`
` CENTER FOR DRUG EVALUATION AND
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`
`
` RESEARCH
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`
`
` APPLICATION NUMBER:
`
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` 208276Orig1s000
`
`
`
`
`
` NON-CLINICAL REVIEW(S)
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`

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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`
`Application NDA number:
`Supporting document/s:
`Received date:
`Review completion date:
`Product:
`Indication:
`
`208276
`Original e-submission, eCTD 0010
`4/15/2016
`8/4/2016
` Remodulin® (treprostinil) implantable system
`For convenient delivery of treprostinil in the treatment of
`pulmonary arterial hypertension
`United Therapeutics Corp., Research Triangle Park, NC
`Cardiovascular and Renal Products
`(DCRP/ODE1/OND/CDER)
`Belay Tesfamariam, PhD
`Reviewer:
`Albert DeFelice, PhD
`Team Leader:
`Norman Stockbridge, MD, PhD
`Division Director:
`Project Manager: Wayne Amchin
`
`Applicant:
`Review Division:
`
`Disclaimer
`Except as specifically identified, all data and information discussed below and necessary for approval
`of NDA 208276 are owned by United Therapeutics Corp. or are data for which United Therapeutics
`Corp. has obtained a written right of reference. Any information or data necessary for approval of
`NDA 208276 that United Therapeutics Corp. does not own or have a written right to reference
`constitutes one of the following: (1) published literature, or (2) a prior FDA finding of safety or
`effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or information
`described or referenced below from reviews or publicly available summaries of a previously approved
`application is for descriptive purposes only and is not relied upon for approval of NDA 208276.
`
`Reference ID: 3968105
`Reference ID: 4409052
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`1
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`NDA #0208276
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`
`
`Reviewer: Belay Tesfamariam
`
`TABLE OF CONTENTS
`
`1
` EXECUTIVE SUMMARY...........................................................................................3
`
`INTRODUCTION .....................................................................................................3
`
`1.1
`1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS .......................................................3
`
`1.3 RECOMMENDATIONS .............................................................................................3
`
`2
` DRUG INFORMATION..............................................................................................4
`
`2.1 DRUG ..................................................................................................................4
`
`2.2 RELATED INDS, NDAS .........................................................................................4
`
`
`2.3 DUG FORMULATION ..............................................................................................4
`
`2.3 CLINICAL INDICATION AND DOSING REGIMEN............................................................5
`
`3 STUDIES SUBMITTED.............................................................................................5
`
`
`4 PHARMACOLOGY ...................................................................................................5
`
`4.1 PRIMARY PHARMACOLOGY ....................................................................................5
`
`4.2 SECONDARY PHARMACOLOGY ...............................................................................5
`
`4.3 SAFETY PHARMACOLOGY ......................................................................................6
`
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .................................................8
`
`5.1 PK/ADME ...........................................................................................................8
`
`TOXICOKINETICS...................................................................................................8
`
`5.2
`6 GENERAL TOXICOLOGY........................................................................................9
`
`6.1 SINGLE-DOSE TOXICITY OF TREPROSTINIL .............................................................9
`
`6.2 REPEAT-DOSE TOXICITY OF TREPROSTINIL ............................................................9
`
`TREPROSTINIL IMPLANTABLE CATHETER IN DOGS.....................................................9
`
`6.3
`7 GENETIC TOXICOLOGY........................................................................................11
`
`
`8 CARCINOGENICITY...............................................................................................11
`
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY.................................11
`
`
`10
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`11
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`12
`
`SPECIAL TOXICOLOGY STUDIES....................................................................12
`
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION..................................12
`
`
`APPENDIX/ATTACHMENTS ..............................................................................14
`
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`Reference ID: 3968105
`Reference ID: 4409052
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`NDA #0208276
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`
`
`Reviewer: Belay Tesfamariam
`
`1
`
`Executive Summary
`
`1.1
`
`Introduction
`Treprostinil (Remodulin®) is a chemically stable prostacyclin (PGI2) analog, with potent
`systemic and pulmonary vasodilating as well as antiplatelet effects, indicated for the treatment
`of pulmonary arterial hypertension (PAH). An injectable formulation of treprostinil has been
`approved for the treatment of PAH by continuous subcutaneous (sc) or intravenous (IV)
`routes. Infusion site pain and reactions, and catheter-related infection or sepsis were
`reported to be the most common adverse events among patients treated per sc or IV
`administration of treprostinil. The sponsor proposes that usage of a sterile implantable
`system may allow delivery of chronic infusion of treprostinil, as well as reduce adverse effects
`associated with the sc or IV routes. The proposed treprostinil implantable system design is
`based on the established drug delivery technology of the Implantable Intravascular Catheter
`(Model 10642), the SynchroMed® II Implantable Infusion System (Model 8637), and the
`N’Vision® Clinician Programmer (Model 8840) with SynchroMed II application software (Model
`8870). The sponsor cross-referenced the studies conducted on treprostinil injection in the
`NDA 21-272 to support the supplemental NDA 208276.
