`US00784 7061B2
`
`c12) United States Patent
`Sanguinetti et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,847,061 B2
`Dec. 7, 2010
`
`(54) TREATMENT OF SHORT BOWEL
`SYNDROME PATIENTS WITH
`COLON-IN-CONTINUITY
`
`(75)
`
`Inventors: Elizabeth Lemaire Sanguinetti, Salt
`Lake City, UT (US); Thomas B.
`Marriott, Sandy, UT (US); Jennifer
`Lopansri, Salt Lake City, UT (US);
`Consuelo Maria Blosch, Mercer Island,
`WA (US)
`
`(73) Assignee: NPS Pharmaceuticals, Inc.,
`Bedminster, NJ (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 11/262,980
`
`(22) Filed:
`
`Nov.1, 2005
`
`(65)
`
`Prior Publication Data
`
`US 2006/0135424 Al
`
`Jun.22,2006
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/623,233, filed on Nov.
`1, 2004.
`
`(51)
`
`Int. Cl.
`A61K 38126
`(2006.01)
`A61K 38118
`(2006.01)
`A61K 35138
`(2006.01)
`(52) U.S. Cl. ............................ 530/308; 514/2; 424/551
`(58) Field of Classification Search ....................... None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,789,379 A
`6,077,949 A
`6,184,201 Bl*
`7,411,039 B2
`
`8/ 1998 Drucker et al.
`612000 Munroe et al.
`2/2001 Drucker et al. ................ 514/12
`8/2008 Thim et al.
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`WO
`
`WO 97/39091 Al
`WO 9739031
`WO 02/066511 A2
`
`10/1997
`10/1997
`8/2002
`
`OTHER PUBLICATIONS
`
`Jeppesen, et al., J. Nutr., 2003, 133, 3721-3724.*
`Jeppesen, et al., JPEN, 1999, 23, Sl01-Sl05.*
`Jeppesen et al. (Gastroenterology 2001;120:806-815).
`K. N. Jeejeebhoy, "Short bowel syndrome: a nutritional and medical
`approach", CMAJ; May 14, 2002, 168 (10), pp. 1297-11302.
`Jeppesen et al., Impaired Meal Stimulated Glucagon-Like. Peptide 2
`Response in Ilea! Resected Short Bowel Pateints with Intestinal Fail(cid:173)
`ure, GUT, 45:559-563 (1999).
`Jeppesen et al., Elevated Plasma Glucagon-like Peptide 1 and 2
`Concentrations in Ileum Resected Short Bowel Patients with a Pre(cid:173)
`served Colon, GUT, 47:370-376 (2000).
`Jeppesen et al., ALX-0600, a Dipeptidyl Peptidase-IV Resistant
`Glucagon-like Peptide-2 ( GLP-2)Analog, Improves Intestinal Func(cid:173)
`tion in Short Bowel Syndrome (SES) Pateints with a Jejunostomy,
`Gastroenterology 122:A-191 (2002).
`Scott et al., GLP-2 Augments the Adaptive Response to Massive
`intestinal Resection in Rat, Am. J. Physiol. (Gastrointest. Liver
`Physiol. 38): G911-G921 (1988).
`Ferrone, et al., "Teduglutide for the treatment of short bowel syn(cid:173)
`drome", The Annals ofPharmacotherapy, 2006, vol. 40, No. 6, 1105-
`1109.
`International Preliminary Report on Patentability and Written Opin(cid:173)
`ion issued in International Application No. PCT/US2005/039222
`dated May 1, 2007.
`International Search Report issued in International Application No.
`PCT/US2005/039222 dated Jul. 17, 2006.
`Jeppesen, et al., "Teduglutide (ALX-0600), adipeptidylpeptidaseIV
`resistant glucagon-like peptide 2 analogue, improves intestinal func(cid:173)
`tion in short bowel syndrome patients", Gut, vol. 54, No. 9, 2005,
`1224-1231.
`Yang, et al., "Novel Agents in the treatment of intestinal failure:
`humoral factors", Gastroenterology, vol. 130, No. 2, 2006, Sl l 7-
`Sl21.
