CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203441Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`Date
`11/8/2012
`
`Ru i He, MD
`From
`m_ Cross-Disci line Team Leader Review
`NDA/BLA #
`NDA 203441
`
`Su u vlement#
`
`
`
`Proprietary Name /
`Established
`S ‘
`
`names
`
`Proposed Indication(s)
`
`Proposed Dosage forms /
`Strength
`
`Recommended:
`
`Glucaon-like ooetide-2 GLP-2 analo
`
`Teduglutide (rDNA 0rigin)/ GATTEX®
`
`The treatment of adult patients with Short Bowel
`Syndrome (SBS). GATTEX is used to improve intestinal
`abso tion of fluid and nutrients.
`
`GATTEX should be administered by subcutaneous (SC)
`injection once daily, alternating sites between 1 of the 4
`quadrants of the abdomen, or into alternating thighs or
`alternating arms. GATTEX should not be administered
`intravenously 0r intramuscularly. The recommended daily
`dose of GATTEXis 0.05 m-
`I recommend that NDA 203441 for Teduglutide (rDNA
`origin)/ GATTEX® be approved for the treatment of adult
`patients with Short Bowel Syndrome (SBS) who are
`dependent on parenteral nutrients/fluids to improve
`intestinal abso tion of fluid and nutrients.
`
`1. Introduction
`
`GATTEX (teduglutide [rDNA origin]) (also known as ALX-0600; or [gly2]-hGLP-2) is being
`developed for the treatment of adult patients with Short Bowel Syndrome (SBS). It is a 33—
`amino acid recombinant analog of human Glucagon-like peptide-2 (GLP-2), a peptide secreted
`primarily from the lower gastrointestinal tract.
`
`The product is administered by subcutaneous (SC) injection. Teduglutide appears to preserve
`mucosal integrity by promoting repair and normal growth of the intestine through an increase of
`villus height and crypt depth. Teduglutide may accelerate intestinal adaptation afler bowel
`resection and enhances selective barrier fimction in the small intestine according to the sponsor.
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`Teduglutide use in humans is expected to produce an increase in intestinal absorption through
`increases in surface area (histological effects in crypts and villi). With increased absorption of
`fluids, nutrients and electrolytes it is expected that subjects will maintain their nutritional status
`while reducing parenteral nutrition/intravenous fluids (PN/I.V.) dependence.
`
`
`2. Background
`
`
`Short bowel syndrome results from surgical resection or congenital defect and is characterized
`by the inability to maintain protein/energy, fluid, electrolyte, and/or micronutrient balance(s)
`when on a conventionally accepted, normal diet. Patients with SBS are highly prone to
`malnutrition, diarrhea, dehydration, and an inability to maintain weight due to the reduced
`intestinal capacity to absorb macronutrients, water, and electrolytes.
`
`Major small intestinal resection resulting in SBS often requires long-term PN/I.V. support due to
`severe malabsorption of nutrients and fluids. Although PN/I.V. support is life-saving in patients
`with intestinal failure, it is often associated with life-threatening complications. Therefore,
`therapies to treat SBS and reduce PN/I.V. dependence offer the potential to improve long-term
`survival and decrease complications secondary to ongoing use of PN/I.V. A reduction in the need
`for parenteral support may also result in clinically meaningful benefits such as an increase in the
`number of days off of PN/I.V. per week, decreased nocturia and less interrupted sleep, reduced
`infusion time per day, decreased stomal output or diarrhea, and reduced costs and resources
`associated with managing patients dependent on PN/I.V.
`
`Historically, clinical care of patients with short bowel syndrome (SBS) has mainly focused on
`optimizing remnant intestinal function through dietary interventions, oral rehydration solutions,
`anti-diarrheal, and anti-secretory agents. Although surgical procedures such as bowel
`lengthening surgery or intestinal transplantation have been suggested as potential treatments,
`both options are associated with significant morbidity and mortality and are therefore considered
`only in selected patients.
`
`For treating patients with SBS, the FDA approved Zorbtive [somatropin (rDNA origin) for
`injection, NDA 021597] in 2003. In 2004 the FDA approved NutreStore [L-glutamine for oral
`solution, NDA 021667] which should be administered as a cotherapy with Zorbtive together with
`optimal management of short bowel syndrome, such as a specialized oral diet. These are the only
`approved drugs for this condition; hence, there continues to exist a substantial need for additional
`treatment options.
