CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203441Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`
`NDA
`Original Submission Dates
`PDUFA Due Date
`Brand Name
`Generic Name
`Primary Reviewer
`Team Leader
`Primary PM Reviewer
`Team PM Leader
`OCP Division
`OND Division
`Sponsor
`Relevant IND(s)
`Submission Type
`Formulation; Strength(s)
`
`Proposed indication
`Proposed Dosage and
`Administration
`
`203441
`11/30/2011
`12/30/2012
`Gattex
`Teduglutide
`Lanyan Fang, Ph.D.
`Yow-Ming Wang, Ph.D.
`Justin Earp, Ph.D.
`Nitin Mehrotra, Ph.D. (Acting)
`DCP III
`DGIEP
`NPS Pharmaceuticals
`58,213
`NME
`Lyophilized powder; 5 mg/vial to be reconstituted with
`0.5 mL sterile water for injection
`Treatment of Short Bowel Syndrome (SBS)
`0.05 mg/kg subcutaneous (SC) injection once daily,
`altering sites between 1 of the 4 quadrants of the
`abdomen, or into alternating thighs or alternating
`arms.
`
`
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY....................................................................................................................2
`1.1 Recommendation..............................................................................................................................2
`1.2 Post-Marketing Requirements..........................................................................................................2
`1.3 Post-Marketing Commitments..........................................................................................................3
`1.4 Summary of Clinical Pharmacology Findings..................................................................................3
`2 QUESTION-BASED REVIEW .............................................................................................................8
`2.1 General Attributes ............................................................................................................................8
`2.2 General Clinical Pharmacology........................................................................................................9
`2.3 Intrinsic Factors..............................................................................................................................32
`2.4 Extrinsic Factors.............................................................................................................................41
`2.5 General Biopharmaceutics..............................................................................................................42
`2.6 Analytical .......................................................................................................................................42
`3 APPENDIX ..........................................................................................................................................51
`
`
`Reference ID: 3191376
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`Page 1 of 51
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`
`1 EXECUTIVE SUMMARY
`
`GATTEX® (teduglutide [rDNA origin], ALX-0600) is a 33–amino acid recombinant analog of
`the human glucagon-like peptide-2 (GLP-2), a peptide that is secreted primarily from the lower
`gastrointestinal tract. Teduglutide is being proposed to treat adult patients with Short Bowel
`Syndrome (SBS), who need parenteral support (parenteral nutrition/intravenous hydration,
`PN/IV) to supplement nutrition, through improving intestinal absorption of fluid and nutrients.
`This proposed indication was granted Orphan Designation (OD) on June 29, 2000.
`
`For treating patients with SBS, the FDA approved ZorbtiveTM [somatropin (rDNA origin) for
`injection, NDA 021597] in 2003. In 2004 the FDA approved NutreStoreTM [L-glutamine for oral
`solution, NDA 021667] which should be administered as a cotherapy with ZorbtiveTM together
`with optimal management of short bowel syndrome, such as a specialized oral diet.
`
`The sponsor submitted an original New Drug Application for GATTEX® (teduglutide [rDNA
`origin], NDA 203441) on 11/30/2011. The submission contains a total of 14 completed clinical
`trials and an interim report of an ongoing open-label, extension study in SBS subjects (CL0600-
`021, Table 1). A total of 623 unique subjects received at least one dose of teduglutide and 198
`subjects treated with placebo in the clinical program. Four in vitro drug-drug interaction study
`reports, six single-dose pharmacokinetic (PK) study reports, three multiple-dose
`pharmacokinetic/pharmacodynamic (PK/PD) study reports, PK/PD data and immunogenicity
`data from four Phase 3 studies with SBS subjects were reviewed in this clinical pharmacology
`review.
`
`Data from four Phase 3 efficacy and safety studies form the basis to support the proposed
`indication. (1) The pivotal double blind, placebo-controlled study (CL0600-020) that compared
`one dose level, 0.05 mg/kg/day, of teduglutide to placebo and (2) its ongoing, open-label
`extension study (CL0600-021); and (3) a supportive double-blind, placebo-controlled study
`(CL0600-004) that compared two dose levels, 0.05 mg/kg/day and 0.10 mg/kg/day, of
`teduglutide to placebo and (4) its randomized, double-blind extension study CL0600-005 that
`studied the long term safety of 0.05 mg/kg/day and 0.10 mg/kg/day daily doses of teduglutide.
