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

`

`Division Safety Deputy Director Review
`GA'ITEX (teduglutide [rDNA origin]) for injection. for subcutaneous use.
`
`NDA 203441
`
`Summary Safety Review for Regulatory Action
`
`Sta n ted date
`
`Joyce Korvick, MD, MPH
`Deputy Director for Safety
`Division of Gastroenterology and Inbom Errors Products
`ODE III, CDER
`FDA
`
`Division Safe Director Summ Review
`
`203441
`
`Sub'ect
`
`NDA #
`
`
` Subcutaneous
`
`A licant Name
`
`NPS Phannaceuticals
`
`Date of Submission
`
`PDUFA Goal Date
`
`November 30, 2011
`
`September 30, 2012,
`ma'or amendment - extended to December 31, 2012
`
`Proprietary Name /
`Name
`Established
`S .
`
`Lyophilized Powder for Injection, 5 mg
`Dosage Forms / Strength
`6-29-2000
`Orphan Drug Designation
`Route of Administration
`
`Gattex (teduglutide [rDNA origin])
`
`Review Classification
`
`Proposed Indication(s)
`
`GATTEX® (teduglutide [rDNA origin]) powder for
`subcutaneous injection is indicated for the treatment of adult
`patients with Short Bowel Syndrome (SBS). Gattex is used to
`im rove intestinal abso tion of fluid and nutrients.
`
`Action/Recommended Action
`
`for NME:
`
`Approval: Indication as per approved labeling
`see a uroval letter
`
`Page 1 of 18
`
`Reference ID: 3235350
`
`

`

`Division Safety Deputy Director Review
`GATTEX (teduglutide [rDNA origin]) for injection, for subcutaneous use. NDA 203441
`
`
`
`
`
`
`
`
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Medical Officer Review
`Statistical Review
`Pharmacology Toxicology Review
`CMC Review.
`Quality Microbiology Review
`(sterile products)
`Clinical Pharmacology Review
`Clinical Pharmacometrics Review
`QT IRT Review
`Immunogenicity Review
`Facilities Review/Inspection
`DCDP of OPDP
`DSI - Division of Bioequivalence and GLP
`Compliance
`Office of Scientific Investigations
`CDTL Review
`OSE/DMEPA
`OSE/DRM
`
`
`Names of discipline reviewers
`John Troiani
`Behrang Vali
`Tamal Chakraborti
`Yichun Sun
`Brian Riley
`
`Lucy Fang
`Anshu Marathe
`Moh Jee Ng
`Joao Pedras-Vasconselos
`Zhong Li
`Kendra Jones/Eunice Chung-Davies
`Young Moon Choi
`
`Khairy Malek
`Ruyi He
`Manizheh Siahpoushan
`Carolyn Yancey
`
`OND=Office of New Drugs
`DCDP of OPDP=Division of Consumer Drug Promotion in the Office of Prescription Drug Promontion
`Division of Drug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DSI=Division of Scientific Investigations
`DMPP=Division of Medical Policy Programs
`DRM=Division of Risk Management
`CDTL=Cross-Discipline Team Leader
`
`Page 2 of 18
`
`Reference ID: 3235350
`
`