`
`1.2 Brief Discussion of Nonclinical Findings
`In this supplemental NDA 505(b)(2), the deliverability of treprostinil was evaluated
`using the intravascular catheter (Model 10642) and the SynchroMed II infusion pump (Model
`8637) implanted via the right jugular vein with final tip advanced into the superior vena cava
`slightly outside of the cardiac shadow in the dog. Animals were continuously infused at a rate
`of 22.5 μL/hr for 26 weeks, which corresponds to a treprostinil dosage of 12.5 ng/kg/min. The
`radiographs of the implanted system showed no evidence of dislocation, kinking or
`discontinuity, indicating stability and integrity of the implanted system. No occlusions of the
`catheters were observed as determined by the analysis of pump volumes, pressure
`waveforms, and radiographs. Gross and histopathological analysis revealed only mild local
`changes in the anterior vena cava associated with the physical presence of the indwelling
`implantable intravascular catheter. Tissue reactions to catheters containing treprostinil
`injection were similar to those containing saline. The plasma concentration of treprostinil
`achieved from the implantable system was comparable to that obtained by sc or IV routes of
`administration. The preclinical studies showed that the implantable pump and catheter
`system using Models 10642 and 8637 appear to deliver treprostinil in a continuous and
`consistent manner, and that catheter patency was maintained throughout the study duration
`with no significant adverse effects.
`
`1.3 Recommendations
`1.3.1 Approvability:
`The extent and scope of the pharmacological and toxicological documentation provided
`are adequate to provide safety information on remodulin as delivered. The approvability of
`the Remodulin Implantable System will rely on the evaluations of the safety of the drug
`delivery device.
`
`Reference ID: 3968105
`Reference ID: 4409052
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`NDA #0208276
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`Reviewer: Belay Tesfamariam
`
`1.3.2 Labeling
`The proposed prescribing information includes an appropriate description of the
`pharmacology, genotoxicity, carcinogenicity and reproductive and developmental toxicology.
`Drug Information
`2
`2.1 Drug
`Trade Name:
` Remodulin®
`
`Generic Name:
`Treprostinil
`Chemical Name: Prostacyclin I2 (PGI2 analog)
`
`Empirical formula: (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3­
`
`hydroxyoctyl]-1Hbenz[f]inden-5-yl]oxy]acetic acid
`Molecular formula:C23H34O5
`Molecular Weight: 390.51
`
`Structure:
`
`
`Pharmacologic Class: Vasodilator
`Route of administration: Implantable pump
`
`2.2 Related INDs, NDAs
`The NDA 21-272 supports the usage of treprostinil IV and sc at a starting infusion rate
`of 1.25 ng/kg/min, with increments of 2.5 ng/kg/min per week, for the treatment of PAH.