`Based on results from these studies, the sponsor proposed a daily teduglutide dose of 0.05 mg/kg
`for the proposed indication.
`
`In this review, teduglutide and ALX-0600 were used interchangeable.
`
`1.1 Recommendation
`
`From a clinical pharmacology perspective, the information submitted to support this NDA is
`acceptable provided that the applicant and the Agency come to a mutually satisfactory agreement
`regarding the language in the package insert.
`
`1.2 Post-Marketing Requirements
`
`The Clinical Pharmacology review team recommends the following post marketing requirement
`(PMR) as a sub-study of long term post-marketing safety trial(s):
`
`
`Reference ID: 3191376
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`The sponsor should assess the long-term impact of anti-drug antibodies (ADA) on safety and
`efficacy to include in vivo determination of ADA levels.
`
`1.3 Post-Marketing Commitments
`
`There are no post-marketing commitments for this submission.
`
`1.4 Summary of Clinical Pharmacology Findings
`
`The pharmacokinetics (PK) of teduglutide was evaluated in both healthy subjects and subjects
`with SBS. Teduglutide formulation strength (and/or SC injection volume) appears to have an
`impact on teduglutide PK upon SC administration (Study CL0600-022); therefore, the summary
`of clinical pharmacology findings are primarily based on data obtained with the to-be-marketed
`formulation strength (10 mg/mL).
`
`Teduglutide PK after SC administration of the to-be-marketed formulation at the proposed
`clinical dose was characterized in the target patient population during Phase 3 study
`CL0600-004. Subjects with SBS appeared to have a lower drug exposure than healthy subjects.
`The overall summary of clinical pharmacology is presented below.
`
`Pharmacokinetics (PK)
`Absorption
`Teduglutide was absorbed with a peak concentration at 3-5 hours after subcutaneous (SC)
`administration at 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 (Study CL0600-006).
`
`Following SC administration of 0.05 mg/kg/day dose 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 (Study CL0600-004).
`
`Relative Bioavailability – alternative injection sites
`The relative bioavailability of teduglutide was 89% and 92% for SC injection at the thigh and the
`arm, respectively, relative to SC injection at the abdomen (based on ANCOVA analysis of
`AUC0-∞) in healthy subjects. The 90% confidence interval (CI) for AUC0-t or AUC0-∞ was within
`the 80% to 125% range, indicating that exposure was similar after SC injection at these 3 sites
`(Study CL0600-015).
`
`Distribution
`Following IV administration in healthy subjects, teduglutide had a mean (±SD) volume of
`distribution at steady state (Vss) of about 103 (± 23) mL/kg (Study CL0600-006), similar to the
`blood volume.
`
`Metabolism
`
`Reference ID: 3191376
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`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 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, 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 (CL0600-006). 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
`Teduglutide PK was evaluated in healthy elderly subjects, subjects with renal impairment, and
`subjects with hepatic impairment. Plasma concentration-time profiles of teduglutide were
`similar for healthy non-elderly and elderly subjects (Study CL0600-018). 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
`Following a single SC administration of 20 mg 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 (CL0600-017). 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
`(Study CL0600-018).
`
`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 by
`50% is recommended in patients with moderate to severe renal impairment and ESRD
`
`Comparability Assessment
`The phase 3 studies used the to-be-marketed formulation. However, the formulation strength
`appears to have impact on the extent of exposure following SC injection based on data in one
`single study that evaluated the same dose of teduglutide administered in two different
`formulation strengths (Study CL0600-022).
`
`Drug-Drug Interaction (DDI)
`No in vivo DDI studies were conducted based on results from in vitro studies in which significant
`inhibition or induction on tested cytochrome P450 isozymes was not observed at 2000 ng/mL
`
`Reference ID: 3191376
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`teduglutide, a concentration significantly greater (55-fold) than of the median Cmax at the clinical
`dose of 0.05 mg/kg. This is acceptable given teduglutide is not a pro-inflammatory cytokine or
`cytokine modulator although the relevance of in vitro studies to in vivo setting is unclear.