`* cited by examiner
`Primary Examiner-Andrew D Kosar
`Assistant Examiner-Satyanarayana R Gudibande
`(74) Attorney, Agent, or Firm-Stoel Rives LLP
`
`(57)
`
`ABSTRACT
`
`Intestinal absorption is enhanced in short bowel syndrome
`patients presenting with colon-in-continuity by treatment
`with a GLP-2 receptor agonist, such as teduglutide.
`
`EP
`
`1231219
`
`8/2002
`
`18 Claims, 2 Drawing Sheets
`
`1
`
`CFAD Exhibit 1072
`CFAD v. NPS
`IPR2015-01093
`
`
`
`U.S. Patent
`
`Dec. 7, 2010
`
`Sheet 1of2
`
`US 7,847,061 B2
`
`Figure 1.
`
`Fecal
`output
`
`Intestinal
`Absorption
`
`0.6 1.3*** 0.3
`
`Urine
`output
`
`6
`
`2.8 2.f" 3.1
`
`1.4 2.0*** 1.4
`
`5
`
`4
`
`3
`
`2 ->.
`ta
`32 1
`~ -....
`C>
`-§,o.._ ________________ ..._ ______________ ___
`·-
`~
`~-1
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`
`-2
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`
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`E
`
`2
`
`
`
`U.S. Patent
`
`Dec. 7, 2010
`
`Sheet 2of2
`
`US 7,847,061 B2
`
`Figure 2.
`
`16
`
`14
`
`12
`
`10
`
`4
`
`2
`
`0
`
`Fecal
`output
`5.5 4.6* 5.7
`
`Intestinal
`Absorption
`6.2 7.0 5.9
`
`B
`A
`s
`E
`L
`I
`N
`
`T
`R
`E
`A
`T
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`
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`0
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`0
`w
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`w
`
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`
`
`
`US 7,847,061 B2
`
`2
`SUMMARY OF THE INVENTION
`
`1
`TREATMENT OF SHORT BOWEL
`SYNDROME PATIENTS WITH
`COLON-IN-CONTINUITY
`
`FIELD OF THE INVENTION
`
`This invention relates to products and methods useful
`medically to treat patients presenting with short bowel syn(cid:173)
`drome. More particularly, the invention relates to glucagon(cid:173)
`like peptide 2 (GLP-2) and other GLP-2 receptor agonists
`effective to improve intestinal function particularly in
`patients presenting with short bowel syndrome with colon(cid:173)
`in-continuity.
`
`BACKGROUND TO THE INVENTION
`
`It has now been determined that intestinal absorption is
`enhanced in SBS patients presenting with colon-in-continu(cid:173)
`ity when those patients are treated with a GLP-2 receptor
`agonist.
`Thus, in one aspect, the present invention provides a
`method for enhancing intestinal absorption in a patient with
`short bowel syndrome, comprising the steps of selecting for
`10 treatment a short bowel syndrome patient presenting with at
`least about 25% colon in continuity with renmant small intes(cid:173)
`tine, and treating said patient with a GLP-2 receptor agonist to
`enhance intestinal absorption by said patient.
`In a related aspect, the present invention provides for the
`15 use ofa GLP-2 receptor agonist in the preparation ofa medi(cid:173)
`cament for enhancing intestinal absorption in short bowel
`syndrome patients presenting with at least about 25% colon in
`continuity with renmant small intestine.
`In a preferred embodiment, the GLP-2 receptor agonist is
`20 [Gly2]hGLP-2, known as teduglutide.
`
`BRIEF REFERENCE TO THE DRAWINGS
`
`Embodiments of the invention are now described with
`25 reference to the accompanying drawings in which:
`FIG. 1 illustrates results measured in terms of fecal wet
`weight, intestinal wet weight absorption and urine weight in
`the individual patients at Baseline (Days -3 to 0), during
`30 treatment (Days 18 to 21), and at follow-up (Days 39 to 42).
`FIG. 2 illustrates results measured in terms of fecal energy
`excretion and intestinal absorption in the individual patients
`at Baseline (Days -3 to 0), during treatment (Days 18 to 21),
`and at follow-up (Days 39 to 42).
`
`DETAILED DESCRIPTION
`
`The positive effect ofGLP-2 receptor agonists on intestinal
`absorption in SBS patients that retain at least some, e.g,.