`
`
`Overview of Regulatory Activity
`Subsequent to a pre-Investigational New Drug (IND) meeting on 20 October 1998, clinical
`development was initiated with the submission of IND 58,213 on 26 April 1999, supporting the
`development of teduglutide for the treatment of SBS. United States (US) orphan drug status was
`granted on 29 June 2000.
`
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`NPS and the Division of Gastroenterology and Inborn Errors Products (DGIEP) participated in
`3 key face-to-face meetings to discuss the designs of the Phase 3 studies. The first of these
`meetings was the 06 October 2003 End-of-Phase 2 meeting wherein the Division agreed to the
`following key elements of the Study CL0600-004 protocol:
`o acceptance of the primary endpoint (subjects achieving a reduction of 20% to 100% from
`baseline in weekly PN/I.V. volume at Week 24),
`o
` selection of the SBS subject population,
`o PN/I.V. volume optimization/stabilization procedure,
`o use of placebo as the control,
`o use of the teduglutide 0.05 mg/kg/day and 0.10 mg/kg/day dose levels to be tested
`o
`the statistical analysis methodology to be employed.
` After the results of Study 004 were known, a Type C Meeting was held on 18 January 2008. At
`this meeting, NPS agreed to perform a confirmatory trial (Study 020). The Division
`acknowledged NPS’ choice of the 0.05 mg/kg/day teduglutide dose for Study 020. Lastly, a
`meeting was held on 14 July 2008 to further discuss the results of Study 004, the planned Phase
`3 Study (020) and the acceptability of the same PN/I.V. reduction volume endpoint of the
`development program for filing a marketing application. The Division confirmed that only one
`additional confirmatory study using a 2-arm design (teduglutide 0.05 mg/kg/day vs placebo)
`would be necessary to support a filing.
`
`
`3. CMC/Device
`
`
`Dr. Yichun Sun is the CMC reviewer for this NDA and he concluded in his review that this
`NDA has provided sufficient information to assure identity, strength, purity, and quality of the
`drug product.
`
` to the drug
`The applicant agreed to add a test method and acceptance criterion for
`substance specification in the amendment dated June 18, 2012. The applicant is currently
`developing a suitable procedure for evaluating teduglutide drug substance and plans to test
`representative batches, establish acceptance criteria, and add this test to the drug substance
`specification. The applicant proposes to implement this process as a post approval commitment.
`Because it is a potential safety concern, we will designate development of this specification as a
`post approval requirement (PMR).
`
`Drug Substance
`The active ingredient is teduglutide (rDNA origin) that is a 33 amino acid glucagon-like peptide-
`2 (GLP-2) analog manufactured using a strain of Escherichia coli (E. coli) modified by
`recombinant DNA technology.
` Teduglutide drug substance is a clear, colorless to light straw colored
`liquid composed of teduglutide in aqueous buffer.
`
`Teduglutide for injection is supplied in a sterile, single-use 3-mL, USP Type I glass vial
`containing 5 mg of teduglutide as a white lyophilized powder. Each vial also contains 3.88 mg L-
`histidine, 15 mg mannitol, 0.644 mg monobasic sodium phosphate monohydrate, and 3.434 mg
`dibasic sodium phosphate heptahydrate. The lyophilized powder is intended to be reconstituted
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`Cross Discipline Team Leader Review
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`with 0.5 mL of sterile Water for Injection (sWFI), USP, which is provided in a prefilled syringe,
`immediately before administration by subcutaneous injection.
`
` A
`
` CMC site inspection/recommendation by the Office of Compliance is still pending as of the
`date of this review. It should be available soon.
`
`Regarding Immunogenicity Assessments, we consulted Laboratory of Immunology, in the Office
`of Biotechnology Products, Division of Therapeutic Proteins. Faruk Sheikh, Ph.D., Staff Fellow,
`and Susan Kirshner, Ph.D., Associate Chief, Laboratory of Immunology found that the validation
`of the antibody screening assay and the neutralizing antibody assay were complete and
`accepteable for use in clinical sample analysis. The review team from the Laboratory of
`Immunology does not recommend additional studies at this time for the issue related to cross
`reaction to endogenous GLP; however, they do recommend that patients in on-going clinical
`studies continue to be tested to provide as much longitudinal immunogenicity data as possible,
`since this will likely be a life long therapy. In addition Dr. Sheikh recommends that the sponsor
`should be prepared to test samples from any patient who loses efficacy to Gattex treatment. I
`agree.