`
`2.3 Dug Formulation
`Treprostinil injection is a sterile solution of treprostinil formulated for sc or IV
`administration. Treprostinil will be supplied in 20 mL multi-dose vials in three strengths for the
`implantable system, containing 50 mg, 100 mg, or 200 mg (2.5 mg/mL, 5 mg/mL or 10
`mg/mL) of treprostinil. Each mL also contains 5.3 mg sodium chloride (except for the 10
`mg/mL strength which contains 4 mg sodium chloride), 3 mg metacresol, 6.3 mg sodium
`citrate
`, and water for injection. Sodium
`hydroxide and hydrochloric acid may be added to adjust pH between 6.0 and 7.2.
`
`
`Impurities from implants:
`Characterization of leachable impurities from the implantable infusion system
`identified 30 organic chemicals and 8 inorganic chemicals per analysis of four leachate peaks
`
`(ICH Q3C Impurities: Residual Solvents). The level of leachables for most
`
`chemicals was less than μg/day with the exception of
`. The margins of safety
`(
`(the ratio of Permitted Daily Exposure to the Daily Exposure/Daily Intake) of all leachables
`
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`Reviewer: Belay Tesfamariam
`
`, indicating that adverse effects are unlikely to occur from the chemicals leaching
`exceed
`from the implantable system at the rates reported.
`2.3 Clinical Indication and dosing regimen
`Treprostinil implantable system is intended for the treatment of PAH by continuous IV
`infusion of treprostinil at mean Remodulin dosages of 72.2±29.5 ng/kg/min (22 to 160
`ng/kg/min) using the implantable intravascular catheter and infusion systems (Models
`10642/8637). The remodulin implantable system delivers treprostinil at a concentration of
`2.5, 5 or 10 mg/mL.
`
`3
`
`Studies Submitted
`Studies Reviewed: The pharmacology, pharmacokinetics, toxicology, genotoxicity,
`carcinogenicity and reproductive toxicology of treprostinil are cross-referenced to the
`information in the original NDA 21-272. In addition, the study on treprostinil implantable
`catheter in the dog is reviewed.
`
`4
`
`Pharmacology
`
`4.1 Primary Pharmacology
`Treprostinil is a direct vasodilator of pulmonary and systemic arterial vascular beds,
`and an inhibitor of platelet aggregation.
`
`4.2 Secondary Pharmacology
`Secondary pharmacodynamics of treprostinil was not conducted.
`
`Remodulin implantable system
`Delivery of treprostinil with the implantable system serves an unmet medical need with a
`meaningful advantage over parenteral delivery using external pumps for drug delivery. The
`implantable system has the potential to address: i) patient convenience by reducing frequency
`of refills from every 2 - 3 days to 1 - 3 months; ii) compliance since there is no patient
`interaction required; iii) daily patient burdens because with an implanted system there is no
`drug admixture, catheter sets or infusion sets requiring patients to actively manage therapy on
`a daily basis; iv) catheter-related complications and infections because the implantable system
`is fully implanted; and overall quality of life issues since patients no longer have the restrictions
`associated with the external system.
`
`Pharmacological activity of treprostinil
`4.2.1. Platelet antiaggregatory activity
`In vitro studies using human platelet-rich plasma showed that treprostinil caused a
`concentration-dependent inhibition of ADP-induced aggregation of human platelets, with an
`IC50 of 28.2 nM (11 ng/ml). Treprostinil was 20-fold less potent than prostacyclin in inhibiting
`the ADP-induced aggregation of human platelets.
`
`Reference ID: 3968105
`Reference ID: 4409052
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`NDA #0208276
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`Reviewer: Belay Tesfamariam
`
`4.2.2. Vascular relaxation effects
`Treprostinil induced a concentration-dependent relaxation of isolated rabbit mesenteric
`artery segments precontracted with the thromboxane A2 mimetic, U-46619. The order of
`
`potency when compared to other prostaglandins was treprostinil > carbacyclin (a stable PGI2
`analogue) > 16-dimethyl-PGE2 > PGE2. Treprostinil was 8 and 45 times more potent in
`inducing vascular relaxation than carbacyclin and PGE2, respectively.