`

`Division Safety Deputy Director Review
`GATTEX (teduglutide [rDNA origin]) for injection, for subcutaneous use. NDA 203441
`
`Division Safety Deputy Director Review
`Introduction
`1.
`The purpose of this review is to highlight the risks and benefits associated with the use of Gattex
`(teduglutide [rDNA origin]) for injection to be used in patients with Short Bowel Syndrome (SBS), as
`well as, commenting on the Risk Evaluation and Mitigation Strategy (REMS), the post-marketing required
`studies (REMS) and the professional labeling including the Medication Guide (MG).
`2. Background
`Small Bowel Syndrome (SBS) results from surgical resection of some or all of the small or large intestine.
`If extensive, it can lead to malabsorption of protein, fluid, electrolytes and micronutrients. Following
`surgery, compensatory increases in bowel absorptive capacity can take up to two years to occur. If after
`two years the SBS patient still requires total parenteral nutritional support, it is unlikely that that patient
`will be completely weaned from such support1.
`
`Teduglutide has been shown to increase villus height and crypt depth of the intestinal epithelium resulting
`in enhanced absorptive capacity of the intestine.
`
`Teduglutide is a 33 amino acid peptide that differs from its natural analog, glucagon-like peptide-2 (GLP-
`2) receptor agonist in the substitution of alanine (in native GLP-2) for glycine at the second position at the
`N-terminus. This single amino acid substitution provides resistance to in vivo degradation of teduglutide
`by dipeptidyl protease-IV (DPP-IV) resulting in an extended half-life. Teduglutide is manufactured using
`a recombinant strain of Escherichia coli.
`
`The European Commission granted marketing authorization for “Revestive-teduglutide” on August 30,
`2012. There is limited post-marketing experience in countries outside of the United States at the time of
`this review.
`
`Regulatory History:
`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 on clinical (Study 004) and nonclinical topics. Key items
`discussed were:
`• Dosing: 0.05 and 0.10 mg/kg/day
`• Standard outpatient care re: PN and concomitant medications
`• Though study population would exclude SBS patients with unstable PN regimens, the results of the
`trial could potentially be extrapolated to such patients
`• Proposed PN optimization/stabilization procedures, performance of colonoscopy in patients with a
`colon, mucosal biopsies of small intestine
`• Primary efficacy endpoint is percent responders (reduction of at least 20% from baseline in weekly
`PN/IV volume at Week-24).
`
`
`1 Buchman AL. The clinical management of short bowel syndrome: steps to avoid parenteral nutrition. 1997. Nutrition. 13(10):
`907-13.
`
`Page 3 of 18
`
`Reference ID: 3235350
`
`

`

`Division Safety Deputy Director Review
`GATTEX (teduglutide [rDNA origin]) for injection, for subcutaneous use. NDA 203441
`
`• Conduct of two (replicative) trials was strongly recommended based on NME status
`06 June 2006: Type C Meeting. FDA gives PK advice for special populations of hepatic and renal
`impairment. No formal drug-drug interaction studies are required, unless evidence arises for interactions.
`(Applicant later submitted hepatic impairment and multi-dose PK studies on 30-Jun-2010; and renal
`impairment study on 13-Sep-2011).
`23 January 2007: Type C Meeting. Primary endpoint change discussed. By this time, Study 004 had
`randomized 84 patients and 55 patients had completed 24 weeks of treatment. Sponsor stated this change
`was not based on an interim analysis. FDA suggested performing a second clinical trial using the new
`primary endpoint. Note: Protocol amendment #4 (13-Feb-2007) incorporates primary endpoint change.
`18 January 2008: Type C Meeting. Results of Study 004 are known. Need for and design of confirmatory
`Phase 3 study (CL0600-020) for at least 24 weeks collecting safety and efficacy data. FDA notes lack of a
`clear dose-response relationship for efficacy in Study 004.
`14 July 2008: Meeting to further discuss the results of Study CL0600-004, the planned Phase 3 Study
`(CL0600-020) and the acceptability of the same PN/I.V. reduction volume endpoint of the development
`program for filing a marketing application. “FDA notes that the study does show some clinical benefit
`however dose response has not been demonstrated. Study 004 has not shown which is the best dose for
`phase 3 studies. FDA indicates that the NPSP is free to select its dose. It would accept a 0.05 mg/kg/day to
`support an NDA; however it is not convinced that 0.05 mg/kg/day is the best dose.” 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”. FDA encourages collection of neutralizing antibody data.
`30 November 2011: NDA submitted to the FDA
`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”, and an orphan medicinal product for human use.
`3 August 2012: FDA received major amendment within 3 months of the user fee goal date, therefore the
`review clock was extended and a new user-fee-goal date of December 30, 2012 was established.
`16 October 2012: FDA held Gastrointestinal Drug Advisory Committee (GIDAC)
`
`Highlights of Review Issues:
`1. New Molecular Entity: first in its class; glucagon-like peptide-2 (GLP-2)
`2. Efficacy: demonstrated by two randomized controlled studies both with extensions. The primary
`efficacy endpoint was amended in one of these during the conduct of the study.
`3. Primary Endpoint: evaluation of clinical meaningfulness, advice sought from the Advisory
`Committee
`4. Safety: potential safety concerns based upon mechanism of action of Gattex.
`5. Risk Mitigation and Evaluation Strategies (REMS): discussion at the GIDAC Meeting.
`3. CMC/Device
`The Chemistry and Manufacturing review concludes that this NDA has provided sufficient information to
`assure identity, strength, purity, and quality of the drug product.
`
`The Amended CMC review concludes that:
`“The updated drug substance specification now includes limits for the Class I metals
`
`, in conformance with USP <232> recommendations. NPS Pharmaceuticals also
`makes a Post Marketing Commitment to add limits to the drug substance specification for the remaining
`metals listed in the USP monograph. This will be done as soon as the method for determining the metals
`is appropriately validated, but no later than March 31, 2013. This approach is considered acceptable since
`
`Page 4 of 18
`
`Reference ID: 3235350
`
`(b) (4)
`
`