`Additionally, teduglutide was neither a substrate nor an inhibitor of P-gp at concentrations above
`2000 ng/mL (P10-005).
`
`However, the potential for PD effect mediated drug-drug interactions exists considering
`teduglutide has demonstrated a PD effect of increasing intestinal absorption. This needs to be
`considered when it 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 (Study C09-001).
`
`Exposure-Response Relationship
`Overall, the dose-response relationship indicates the proposed dose, i.e., 0.05 mg/kg/day, had
`better efficacy and safety profiles compared to 0.1 mg/kg/day.
`
`Efficacy
`In the 24-week study (CL0600-004), changes in weekly PN/IV volume were evaluated with two
`dose levels of teduglutide (0.05 and 0.10 mg/kg/day) in subjects with PN/IV-dependent SBS. For
`the primary efficacy endpoint, i.e., the proportion of subjects achieving a 20% to 100% reduction
`in PN/IV at Weeks 20 and 24 (responder), the teduglutide 0.05 mg/kg/day group, was
`statistically significantly higher compared with the placebo group (45.7% vs. 6.3%; p = 0.005).
`However, the teduglutide 0.10 mg/kg/day group did not have statistically significant difference
`compared to the placebo group (25.0% vs. 6.3%; p = 0.172). The sponsor proposed several
`arguments to explain why the responder rate of the 0.10 mg/kg/day group was lower than that of
`the 0.05 mg/kg/day group, including higher baseline PN/IV in 0.10 mg/kg/day group.
`
`As to the secondary efficacy endpoint, the absolute change from baseline in weekly PN/IV
`volume at Week 24, both active treatment groups demonstrated a mean weekly decrease in
`PN/IV volume of 2.5 L compared to 0.9 L in the placebo group (p = 0.08 for each comparison)
`indicating that both active doses have similar efficacy (p = 0.98).
`
`Altogether, it seems that the teduglutide efficacy reached the plateau around 0.05 mg/kg/day dose.
`
`Safety
`The percentage of subjects who experienced a treatment-emergent adverse event (TEAE) in the
`teduglutide 0.10 mg/kg/day group (97%, 31/32) was numerically higher than in either the
`teduglutide 0.05 mg/kg/day group (88%, 68/77) or the placebo group (83%, 49/59) based on
`combined data from Studies CL0600-004 and CL0600-020. However, the overall high incidence
`and nature of the TEAEs in this population across both the teduglutide-treated and placebo-
`treated subjects most likely represent both the underlying disease and parenteral support
`complications often observed in the SBS population.
`
`Immunogenicity
`
`Reference ID: 3191376
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`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. One additional
`subject (Patient 0136-1002) had positive ADA at baseline however remained negative post-
`baseline during Study CL-0600-020 and the extension Study CL0600-021.
`
`In the Phase 3 open label extension study (CL0600-021) 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%) was ADA positive at one or more time points post baseline up to the approximate
`1-year cut (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.
`
` discovery
`Of note, the immunogenicity assessment was based on a validated
`electrochemiluminescent
` ECL) assay which has a drug tolerance significantly higher than
`the observed mean Cmax at the clinical dose, 0.05 mg/kg.
`
`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 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 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.
`
`Reference ID: 3191376
`
`Page 6 of 51
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`(b) (4)
`
`(b) (4)
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`

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`
`
`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 hypersensitivity adverse event (AE) or immune related clinical
`symptoms in CL0600-020 study. For 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.
`
`In summary, the sponsor should assess the long term safety impact of ADA in post-marketing
`studies, as immunogenicity incidence rate increased with treatment duration during clinical trials.
`Furthermore, anti-teduglutide antibody has cross-reactivity to native GLP-2. The implication of
`this cross-reactivity with endogenous GLP-2 for the safety of long term treatment with
`teduglutide is unknown.