`
`4.2.3. Antiproliferative effects
`Treprostinil markedly reduced proliferation of cultured human pulmonary artery smooth
`
`muscle cells, as measured by cell counting (92% reduction) and [3H]-thymidine incorporation
`(61% reduction). In addition, treprostinil induced increase in intracellular cAMP to levels that
`were about 6-fold higher than control at 72 hours after drug treatment, indicating that
`treprostinil exerts persistent antiproliferative effect via a cAMP-dependent pathway in
`
`pulmonary artery smooth muscle cells.
`
`4.2.5. Effects of Treprostinil on plasma angiotensin II concentrations
`Treprostinil infusions dose-dependently increased plasma angiotensin ll concentrations
`(50 - 263 pg/ml) that correlated inversely with reduced mean arterial blood pressure in
`anesthetized dogs. Prostacyclin (PGI2), when given to anesthetized dogs for 4 hours at 0.01
`to 0.3 μg/kg/min, produced vascular and cardiac effects similar to those produced by
`treprostinil; however, PGI2 was 10 times more potent than treprostinil. PGI2 infusions also
`dose-dependently increased plasma angiotensin ll concentrations. Pretreatment with an
`angiotensin converting enzyme inhibitor, enalapril (0.3 mg/kg, iv), prevented the treprostinil­
`induced increases in plasma angiotensin II concentrations. Digoxin (100 mg/kg) pretreatment
`attenuated the ability of treprostinil to elevate plasma angiotensin II levels while pretreatment
`with a loop diuretic (furosemide, 1 mg/kg) potentiated the increase in plasma angiotensin II
`concentrations induced by treprostinil. These observations suggest that pretreatment with
`enalapril, digoxin or furosemide may enhance the cardiovascular effects of treprostinil.
`
`4.3 Safety Pharmacology
`4.3.1. Central nervous system:
`
`
`In anesthetized cats, IV infusion of treprostinil, at 3 - 30 μg/kg/min for 20 minutes, had
`no effect on nictitating membrane contractions induced by cervical sympathetic nerve
`stimulation, or on bradycardia induced by vagal nerve stimulation, indicating that treprostinil
`had no effect on either the sympathetic or the parasympathetic components of the
`autonomic nervous system.
`
`4.3.2. Respiratory system:
`
`Treprostinil (10 - 100 nM) produced weak contractile responses in guinea pig isolated
`tracheal segments. In precontracted guinea pig tracheal preparations, treprostinil (10-8 - 10-3
`
`M) caused concentration-related relaxation, with an ED50 of 270 nM. Treprostinil was
`equipotent with PGE2 (ED50 = 220 nM) and about 400 times more potent than the stable
`prostacyclin analogue, carbacyclin (ED50 = 100 μM). In anesthetized cats, IV infusion of
`treprostinil (3 - 30 μg/kg/min for 20 minutes) had minimal effects on both respiratory rate and
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`Reviewer: Belay Tesfamariam
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`tidal volume except at the high dosage which increased respiratory rate by 10 - 15
`breaths/min.
`
`4.3.3. Cardiovascular (in anesthetized dogs):
`Four hour IV infusions of treprostinil (0.1, 0.3, 1 and 3 μg/kg/min) in anesthetized dogs
`produced dose-dependent decreases in MAP (10 - 68%) and total peripheral resistance
`(TPR, 20 - 73%). Although decreases in pulmonary artery pressure and pulmonary vascular
`resistance (PVR, 9 - 33%) were observed, these effects were not dose-related. The vascular
`
`effects were rapid in onset, achieving maximum effect within 5 - 10 min of infusion with rapid
`recovery on termination of infusion. The effects on PVR were not dose-related, and plasma
`sample analysis showed a close relationship between plasma concentrations of treprostinil
`and changes in TPR and PVR. Pharmacodynamic modeling predicted maximum decreases
`in TPR of 66% and PVR of 22%. The plasma concentrations of treprostinil producing 50% of
`the maximum effect on systemic and pulmonary vascular resistances were 8.6 ng/ml and 11.3
`ng/ml, respectively.