`

`Division Safety Deputy Director Review
`GATTEX (teduglutide [rDNA origin]) for injection, for subcutaneous use. NDA 203441
`
`the primary safety concern regarding trace metals that can be present in the drug product comes from the
`Class I metals
` The proposed limits ensure that no unsafe levels
`of these metals will be present in the drug substance. Limits for the additional metals will further improve
`the quality of the drug substance, but these metals do not pose the same potential safety hazard as those of
`the Class 1 metals.”
`
` concur with the conclusions reached by the chemistry reviewer regarding the acceptability of the
`manufacturing of the drug product and drug substance. Manufacturing site inspection is acceptable.
`There are no outstanding issues.
`4. Nonclinical Pharmacology/Toxicology
`The applicant has conducted adequate nonclinical studies with teduglutide which included pharmacology,
`safety pharmacology, pharmacokinetics, acute toxicology studies mice, repeated dose toxicology studies
`in mice (14 days to 26 weeks duration), rats (14 day to 13 weeks duration), 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, embryofetal
`development in rats and rabbits, and pre and postnatal development in rats), and special toxicology studies
`(antigenicity and local tolerance studies). Toxicology studies were conducted using the subcutaneous (SC)
`route, the intended clinical route of administration.
`
`In pivotal repeated dose toxicology studies, major treatment-related effects were related to the
`pharmacological activity of teduglutide which were seen in all species. These included epithelial and
`villus hypertrophy and hyperplasia in the small and large intestine, gall bladder epithelial hypertrophy and
`hyperplasia accompanied by subacute inflammation in the gall bladder, mucosal hyperplasia of the
`stomach, hypertrophy/hyperplasia of the pancreatic duct epithelium, epithelial hypertrophy and
`hyperplasia of the bile duct in the liver, and mucosal hypertrophy/hyperplasia of the gall bladder.
`
`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 subcutaneous route in Wistar Han rats at 3, 10 and 35mg/kg/day
`(about 60, 200 and 700 times the recommended daily human dose of 0.05mg/kg, respectively), 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.
`
`The non-clinical pharmacology review concludes:
`“Overall, 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 hyperplastic changes including carcinogenicity in humans.”
`
`
` I
`
`Page 5 of 18
`
`Reference ID: 3235350
`
`(b) (4)
`
`

`

`Division Safety Deputy Director Review
`GATTEX (teduglutide [rDNA origin]) for injection, for subcutaneous use. NDA 203441
`
`In addition, Pregnancy Category B was recommended based upon animal reproduction studies.
`
`These findings were discussed at the Advisory Committee and will be mentioned in the context of the
`professional labeling, Medication Guide and Risk Evaluation and Mitigation Strategies (REMS) below.
`
`The reviewer recommended approval.
`
` I
`
`
`
`
`
` concur with the conclusions reached by the pharmacology/toxicology reviewer that there are no
`outstanding non-clinical pharmacology/toxicology issues that preclude approval.
`
` Clinical Pharmacology/Biopharmaceutics
`5.
`Clinical Pharmacology is detailed in the approved professional labeling. I will mention clinical
`pharmacology studies and findings which are relevant to the safety of Gattex.
`
`Pharmacodynamic Studies:
`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. These findings agree with the mechanistic action of Gattex by stimulation of the GLP-2
`receptors in the gastrointestinal tract. The studies demonstrated increased villus height, and crypt depth,
`as well as increased absorption of fluids.
`
`Potential for Increased Absorption of Oral Medications:
`Based upon the pharmacodynamic effect of Gattex, there is a potential for increased absorption of
`concomitant oral medications, which should be considered if the concomitant drugs require titration or
`have a narrow therapeutic index.
`
`Renal Impairment:
`Fifty percent (50%) dosage reduction was recommended in subjects with moderate to severe renal
`impairment and end stage renal disease (ESRD) patients based on the results from Study CL0600-018.
`
`Through QT (TQT) interval Studies: The effect of Gattex on the QT interval was studied in the TQT study
`(Study C09-001)
`
`
`The reviewers comment:
`“The effect of single subcutaneous dose of teduglutide 5 mg and 20 mg on QTc interval was
`evaluated in a randomized, placebo- and active- controlled (moxifloxacin 400 mg) four-period
`crossover thorough QT study in 70 healthy subjects. In a study with demonstrated ability to detect
`small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo
`adjusted, baseline-corrected QTc based on Fridericia’s correction method (QTcF) was below 10
`ms, the threshold for regulatory concern. The dose of 20 mg is expected to cover the high exposure
`clinical scenario. No significant QTc prolongation was detected at a supra- therapeutic teduglutide
`dose of 20 mg in the TQT study.”
`
`Page 6 of 18
`
`Reference ID: 3235350
`
`