`
`Reference ID: 3191376
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`
`
` 2
`
` QUESTION-BASED REVIEW
`
`
`2.1 General Attributes
`
`2.1.1 What are the highlights of the chemistry and physical-chemical properties of the drug
`substance and the formulation of the drug product?
`
`Teduglutide (rDNA origin) is a 33 amino acid glucagon-like peptide-2 (GLP-2) analog
`manufactured using a strain of Escherichia coli modified by recombinant DNA technology. Its
`chemical name is L-histidyl-L-glycyl-L-aspartyl-L-glycyl-L-seryl-L-phenylalanyl-L-seryl-L-
`aspartyl-L-glutamyl-L-methionyl-L-asparaginyl-L-threonyl-L-isoleucyl-L-leucyl-L-aspartyl-L-
`asparaginyl-L-leucyl-L-alanyl-L-alanyl-L-arginyl-L-aspartyl-L-phenylalanyl-L-isoleucyl-L-
`asparaginyl-L-tryptophanyl-L-leucyl-L-isoleucyl-L-glutaminyl-L-threonyl-L-lysyl-L-isoleucyl-
`L-threonyl-L-aspartic acid. The structural formula is:
`
`Figure 1. Structural formula of teduglutide
`
`
`
`
`
`Teduglutide has a molecular weight of 3752 Daltons. Teduglutide drug substance is a clear,
`colorless to light-straw–colored liquid.
`
`Teduglutide has one amino acid substitution of alanine by glycine at the second position of the
`N-terminus of GLP-2. The single amino acid substitution relative to naturally occurring GLP-2
`results in resistance to in vivo degradation by the enzyme dipeptidyl peptidase-IV (DPP-IV),
`resulting in an extended half-life.
`
`Each vial of GATTEX contains 5 mg of teduglutide as a white lyophilized powder for solution
`for subcutaneous injection. In addition to the active pharmaceutical ingredient (teduglutide),
`each vial of GATTEX contains L-histidine, mannitol, monobasic sodium phosphate
`monohydrate, and dibasic sodium phosphate heptahydrate as excipients. No preservatives are
`present.
`
`At the time of administration the product is reconstituted with 0.5 mL of sterile water for
`injection, which is provided in a prefilled syringe. A nominal 10 mg/mL solution concentration
`is obtained after reconstitution. Up to 0.38 mL of solution can be withdrawn for subcutaneous
`injection upon reconstitution with the 0.5 mL sterile water for injection (sWFI) provided in the
`prefilled syringe.
`
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`2.1.2 What are the proposed mechanism(s) of action and therapeutic indication(s)?
`
`Teduglutide is an analog of naturally occurring human glucagon-like peptide-2 (GLP-2), a
`peptide secreted by L-cells of the distal intestine. Teduglutide binds to the glucagon-like
`peptide-2 receptors located in intestinal subpopulations of enteroendocrine cells, subepithelial
`myofibroblasts and enteric neurons of the submucosal and myenteric plexus. Activation of these
`receptors results in the local release of multiple mediators including insulin-like growth factor
`(IGF)-1, nitric oxide, and keratinocyte growth factor (KGF).
`
`As with GLP-2, teduglutide has been shown to preserve mucosal integrity by promoting repair
`and normal growth of the intestine. Teduglutide increases villus height and crypt depth of the
`intestinal epithelium resulting in enhanced intestinal absorptive capacity as demonstrated by
`greater absorption of fluids, electrolytes and nutrients, and reduced fecal fluid loss. Therefore,
`GATTEX® (teduglutide [rDNA origin]) powder for subcutaneous injection is used to improve
`intestinal absorption of fluid and nutrients, thus is proposed to be indicated for the treatment of
`adult patients with Short Bowel Syndrome (SBS).
`
`2.1.3 What are the proposed dosage(s) and route(s) of administration?
`The recommended daily dose of GATTEX is 0.05 mg/kg body weight. GATTEX should be
`administered by subcutaneous (SC) injection once daily, alternating sites between 1 of the 4
`quadrants of the abdomen, or alternating thighs, or alternating arms. GATTEX should not be
`administered intravenously or intramuscularly.