`
`Most patients with SBS have part of their intestine removed and therefore may produce very low
`amount of endogenous GLP-2, therefore the impact of cross reactivity may not have much effect
`on treatment efficacy. Since, subjects with persistent antibodies to either teduglutide or GLP-2
`continued to respond to treatment and did not show any evidence of clinical pathologies
`associated with immune-mediated reactions, the Laboratory of Immunology does not
`recommend additional studies at this time. See Dr. Sheikh’s review for details.
`
`
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`Dr. Tamal Chakraborti is the reviewer and Dr. Sushanta Chakder is the team leader for this
`NDA and they concluded in the review that from a nonclinical standpoint, this NDA is
`recommended for approval and has no recommendation for Post-Marketing Commitments,
`Agreements, Post-Markeeting Requirements and/or Risk Management Steps.
`
`Based on the Dr. Chakraborti’s review, the applicant has conducted adequate nonclinical studies
`with teduglutide which included pharmacology, safety pharmacology, pharmacokinetics, and
`acute toxicology studies in mice; and repeated dose toxicology studies in mice (14 days to 26
`weeks duration), rats (14 day to 13 weeks duration), and Cynomolgus monkeys (14 to 1 year
`duration); toxicology studies in juvenile minipigs (14 days to 90 days duration); genotoxicity
`studies (Ames test, chromosome aberration test in Chinese hamster ovary cells, in vivo
`micronucleus test in mice), reproductive toxicology studies (fertility and early embryonic
`development in rats, and embryo-fetal development in rats and rabbits; pre and postnatal
`development studies in rats); and special toxicology studies in rabbits (antigenicity and local
`tolerance studies).
`
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`In toxicology studies, teduglutide was administered subcutaneously to mice (26-week treatment)
`up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg), rats
`(13-week treatment) up to 50 mg/kg/day (about 1000 times the recommended daily human dose
`of 0.05 mg/kg), and Cynomolgus monkeys (1-year treatment) up to 25 mg/kg/day (about 500
`times the recommended daily human dose of 0.05 mg/kg).
`In pivotal repeated dose toxicology studies, major treatment-related effects were related to the
`pharmacological activity of teduglutide and were seen in all species. In the 26-week study in
`mice at 2, 10 and 50 mg/kg/day, major treatment-related histopathological changes were seen at
`all doses in the small and large intestine (epithelial and villus hypertrophy and hyperplasia), gall
`bladder (epithelial hypertrophy and hyperplasia accompanied by subacute inflammation), sternal
`bone marrow (myeloid hyperplasia) and injection site (inflammation and necrosis). In the 13-
`week study in rats at 10, 25 and 50 mg/kg/day, major treatment-related histopathological changes
`were seen at all doses in the small and large intestine (mucosal hypertrophy and hyperplasia) and
`injection site (inflammation and necrosis). In the 1-year study in Cynomolgus monkeys at 1, 5
`and 25 mg/kg/day, major treatment-related histopathological changes were seen at all doses in
`the small and large intestine (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) and injection site (inflammation and necrosis).
`
`Teduglutide was negative 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 Wistar Han rats at 3, 10 and 35 mg/kg/day, teduglutide
`caused statistically significant increases in the incidences of adenomas in the bile duct and
`jejunum of male rats. There were no drug related tumor findings in females. A 2-year mouse
`carcinogenicity study is ongoing. By virtue of its mechanism of action (intestinotrophic activity
`or growth promoting pharmacological effect) and the findings of the carcinogenicity study in rats,
`teduglutide has the potential to cause hyperplastic changes including carcinogenicity in humans.