`>25%, of their colon is particularly surprising. These patients
`have essentially retained GLP-2 producing tissue and,
`indeed, show elevated basal levels of the endogenous GLP-2
`that can be as high as meal stimulated levels in normal,
`healthy individuals and that, in normal individual, is respon(cid:173)
`sible for maintenance of the intestinal lining required for
`intestinal absorption. There is nevertheless significant clini-
`cal benefit for these patients, manifest principally as
`enhanced intestinal absorption as indicated by increased
`absolute wet weight absorption, when they are treated in
`50 accordance with the present method.
`More particularly, patient candidates for the present treat(cid:173)
`ment are those presenting with SBS resulting from small
`intestine resection which may be secondary to Crohn's dis(cid:173)
`ease, vascular ischemic disease, malrotation or volvulus,
`trauma, congenital anomalies, or multiple strictures due to
`adhesions or radiation and who require parenteral nutrition to
`meet their needs. As patients presenting with short bowel
`syndrome, such patients typically retain, following resection,
`a length of small intestine that is within the range from at least
`about 25 cm and at most about 200 cm., e.g., from about
`50-150 cm. Such SBS patients include those patients present(cid:173)
`ing withjejunostomy, in which part of the jejunum is resected
`and generally all of the ileum, and/or ileostomy in which part
`of the ileum is resected and the jejunum may or may not be
`present. SBS patients withjejunostomy or ileostomy gener(cid:173)
`ally do not have any remaining colon, but if they do, it is not
`in continuity with the renmant small intestine.
`
`4
`
`The estimated prevalence of short bowel syndrome (SBS)
`patients with non-malignant disease
`requiring home
`parenteral nutrition (HPN) is at least 40 per million of the U.S.
`population. SBS usually results from surgical resection of
`some or most of the small intestine for conditions such as
`Crohn's disease, mesenteric infarction, volvulus, trauma,
`congenital anomalies, and multiple strictures due to adhe(cid:173)
`sions or radiation. Surgical resection may also include resec(cid:173)
`tion of all or part of the colon. SBS patients suffer from
`malabsorption that may lead to malnutrition, dehydration and
`weight loss. Some patients can maintain their protein and
`energy balance through hyperphagia; more rarely they can
`sustain fluid and electrolyte requirements to become indepen(cid:173)
`dent from parenteral fluid.
`Although long-term parenteral nutrition (PN) is life saving
`in patients with intestinal failure, it is expensive, impairs
`quality of life and is associated with serious complications
`such as catheter sepsis, venous occlusions and liver failure.
`Treatments that amplify absolute intestinal absorption, and 35
`eliminate or minimize the need for PN have great potential
`significance to SBS patients.
`The endogenous meal-stimulated hormone, glucagon-like
`peptide-2 (GLP-2), raises considerable interest for SBS
`patients. GLP-2 functions to slow gastric emptying, reduce 40
`gastric secretions, increase intestinal blood-flow and stimu(cid:173)
`late growth of the small and large intestine. In animal studies,
`GLP-2 administration induces mucosa! epithelial prolifera(cid:173)
`tion in the stomach and small and large intestine by stimula(cid:173)
`tion of crypt cell proliferation and inhibition of enterocyte 45
`apoptosis.
`SBS patients with end-jejunostomy and no colon have low
`basal GLP-2 levels andlimitedmeal-stimulated GLP-2 secre(cid:173)
`tion due to removal of GLP-2 secreting L-cells, which are
`located primarily in the terminal ileum and colon. This GLP-2
`deficiency results in a minimal adaptive response following
`resection and could explain the gastric hypersecretion, rapid
`intestinal transit and lack of intestinal adaptation observed in
`these SBS patients.
`Jeppesen et al. (Gastroenterology 2001; 120:806-815) 55
`have described positive benefit in an open-label study using
`pharmacologic doses of native GLP-2 in SBS jejunostomy
`patients. There was significant improvement in intestinal wet
`weight absorption and a more modest improvement in energy
`absorption that led to an increase in body weight, lean body 60
`mass and a rise in urinary creatinine excretion.
