CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203441Orig1s000
`
`OFFICE DIRECTOR MEMO
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`MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES
` PUBLIC HEALTH SERVICE
` FOOD AND DRUG ADMINISTRATION
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`DATE: December 21, 2012
`TO: NDA 203441
` Gattex (teduglutide [rDNA] powder for subcutaneous injection)
` NPS Pharmaceuticals
`
`FROM: Victoria Kusiak, M.D.
` Deputy Director, Office of Drug Evaluation III
`
`Subject: Approval Action
`
`SUMMARY:
`
`Gattex is a 33 amino acid recombinant analog of the human glucagon-like peptide-2
`(GLP2), a peptide that is secreted primarily from the lower gastrointestinal tract and
`increases intestinal absorptive capacity. Gattex is indicated for the treatment of adult
`patients with Short Bowel Syndrome (SBS) who are dependant on parenteral support
`(parenteral nutrition/ intravenous hydration [PN/IV]). Gattex received Orphan
`Designation (OD) for this proposed indication on June 29, 2000.
`
`Gattex differs from GLP-2 in the substitution of glycine for alanine at the second position
`of the N terminus. The glycine substitution results in resistance to degradation, extending
`the pharmacological activity of Gattex. Gattex binds to the GLP-2 receptors located in
`subpopulations of enteroendocrine cells, subepithelial myofibroblasts, and enteric
`neurons of the submucosal and myenteric plexus with receptor activation releasing
`intermediary growth factors locally, which act on epithelial cells. It has been shown to
`preserve mucosal integrity by promoting repair and normal growth of the intestine.
`Gattex increases villus height and crypt depth of the intestinal epithelium resulting in
`enhanced absorptive capacity of the intestine as demonstrated by greater absorption of
`fluids, electrolytes, and nutrients, reduced fecal fluid loss, and diminished diarrhea. In
`addition, Gattex has been shown to accelerate intestinal adaptation, increase nutrient
`transporter activity, enhance barrier function of the small intestine, and decrease
`intestinal inflammation. These effects form the rationale for use in patients with SBS.
`
`SBS is caused by a reduction in intestinal surface area, leading to inadequate absorptive
`capacity and typically follows major surgical resection of the small intestine with or
`without complete or partial resection of the colon. SBS also occurs (rarely) secondary to
`congenital intestinal abnormality or underlying intestinal disease. Reduction in small
`intestine surface area leads directly to reduction of absorption of macro-nutrients, water
`and electrolytes, resulting in malnutrition, diarrhea, dehydration, and weight loss. The
`amount of nutritional and fluid impairment is dependant upon multiple factors including
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`the amount of residual intestine and colon, the presence or absence of an ileal segment,
`and the degree of spontaneous intestinal adaptation. For many patients SBS is a lifelong
`disease associated with significant increases in morbidity and mortality. PN/IV therapy
`itself is associated with increases in morbidity and mortality. Catheter related infections,
`central venous thrombosis and /or embolism and liver disease with eventual liver failure
`are known complications in SBS patients being treated with PN/IV. In the United States
`there are approximately 10,000 to 15,000 adult SBS patients requiring chronic PN/IV
`therapy which is typically given for 10 or more hours per day for 5-7 days a week.
`
`The recommended dose of Gattex is 0.05mg/kg administered once daily by subcutaneous
`injection, alternating sites of injection between the four quadrants of the abdomen, or
`alternating thighs, or alternating arms.
`
`This memorandum documents my concurrence with the Division of Gastroenterology
`and Inborn Errors of Metabolism Product’s (DGIEP’S) approval recommendation for
`Gattex 0.05 mg/kg administered subcutaneously once daily for the treatment of adult
`patients with SBS who are dependant on parenteral support.
`
`REGULATORY HISTORY
`
`The following espouses the regulatory activity associated with the Gattex application:
`
`20 October, 1998: Pre-IND meeting.
`
`26 April, 1999: IND 58,213 submission for teduglutide in SBS.
`
`29 June, 2000: US Orphan Drug designation granted.