`
`In the subcutaneous fertility and early embryonic development study in rats at 2, 10 and
`50 mg/kg/day, teduglutide did not show any adverse effects on early embryonic development or
`fertility parameters up to 50 mg/kg/day (about 1000 times the recommended daily human dose of
`0.05 mg/kg). In the subcutaneous embryofetal development study in rats at 2, 10 and 50
`mg/kg/day, teduglutide was not teratogenic up to 50 mg/kg/day (about 1000 times the
`recommended daily human dose of 0.05 mg/kg). In the subcutaneous embryofetal development
`study in rabbits at 2, 10 and 50 mg/kg/day, teduglutide was not teratogenic up to 50 mg/kg/day
`(about 1000 times the recommended daily human dose of 0.05 mg/kg). In the subcutaneous pre
`and postnatal development study in rats at 10, 25 and 50 mg/kg/day, teduglutide did not show
`any significant adverse effect on pre and postnatal development up to 50 mg/kg/day.
`
`Overall, based on Dr. Chakraborti’s review, nonclinical safety of teduglutide has been
`adequately tested in several toxicology studies. Nonclinical studies conducted with teduglutide
`provide adequate assurance of safety and support its proposed use at the intended therapeutic
`dosage and in accordance with the proposed product labeling. However, by virtue of its
`mechanism of action (intestinotrophic activity or growth promoting pharmacological effect) and
`the findings of the carcinogenicity study in rats, teduglutide has the potential to cause
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`hyperplastic changes including carcinogenicity in humans. For detail, please see Dr.
`Chakraborti’s review.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`Dr. Lanyan Fang is the Clinical Pharmacology reviewer for this NDA and Dr. Yow-Ming Wang,
`is the Team Leader. They reviewed the NDA and concluded that NDA 203441 is approvable.
`They recommend a post marketing requirement (PMR) as a sub-study of the long term post-
`marketing safety trial to assess the long-term impact of anti-drug antibodies (ADA) on safety and
`efficacy (to include in vivo determination of ADA levels). See Dr. Fang’s review for details.
`
`Based on the review provided by Dr. Fang, Clinical Pharmacology Findings are summarized as
`follows:
`
`Pharmacokinetics (PK)
`Absorption
`Teduglutide was absorbed with a peak concentration at 3-5 hours after subcutaneous (SC)
`administration at the abdomen, thigh, or arm with the to-be-marketed concentration (10 mg/mL).
`The maximal plasma concentration and exposure (Cmax and AUC) of teduglutide was dose
`proportional over the dose range of 0.05 to 0.4 mg/kg. No accumulation of teduglutide was
`observed following repeated daily SC administration. In healthy subjects, teduglutide had an
`absolute bioavailability of 88% after abdominal SC administration. Following SC administration
`of 0.05 mg/kg/day of teduglutide to subjects with SBS, median peak teduglutide concentration
`(Cmax) was 36.8 ng/mL and overall median area under the curve (AUC0-τ) was 0.15 μg•hr/mL.
`
`Metabolism
`The metabolic pathway of teduglutide was not investigated in humans; however, as an analog to
`native GLP-2, teduglutide is expected to be degraded into small peptides and amino acids via
`catabolic pathways in the same manner as endogenous GLP-2. Teduglutide 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, teduglutide plasma clearance was
`approximately 127 mL/hr/kg which is roughly equivalent to the GFR suggesting that teduglutide
`is primarily cleared by the kidney. Teduglutide was rapidly eliminated with a mean terminal half
`life (t1/2) of approximately 2 hours in healthy subjects and 1.3 hours in SBS subjects.
`
`Special Population
`Plasma concentration-time profiles of teduglutide were similar for healthy younger and elderly
`subjects. Except for creatinine clearance (CLcr), none of the evaluated intrinsic factors including
`age, gender, and hepatic impairment had a significant effect on the PK of teduglutide.
`
`Hepatic Impairment
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`Following a single SC administration of 20 mg of teduglutide to subjects with moderate hepatic
`impairment, teduglutide Cmax and AUC were lower (10 ~15%) compared to those in healthy
`matched control subjects; no dose adjustment is needed when administered to individuals with
`moderate hepatic impairment. Teduglutide was not assessed in subjects with severe hepatic
`impairment.
`
`Renal Impairment
`Following a single SC administration of 10 mg teduglutide to subjects with moderate to severe
`renal impairment or end stage renal disease (ESRD), teduglutide Cmax and AUC0-∞ increased
`with increasing degree of renal impairment. The primary PK parameters of teduglutide increased
`up to a factor of 2.6 (AUC0-∞) and 2.1 (Cmax) in ESRD subjects compared to healthy subjects.
