cellular
`
`ion flux. Given the prevalence of inflammatory conditions in Western societies a need exists to
`
`’
`
`0008
`
`

`

`improve the treatment options for inflammatory conditions, particularly of the gastrointestinal
`
`tract.
`
`[09]
`
`Peptide agonists of guanylate cyclase C agonists ("GCC agonists”) are described
`
`in U.S, Patent Nos. 7,041,786, 7,799,897, and U.S. Patent Application Publication Nos,
`
`US2009/0048173, US 2010/0069306, US 2010/0120694, US 2010/0093635, and US
`
`2010/0221329. However, the formulation of peptides for pharmaceutical delivery presents a
`
`number of special problems. For example, peptides are subject to structural modifications by a
`
`variety of degradation mechanisms resulting in problems of chemical and physical instability of
`
`the formulation.
`
`SUMMARY OF THE INVENTION
`
`[10]
`
`The present invention provides low-dose formulations of peptide agonists of
`
`guanylate cyclase C (“GCC”) and methods for their use in the treatment and prevention of
`
`human diseases and disorders, such as a gastrointestinal motility disorder, irritable bowel
`
`syndrome, a functional gastrointestinal disorder, gastroesophageal reflux disease, functional
`
`heartburn, dyspepsia, functional dyspepsia, nonulcer dyspepsia, gastroparesis, chronic intestinal
`
`pseudo-~obstruction, colonic pseudo-obstruction; Crohn's disease, ulcerative colitis, inflammatory
`
`bowel disease, colonic pseudo-obstruction, obesity, congestive heart failure, and benign prostatic
`
`hyperplasia. In certain embodiments, the formulations are stabilized against chemical
`
`degradation of the peptide. The low-dose formulations of the invention have unexpected
`
`efficacy in humans in a dosage range that was not predicted based on studies in primates. The
`
`formulations of the invention are particularly useful for the treatment or prevention of chronic
`
`idiopathic constipation. In certain embodiments, the GCC agonists are analogs of uroguanvlin
`
`and bacterial ST peptides. In preferred embodiments, the analogs have superior properties
`
`compared to the naturally occurring or “wild-type” peptides. Examples of such superior
`
`properties include a high resistance {o degradation at the N-terminus and C-terminus from
`
`carboxypeptidases, aminopeptidases, and/or by other proteolytic enzymes present in the
`
`stimulated human testinal juices and human gastric juices. Examples of GCU agonists that can
`
`be used in the formulations and methods of the invention are described in more detail below and
`
`in U.S. Patent Nos. 7,041,786, 7,799,897, and U.S. Patent Application Publication Nos.
`
`4
`
`0009
`
`

`

`LiS2009/0048175, US 2010/0069306, US 2010/0120694, US 2010/0093635, and US
`
`2010/0221329, each of which is incorporated herein by reference in its entirety.
`
`[11]
`
`The invention provides an oral dosage formulation comprising at least one GCC
`
`agonist peptide, wherein the amount of GCC agonist peptide per unit dose is from 0.01 mg to 9.5
`
`mg, and wherein the GCC agonist peptide 1s selected {rom the group consisting of SEQ 1D NOs:
`
`1-249. lun one embodiment, the GCC agonist peptide is selected from the group consisting of
`
`SEQ ID NOs: 1, 8, 9, 55 or 56.
`
`In one embodiment, the GCC agonist peptide is selected from
`
`the group consisting of SEQ ID NOs: t and 9.
`
`In one embodiment, the amount of GCC agonist
`
`peptide per umt dose 1s 0.1 mg, 0.3 mg, 1.0 mg, 3.0 mg, 9.0 mg or 9.5 mg.
`
`[12]
`
`In one embodiment, the formulation is a solid formulation. In one embodiment,
`
`the formufation is in the form of a powder, granule, sachet, troche, tablet, or capsule. In another
`
`embodiment, the formulation is a liquid formulation and the GCC agonist peptide is in solution
`
`or suspension in a lipophilic liquid.
`
`In one embodiment, the liquid 1s a refined specialty oil or a
`
`medium chain triglyceride or related ester.
`
`In one embodiment, the refined specialty oil is
`
`selected from Arachis oll, Castor oil, cottonseed oil, maize (corn) oil, olive oil, sesame oil,
`
`soybean oi, and sunflower oil.
`
`In one embodiment, the medium chain triglyceride or related
`
`ester is AKOMED FE, AKOMED R, CAPTEX 355, LABRAFAC CC, LABRAFAC PG,
`
`LAUROGLYCOL FCC, MIGLYOL 810, MIGLYOL 812, MIGLYOL 829, MIGLYOL 840,
`
`and SOFTISAN 645. In one embodiment, the liquid is selected from the group consisting of
`
`medium chain triglycerides, propylene glycol dicapryiocaprate, vitamin E, and sovbean oil.
`
`In
`
`one embodiment, the unit dose is a powder, tablet, or capsule. In one embodiment, the anit dose
`
`is a liquid-filled capsule. In one embodiment, the capsule or tablet is in a blister pack or strip.
`
`Preferably, the blister pack or strip is made of a material that is impermeable to water vapor and
`
`oxygen. In one embodiment the blister pack is comprised of a metal foil.
`
`In one embodiment,
`
`the container of the blister pack is flushed with an inert gas such as nitrogen or argon. In one
`
`embodiment, the container further includes a dessicant. In a preferred embodiment the desstcant
`
`is a molecular sieve.
`
`In one embodiment, the unit dose is in a high density polyethylene bottle
`
`having a seal.
`
`In one embodiment, the bottle further comprises a dessicant. In one embodiment,
`
`the botile further comprises an oxygen scavenger or molecular sieve.
`
`0010
`
`