`In contrast, SBS patients with colon-in-continuity have
`elevated basal endogenous GLP-2 levels resulting in an adap(cid:173)
`tive response to resection characterized by improved wet
`weight gain and energy absorption. The potential for added 65
`benefit of pharmacologic doses ofGLP-2 receptor agonists in
`these patients is not obvious and has not been studied.
`
`
`
`US 7,847,061 B2
`
`20
`
`3
`SBS patients selected for treatment by the present method
`are those who retain, in continuity with renmant small intes(cid:173)
`tine, at least some length of their colon, such as at least about
`25%, and desirably 30%, 35%, 40%, 45% and preferably at
`least 50%, 60%, 70%, 80%, 90% or more. The remaining
`length of colon typically will be determined from the surgical
`records of a patient candidate. Expressed in other terms,
`preferred candidates for the present treatment are short bowel
`syndrome patients who retain colon sufficient to produce
`endogenous GLP-2 at levels that are at least greater than the 10
`negligible levels produced by patients with no colon, and
`ideally are similar to those GLP-2 levels produced by healthy
`volunteers. Endogenous GLP-2 levels for normal, healthy
`individuals are 15±2 pmol/L fasted, and 61±9 pmol/L fed.
`Candidates for the present treatment thus are SBS patients 15
`that retain sufficient functional colon to produce at least about
`10%, 20%, 30%, 40%, 50% or more of such levels in the fed
`state, e.g., at least about 5 pmol/L fed, and desirably 10, 15,
`20, 25, 30, 35, 40, 45, 50, 55, 60, 65 and 70 pmol/L endog(cid:173)
`enous GLP-2 in the fed state.
`In a preferred embodiment, treatment candidates are those
`short bowel syndrome patients who retain at least 50% or
`more of colon length in continuity with renmant small intes(cid:173)
`tine. Such a treatment candidate is identified herein as a
`patient with ~50% colon-in-continuity. In other preferred
`embodiments, the SBS patient with colon in continuity has a
`renmant small intestine at least about 50 cm in length which,
`desirably but not essentially, incorporates at least a portion of
`the ileum.
`The patients can be selected for treatment by the present
`method at any time following the surgical resection. That is,
`patients that are undergoing adaptation, as well as those who
`have had sufficient time to adapt following the surgery, are
`acceptable treatment candidates.
`Treatment of short bowel syndrome patients presenting
`with colon-in-continuity, in accordance with the present
`method, is effective to enhance intestinal absorption, particu(cid:173)
`larly of fluid including water and salts, but including nutrients
`as well. This effect is revealed particularly as a treatment(cid:173)
`mediated, statistically significant increase in absolute wet
`weight absorption, which is determined by subtracting fecal
`wet weight from diet wet weight using a vigorous nutrient
`absorption test. The effect of treatment is also generally seen
`as a reduction in fecal wet weight, an increase in urine wet
`weight, a reduction in energy excretion (measured as herein
`described), and in other respects noted in the examples herein.
`The present treatment method entails dosing the selected
`patient with a GLP-2 receptor agonist using a treatment regi(cid:173)
`men effective to enhance intestinal absorption. Such GLP-2 50
`receptor agonists are characterized as molecules that bind
`with, preferably selectively, and stimulate the human GLP-2
`receptor, as reported by Monroe et al. in U.S. Pat. No. 6,077,
`949 issued Jun. 20, 2000, incorporated herein by reference.
`Briefly, GLP-2 receptor agonists are revealed as agents that
`trigger production of, or trigger an elevation in the level of, a
`second messenger coupled to the human GLP-2 receptor,
`when exposed to a host cell that produces that receptor natu(cid:173)
`rally or is transfected with DNA encoding that receptor.
`In one embodiment of the invention, the GLP-2 receptor
`agonist is human GLP-2. In other embodiments, the GLP-2
`receptor agonist is a vertebrate, e.g., manmialian, homo log of
`human GLP-2. Thus, GLP-2 receptor agonists useful in
`embodiments of the present invention include GLP-2 having
`the sequence found in GLP-2 endogenous to human, cow, pig,
`primate, sheep, rodents including mouse, rat, degu and the
`like, and other vertebrate species.