`Treprostinil produced dose-dependent decreases in left ventricular inotropic (+dP/dt)
`
`activity at 1 and 3 μg/kg/min dosages, and significant dosage-dependent decreases in left
`ventricular lusitropic (-dP/dt) activity at dosages of 0.3 μg/kg/min and above. At 3 μg/kg/min,
`both +dP/dt and -dP/dt exhibited an apparent rebound above control values on termination of
`infusion. Significant decreases in left ventricular end diastolic pressure were noted at all dose
`levels. Cardiac output was significantly increased at 0.3 μg/kg/min and above and heart rate
`was increased at 0.3 and 3 μg/kg/min (30 - 68%). Treprostinil produced dose-dependent
`decreases in PR and QRS intervals with no significant effect on QTc.
`
`4.3.4. Cardiovascular (in conscious dogs):
`(Study #: B071362, 12/2008)
`In dogs, ten-minute IV infusions of treprostinil (0.3, 1 and 3 μg/kg/min) produced dose-
`related reductions of both systolic (18 - 40 mmHg) and diastolic (13 - 45 mmHg) blood
`pressures with increases in heart rates (13 - 30 bpm). These effects were rapid in onset and a
`full recovery was evident within 5 - 10 minutes of termination of infusion.
`In conscious dogs, sc administration of treprostinil at dosages up to 0.03 mg/kg had no
`effect on blood pressure, heart rate, and electrocardiographic parameters, but at higher
`dosages ≥0.1 mg/kg significant decrease in systolic, diastolic, and mean blood pressure were
`observed at 0.5 hour, and significant increase in heart rate were observed at 1 and 2 hours
`after administration as compared to the vehicle control group (n=4 M/dose group). Treprostinil
`at 0.3 mg/kg had no effects on PR interval and QRS duration; however, significant decrease in
`systolic and diastolic blood pressure and mean blood pressure, and significant increase in
`heart rate, and significant prolongation in QTc values at 2 hours after administration were
`observed. These results indicate that treprostinil has effects on the blood pressure and heart
`rate at ≥0.1 mg/kg, and on QT interval at 0.3 mg/kg in conscious dogs. The high dosage of 0.3
`mg/kg achieved a Cmax 116.1 ng/ml, which is approximately 30-fold higher than the Cmax of
`3.6 ng/ml achieved in the clinical studies.
`
`4.3.5. Gastrointestinal system:
`
`Treprostinil exhibited weak contractile effects on isolated segments of guinea pig ileum,
`rat stomach or rat colon. When given orally, treprostinil inhibited GI motility and fluid secretion
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`ORIGINAL
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`NDA #0208276
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`Reviewer: Belay Tesfamariam
`
`in the rat small intestine. In rats, treprostinil inhibited ulcer formation induced by indomethacin
`or ethanol, suggesting that the anti-ulcer activity may be due to a cytoprotective rather than an
`antisecretary effect. In rats, pretreatment with a single dose of treprostinil (0.5 and 5 mg/kg,
`po) reduced the severity of carbon tetrachloride-induced hepatotoxicity. Treprostinil (0.03 - 10
`mg/kg, po) had no effect on pentobarbital metabolism in rats, as measured by sleep duration,
`indicating absence of interaction with liver enzyme function.
`
`5
`
`Pharmacokinetics/ADME/Toxicokinetics
`
`5.1 PK/ADME
`Nonclinical pharmacokinetics of treprostinil is cross-referenced with the information in
`the NDA 21-272 and in peer-reviewed journals on treprostinil administered sc and IV.
`5.1.1. Absorption
`Treprostinil is relatively rapidly and completely absorbed after sc infusion, with an
`absolute bioavailability approximating 100% relative to intravenously administered
`treprostinil. Intravenously and subcutaneously administered treprostinil at a dosage of 10
`ng/kg/min for 72 hrs achieved steady state plasma concentration of 1.09±0.23 and
`1.15±0.19 ng/ml, respectively, and were considered to be bioequivalent.1-3 The elimination
`half-life of treprostinil was 4.4 and 4.6 hours following IV and sc administration, respectively,
`which further demonstrates comparability of the two routes of administration at steady state.