`
`06 October, 2003: End of Phase 2 meeting to discuss clinical (Study 004) and
`nonclinical topics. Key items discussed were:
`o Dosing: 0.05 and 0.10 mg/kg/day.
`o Standard outpatient care with regard to PN and concomitant medications.
`o Potential extrapolation of trial results to the excluded population of SBS patients
`with unstable PN regimens (allowed).
`o Proposed PN optimization/stabilization procedures, performance of colonoscopy
`in patients with a colon, mucosal biopsies of small intestine.
`o Primary efficacy endpoint as percent responders (reduction of at least 20% from
`baseline in weekly PN/IV volume at Week-24).
`o Strong recommendation to conduct two replicate trials given the NME status of
`Gattex.
`
`
`06 June 2006: Type C Meeting to discuss special populations and pharmacokinetic (PK)
`studies. Key items discussed were:
`o PK advice for conduct of studies in special populations of hepatic and renal
`impairment. (The applicant later submitted hepatic impairment and multi-dose
`PK studies on 30-Jun-2010; and a renal impairment study on 13-Sep-2011).
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`o
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` No requirement for formal drug-drug interaction studies, unless evidence arises
`for specific interactions
`
`
`23 January 2007: Type C Meeting to discuss the primary efficacy analysis. Key items
`discussed were:
`o Applicant’s amended primary efficacy analysis for Study 004, which had
`randomized 84 patients with 55 having completed 24 weeks of therapy. The
`amendment of the primary endpoint analysis was not based upon an interim
`analysis.
`o FDA recommendation to perform a second clinical trial using the new primary
`endpoint.
`
`
`18 January 2008: Type C Meeting to discuss the results of Study 004. Key items
`discussed were:
`o Need for and design of a confirmatory Phase 3 study (CL0600-020) of at least 24
`weeks to collect safety and efficacy data.
`o Lack of a clear dose-response relationship for efficacy in Study 004.
`o Monitoring of Immunogenicity
`o Need for a thorough QT study (Study 001).
`
`
`14-July-2008 Meeting: Type C Meeting to discuss the results of Study 004 and the
`planned Phase 3 Study (CL0600-020) with regard to the acceptability of the same
`primary endpoint of reduction in volume of PN/I.V. used in study 004 as acceptable in
`Study CL0600-020. Key items discussed were:
`o Lack of demonstration of dose response in Study 004
`o Lack of dose justification for study CL0600-020. FDA indicates that NPS is free
`to select the dose used for the trial.
`o FDA will accept a 0.05 mg/kg/day to support an NDA
`o FDA confirms that one additional study is needed and that a 2 arm design (0.05
`mg/kg/day vs. placebo) would be acceptable to support an NDA.
`o FDA encourages collection of neutralizing antibody data.
`
`
`25 April 2011: Type B Pre-submission Meeting to discuss clinical data, nonclinical
`data, and submission logistics. Key items discussed were:
`o FDA recommendation to delay submission until approximately 64 patients with at
`least 12 months of exposure are enrolled in the initial safety and efficacy
`databases.
`o Applicant to characterize the impact of immunogenicity on PK, efficacy, safety.
`o Inclusion of clinically meaningful measures of nutritional status. Analyses of
`these measures could be supportive of the primary endpoint and should be
`included in the NDA.
`o A pediatric waiver is not required based on Orphan Designation.
`
`
`30 November 2012: NDA submitted to the FDA.
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` and lyophilized. There are no
`
`10 August 2012: NDA amendment submission extends review date to 30 December
`2012.
`
`30 August 2012: European Commission adopted the CHMP decision granting marketing
`authorization for “Revestive-teduglutide”, an orphan medicinal product for human use.
`
`CHEMISTRY MANUFACTURING and CONTROLS
`
`This NDA has provided sufficient information to assure identity, strength, purity, and
`quality of the drug product for the requested dosage form.