`
`2.2 General Clinical Pharmacology
`
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used to
`support dosing or claims?
`
`Table 1 is a summary of clinical pharmacology studies and clinical studies (a total of 15 studies)
`that provide PK, PD, efficacy, and safety information. There are 9 clinical pharmacology studies
`(6 in healthy subjects and 2 in otherwise healthy subjects with organ dysfunction), 1 Phase 2
`dose-ranging study in subjects with SBS, 2 Phase 3 efficacy and safety studies (both placebo-
`controlled, 1 pivotal study and 1 supportive study) with PK and/or PD components in subjects
`with SBS, 2 extension studies (1 uncontrolled, blinded extension, and 1 [ongoing] uncontrolled,
`open-label) of the Phase 3 studies, and 2 studies in subjects with Crohn’s Disease (CD). With the
`exception of one open-label (2-year) study in SBS subjects, all studies have been completed.
`
`
`Reference ID: 3191376
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`

`Table 1. Outline of Clinical Pharmacology Studies and Clinical Studies with PK and/or PD Components
`Healthy Subjects or
`Type of Study
`Study
`Number of
`Study objective
`Study Design and Type of
`Teduglutide dose and
`Diagnosis of Patients
`Subjects
`Number
`Control
`routes (site); Control
`enrolled
`14
`(all teduglutide)
`
`Phase 1, single centre,
`open-label, randomized, 2-way
`crossover (two treatment, two
`sequence) trial
`
` 0.12 mg/kg IV or SC
`
`Healthy male and female
`subjects
`
`
`
`Bioavailability
`(SC vs. IV)
`
`Bioavailability
`(thigh, arm vs.
`abdomen)
`
`Bioavailability
`(single & multiple
`dose)
`
`
`
`CL0600-006 PK, absolute
`bioavailability of
`SC relative to a
`1-hour IV infusion
`in fasted
`CL0600-015 PK, relative
`bioavailability
`(thigh and arm,
`relative to
`abdomen)
`PK, ascending
`single SC doses
`
`1621/13
`
`CL0600-022 PK, multiple SC
`doses
`
`Intrinsic Factor PK
`
`
`CL0600-017 PK, single dose,
`hepatic impairment
`
`CL0600-018 PK, single dose,
`renal impairment
`
`PK/PD
`in healthy subjects
`
`C09-001
`
`QTC study
`
`C10-003
`
`PD, gastric
`emptying
`(using
`acetaminophen
`absorption kinetics)
`
`PK/PD
`in SBS patients
`
`ALX-0600
`-92001
`
`PK and PD,
`multiple SC doses
`
`Healthy male subjects
`
`Single dose
`
`ELISA
`
`Phase 1, randomized,
`open-label, 3-way crossover
`trial
`
`10 mg SC
`
`18
`(all teduglutide)
`
`Healthy male and female
`subjects
`
`Phase 1, single-blind, placebo-
`controlled trial
`
`Phase 1, double-blind,
`randomized, placebo-
`controlled, multi-dose trial
`Phase 1, open-label, parallel-
`group, prospective, controlled
`trial
`Phase 1, open-label, parallel
`group, prospective trial
`
` 2.5, 5, 7 and 10 mg SC;
`
`placebo control
`10, 15, 20, 25, 30, 50, 80
`mg SC (abdomen);
`placebo control
`20 mg SC (abdomen)
`
`10 mg SC (abdomen)
`
`Phase 1, single centre, single
`dose, placebo and positive
`controlled, 4-period, change
`over design
`
`Phase 1, randomized, double-
`blind, placebo-controlled,
`multiple-dose, parallel-group
`study
`
`Phase 2, open-label,
`multicentre, dose-ranging,
`pilot study
`
`5 and 20 mg SC;
`
`
`Positive control
`moxifloxacin 400 mg PO
`Placebo negative control
`4 mg SC
`
`Placebo control
`Other agent:
` Acetaminophen 1000
`mg
`0.03, 0.1, 0.15 mg/kg/day
`SC (abdomen)
`
`32
`(8 placebo;
`24 teduglutide)
`95
`(24 placebo
`71 teduglutide)
`24
`(12 impaired;
`12 healthy)
`36
`(18 impaired;
`18 healthy)
`
`72
`(all treated w/