`
`5.1.2. Distribution
`The volume of distribution of treprostinil in the central compartment is approximately
`14L/70 kg ideal body weight. The pharmacokinetics of continuous sc administration of
`treprostinil were linear over the dose range of 1.25 to 125 ng/kg/min (corresponding to
`plasma concentrations of about 15 pg/mL to 18,250 pg/mL) and can be described by a two-
`compartment model. Treprostinil is 91% bound to human plasma protein.
`
`5.1.2. Metabolism
`Treprostinil is substantially metabolized by the liver, primarily by CYP2C8. Five
`metabolites were detected in the urine, ranging from 10.2% to 15.5% and representing
`64.4% of the dose administered. Four of the metabolites are products of oxidation of the 3­
`hydroxyloctyl side chain and one is a glucuro-conjugated derivative (treprostinil glucuronide).
`The identified metabolites do not appear to have activity. Based on in vitro studies,
`treprostinil does not inhibit or induce major CYP enzymes.
`
`5.1.3. Excretion
`Administration of a single 8-hour sc infusion of [14C]-treprostinil (15 ng/kg/min), urinary
`excretion was the main route of elimination of [14C]-treprostinil-derived radioactivity (about 78%
`of the administered dose). Fecal elimination accounted only for about 12% of the administered
`dose.
`5.2 Toxicokinetics
`Toxicokinetics of treprostinil are cross-referenced to the information in the NDA 21-272.
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`NDA #0208276
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`Reviewer: Belay Tesfamariam
`
`6 General Toxicology
`The general toxicology of treprostinil is cross-referenced to the previous studies in the
`NDA 21-272.
`
`6.1 Single-Dose Toxicity of Treprostinil
`In an acute dose study of treprostinil administered subcutaneously for 3 hrs in Sprague
`Dawley rats at dosages up to 500 ng/kg/min showed no adverse clinical signs.
`
`6.2 Repeat-Dose Toxicity of Treprostinil
`In a 14-day continuous sc infusion study at dosages ≥400 ng/kg/min in Beagle dogs,
`gross necropsy examination revealed intestinal intussusception and rectal prolapse.
`Histopathology findings consisted of moderate intussusception with hemorrhage,
`inflammatory cellular infiltrate, necrosis of the everted ileum and edema of rectum. The
`clinical signs observed in high dose animals included hypoactivity, emesis and loose stool.
`Edema with or without skin lesions at the injection sites was seen in treated and control
`dogs. There were no treatment-related hematology, clinical chemistry, EKG and organ
`weight findings in this study. The no-observed-adverse-effect-level (NOAEL) was
`considered to be 200 ng/kg/min.
`In a 26-week sc continuous infusion toxicity study in rats at dosages up to 450
`ng/k/min, the most frequently observed clinical signs included the presence of lumps,
`swellings and/or thickening of the skin at or around the infusion site. The incidence and
`frequency of occurrence of infusion site findings were higher in all drug-treated groups
`compared to control groups, and also, the incidence of lesions at the site of infusion was
`greater in the high dosage animals than in lower dosage group animals. Dosage-related
`increased incidences of redness of the nose, pinnae, paws and/or tail were seen at 450
`ng/kg/min (Css 20 ng/ml).