`

`[13]
`
`In one embodiment, the formulation further comprises an inert carrier.
`
`In one
`
`embodiment, the inert carrier is a selected from mannitol, lactose, a microcrystalline cellulose, or
`
`starch. In one embodiment, the inert carrier has a particle size of from 50 to 200 microns, from
`
`73 fo 150 microns, from 75 to 200 microns, or from 75 fo 300 microns.
`
`[14]
`
`In one embodiment, the GCC agonist peptide is stabilized against chemical
`
`degradation for a period of at {east [8 months at 25C and 60% relative humidity or at least 18
`
`months at 2-8C.
`
`[15]
`
`The invention also provides a process tor making the oral dosage formulations
`
`described herein, wherein the process comprises a step of dry granulation or wet granulation. In
`
`another embodiment, the process comprises a step of dry mixing. In a preferred embodiment the
`
`step of dry mixing includes geometric blending. In one embodiment, the process comprises a
`
`step of direct compression.
`
`[16]
`
`The invention also provides a method for treating or preventing a disease or
`
`disorder in a subject in need thereof, comprising administering to the subject an oral dosage
`
`formulation comprising al feast one GCC agonist peptide, wherein the amount of GCC agonist
`
`peplide per umt dose 1s from 0.01 mg to 9.5 mg, and wherein the GCC agonist peptide 1s selected
`
`from the group consisting of SEQ 1D NOs: 1-249. Preferably, the subject 1s a human subject.
`
`In
`
`one embodiment, the GCC agonist peptide is selected from the group consisting of SEQ ID NOs:
`
`1, 8,9, 53 or 56.
`
`In one embodiment, the GCC agonist peptide is selected from the group
`
`consisting of SEQ ID NOs: 1 and 9.
`
`In one embodiment, the amount of GCC agonist peptide per
`
`anit dose is 0.1 mg, 0.3 mg, 1
`
`Omg, 3.0 mg, 9.0 mg or 8.53 mg
`
`[17]
`
`In one embodiment, the disease or disorder is a gastrointestinal disease or disorder
`
`selected from the group consisting of irritable bowel syndrome, non-ulcer dyspepsia, chronic
`
`intestinal pseudo-obstruction, functional dyspepsia, colonic pseudo-obstruction, duodenogastric
`
`reflux, gastro esophageal reflux disease, constipation, gastroparesis, heartburn, gastric cancer,
`
`and H. pylori infection. In a preferred embodiment, the gastrointestinal disease or disorder is
`
`chronic idiopathic constipation.
`
`6
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`0011
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`