`

`Division Safety Deputy Director Review
`GATTEX (teduglutide [rDNA origin]) for injection, for subcutaneous use. NDA 203441
`
`Immunogenicity:
`Consistent with the potentially immunogenic properties of medicinal products containing peptides,
`administration of Gattex may trigger the development of antibodies. In a randomized, double-blind,
`placebo-controlled, parallel-group, multi-national, multi-center, clinical trial (CL0600-020) in adults with
`SBS, the incidence of anti-Gattex antibody was 0% (0/16) at Week 12 and 18% (6/34) at Week 24 in
`subjects who received subcutaneous administration of 0.05 mg/kg Gattex once daily. The anti-Gattex
`antibodies were cross-reactive to native glucagon-like peptide (GLP-2) in five of the six subjects (83%)
`who had anti-Gattex antibodies. In the extension study (CL0600-021), the immunogenicity incidence rate
`increased over time to 27% (14/51) at 12 months and 38% (13/34) at 18 months. Anti-Gattex antibodies
`appear to have no impact on short term (up to 1.5 years) efficacy and safety although the long-term impact
`is unknown.
`
` A
`
` total of 40 subjects were tested for neutralizing antibodies--20 of these subjects had no neutralizing
`antibodies, and the remaining 20 subjects had no detectable neutralizing antibodies although, the presence
`of teduglutide at low levels in these study samples could have resulted in false negatives (no neutralizing
`antibody detected although present).
`
`Finally, 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. The
`sponsor is continuing to evaluate this issue in the long-term clinical study CL0600-021.
`
`The reviewers did not recommend PMR/PMCs (Postmarket Requirement/Postmarket commitment).
`
` I
`
` I
`
` concur with the conclusions reached by the clinical pharmacology/biopharmaceutics reviewer that there
`are no outstanding clinical pharmacology issues that preclude approval.
`6. Clinical Microbiology
`Quality microbiology reviewer (for product sterility) has recommended approval. No issues are raised.
`
` concur with the conclusions reached by the clinical microbiology reviewer that there are no outstanding
`clinical microbiology or sterility issues that preclude approval.
`7. Clinical/Statistical-Efficacy
`Efficacy was assessed by analyzing the data from the two SBS placebo-controlled trials (Study 004
`{CL0600-004] and Study 020 [CL0600-020]). Each of these trials had non-randomized open-label
`extensions (Study 005 [CL0600-005] and Study 021[CL0600-020], respectively). These were
`multinational trials conducted in the US, Canada, and Europe.
`
`Study 004 and Study 020 were conducted sequentially. Study 004 was a three arm placebo-controlled
`study: teduglutide 0.05 mg/kg/day; teduglutide 0.10 mg/kg/day. The preliminary results of Study 004
`were available during discussions regarding the design of the primary endpoint and statistical analysis
`plan of Study 020. While these studies are similar in design there were several key differences worth
`noting: the fluid management algorithm, primary endpoint and statistical analysis plans.
`
`
`
`
`Page 7 of 18
`
`Reference ID: 3235350
`
`