`
`4
`In other embodiments, the GLP-2 receptor agonist is an
`analog ofhuman GLP-2, which incorporates at least one, and
`usually not more than 5, e.g., 1, 2 or 3, amino acid substitu(cid:173)
`tions or additions, and may also have a C-terminal truncation
`of from 1 to 5 or more amino acids.
`In a preferred embodiment, the GLP-2 receptor agonist is a
`GLP-2 peptide analog that is altered to prolong serum half(cid:173)
`life. In a particularly preferred embodiment, the GLP-2 pep(cid:173)
`tide incorporates an amino acid substitution that renders the
`peptide resistant to the endogenous enzyme dipeptidyl pep(cid:173)
`tidase IV (DPP-IV). Such analogs incorporate an appropriate
`substitution of the Ala2 residue desirably, but not essentially,
`by a genetically encoded amino acid, to permit recombinant
`production of the desired protein. Amino acids that can use(cid:173)
`fully substitute at Ala2 to provide GLP-2 analogs that retain
`GLP-2 receptor agonist activity and are less susceptible to
`DPP-IV include GLy, D-Ala, Val, Glu, Lys, Arg, Leu and Ile.
`Still other GLP-2 analogs include those substituted at MetlO
`by an amino acid that is less sensitive to oxidation.
`In alternative embodiments, the GLP-2 peptide, or GLP-2
`peptide analog is derivatized, for instance at an internal or
`substituted lysine, to prolong serum half-life by conjugation
`with lipophilic groups, with polyethylene glycol groups, with
`albumin or with any other functional group having the desired
`25 effect of reducing the rate at which the peptide is degraded
`endogenously following its administration. Such derivatized
`forms may be derivatized analogs of GLP-2, which carry
`substitutions, such as conserved or non-conserved lysine sub(cid:173)
`stitutions, having no appreciable negative effect on GLP-2
`30 receptor activation but allowing for conjugation of the desired
`functional group. It will be appreciated that these derivatized
`forms of GLP-2 or of GLP-2 analogs are considered to be
`GLP-2 receptor agonists if they exert their endogenous effect
`through the GLP-2 receptor after administration, even if this
`35 GLP-2 receptor agonist property is not displayed while in the
`pro-drug, pre-administration form.
`A wide variety of useful active GLP-2 analogs and deriva(cid:173)
`tives have been described in the literature, as revealed in U.S.
`Pat. No. 5,789,379 issued Jun. 20, 2000 and related W097/
`40 39031 published Oct. 23, 1997 which teach site-specific
`GLP-2 analogs; in W002/066511 published Aug. 27, 2003
`which teaches albumin-derivatized forms of GLP-2 and ana(cid:173)
`logs, and in W099/43361 published Oct. 14, 1999, W004/
`035624 published Apr. 29, 2004 and W004/085471 pub-
`45 lished Oct. 7, 2004 which describe lipophilic-derivatized
`forms ofGLP-2 and analogs.
`In a particularly preferred embodiment of the present
`invention, the GLP-2 receptor agonist is [Gly2]hGLP-2,
`known as teduglutide.
`The dosing regimen effective to treat the SBS patients with
`colon-in-continuity entails delivering the selected GLP-2
`receptor agonist to the patient for a time and at a dose suffi(cid:173)
`cient to enhance intestinal absorption. As noted in the
`examples herein, and according to a preferred embodiment of
`55 the present invention, one suitable treatment regimen entails
`once daily administration of teduglutide, by subcutaneous
`injection in the abdomen, thigh or arm, at a dose in the range
`from 30 to 150 ug/kg/day for a period of about 21 days. It is
`anticipated that effective daily doses ofteduglutide, as well as
`60 human GLP-2 per se and other GLP-2 receptor agonist with
`comparable properties, will lie generally in the broader range
`from about 5 to 500 ug/kg/day e.g., from 10 to 400 ug/kg/day,
`such as 20 to 300 ug/kg/day.