`
`The Applicant was requested to add a test method and acceptance criteria for
` to the drug substance specification and is currently developing a suitable
`procedure. The Applicant will implement this addition to the drug substance specification
`as a Post Approval Commitment (PMC).
`
`
`CLINICAL MICROBIOLOGY
`
`The drug product is sterile
`Clinical Microbiology issues.
`
`NONCLINICAL PHARMACOLOGY/TOXICOLOGY
`
`The applicant has conducted adequate nonclinical studies with Gattex which included
`pharmacology, safety pharmacology, pharmacokinetic, and acute and chronic toxicology
`studies. In mice, acute toxicology studies were conducted as well as repeated dose
`toxicology studies (14 days to 26 week duration); in rats, repeated dose toxicology
`studies were conducted (14 days to 26 weeks duration); in cynomolgus monkeys,
`repeated dose toxicology studies were conducted (14 weeks to 1 year duration); and in
`juvenile mini-pigs, repeated dose toxicology studies were conducted (14 days to 90 days
`duration).
`
`Genotoxicity studies (Ames, chromosome aberration test in Chinese hamster ovary cells,
`in vivo micronucleus test in mice), reproductive toxicology studies (fertility and early
`embryo-fetal development in rats, embryo-fetal development in rats and rabbits and pre
`and postnatal development in rats), and special toxicology studies (antigenicity and local
`tolerance studies) were conducted. All toxicology studies were conducted using the
`subcutaneous (SC) route of administration which is the intended clinical method of use.
`
`Doses administered subcutaneously to mice and rats were up to 1000 times the
`recommended daily human dose (50/mg/kg/day), while cynomolgus monkeys received
`approximately 500 times the recommended human daily dose (25/mg/kg/day).
`
`Pharmacology studies examined the intestinotrophic activity of teduglutide in several
`animal species. In mice, teduglutide increased weight and length of the small intestine
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`(b) (4)
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`and enhanced epithelial barrier function. Teduglutide also increased the absorptive
`function of the intestinal mucosa in rats and monkeys. In a rat model of SBS, teduglutide
`increased the rate or magnitude of the intestinal adaptive response to intestinal resection
`at a dose of 0.2 mg/kg/day. In neonatal piglets with jejuno-ileal resection, teduglutide
`showed significant improvements in crypt-villus architecture in the small intestine, as
`well as in duodenal, jejunal and ileal glucose transport and jejunal glutamine transport.
`
`In pivotal toxicology studies, major treatment-related effects (hypertrophy/hyperplasia)
`were related to the pharmacological activity of teduglutide. In the 26-week toxicity study
`in mice at 2, 10 and 50 mg/kg/day, major treatment-related histopathological changes
`were seen in the small and large intestines (epithelial and villus hypertrophy and
`hyperplasia), gall bladder (epithelial hypertrophy and hyperplasia accompanied by
`subacute inflammation), and sternal bone marrow (myeloid hyperplasia). In the 1-year
`toxicity study in cynomolgus monkeys at 1, 5 and 25 mg/kg/day, major treatment-related
`histopathological changes were seen in the small and large intestines (mucosal
`hyperplasia), stomach (mucosal hyperplasia), pancreas (hypertrophy/hyperplasia of the
`pancreatic duct epithelium), liver and gall bladder (epithelial hypertrophy and hyperplasia
`of the bile duct in the liver and mucosal hypertrophy/hyperplasia of the gall bladder). In
`juvenile minipigs, similar treatment-related histopathological changes were observed in
`the small intestine (minimal/slight villous hypertrophy), gall bladder (cystic mucosal
`hyperplasia), and extrahepatic bile duct (cystic mucosal hyperplasia).
`
`In the subcutaneous fertility and early embryonic study in rats, teduglutide did not show
`any adverse effects on early embryonic development or fertility parameters at doses up to
`1000 times the recommended daily human dose. In the subcutaneous embryofetal
`development in rats and rabbits, teduglutide was not teratogenic at doses up to 1000 times
`the recommended daily human dose. Likewise in the subcutaneous pre and postnatal
`development study in rats, teduglutide did not show significant adverse effects on pre or
`postnatal development at doses up to 1000 times the recommended daily human dose.