`

`Division Safety Deputy Director Review
`GATTEX (teduglutide [rDNA origin]) for injection, for subcutaneous use. NDA 203441
`
`Fluid management algorithm:
`Gattex patients were to have their fluid requirements managed according to protocol algorithm during the
`conduct of the study. Study 004 and Study 020 had different fluid management algorithms to guide the
`clinicians in the selection of the PN/I.V. (parenteral nutrition/intravenous) fluid administered. Study 004
`allowed only a 10% fluid reduction at key time points, while Study 020 allowed a 30% reduction in fluid.
`Thus, the absolute change in volume during the study period for Study 004 appears to be smaller than that
`of Study 020.
`
`In Study 004 at Weeks 4, 8, 12, 16, and 20, investigators adjusted each patient’s PN/I.V. volume based on
`percent change in urine output. In Study 020, an additional fluid adjustment occurred at Week 2.
`
`Primary Efficacy Endpoint:
`Study 004 amended the primary endpoint from a clinical response of a ≥20% decrease in PN/I.V. fluid
`volume at Weeks 20 and 24 to be a 6-level categorical “graded response score” during the conduct of the
`study. NPS felt that this endpoint would more clearly differentiate the clinical efficacy of teduglutide.
`
`Statistical Analysis Plan:
`The analysis plan for Study 004 was a pre-specified efficacy hypothesis testing order where the graded
`score was first tested for the comparison of 0.10 mg/kg/day group versus placebo. Since statistical
`significance was not demonstrated in this comparison all subsequent reported p-values were deemed
`exploratory in nature. The comparison of teduglutide 0.05 mg/kg/day and placebo demonstrated an effect, but
`statistical significance could not be established due to the prespecified hierarchical multiplicity adjustment
`testing strategy. The key secondary endpoint for Study 004 had been the original endpoint prior to the
`amendment. Again, due to the testing procedure statistical significance could not be determined.
`
`Efficacy of Gattex was not demonstrated for Study 004 based upon the pre-specified primary outcome
`variable and analysis plan. Possible reasons included the following:
`1. Change in primary endpoint from a simple responder endpoint (clinical response of ≥20%
`decrease in PN/I.V. fluid volume at Weeks 20 and 24) to a 6-level categorical ‘graded response
`score’.
`2. PN/I.V. fluid volume adjustment was limited to no more than 10% in Study 004
`3. The first PN/I.V. fluid volume adjustment occurred at Week 4 in Study 004, as opposed to
`earlier in the trial.
`4. The high-dose group (0.10 mg/kg/day), which also had a 32% higher baseline weekly PN/I.V.
`volume relative to the 0.05 mg/kg/day dose group, was tested first in the hierarchical
`hypothesis testing procedure and failed to demonstrate efficacy (p=0.161). Therefore, testing
`stopped after the high-dose group, so that testing was not able to proceed to the (0.05
`mg/kg/day dose group.
`5. Higher baseline weekly PN/I.V. fluid requirement in the 0.10 mg/kg/day group led to
`numerically smaller percent change results, and hence fewer patients who achieved clinically
`relevant response in the 0.10 mg/kg/day group relative to the 0.05 mg/kg/day dose group.
`
`
`The design of Study 020 was modified based on the preceding considerations. The primary endpoint for
`the study was designated as the attainment of at least 20% reduction from Baseline in PN/I.V. volume at
`Weeks 20 and 24. This study tested the efficacy of teduglutide 0.5mg/kg/day vs. placebo.
`
`
`
`
`Page 8 of 18
`
`Reference ID: 3235350
`
`