`It will be appreciated from these results that a similarly
`65 beneficial effect can be expected when using either tedug(cid:173)
`lutide, or when using a related GLP-2 receptor agonist, in an
`alternative dosing schedule. With respect to teduglutide per
`
`5
`
`
`
`US 7,847,061 B2
`
`5
`se, administration twice daily or still more frequently can be
`beneficial. Twice daily (every 12 hours) dosing usefully deliv-
`ers about 5 to 250 ug/kg/dose. Benefits can also accrue to
`schedules that entail shorter or, more desirably, longer term
`dosing, such as from about 14 days to many months or even
`years. Maintenance dosing also is desirable, in which patients
`receive either continued or follow up dosing. Follow-up dos(cid:173)
`ing usefully occurs at regular frequencies such as weekly,
`biweekly, every month, every three months, etc. Continued
`dosing usefully provides to the patient a dose efficient to 10
`maintain the benefits of increased absorptive surface area
`with increased intestinal absorption that arise from initial
`treatment, and can be effected by dosing the patient at least
`once within every 1-28 days, e.g., every other day, 2-3 times
`per week, once per week, etc. Continued or follow-up dosing 15
`can be important to preserve the medical benefits mediated by
`the GLP-2 receptor agonist; as noted in the examples,
`improvements in intestinal absorption following treatment
`with teduglutide for instance, can be lost rapidly, for example
`within four weeks following cessation of dosing.
`The teduglutide dosing regimen herein described is useful
`to determine effective dosing schedules for other GLP-2
`receptor agonists for which pharmacokinetics properties are
`either already known or can be determined, by relating phar(cid:173)
`macologic, pharmacokinetic and pharmacodynamic proper- 25
`ties, in accordance with standard practise in drug develop-
`ment.
`It will be appreciated that the route of administration, and
`the particular dosage form of the GLP-2 receptor agonist, will
`be chosen to preserve and desirably optimize the effect of the
`drug. Administration by injection, such as subcutaneous,
`intramuscular, intravenous, etc., is suitable. Alternatively, the
`drug may be administered by infusion or by any other route
`that delivers the drug to the target site on the serosal side of the
`intestinal tissue, such as by depot injection. If delivered by
`injection, the drug can be formulated as a lyophilized powder
`for reconstitution by the user, and as either unit or multiple
`doses. One formulation of teduglutide, for instance, is
`described in WOOl/49314 published Jul. 12, 2001, and pro(cid:173)
`vides a powder for reconstitution in which teduglutide is
`present with L-histidine, mannitol and sodium phosphate.
`This is usefully provided as a 3 mL glass vial containing 10
`mg teduglutide, for reconstitution with 1 mL water for injec(cid:173)
`tion and self-administration. An alternative formulation pro(cid:173)
`vides 10 mg of teduglutide in a smaller volume of aqueous 45
`vehicle, such as 0.5 mL water for injection.
`Most suitably, the chosen treatment parameters, including
`choice of GLP-2 receptor agonist, and dosing schedule, are
`selected to provide optimal enhancement of intestinal absorp(cid:173)
`tion, e.g. to provide for an increase in the volume of fluid and 50
`the nutrients absorbed by the patient, which is revealed for
`instance as a decrease of at least about 5%, 10%, 15%, 20% or
`more in fecal wet weight, and/or an increase of at least about
`5%, 10% or more in urine weight.
`Embodiments of the invention are exemplified below:
`
`Patients
`Study subjects were recruited from centers in the U.S. and
`Denmark that care for patients receiving PN. All patients had
`undergone extensive resection of the small intestine without
`any surgical resection of the stomach, duodenum or pancreas.
`Study inclusion criteria were: Over 18 years of age; diag(cid:173)
`nosis of SBS that could be secondary to Crohn's disease,
`volvulus, injury or vascular ischemia, remnant small intestine
`of 150 cm or less; no clinical evidence of active inflanimatory
`bowel disease (IBD) or fistulas; no history of radiation enteri(cid:173)
`tis, or sprue; no alcohol or drug abuse; no significant renal,
`
`6
`hepatic or cardiac diseases; no glutamine for at least four
`weeks prior to screening; no growth factors or participation in
`any clinical trial within three months of screening (except use
`of teduglutide in patients in the rechallenge group). SBS
`patients with ~50% colon-in-continuity had a demonstrated
`fecal weight exceeding 1 kg/day and fecal energy loss
`exceeding 2 MJ/day [478 Kcal/day].