`
`Teduglutide was not genotoxic in the Ames test, in vitro chromosomal aberration test in
`Chinese hamster ovary (CHO) cells, and in vivo mouse micronucleus test. In a 2-year
`carcinogenicity study by the subcutaneous route in rats at 3, 10 and 35 mg/kg/day (about
`60, 200 and 700 times the recommended daily human dose of 0.05 mg/kg, respectively),
`teduglutide caused statistically significant increases in the incidences of adenomas in the
`bile duct (0/50, 0/50, 1/50 and 4/50 at 0, 3, 10 and 35 mg/kg/day, respectively; p=0.0037,
`trend test) and jejunum (0/50, 1/50, 0/50 and 5/50 at 0, 3, 10 and 35 mg/kg/day,
`respectively; p=0.0031, trend test) of male rats. There were no drug related tumor
`findings in females.
`
`Gattex will be labeled as a pregnancy category B, as there are no adequate and well
`controlled studies in pregnant women.
`
`
`Due to its growth promoting pharmacological effects, teduglutide has a potential to cause
`hyperplastic changes, including tumor formation, and this potential will be included in
`the product labeling.
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`CLINICAL PHARMACOLOGY
`
`The pharmacokinetics of Gattex were evaluated in both healthy subjects and subjects
`with SBS. Subjects with SBS had a lower drug exposure than healthy subjects.
`
`Absorption: With the to-be-marketed formulation, Gattex reached peak plasma
`concentration 3-5 hours after SC administration in the abdomen, thigh or arm. A formal
`relative bioavailability study evaluating the relative bioavailability of Gattex after
`administration in these 3 sites indicated that exposure was similar. The maximal plasma
`concentration and exposure (Cmax and AUC) of Gattex was dose proportional over the
`dose range of 0.05-0.4 mg/kg. The Cmax in subjects with SBS following SC
`administration was 36.8 ng/mL at the 0.05 mg/kg/day SC dose and the AUC was
`0.15µg·hr /ml. No accumulation of Gattex was observed following repeated daily SC
`administration.
`
`Distribution: Following intravenous administration in healthy subjects, Gattex had a
`mean volume of distribution at steady state of approximately 103 (±23) mL/kg, similar to
`blood volume.
`
`Metabolism: The metabolic pathway of Gattex was not investigated in humans;
`however, as an analog to native GLP-2, Gattex is expected to be degraded into small
`peptides and amino acids via catabolic pathways in the same manner as the endogenous
`GLP-2. It is not likely to be metabolized by common drug metabolizing enzymes such as
`CYP, glutathione-S-transferase, or uridine-diphosphate glucuronyltransferase.
`
`Elimination: Following IV administration in healthy subjects Gattex plasma clearance
`was 127 mL/kg/hr which is roughly equivalent to the GFR, suggesting that Gattex is
`primarily cleared by the kidney. Gattex was rapidly cleared with a mean terminal half life
`(t½) of approximately 2 hours in healthy subjects and 1.3 hours in subjects with SBS.
`
`Special Populations:
`
`Age and Gender: Plasma concentration time profiles and pharmacokinetics of Gattex
`were similar in healthy elderly subjects and younger subjects, and in men and women.
`
`Renal Impairment: Following a single 10 mg SC dose in subjects with moderate to
`severe renal impairment, Cmax and AUC increased with increasing degree of renal
`impairment. The primary pharmacokimetic parameters of Gattex increased up to a factor
`of 2.6 (AUC) and 2.1 (Cmax) in subjects with end stage renal disease (ESRD) compared to
`healthy subjects. In subjects with moderate to severe renal impairment and ESRD, dosage
`reduction by 50% is recommended, because of decreased renal clearance.
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`Hepatic Impairment: In subjects with moderate hepatic impairment, the Cmaxx and
`AUC of Gattex were only slightly lower (~10% to15%) after a single 10 mg SC dose
`compared to healthy matched control subjects, therefore no dosage adjustment is
`necessary in subjects with moderate hepatic impairment. The pharmacokinetics of Gattex
`was not assessed in subjects with severe hepatic impairment.