`

`Division Safety Deputy Director Review
`GATTEX (teduglutide [rDNA origin]) for injection, for subcutaneous use. NDA 203441
`
`Study 020 demonstrated a statistically significant (p=0.002) difference between teduglutide and placebo
`for the primary endpoint (percent responders in each study group who achieved at least 20% reduction in
`weekly PN/I.V. volume at Weeks 20 and 24): 62.8% versus 30.2% (teduglutide versus placebo). The
`percent volume reductions in Study 020 were 32% (teduglutide) and 21% (placebo) (p=0.025). Mean
`reduction of weekly PN/I.V. (L/week) was 4.4 L/week for teduglutide and 2.3 L/week for placebo
`(p<0.001).
`
`Although Study 004 did not meet the protocol-specified primary endpoint (i.e., difference between
`teduglutide 0.10 mg/kg/day and placebo for the graded response analysis was not statistically significant),
`the key secondary endpoint in Study 004 did demonstrate a nominal benefit. The percent responders in the
`teduglutide 0.05 mg/kg/day group was greater than placebo (16/35, 45.7% vs 1/16, 6.3%). This analysis
`supports the efficacy findings of Study 020. Additionally, two patients who received the teduglutide 0.05
`mg/kg/day regimen were able to be totally weaned off parenteral support by Week 24. Treatment with this
`teduglutide regimen resulted in a 2.5 L/week reduction in parenteral support requirements versus 0.9
`L/week for placebo at 24 weeks.
`
`The preceding data were determined to be sufficient to approve Gattex (teduglutide) for the following
`agreed upon indication:
`
`“GATTEX® (teduglutide [rDNA origin]) for injection is indicated for the treatment of adult patients with
`Short Bowel Syndrome (SBS) who are dependent on parenteral support.”
`8. Safety
`Across all clinical studies, 566 subjects were exposed to at least one dose of Gattex (190 patient-years of
`exposure; mean duration of exposure was 17 weeks). Of the 566 subjects, 173 subjects were treated in
`Phase 3 SBS studies (134/173 [77%] at the dose of 0.05 mg/kg/day and 39/173 [23%] at the dose of 0.10
`mg/kg/day).
`
`The most commonly reported (≥ 10%) adverse reactions in patients treated with Gattex across all clinical
`studies (n = 566) were: abdominal pain (30.0%); injection site reactions (22.4%); nausea (18.2%);
`headaches (15.9%); abdominal distension (13.8%); upper respiratory tract infection (11.8%).
`
`The rates of adverse reactions in subjects with SBS participating in two randomized, placebo-controlled,
`24-week, double-blind clinical studies (Study 1 and Study 3) are summarized in Table 1. Only those
`reactions with a rate of at least 5% in the Gattex group, and greater than placebo group, are summarized in
`Table 1. The majority of these reactions were mild or moderate. Of subjects receiving Gattex at the
`recommended dose of 0.05 mg/kg/day, 88.3% (N=68/77) experienced an adverse reaction, as compared to
`83.1% (49/59) for placebo. Many of these adverse reactions have been reported in association with the
`underlying disease and/or parenteral nutrition.
`
`
`Table 1: Adverse reactions in ≥5% of GATTEX-treated SBS subjects and
`more frequent than placebo: Studies 1 and 3
`Placebo
`(N=59)
`n (%)
`
`Adverse Reaction
`
`GATTEX
`0.05mg/kg/day
`(N=77)
`n (%)
`
`Page 9 of 18
`
`Reference ID: 3235350
`
`

`

`Division Safety Deputy Director Review
`GATTEX (teduglutide [rDNA origin]) for injection, for subcutaneous use. NDA 203441
`
`16 ( 27.1)
`8 ( 13.6)
`12 ( 20.3)
`1 ( 1.7)
`6 ( 10.2)
`4 ( 6.8)
`4 ( 6.8)
`3 ( 5.1)
`2 ( 3.4)
`0
`0
`1 ( 1.7)
`
`
`
`29 ( 37.7)
`20 ( 26.0)
`19 ( 24.7)
`15 ( 19.5)
`9 ( 11.7)
`9 ( 11.7)
`7 ( 9.1)
`6 ( 7.8)
`5 ( 6.5)
`4 ( 5.2)
`4 ( 5.2)
`4 ( 5.2)
`
`
`
`Abdominal Pain
`Upper Respiratory Tract Infection
`Nausea
`Abdominal Distension
`Vomiting
`Fluid Overload
`Flatulence
`Hypersensitivity
`Appetite Disorders
`Sleep Disturbances
`Cough
`Skin Hemorrhage
`Subjects with Stoma
`a
`a
`
`Gastrointestinal Stoma Complication
`13 (41.9)
`
`3 (13.6)
`aPercentage based on 53 subjects with a stoma (N = 22 placebo; N = 31
`GATTEX 0.05 mg/kg/day)
`
`In placebo-controlled Studies 1 and 3, 12% of patients in each of the placebo and Gattex study groups
`experienced an injection site reaction.
`
`Deaths
`A total of 3 deaths were reported during the drug development. Two were enrolled in Study 021 and had
`a diagnosis of malignancy (cases discussed below). One died prior to treatment with teduglutide during
`the screening period.
`
`Adverse Reactions of Special Interest
`
`Malignancy. Three subjects were diagnosed with malignancy in the clinical studies, all of whom were
`male and had received Gattex 0.05 mg/kg/day in Study 2. One subject, who had a history of abdominal
`radiation for Hodgkin’s disease two decades prior to receiving Gattex and a liver lesion on CT scan prior
`to receiving study drug, was diagnosed with metastatic adenocarcinoma of unconfirmed origin after 11
`months of exposure to Gattex. Two subjects had extensive smoking histories, and were diagnosed with
`lung cancers (squamous and non-small cell) after 12 months and 3 months of Gattex exposure,
`respectively.
`
`Colorectal Polyps. In the clinical studies, 6 subjects were diagnosed with polyps of the G.I. tract after
`initiation of study treatment. In the SBS placebo-controlled studies, 1/59 (1.7%) of subjects on placebo
`and 1/109 (0.9%) of subjects on Gattex 0.05 mg/kg/day were diagnosed with intestinal polyps
`(inflammatory stomal and hyperplastic sigmoidal after 3 and 5 months, respectively). The remaining 4
`polyp cases occurred in the extension studies--two colorectal villous adenomas (onset at 6 and 7 months in
`Gattex 0.10 and 0.05 mg/kg/day dose groups, respectively), one hyperplastic polyp (onset 6 months in
`Gattex 0.10 mg/kg/day dose group), and one small duodenal polyp (onset at 3 months in Gattex 0.05
`mg/kg/day dose group).
`
`Gastrointestinal Obstruction. Overall, 12 subjects experienced one or more episodes of intestinal
`obstruction/stenosis: 6 in SBS placebo-controlled studies and 6 in the extension studies. The 6 subjects in
`the placebo-controlled trials were all on Gattex: 3/77 (3.9%) on Gattex 0.05 mg/kg/day and 3/32 (9.4%)
`on Gattex 0.10 mg/kg/day. No cases of intestinal obstruction occurred in the placebo group. Onsets
`ranged from 1 day to 6 months. In the extension studies, 6 additional subjects (all on Gattex 0.05
`mg/kg/day) were diagnosed with intestinal obstruction/stenosis with onsets ranging from 6 days to
`7 months. Two of the 6 subjects from the placebo-controlled trials experienced recurrence of obstruction
`
`Page 10 of 18
`
`Reference ID: 3235350
`
`