`teduglutide)
`
`Healthy male and female
`subjects
`
`Hepatically impaired
`subjects and healthy
`matched control subjects
`Subjects with renal
`impairment (moderate or
`severe renal impairment,
`or end stage renal disease)
`or healthy subjects
`Healthy male or female
`subjects
`
`36
`(13 placebo
`23 teduglutide)
`
`Healthy male or female
`subjects
`
`17
`(all treated w/
`teduglutide)
`
`Male or female SBS
`patients without colon or
`with ≥50 of their colon
`continuity
`
`Total duration of Trea PK Assay Method
`
`Single dose
`(IV as 1-hour
`infusion)
`
`Single dose on
`3 occasions
`separated by
`3 days
`
`ELISA
`
`ELISA
`LC-MS/MS
`
`qd for 8 days
`
`LC-MS/MS (US)
`
`Single dose
`
`LC-MS/MS (US)
`
` Single dose
`
`LC-MS/MS (EU)
`
`LC-MS/MS (EU)
`
`LC-MS/MS (US)
`
`Single dose
`in 4 treatment
`periods
`
`qd for 10 days
`
`Acetaminophen at
`Days 0 and 10
`
`qd or bid for 21 days ELISA
`
`Reference ID: 3191376
`
`Page 10 of 51
`
`

`

`
`
`Type of Study
`
`Study
`Number
`
`Study objective
`
`Study Design and Type of
`Control
`
`Teduglutide dose and
`routes (site); Control
`
`Pivotal Phase 3, placebo-
`controlled study
`
`0 05 mg/kg SC
`
`Placebo control
`
`Number of
`Subjects
`enrolled
`85 dosed
`
`(43 placebo
`42 teduglutide)
`
`Healthy Subjects or
`Diagnosis of Patients
`
`Male and female parenteral
`nutrition-dependent SBS
`patients
`
`Total duration of Trea PK Assay Method
`
`qd for 24 weeks
`
`No PK
`
`Efficacy and safety
`studies in SBS patients
`Placebo controlled
`
`
`Efficacy and safety
`studies in SBS patients
`Open-label extension
`
`
`Efficacy and safety
`studies in CD patients
`
`
`CL0600-004
`(Supportive)
`
`CL0600-020
`(Pivotal)
`
`To evaluate the
`efficacy, safety,
`tolerability and
`pharmacokinetics of
`Teduglutide compared
`with placebo in
`patients with parenteral
`nutrition-dependent
`SBS
`To evaluate the
`efficacy, safety,
`tolerability and
`pharmacokinetics of
`Teduglutide compared
`with placebo in
`patients with parenteral
`nutrition-dependent
`SBS
`CL0600-021 A Study of the Safety
`and Efficacy of
`Teduglutide in
`Subjects with
`Parenteral Nutrition-
`Dependent Short
`Bowel Syndrome Who
`Completed Protocol
`CL0600-020
`CL0600-005 A Study of the Safety
`and Efficacy of
`Teduglutide in
`Subjects with
`Parenteral Nutrition-
`Dependent Short
`Bowel Syndrome Who
`Completed Protocol
`CL0600-004
`CL0600-008 To assess the efficacy
`of different doses of
`Teduglutide in subjects
`with moderately active
`Crohn’s disease (CD)
`as compared to placebo
`CL0600-009 An open label
`extension study of the
`safety & efficacy of
`Teduglutide (ALX-
`0600) in subjects with
`Crohn's Disease who
`completed the study
`protocol CL0600-008
`
`Phase 3, placebo-controlled study
`
`0 05, 0 10 mg/kg SC
`
`placebo control
`
`
`83
`
`(16 placebo
`67 teduglutide)
`
`Male and female parenteral
`nutrition-dependent SBS
`patients
`
`qd for 24 weeks
`
`LC-MS/MS (US)
`
`Phase 3, extension study of
`CL0600-020
`
`0 05 mg/kg/day SC
`
`88
`(all teduglutide)
`
`Patients with parenteral
`nutrition-dependent SBS who
`completed study CL0600 020
`
`qd for 28 weeks (on-
`going study)
`
`No PK
`
`Phase 3, extension study of
`CL0600-004
`
`0 05, 0 10 mg/kg/day SC
`
`65
`(all teduglutide)
`
`Patients with parenteral
`nutrition-dependent SBS who
`completed study CL0600-004
`
`qd for 28 weeks
`
`No PK
`
`Phase 2, randomized, double-
`blind, placebo-controlled study
`
`0 05, 0 10, or 0 20 mg/kg/day