`
`Drug-Drug Interaction(s) (DDI):
`
`No in vivo DDI studies were conducted based on results from in vitro studies in which
`significant inhibition or induction of cytochrome P450 isozymes was not observed at
`doses of Gattex up to 2000 ng/mL, a concentration significantly greater (55-fold) than
`that of the Cmax observed at the clinical dose of 0.05 mg/kg. As Gattex is not a pro-
`inflammatory cytokine or cytokine modulator, DDI studies are not required even though
`the relevance of in vitro studies to the in vivo setting is unclear. Additionally, Gattex was
`neither a substrate nor an inhibitor of P-gp at concentrations above 2000 ng/mL.
`
`It is important to note that the potential for pharmacodynamic (PD) mediated drug-drug
`interactions exists because Gattex has demonstrated the PD effect of increasing intestinal
`absorption. This effect should be considered when Gattex is co-administered with drugs
`requiring titration or having a narrow therapeutic index. This information will be included
`in the product labeling.
`
`Thorough QT Study:
`
`No significant QTc prolongation was detected with SC administration of 5 mg of Gattex
`or at a supra-therapeutic dose of 20 mg in the Thorough QT (TQT) study. This study was
`a randomized, partially blinded, single dose, four-way cross over, active and placebo
`controlled study. 70 healthy subjects received Gattex 5 mg SC, Gattex 20 mg SC, placebo
`and moxifloxacin 400 mg. The 20 mg SC supratherapeutic dose produced mean Cmax
`concentrations 3.8 fold above the Cmax for the 5 mg SC dose. At these concentrations
`there was no detectable prolongation of the QT interval. Of note, the Cmax at the 20 mg
`SC dose produced concentrations above those expected in subjects with ESRD.
`
`
`Immunogenicity:
`
`Overall, the immunogenicity incidence (anti-drug antibody) rate increased with the
`duration of treatment (18% at 6 months, 27% at 12 months and 38% at 18 months) and
`the majority of subjects had the first occurrence of anti-drug antibody (ADA+) finding at
`6 months after treatment initiation. Among 34 subjects who were treated with Gattex in
`both the pivotal study and the extension study, 6 subjects tested ADA+ at baseline (of
`which 5 continued to be ADA+ in the extension study) and 8 additional subjects became
`ADA+ post-baseline. The incidence rate was 38% (13/34) for subjects who received
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`Gattex treatment for the duration of 18 months. Among 51 subjects who initiated Gattex
`treatment in the extension study, 14 subjects were ADA+ (14/51, 27%) during the
`extension study after 12 months of Gattex treatment.
`
`Anti-teduglutide specific antibodies showed evidence of cross reactivity against the
`native GLP-2 protein in 5 out of 6 ADA+ subjects at 6 months post treatment in the
`pivotal study. It has not been established if these antibodies are neutralizing. The average
`weekly response for these six subjects trended toward improvement during the 6 months
`of the trial and appeared to stabilize in the extension study. This response was similar to
`the mean response in the subjects who did not have an ADA positive status at week 24.
`
`The impact of ADA on PK is unknown and has not been adequately assessed. All ADA+
`subjects were responders during the controlled treatment period up to 1.5 years and 26 of
`the 27 subjects who developed antibodies post baseline had reduced PN/IV volume at the
`time of last dosing; however, the long term impact of the presence of ADA is unknown.
`This information will be included in the product labeling.
`
`EFFICACY:
`
`Efficacy of Gattex in SBS was assessed in two randomized, double blind, placebo-
`controlled, parallel group, multinational, multicenter trials (Study 004 and Study 020).