`Based on these results, SBS patients with renal impairment would be exposed to higher levels of
`teduglutide due to a decrease in the renal clearance of the drug. Therefore, a dose reduction of
`50% is recommended in patients with moderate to severe renal impairment and ESRD.
`
`Drug-Drug Interaction (DDI)
`No in vivo DDI studies were conducted based on results from in vitro studies in which significant
`inhibition or induction of tested cytochrome P450 isozymes was not observed at 2000 ng/mL
`teduglutide, a concentration significantly greater (55-fold) than of the median Cmax at the
`clinical dose of 0.05 mg/kg.
`
`The potential for teduglutide mediated drug-drug interactions exists considering teduglutide has
`demonstrated a PD effect of increasing intestinal absorption. This effect needs to be considered
`when teduglutide is co-administered with drugs requiring titration or having a narrow therapeutic
`index.
`
`QTc Prolongation
`No significant QTc prolongation was detected at a supra-therapeutic teduglutide dose of 20 mg
`in the TQT study. The largest upper bounds of the 2-sided 90% CI for the mean differences
`between teduglutide (5 mg and 20 mg) and placebo were below 10 ms, the threshold for
`regulatory concern as described in ICH E14 guidelines. The largest lower bound of the 2-sided
`90% CI for the ΔΔQTcF for moxifloxacin was greater than 5 ms, indicating that the magnitude
`of moxifloxacin can be detected in this study.
`
`Immunogenicity
`Immunogenicity incidence – anti-drug antibody (ADA)
`In the pivotal Phase 3 study (CL0600-020), the incidence of anti-teduglutide IgG antibody was
`0% (0/16) at Week 12 and 18% (6/34) at Week 24 in subjects who received SC administration of
`0.05 mg/kg teduglutide once a day. Of the 16 subjects, who were ADA negative (ADA-) at
`Week 12, 2 subjects were confirmed to be ADA positive (ADA+) at Week 24. This suggests that
`the immunogenicity incidence rate increased with the duration of treatment.
`
`In the Phase 3 open label extension study (021) where subjects had the option to continue taking
`teduglutide 0.05 mg/kg/day for up to 2 years, twenty-seven out of 85 subjects (27/85, 32%) were
`ADA positive at one or more time points post baseline up to the approximate
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`1-year data cut (study currently ongoing). Among 34 subjects who were treated with teduglutide
`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 teduglutide treatment for
`the duration of 18 months. Among 51 subjects who initiated teduglutide treatment in the
`extension study, 14 subjects were ADA+ (14/51, 27%) during the extension study after
`teduglutide treatment of 12 months.
`
`Overall, the immunogenicity incidence 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 ADA+ finding at Month 6 post-treatment.
`
`Cross-reactivity of ADA to GLP-2
`Anti-teduglutide specific antibodies showed evidence of cross reactivity against the native GLP-
`2 protein in five out of the six ADA positive subjects in Study CL0600-020.
`
`Immunogenicity incidence – neutralizing antibody
`No subjects in the SBS population developed neutralizing antibodies during the clinical trials.
`This result should be interpreted with caution as circulating drug concentration could interfere
`with the assay for neutralizing antibodies as the assay has a drug tolerance of 1.5 ng/mL.
`
`Immunogenicity Impact on PK, Efficacy and Safety
`The impact of ADA on PK is unknown as it has not been adequately assessed. The sponsor’s
`population PK analysis was unsuccessful in evaluating the effect of ADA on teduglutide PK due
`to an inadequate design.
`
`ADA appears to have no impact on the short term clinical efficacy up to 1.5 years; however, the
`long term impact is unknown. In the pivotal Phase 3 study (CL0600-020), all 6 subjects who
`were ADA positive ADA at Week 24 were responders. In the extension study (CL0600-021), 26
`out of 27 subjects who developed positive ADA post baseline had reduced PN/IV volume at the
`time of last dosing visit.
`
`ADA appears to have no impact on the short term clinical safety up to 1.5 years; however, the
`long term impact is unknown. None of the 6 subjects who developed positive ADA in CL0600-
`020 study had evidence of a hypersensitivity adverse event (AE) or immune related clinical
`symptoms. In the open-label extension CL0600-021 study, 3 of 27 subjects who tested positive
`for ADA experienced an injection site reaction without evidence of any other hypersensitivity
`reactions.