`

`Division Safety Deputy Director Review
`GATTEX (teduglutide [rDNA origin]) for injection, for subcutaneous use. NDA 203441
`
`in the extension studies. Of all 8 subjects with an episode of intestinal obstruction/stenosis in these
`extension studies, 1 subject required endoscopic dilation and none required surgical intervention.
`
`
`Gallbladder, Biliary and Pancreatic Disease. For gallbladder and biliary disease in the placebo-
`controlled studies, 3 subjects were diagnosed with cholecystitis, all of whom had a prior history of
`gallbladder disease and were in the Gattex 0.05 mg/kg/day dose group. No cases were reported in the
`placebo group. One of these 3 cases had gallbladder perforation and underwent cholecystectomy the next
`day. The remaining 2 cases underwent elective cholecystectomy at a later date. In the extension studies,
`3 subjects had an episode of acute cholecystitis; 2 subjects had new-onset cholelithiasis; and 1 subject
`experienced cholestasis secondary to an obstructed biliary stent. For pancreatic disease in the placebo-
`controlled studies, 1 subject (Gattex 0.05 mg/kg/day dose group) had a pancreatic pseudocyst diagnosed
`after 4 months of Gattex. In the extension studies, 1 subject was diagnosed with chronic pancreatitis; and
`1 subject was diagnosed with acute pancreatitis.
`
`Fluid Overload. In the placebo-controlled trials, fluid overload was reported in 4/59 (6.8%) of subjects on
`placebo and 9/77 (11.7%) subjects on Gattex 0.05 mg/kg/day. Of the 9 cases in the Gattex group, there
`were 2 cases of congestive heart failure (CHF), 1 of whom was reported as a serious adverse event and the
`other as non-serious. The serious case had onset at 6 months, and was possibly associated with previously
`undiagnosed hypothyroidism and/or cardiac dysfunction.
`
`Concomitant Oral Medication. Gattex can increase the absorption of concomitant oral medications such
`as benzodiazepines and psychotropic agents. In the placebo-controlled trials, an analysis of episodes of
`cognition and attention disturbances was performed for subjects on benzodiazepines. One of the subjects
`in the Gattex 0.05 mg/kg/day group (on prazepam) experienced dramatic deterioration in mental status
`progressing to coma during her first week of Gattex therapy. She was admitted to the ICU where her
`benzodiazepine level w