`Each of these trials had a non-randomized open-label extension study (Study 005 and
`Study 021, respectively). Study 020 demonstrated a statistically significant (p=0.002)
`difference between Gattex and placebo for the primary endpoint which is percent
`responders in each study group who achieved at least a 20% reduction in weekly PN/IV
`volume at weeks 20 and 24: (63% [27/43] versus 30% [13/43] Gattex and placebo
`respectively). Study 004 did not meet the protocol specified primary endpoint (the
`difference between Gattex 0.10 mg/kg/day and placebo in percent responders who
`achieved at least a 20% reduction in weekly PN.IV volume at weeks 20 and 24 as a
`graded response analysis) but did demonstrate benefit for the key secondary endpoint of
`difference between Gattex 0.05 mg/kg/day and placebo in percent responders (46%
`Gattex, 6% placebo). The pre-specified graded categorical response analysis did not
`allow for statistical testing beyond the primary endpoint which involved the 0.10
`mg/kg/day dose, but nevertheless, the 0.05 mg/kg/day dose demonstrated a clear benefit
`compared to placebo and provides robust support for study 020.
`
`Study 004 enrolled 83 subjects with SBS who required PN/IV at least 3 times weekly and
`randomized them to Gattex 0.10 mg/kg/day (N=32), Gattex 0.05 mg/kg/day (N=35) or
`placebo (N=16) for up to 24 weeks. Subjects’ PN/IV status was optimized during a
`maximal 8 week baseline period. At weeks 4, 8, 12, 16, and 20, investigators adjusted
`each subject’s PN/IV volume based upon percent change in urine output. For increases in
`urine output < 2 liters a day, PN/IV could be decreased by no more than 10% while for
`urine outputs > 2 liters a day PN/IV could be decreased based upon the investigator’s
`clinical judgment. The proportion of subjects achieving at least a 20% reduction of PN/IV
`volume both at week 20 and week 24 (responders) was statistically significantly different
`from placebo (46% vs. 6.3%, p < 0.01) for those subjects receiving the recommended
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`Gattex dose of 0.05 mg/kg/day. The difference in responders compared to placebo for the
`Gattex 0.10 mg/kg/day group was not statistically significant. Two subjects on the Gattex
`0.05 mg/kg/day dose were able to be totally weaned from parenteral support by week 24.
`Treatment with Gattex resulted in a 2.5 L/week reduction in parenteral support
`requirements versus 0.9 L/week reduction for placebo at 24 weeks. As per protocol, after
`6 months of treatment, 77 subjects underwent small and large intestine biopsy resulting in
`390 individual pathology specimens. No features of dysplasia were seen in any biopsy.
`Gattex treatment resulted in expansion of the absorptive epithelium by significantly
`increasing villus height in the small intestine.
`
`Sixty–five subjects from study 004 entered a long term Trial (005) for up to an additional
`28 weeks of treatment. Subjects on Gattex retained their original dose assignment (Gattex
`0.10 or 0.05 mg/kg/day), while patients originally assigned to placebo were randomized
`to active treatment (Gattex 0.10 or 0.05 mg/kg/day). Of the responders in the original trial
`who entered the extension phase, 75% sustained response on Gattex after up to 1 year of
`continuous treatment. In the recommended dose group (0.05 mg/kg/day) 68% of subjects
`achieved at least a 20% reduction in parenteral support after an additional 28 weeks of
`treatment (17/25 subjects). The mean reduction of weekly parenteral support volume was
`4.9 L/week (a 52% reduction from baseline) after 1 year of continuous treatment. One
`additional subject in the extension phase of the study was weaned from parenteral
`support, with a total of 3 subjects on the 0.05 mg/kg/day dose able to discontinue
`parenteral support.
`
`Study 020 sequentially followed Study 004. Results from Study 004 were used to inform
`the design of 020. In Study 020, only the 0.05 mg/kg/day dose was evaluated. Study 020,
`added an earlier time point for fluid adjustment at week 2 (performing adjustments at
`weeks 2, 4, 8, 16 and 20), allowed up to a 30% reduction in fluid at each adjustment time
`point, and used the difference in percent responders between groups (responders defined
`as those who had a reduction of 20% to 100% in PN/IV volume at weeks 20 and 24
`compared to baseline) as the primary endpoint.