`
`Young Moon Choi, Ph.D., Pharmacologist and Michael F. Skelly, Ph.D., Pharmacologist from
`the Bioequivalence Branch, Division of Bioequivalence and GLP Compliance, Office of
`Scientific Investigations conducted audits of the pharmacokinetic bioanalytical portions of
`safety-efficacy study 004 and its extension Study 005. They recommend that pharmacokinetic
`portions of study CL0600-004 be accepted for agency review. The reviewers recommend that
`the immunologic assessments from Tandem Labs for studies CL0600-004 and CL0600-005 be
`accepted for agency review.
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`6. Clinical Microbiology
`
`
`Bryan S. Riley, Ph.D. did a Product Quality Microbiology Review for this NDA and concluded
`that the drug product is sterile
` and lyophilized and recommends that the
`NDA be approved. For a detailed Product Quality Microbiology evaluation, please see Dr.
`Riley’s review.
`
`
`7. Clinical/Statistical- Efficacy
`
`
`Evidence of efficacy of teduglutide 0.05 mg/kg/day for the treatment of SBS is provided by the
`two Phase 3 studies (020 and 004), the completed long-term extension study to 004 (Study 005),
`and the ongoing extension study to 020 (Study 021). Dr. John Troiani is the medical officer and
`Behrang Vali is the statistician for this NDA.
`
`Both Phase 3 studies, 020 and 004 were prospective, randomized, double-blind, placebo-
`controlled, parallel-group, multinational, multicenter studies. The population enrolled in these
`studies was adult subjects with SBS due to intestinal resection who were dependent on parenteral
`support for at least 12 months (including PN/I.V. support) and for at least 3 times per week. The
`studies were conducted in the United States, Canada, and Europe at a total of 27 and 32 centers
`for Studies 020 and 004, respectively. The underlying cause and severity of SBS was comparable
`among centers.
`
`Studies 020 and 004 included a screening visit, baseline treatment optimization period, and a
`stabilization period prior to randomization. If at screening subjects did not have a stable PN/I.V.
`volume as indicated by a targeted urine output of 1.0-2.0 L/day, they entered an optimization
`period (8 weeks maximum). The purpose of the optimization period was to establish each
`subject’s tolerated baseline PN/I.V. fluid volume which would result in urine output between 1.0
`and 2.0 L/day. Following the optimization period, all subjects entered a 4 to 8 week stabilization
`period during which they were maintained on the stabilized, tolerated PN/I.V. volume. Subjects
`who demonstrated PN/I.V. volume stability for at least 4 consecutive weeks were eligible for
`randomization and entry into the treatment period. If a subject failed to remain stable for at least
`4 consecutive weeks immediately prior to randomization, the subject was allowed to start the
`optimization period again. Those subjects who failed to stabilize after 2 attempts were not
`randomized.
`
`Following the optimization and stabilization period, subjects were randomized into a 24-week
`treatment phase. For Study 020, subjects were randomized in a 1:1 ratio into the teduglutide 0.05
`mg/kg/day or placebo treatment groups. In Study 004, subjects were randomized in a 2:2:1 ratio
`to teduglutide 0.05 mg/kg/day, teduglutide 0.10 mg/kg/day or placebo treatment groups,
`respectively. The choice of dose for Study 004 was based upon the results of a phase 2 study
`wherein a highly significant increase in gastrointestinal fluid absorption of approximately 750 to
`1000 mL/day (corresponding to a relative increase of up to 30%) was observed at the end of
`treatment with both doses of 0.10 and 0.15 mg/kg/day, but not with the dose of 0.03 mg/kg/day.
`The 0.10 mg/kg/day dose was selected as the high dose because there was no difference observed
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`between the 0.10 mg/kg/day and 0.15 mg/kg/day groups and 0.05 mg/kg/day was selected as the
`low dose to determine whether a dose lower than 0.10 mg/kg/day but greater than 0.03
`mg/kg/day was effective. In Study 020, the dose of 0.05 mg/kg/day was chosen to confirm the
`results from Study 004 observed in the corresponding dose group. In Study 004, the 0.10
`mg/kg/day dose group provided no further clinical benefit as compared with the 0.05 mg/kg/day
`group at the end of the treatment period; therefore, 0.05 mg/kg/day of teduglutide was selected as
`the dose for Study 020.