`
`6.3 Treprostinil implantable catheter in dogs
`Implanted catheter and pump drug delivery study
`Study no.:
`S1094
`Study report location:
`Date of study completion:
`September 23, 2005
`GLP compliance: Yes
`Drug:
`Treprostinil (1 mg/ml)
`
`Formulation/Vehicle: Saline (0.9% NaCL)
`Route: Venous catheter (Model 10642), connected to implanted
`drug pump (Model 8637, SynchroMed II, Medtronic)
`Dosages:
`540 μL/day (0.0225 mL/hr) = 12.5 ng/min/kg
`Species Canine
`
`Weight:
` 25 – 30 kg
`Number of rats: N=12 (6/group), M/F
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`Reference ID: 3968105
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`NDA #0208276
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`
`Reviewer: Belay Tesfamariam
`
`Study design: In a chronic 26-week study to evaluate the deliverability and safety of
`the venous catheter (Model 10642) connected to implanted drug pump (Model 8637
`SynchroMed II), a total of twelve dogs were implanted via the right jugular vein with final tip
`advanced into the superior vena cava slightly outside of the cardiac shadow. At the time of
`
`implant, each pump was filled with 18 mL of infusate of either treprostinil (1 mg/mL) or saline.
`Animals were continuously infused via SynchroMed II infusion system programmed to deliver
`540 μL/day (3.8 mL/week) for 26 weeks, which computes to a treprostinil dosage of 15 or 12.5
`ng/min/kg for a 25 kg and 30 kg dog, respectively. No anticoagulant was used.
`Catheter stability: The radiographs of the implanted system showed no evidence of
`dislocation, kinking, or discontinuity thereby demonstrating stability and integrity of the
`implanted system. No occlusions of the catheters were observed in the study, as indicated by
`analysis of pump refill volumes, pressure waveforms, radiographs, and plasma treprostinil.
`Accuracy of drug delivery: The average error over the study for each animal ranged
`from +7.3% (more volume delivered than programmed) to -1.2% (less volume delivered than
`programmed volume), which was well within the expected delivery accuracy specification of
`the SynchroMed II drug pump (±14.5%).
`Histopathology: Only mild local changes in the anterior vena cava associated with
`the physical presence of the indwelling implantable intravascular catheter were observed.
`Tissue reactions to catheters containing saline or treprostinil infusate were similar. Tissue
`morphological changes were similar to those previously reported in the implanted pacing
`leads in the right heart.
`Plasma treprostinil: Mean plasma treprostinil concentrations of 1.03±0.29 ng/mL
`
`were achieved, with an estimated plasma clearance of 364 mL/min (Figure 1, Panel A). The
`variances in treprostinil plasma levels were consistent and comparable between dogs over
`the 26-week study period (Figure 1, Panel B). Plasma treprostinil data reflect continuous and
`consistent delivery of treprostinil injection, which indicates that the catheters were patent
`throughout the study duration.
`Panel A
`
`Panel B
`
`Figure 1. Panel A: Mean treprostinil plasma concentrations over 26 weeks (N=3-6).
`
`Panel B: Variation in mean treprostinil plasma concentrations for each dog.
`
`Summary: The implantable system showed continuous and consistent delivery of
`treprostinil with no significant adverse effects. The radiographs of the catheter body showed
`no evidence of kinking or a discontinuity indicating patency of the catheter body throughout
`the study duration. The plasma concentrations of treprostinil achieved from the implantable
`system were comparable to those achieved by sc or IV administration of treprostinil (4 Morris et
`al., 2008).
`
`Reference ID: 3968105
`Reference ID: 4409052
`
`10
`
`

`

`NDA #0208276
`
`
`
`Reviewer: Belay Tesfamariam
`
`7 Genetic Toxicology
`In vitro and in vivo genetic toxicology studies did not demonstrate any mutagenic or
`clastogenic effects of treprostinil.
`7.1. In vitro mammalian cell mutation assay (in mouse lymphoma TK assay)
`
`Study no.:
`963729
`
`Conducting laboratory:
`
`
`Report date: Jan 25, 2011
`GLP compliance: Yes,
`QA statement: Yes
`Drug:
`Treprostinil,
`
` Batch #: RD-UT-1066-082
`
`Positive control:
`4-Nitroquinoline-N-oxide (NQO), and Benzo(a)pyrene (BaP)
`
`Negative control:
`Vehicle DMSO
`Strains/cell line: Mouse lymphoma L5178Y cells TK+/­
`The ability of treprostinil to induce forward mutation in the mouse lymphoma L5178Y
`cells at the thymidine kinase locus was determined using concentrations of test article
`selected on the basis of viability of treated cells (Table 1). No substantial increases in
`mutation frequency were observed after treatment of cells with treprostinil at concentration
`levels up to the limit of toxicity in the presence and absence of metabolic activation (Table 1).