`
`Study 020 was a two stage trial, with the first stage requiring optimization of the subject’s
`PN/IV for a maximum of 8 weeks followed by an 8 week PN/PV stabilization period
`where PN/IV remained the same. During optimization, PN/IV could be adjusted up to a
`30% decrease based upon urine output and oral intake. Following stabilization, 86
`subjects were randomized to Gattex 0.05/mg/kg/day SC (n=43, of which 42 received
`Gattex) or placebo (N=42) daily for 24 weeks of treatment. The primary efficacy
`endpoint was the difference between groups in the number of responders defined on a per
`subject basis as achievement of a 20%-100% reduction from baseline in weekly PN/IV
`volume.
`
`The mean age of the patients enrolled was 50.3 years. The average length of time of
`PN/IV dependency was 6.25 years (range 1-25.8 years). The most common reasons for
`intestinal resection were: vascular disease, 34%; Crohn’s disease, 21%; and other 21%. A
`stoma was present in 45% with the most common type being a jejunostomy/ileostomy
`(82%). The mean length of the remaining small intestine was 77.3 ± 64.4 cm (range 5-
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`343 cm). The colon was not in continuity in 44% of subjects. The baseline mean number
`of prescribed PN/IV perfusion days was 5.73 with a standard deviation of ± 1.59 days.
`
`The results of the trial showed that 63% (27/43) of Gattex treated subjects responded to
`treatment as opposed to 30% (13/43) of placebo treated subjects (p = 0.002). At week 24,
`the mean reduction in PN/IV volume was 4.4 L/week from a baseline of 12.9 L/week for
`Gattex treated subjects versus a mean reduction of 2.3 L/week from a baseline of 13.2
`L/week for placebo treated subjects (p < 0.001). Twenty-one subjects on Gattex (53.8%
`as compared to 9 (23.1%) on placebo achieved at least a one day reduction in PNIV
`administration (p=0.005).
`
`Subjects that were enrolled in Study 020 could elect to continue treatment in the ongoing
`open label extension, Study 021. 97% of subjects (76/78) continued into the extension
`where all subjects receive 0.05 mg/kg/day SC for up to an additional 2 years. By trial
`design, subjects continue to take Gattex even if they no longer require PN/IV support.
`The trial is ongoing. An interim assessment of this trial (021) was performed on patients
`who had completed one year of therapy on Gattex: 6 months in Study 020 and 6 months
`in Study 021 (N=34). 91.2% of these patients (31/34) showed continued response in
`reduction of PN/IV volume. 3 Subjects were completely weaned from PN/IV therapy at
`the time of the interim report. 52.9% (18/34) subjects have achieved at least a 1 day per
`week reduction; 13 (38.2%) at least a 2 day reduction and 8 (23.5%) at least a 3 day
`reduction in PN/IV requirement.
`
`
`SAFETY
`
`Overall, 566 (safety population) subjects were exposed to Gattex and 198 to placebo
`across 15 clinical trials as follows:
`
`
`• 299 subjects in the clinical pharmacology studies
` 89 (16% of 566) for less than 6 months
`135 (24% of 566) for at least 6 months but no more than 12 months
` 75 (13% of 566) for at least 12 months
`• 173 subjects in the SBS Efficacy and Safety trials
`•
` 94 subjects in other studies (Crohn’s Disease)
`
`
`The incidence of adverse events in subjects with SBS was evaluated in two randomized,
`double blind, placebo controlled trials (Study 004 and Study 020), in which a total of 77
`subjects received Gattex 0.05 mg/kg/day SC and 59 subjects received placebo. Overall
`68/77 (88.3%) of subjects receiving Gattex had an adverse event as compared to 49/59
`(83.1%) taking placebo. In general the events were mild or moderate. The overall high
`rate of adverse events in this population (both Gattex and placebo treated) reflects both
`the underlying disease and the necessity for parenteral support and its associated
`complications.