`Women of childbearing age had to have a negative blood
`~-human chorionic gonadotropin test before inclusion in the
`study and used effective contraceptives during the study.
`Usual medications such as proton pump inhibitors, codeine,
`loperamide, and oral and parenteral supplements were kept
`constant. Local Ethics Committees or Institutional Review
`Boards approved the protocol. Procedures were in accor(cid:173)
`dance with ethical standards of the Helsinki Declaration of
`1964 as modified by the 48'h World Medical Association in
`1996. Each eligible patient signed an informed consent form
`prior to study.
`
`20 Study Protocol
`This was an open-label, pilot study to determine the safety
`and effect of teduglutide in patients with short bowel syn(cid:173)
`drome (SBS). The patient's history was reviewed and a physi(cid:173)
`cal examination performed to determine eligibility before
`inclusion in the study. Estimated residual small intestine and
`colon lengths were determined by reviewing operative
`reports and available radiographic studies. Eligible patients
`were admitted as inpatients to hospital wards or General
`Clinic Research Centers (GCRC) on three separate occa-
`30 sions, 18 days apart, for the last four days and three nights of
`the baseline period and at the end of the treatment and follow(cid:173)
`up periods. Treatment consisted of recombinant teduglutide
`(supplied by NPS Allelix, Mississauga, ON, Canada) formu(cid:173)
`lated as a lyophilized powder with L-histidine, mannitol, and
`35 monobasic and dibasic sodium phosphate (Lot 8502901).
`Water was added to reconstitute the drug for administration
`by subcutaneous ( s.c.) injections in the abdomen or thigh. Ten
`SBS patients withjejunostomy received 0.03 mg/kg/d, 0.10
`mg/kg/d or 0.15 mg/kg/d once daily for 21 days. Five SBS
`40 patients with ~50% colon-in-continuity received teduglutide
`0.10 mg/kg/d once daily for 21 days.
`During each inpatient period, patients underwent 72-hour
`nutrient balance and D-Xylose absorption studies, and a
`proximal or distal endoscopy to ascertain the condition of the
`intestinal mucosa and obtain biopsy samples. Injejunostomy
`patients, biopsies were obtained through the jejunostomy
`stoma or by upper gastrointestinal endoscopy. In patients with
`colon-in-continuity, colo-rectal biopsies were obtained.
`Teduglutide treatment began on Day 1 (immediately after the
`baseline period) and continued once-daily for 21 days. On the
`first and last day of dosing, all patients had blood collections
`for plasma levels and pharmacokinetic parameters and to test
`for any antibodies to teduglutide or E. coli protein. Patients
`were monitored for safety (adverse events, physical exams,
`55 vital signs, ECGs, laboratory results, and injection site exami(cid:173)
`nations) during the inpatient periods and during outpatient
`visits on days 7 and 14.
`The 72-hour nutrient balance studies were completed with
`each patient eating their usual diet, calculated from a seven-
`60 day food diary completed by the patient during the screening
`period. It was intended that patients eat the same quantity and
`quality of food and beverages during each admission. During
`the 72-hour balance periods, all oral intake (duplicate meals
`and beverages and declined food), fecal/stomal output, and
`65 urine were collected and weighed. All stool samples were
`refrigerated during the collection period. Stools and diets
`were separately homogenized and analyzed for energy con-
`
`6
`
`
`
`US 7,847,061 B2
`
`8
`
`Compliance
`Jejunostomy patient 03, who was found to have a segment
`of colon-in-continuity, and patient 20, known to have colon(cid:173)
`in-continuity, did not complete the follow-up period. Drug
`compliance (counting the numberofretumed vials) was com(cid:173)
`plete in all patients participating during the nutrient balance
`periods. During the 21 day treatment period, drug compliance
`was complete, except in one patient with colon-in-continuity,
`who administered the full dose for 15 days, half-doses for two
`days, and no dose for four days.
`
`7
`tent (by bomb calorimetry), nitrogen (by the macro(cid:173)
`Kjeldahl's method), fat (by the gravimetric technique), and
`sodium and potassium (by atomic absorption).