`It is concluded that treprostinil did not show any evidence of genotoxicity. In summary,
`treprostinil is not a mutagen in the mouse lymphoma cell assay.
`
` Table 1: Percent increase in mutant frequency in mouse Lymphoma L5178 cell line
`- S9 mix
`+ S9 mix (3 hr activation)
`(24 hr activation)
`Treprostinil Cell growth Mutant
`Treprostinil Cell growth
`Mutant
`
`
`
`
`(% viability) Frequency
`μg/mL (% viability) Frequency
`μ/mL)
`
`
` 0
`82
`106
` 0
` 80
`145
` 80
`123
`112
`30.8
`83
`137
`220
`95
`111
`61.5
`81
`108
`247
`68
`108
`123
`70
`193
`277
`56
`131
`149
`74
`130
`BaP (1 μg/mL) 66
`447*
`
`
` 56
`NQ) (0.1 μg/mL)
`Positive control: NQO = 4-Nitroquinoline-N-oxide, BaP = Benzo(a)pyrene
`
`
`
`
`
`
`
`464*
`
`
`
`
`
`
`
`
`
`
`
`8 Carcinogenicity
`Long-term studies have not been performed to evaluate the carcinogenic potential of
`treprostinil.
`
`9 Reproductive and Developmental Toxicology
`Treprostinil did not affect fertility or mating performance of male or female rats given
`continuous sc infusions at rates of up to 450 ng/kg/min [HED 73 ng/kg/min, about 59 times
`the recommended starting human rate of infusion (1.25 ng/kg/min) and about 8 times the
`average rate (9.3 ng/kg/min) achieved in clinical trials]. In pregnant rats, continuous sc
`infusions of treprostinil during organogenesis and late gestational development, at rates as
`high as 900 ng/kg/min (HED 146 ng/kg/min, about 117 times the starting human rate of
`infusion, and about 16 times the average rate achieved in clinical trials), resulted in no
`evidence of harm to the fetus. In pregnant rabbits, effects of continuous sc infusions of
`
`Reference ID: 3968105
`Reference ID: 4409052
`
`11
`
`(b) (4)
`
`

`

`NDA #0208276
`
`
`
`Reviewer: Belay Tesfamariam
`
` treprostinil during organogenesis were limited to an increased incidence of fetal skeletal
`
`variations (bilateral full rib or right rudimentary rib on lumbar 1) associated with maternal
`toxicity (reduction in body weight and food consumption) at an infusion rate of 150 ng/kg/min
`(HED 49 ng/kg/min, about 41 times the starting human rate of infusion, and 5 times the
`average rate used in clinical trials). In rats, continuous sc infusion of treprostinil from
`implantation to the end of lactation, at rates of up to 450 ng/kg/min, did not affect the growth
`and development of offspring.
`
`10 Special Toxicology Studies
`No special toxicology studies were performed.
`
`11
`
`
`Integrated Summary and Safety Evaluation
`Treprostinil, a prostacyclin analogue is approved for delivery either subcutaneously or
`intravenously via an indwelling central venous catheter implant connected to an external
`
`(wearable) pump that stores and dispenses treprostinil. Subcutaneous delivery is associated
`with site pain and reactions which are sometimes intolerably severe. Studies have shown that
`the most common adverse effect of sc treprostinil is infusion site pain, which may lead to
`discontinuation of treatment. The proposed treprostinil implantable system is built upon the
`established drug delivery technology of the Medtronic SynchoMed II® platform (Models 8637,
`10642) to provide a more convenient delivery of treprostinil in patients with pulmonary artery
`hypertension. In this supplemental NDA 208276, the sponsor is cross referencing the
`preclinical studies conducted for treprostinil (Remodulin®