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`Adverse reactions reported in ≥ 5% of Gattex treated subjects (0.05 mg/kg/day SC) and
`at a rate greater than placebo were as follows: Abdominal pain: 37.7% Gattex, 27.1%
`placebo; Upper Respiratory Tract Infection: 26.0% Gattex, 13.6% placebo; Nausea:
`24.7% Gattex, 20.3% placebo; Abdominal Distention: 19.5% Gattex, 1.7% placebo;
`Vomiting: 11.7% Gattex, 10.2% placebo; Fluid Overload: 11.7% Gattex, 10.2% placebo;
`Flatulence: 9.1% Gattex, 6.8% placebo; Hypersensitivity: 7.8% Gattex, 5.1% placebo;
`Appetite Disorders: 6.5% Gattex, 3.4% placebo; Sleep Disturbance 5.2% Gattex, 0%
`placebo; Coughing: 5.2% Gattex, 0% placebo; Skin Hemorrhage: 5.2% Gattex, 1.7%
`placebo; Stoma Complication: 13/31 (41.9%) Gattex, 3/22 (13.6%) placebo. (53 subjects
`total had a stoma in controlled trials; 22 in the placebo group, 0 in the Gattex 0.10
`mg/kg/day, and 31 in the Gattex 0.05 mg/kg/day group. The stomas were of differing
`surgical types, they supported different types of anatomical anastamoses and they had
`variable histories with regard to obstruction prior to study initiation. The subject numbers
`are too small to draw a conclusion with regard to association of treatment with Gattex
`and stomal obstruction).
`
`Injection site reactions were observed at a similar incidence in Gattex and placebo treated
`subjects.
`
`
`The most commonly reported (≥ 5%) adverse reactions across all studies including long
`term open label safety studies (N=566 Gattex treated subjects) were: abdominal pain
`(30.0%); injection site reaction (22.4%); nausea (18.2%); headache (15.9%); abdominal
`distention (13.8%); upper respiratory tract infection (11.8%); asthenic conditions (9.5%);
`vomiting (8.8%); musculoskeletal pain (8.5%); catheter sepsis (7.8%); cognition and
`attention disorders and disturbances (7.8%); constipation (7.4%); fluid overload (6.9%);
`diarrhea (6.9%); stoma complication (6.5%); hypersensitivity (6.4%); flatulence (6.2%);
`urinary tract infection (6.2%); febrile disorder (6.0%); and increased hepatic enzymes
`(5.5%).
`
`In the pooled Gattex treated group in the SBS placebo-controlled study data (N=109
`Gattex, 0.05 or 0.10 mg/kg/day SC; N=59 placebo) 12% of subjects discontinued. The
`most common reason for discontinuation was adverse events (8%) of which the most
`common were constipation and abdominal distension, for which there were no
`discontinuations in the placebo group. In the pooled placebo group (N=59), the most
`common reason for discontinuation was adverse event (7%) which included catheter
`sepsis, increased stool (frequency, volume), intestinal polyp, and transplantation, none of
`which except for catheter sepsis occurred in the Gattex group.
`
`In the long term extension trial (Study 005), 7 of 8 discontinuations for adverse events
`were in patients previously treated with Gattex in Study 004. The reasons for
`discontinuation in these 7 patients included abdominal pain, hyperplastic colon polyp,
`irritable bowel disease, vomiting, nausea, cough, and cerebrovascular accident (CVA).
`The case of CVA occurred in a 64 year old white female (005-0145-0005) with history of
`stroke, who had been on Gattex for 59 days.
`
`
`
`Reference ID: 3235648
`
`11
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`

`
`There were 3 deaths reported during the drug development program: two subjects were
`receiving Gattex 0.05 mg/kg/day SC during extension studies and one subject died during
`the screening period. One patient on Gattex died of metastatic adenocarcinoma, origin
`presumed to be gastrointestinal (GI), and one died of small cell lung cancer. The patient
`who died in screening suffered a massive upper GI bleed.
`
`
`Potential Safety Concerns with Gattex:
`
`The safety