`
`In both studies, teduglutide or matching placebo was to be administered by subcutaneous
`injection once daily into 1 of the 4 quadrants of the abdomen, either thigh, or in Study 020 only,
`into either arm. Adjustments of PN/I.V. volume were to be made at dosing Weeks 2 (Study 020
`only), 4, 8, 12, 16, and 20. These adjustments were to be made by the investigator in accordance
`with the protocol-established guidance based on 48-hour urinary output collected just before the
`study visit. PN/I.V. fluid volume reductions were to be made if adequate hydration was
`demonstrated with an increase of at least 10% in urinary output from the baseline value. The
`PN/I.V. volume adjustment was maintained until the next dosing visit if the subject tolerated the
`reduction (i.e., was not dehydrated) at an interim safety evaluation conducted by the investigator.
`
`The efficacy endpoints for both studies were related to the reduction from baseline in PN/I.V.
`volume at various subsequent study time points, however, the primary efficacy variables differed
`between studies. For Study 020, the primary efficacy variable was the percentage of subjects that
`demonstrated a relevant response (i.e., a reduction of 20% to 100% from baseline in PN/I.V.
`volume) at Week 20 and 24 of treatment. Subjects who met these criteria were deemed
`“responders” and as such, the primary efficacy analysis in Study 020 is also referred to as the
`“responder analysis.” For patients requiring parenteral support 5 times per week, a 20%
`reduction could translate into a reduction of parenteral support by 1 day per week. Further,
`reductions in PN/I.V. volume might result in a reduction in the number of days per week of
`PN/I.V. support. Slower infusion rates leading to decreased frequency of nocturia and less
`interrupted sleep, reduced infusion time per day, decreased stomal output or diarrhea, and
`reduced costs and resources associated with managing patients on long-term PN/I.V. support. A
`reduction in the burden of parenteral support can also be translated into decreased infusion time
`which would have several clinical advantages, in particular the potential decrease of the risk of
`I.V.-catheter associated sepsis and/or other complications secondary to the chronic use of
`parenteral support such as liver disease. Therefore, this primary endpoint, even at the 20%
`reduction level, is clinically meaningful.
`
`For Study 004, the original protocol stated that the primary efficacy variable was also to be a
`responder analysis defined as it was in Study 020. However, per Study 004 Protocol
`Amendments 4 and 4b (finalized prior to the blind being broken), the primary efficacy analysis
`was modified to incorporate both the intensity and duration of the reduction in PN/I.V. volume
`(i.e., graded response). Following the amendment, the responder analysis was retained as a
`secondary efficacy analysis in Study 004.
`
`Study CL0600-020
`Study 020 was a randomized, double-blind, placebo-controlled, parallel-group, multinational,
`multicenter study. The entire study was comprised of 2 stages (Figure 1).
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`Page 10 of 36
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`Reference ID: 3216277
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`Cross Discipline Team Leader Review
`
`Stage 1 included a screening visit, an optimization period of a maximum of 8 weeks, and a
`stabilization period that demonstrated stable administration of PN/I.V. volume for a minimum of
`4 weeks up to a maximum of 8 weeks.
`
`BEST AVAILABLE COPY
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`Figure 1:
`
`Study Design — Study CL0600-020
`
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`Stage 2
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`PN/I.V.: Parenteral nutrition‘intraveuous fluids; V:V'isit'. szWeek
`
`The purpose of the optimization period was to establish each subject’s tolerated baseline PN/I.V.
`volume which would result in urine output between 1.0 and 2.0 L/day. Subjects who
`demonstrated PN/I.V. volume stability for at least 4 weeks were eligible for randomization and
`entry into the treatment period. Baseline values were determined at the end of the stabilization
`period just prior to the start of the dosing period. Stage 2 was to be a dosing period of 24 weeks.
`Randomization was to be stratified by PN/I.V. consumption level at baseline (36 L/week, >6
`L/week).
`
`Efficacy Endpoints:
`The primary efficacy variable was the percentage of subjects who demonstrated a res