`[18]
`
`In one embodiment, the method further comprises administering to the subject an
`
`effective amount of an inhibitor of a cGMP-specific phosphodiesterase. In one embodiment, the
`
`cGMP-dependent phosphodiesterase inhibitor is selected from the group consisting of suldinac
`
`sulfone, zaprinast, and motapizone, vardenifil, and suldenifil.
`
`[19]
`
`In one embodiment, the method further comprises administering to the subject an
`
`effective amount of at least one laxative. ln one embodiment, the at least one laxative 1s selected
`
`from the group consisting of SENNA, MIRALAX, PEG, or calcium polycarboplul.
`
`[20]
`
`In one embodiment, the method further comprises administering to the subject an
`
`effective amount of at least one anti-inflammatory agent.
`
`fra
`
`[21]
`
`The invention also provides pharmaceutical compositions comprising the
`
`formulations described herein.
`
`[22
`
`Other features and advantages of the invention will be apparent from and are
`
`encompassed by the following detailed description and claims.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figure 1: Plecanatide (SP-304) treatment reduced time to first BM following daily
`
`Figure 2: Effect of daily treatment with plecanatide on spontaneous bowel
`
`[23]
`
`dose.
`
`[24]
`
`movements (SBM) in chronic constipation patients.
`
`DETAILED DESCRIPTION
`
`[25]
`
`The invention provides pharmaceutical formulations of peptide GCC agonists. It
`
`is intended that the formulations of the invention are “pharmaceutical” formulations, meaning
`
`that they are suitable for pharmaceutical use. Accordingly. the term “formulations” as used
`
`herein is meant to encompass pharmaceutical formulations even if “pharmaceutical” is not
`
`expressly stated. Pharmaceutical compositions comprising the formulations described herein are
`
`also provided by the vention. The formulations of the vention preferably provide stability
`
`7
`li
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`
`
`0012
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`

`

`against chemical and physical degradation of the peptide. The invention is based in part upon
`
`the discovery that mannitol mixes very effectively with the GCC agonist peptides described
`
`herein and provides stability against degradation, allowing the peptides to be formulated at very
`
`low doses. The invention is also based in part on the discovery that very low doses of the GCC
`
`agonist peptides described herein are effective for the treatment of diseases and disorders in
`
`humans. The dosage range found to be effective was not predicted based on animal studies.
`
`[26]
`
`The formudations of the invention are particularly useful for the treatment or
`
`prevention of a gastrointestinal disease or disorder selected from the group consisting of irritable
`
`bowel syndrome, non-nlcer dyspepsia, chronic intestinal pseado-obstruction, functional
`
`dyspepsia, colonic pseudo-obstruction, duodenogastric reflux, gastro esophageal reflux disease,
`
`chronic idiopathic constipation, gastroparesis, heartburn, gastric cancer, and H. pylori infection.
`
`[27]
`
`In one embodiment, the formulations of the invention are used in a method for the
`
`treatment of constipation. Chaically accepted criteria that define constipation range {rom the
`
`frequency of bowel movements, the consistency of feces and the ease of bowel movement. One
`
`common definition of constipation 1s less than three bowel movements per week. Other
`
`definitions include abnormally hard stools or defecation thal requires excessive straining.
`
`Constipation may be idiopathic (functional constipation or stow transit constipation} or
`
`secondary to other causes including neurologic, metabolic or endocrine disorders. These
`
`disorders include diabetes mellitus, hypothyroidism, hyperthyroidism, hypocalcaemia, Multiple
`
`sclerosis, Parkinson's disease, spinal cord lesions, Neurofibromatosis, autonomic neuropathy,
`
`Chagas disease, Hirschsprung disease and cystic {ibrosis. Constipation may also be the result of
`
`surgery or due to the use of drugs such as analgesics (like opioids), antihypertensives,
`
`anticonvulsants, antidepressants, antispasmodics and antipsychotics. In a preferred embodiment,
`
`the constipation is chronic idiopathic constipation.
`
`[28]
`
`The stabilized formulations of the invention comprise at {east one GCC agonist
`
`peptide formulated with one or more excipients such that the peptide is stabilized against
`
`cheniical degradation. Chemical degradation of peptides results from a number of mechanisms
`
`including oxidation, water-mediated degradation, and reaction with aldheydes or reducing
`
`sugars. The ideal excipient or combination of excipients will be non-hygroscopic, have few or
`
`0013
`
`

`

`no reducing sugars, and be substantially free of contaminants such as iron, peroxide, and
`
`formaldehyde. The formulations of the invention are preferably substantially free of water. In
`
`this context “substantially” free of water means that the water conten