`D-Xylose was used to test intestinal carbohydrate absorp(cid:173)
`tion. After an overnight fast, patients drank a test solution of 5
`25 g D-Xylose in 200-mL distilled water over a 2-3 minute
`period. A blood sample was taken at two hours and urine
`collected for 5-hours following ingestion.
`
`10
`
`Morphological Analysis
`Endoscopic examinations were performed in each subject
`at the completion of baseline, treatment and follow-up
`phases. All tissue samples for measurement of villus height
`and crypt depth were prepared and analyzed in a blinded
`fashion by the same pathologist. Villus height and crypt depth 15
`were measured using light microscopy (eyepiece microme(cid:173)
`ter) as the mean of ten well-oriented villi and crypts. The
`number of mitotic figures per 100 crypt epithelial cells was
`calculated.
`
`Statistics
`Using the SAS (Version 8.2; SAS Institute, Cary, N.C.)
`statistical program, a Student's paired t test was employed
`that compared treatment to baseline values, and follow-up to
`baseline values. No comparisons were made between patients
`on different doses or with different anatomy due to the limited
`number of patients in the study. Data are expressed as
`mean±SD. A value of p<0.05 was considered significant.
`
`Results
`
`Safety Results
`All patients were monitored for safety. There were no
`deaths and no withdrawals due to adverse events (AEs). Two
`patients with evaluable data reported a serious AE of catheter(cid:173)
`related infection or catheter-related complication following
`dosing. None of these were judged to be related to tedug(cid:173)
`lutide. The incidence of AEs was similar between groups. The
`20 most commonAEs were edema of the lower limbs, and local(cid:173)
`ized swelling of the jejunostomy nipple. Other AEs included
`headache and abdominal pain. Three patients had minor
`injection site reactions (single events of bruising, induration,
`rash; four events of erythema). No clinically significant
`25 abnormal laboratory values were identified in relation to tedu(cid:173)
`glutide treatment. No safety concerns were raised from vital
`signs or ECGs. No antibodies to teduglutide were detected.
`One patient had a relative E. coli protein antibody titer of
`1: 1624, and six patients had relative titers between 1: 107 and
`30 1 :228, after treatment.
`Endogenous GLP-2 Levels
`For patients with ~50% colon-in-continuity, fasting con(cid:173)
`centrations of endogenous GLP-2 were measured prior to
`administration of teduglutide. For four of the five subjects,
`their concentrations were between the mean levels for fasted
`and fed healthy volunteers (fasted (15±2 pmol/L) and fed
`(61±9 pmol/L)), measured as described by Hartmami et al.
`(Peptides 21 2000; 73-80, incorporated herein by reference).
`The levels for the five subjects were 16, 27, 37, 41, and 73
`pmol/L.
`
`Patients
`Sixteen SBS patients (nine females, seven males) enrolled
`in this open-label, multicenter, dose-ranging pilot study and
`received teduglutide. Four U.S. sites recruited 6 patients and
`one Danish site recruited 10 patients. The baseline character- 35
`istics of these 16 patients treated are given in Table 1. These
`patients were subdivided into an end-jejunostomy group of 10
`(Group 2) and ~50% colon-in-continuity group of 5 (Group
`3 ). There were originally 11 jejunostomy patients, but patient
`03 was found on biopsy to have a renmant segment of colon, 40
`later estimated to be 30%. This individual was not included in
`any subgroup analysis. As judged from analysis of duplicate
`meals adjusted for declined food, some patients had better
`dietary consistency than others. Patients who had an oral food
`intake where the dietary wet weight and energy content at 45
`treatment did not differ more than 10% from baseline values
`were termed "high dietary compliance". Ten patients had a
`high dietary compliance ( <l 0% variability from baseline
`value), 5 with end-jejunostomy and 5 with ~50% colon-in(cid:173)
`continuity (Group 4).
`The demographics of the two groups ofSBS patients, those
`with end-jejunostomy and those with colon-in-continuity,
`were similar with ages ranging from 27-74 years, weights
`ranging from 38.9-79 .2 kg, heights ranging from 158-180 cm,
`BMI ranging from 15.0-26.9 kg/m2
`, years since last intestinal
`resection ranging from 2.4-20 years (except one patient 0.9
`years post-resection, whose results were similar to others who
`received0.15 mg/kg/day), andren