`SC;
`placebo
`
`100
`
`(25 placebo
`75 teduglutide)
`
`Male and female subjects with
`moderately active Crohn’s
`disease
`
`qd for 8 weeks (self-admin LC-MS/MS (US)
`
`Phase 2, open-label extension of
`the study CL0600-008
`
`0 10 mg/kg/day SC
`
`67
`(all teduglutide)
`
`Patients who completed study
`CL0600-008
`
`qd for 12 weeks
`
`No PK
`
`Reference ID: 3191376
`
`Page 11 of 51
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`
`2.2.2 What is the basis for selecting the response endpoints or biomarkers and how are they
`measured in clinical pharmacology and clinical studies?
`
`Primary Efficacy Endpoint:
`The primary efficacy endpoint in the pivotal Phase 3 study (CL0600-020) and the supportive
`Phase 3 study (CL-0600-004) was based on the percentage of subjects who achieved a reduction
`of 20% to 100% in PN/IV volume from baseline. This endpoint was used to support the US
`approval for Zorbtive. The primary efficacy endpoints of Studies CL0600-020 and CL0600-004
`are below:
`
`
`• Study CL0600-020 utilized a binary (responder and non-responder) endpoint that
`assessed the difference between treatment groups (teduglutide 0.05 mg/kg/day and
`placebo) in the number and percentage of subjects who achieved a reduction of 20% to
`100% from baseline in PN/IV volume response at Week 20 and at Week 24.
`
`• Study CL0600-004 used a graded response endpoint that accounted for the intensity and
`duration of the PN/IV volume reduction at the end of the 24-week treatment period.
`
`• Each study included the endpoint from the other study as a secondary efficacy endpoint.
`
`
`
`Clinically Meaningful Exploratory Biomarkers
`
`Exploratory PD biomarkers were assessed during the clinical development process. Two
`clinically meaningful ones are listed below (refer to section 2.2.6 for study results):
`
`1. Parameters of gastrointestinal absorption
`
`A 72-hour nutrient absorption sub-study was included in Studies ALX-0600-92001 and
`CL0600-004 to evaluate effects of teduglutide administration on absolute and relative
`absorption of fat, nitrogen, sodium, potassium, calories and g.i. fluid. The studies also
`provide information on stomal or fecal output of fat, nitrogen, sodium, potassium,
`calories and fluid.
`
`2. Structural/histological mucosal changes of small and large intestine
`
`In Studies ALX-0600-92001 and CL0600-004, endoscopies were performed and
`mucosal biopsy samples were obtained for histopathological examination of absorptive
`epithelium including villus height, crypt depth, and mitotic index, and to evaluate
`biological parameters, including compositional and functional analyses.
`
`Other Exploratory Biomarkers:
`Several other biomarkers were also assessed, but the clinical relevance was questionable in that
`the assessment was conducted in healthy subjects rather than the SBS patients or the study
`results were not different between placebo and treatment groups. As such, the data and the
`associated bioanalytical assays from these biomarkers were not reviewed in depth.
`
`Reference ID: 3191376
`
`Page 12 of 51
`
`

`

`
`
`
`
`
`
`1. Gastric emptying
`The effect of teduglutide on gastric emptying was examined in healthy subjects in Study
`C10-003 where acetaminophen absorption kinetics was determined at before teduglutide
`treatment and after once daily dosing of teduglutide at 4 mg for 10 consecutive days.
`An LC-MS/MS assay was used for the qua