CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203496Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
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`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`NDA
`Submission Date
`Brand Name
`Generic Name
`Sponsor
`Submission Type
`Therapeutic Class
`Formulation
`(Strengths)
`Indication
`Dosing Regimen
`
`
`Proposed indication
`
`203496
`December 27, 2011
`TBD
`Treprostinil diolamine
`United Therapeutic Corporation
`505(b)(1)
`Prostacyclin analog (vasodilatory action)
`Oral extended release tablet
`(0.125 mg, 0.25 mg,
` 1.0 mg, 2.5 mg)
`Pulmonary Arterial Hypertension (PAH)
`Initial starting dose of 0.25 mg administered
`twice-daily with food. Doses titrated based on
`tolerability. Recommended titration increment is
`0.25 mg twice-daily every 3-4 days as tolerated.
`
`Treatment of PAH (WHO Group 1) by improving
`the exercise capacity
`
`OCP Division
`Division of Clinical Pharmacology I
`OND Division
`Division of Cardiovascular and Renal Products
`Primary OCP Reviewer
`Sudharshan Hariharan, Ph.D.
`Secondary PM Reviewer
`Satjit Brar, Pharm.D., Ph.D.
`Clinical Pharmacology Team Leader Rajanikanth Madabushi, Ph.D.
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`Reference ID: 3198107
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`(b) (4)
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`

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`NDA 203496 – Treprostinil diolamine, PAH
`Clinical Pharmacology Review
`
`
`TABLE OF CONTENTS
`
`
`1. Executive Summary.....................................................................................................................4
`1.1. Recommendations.................................................................................................................4
`1.2. Phase 4 Commitments...........................................................................................................4
`1.3. Summary of Clinical Pharmacology Findings......................................................................5
`2. Question Based Review ...............................................................................................................6
`2.1. General Attributes of the Drug .............................................................................................6
`2.2. General Clinical Pharmacology ............................................................................................7
`2.3. Exposure-Response Relationship........................................................................................10
`2.4. Pharmacokinetics ................................................................................................................16
`2.5. Intrinsic Factors ..................................................................................................................22
`2.6. Extrinsic Factors .................................................................................................................23
`2.7. General Biopharmaceutics..................................................................................................26
`2.8. Bioanalytical method validation .........................................................................................29
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`Reference ID: 3198107
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`2
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`

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`NDA 203496 – Treprostinil diolamine, PAH
`Clinical Pharmacology Review
`
`
`LIST OF TABLES
`
`
`Table 1: Design features of clinical studies supporting this application.........................................7
`Table 2: Design features of relevant clinical pharmacology & biopharmaceutics studies .............8
`Table 3: Display of Hodges-Lehmann estimates of treatment effect from pivotal trials................9
`Table 4: Treprostinil and metabolites in urine and feces following oral administration. .............17
`Table 5: Important PK metrics following SD and MD of 1 mg oral TDE ...................................19
`Table 6: Impact of renal impairment on the pharmacokinetics of treprostinil..............................22
`Table 7: Impact of hepatic impairment on the pharmacokinetics of treprostinil..........................23
`Table 8: List of compounds tested for potential drug interaction with treprostinil ......................24
`
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`
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`LIST OF FIGURES
`
`
`Figure 1: Chemical structure of treprostinil diolamine...................................................................6
`Figure 2: Mean steady state treprostinil concentrations from oral ER tablet and Remodulin®...11
`Figure 3: Relationship between last stabilized dose and corresponding percent change from
`baseline in peak 6-minute walk distance at week 12 from Study TDE-PH-302 ...........................12
`Figure 4: Relationship between last stabilized dose and corresponding percent change from
`baseline in trough 6-minute walk distance at week 11 from Study TDE-PH-302.........................13
`Figure 5: Relationship between last stabilized dose and corresponding percent change from
`baseline in peak 6-minute walk distance at week 16 from Studies TDE-PH-301 and -308..........13
`Figure 6: Relationship between cumulative dose and corresponding percent change from
`baseline in 6-minute walk distance from Study TDE-PH-302 (ITT analysis)...............................14
`Figure 7: Comparison of mean steady state concentration-time profile for treprostinil
`administered as oral ER tablet administered as 3.5 mg BID and 2.25 mg TID.............................15
`Figure 8: Metabolites of treprostinil following oral administration .............................................18
`Figure 9: Mean concentration-time course of treprostinil following SD and MD of 1 mg TDE .19
`Figure 10: Concentration-time courses of treprostinil as seen across healthy volunteers
`following single oral dose of 1 mg treprostinil diolamine ER tablet.............................................20
`Figure 11: Concentration-time courses of treprostinil as seen within healthy volunteers
`following single oral dose of 1 mg treprostinil diolamine ER tablet on day 1 and day 13............21
`Figure 12: Impact of co-administered drugs on systemic exposure to treprostinil.......................25
`Figure 13: Mean concentration-time course following oral administration of (i) 1 mg ER tablet
`(ii) solution administered as 4 x 0.25 mg dose staggered every 2 h ..............................................27
`Figure 14: Mean concentration-time course of treprostinil administered as 1 mg oral ER tablet in
`fed (high calorie, high fat) vs fasted state ......................................................................................28
`Figure 15: Impact of food and the effect of varying caloric/fat content on the systemic exposure
`to treprostinil..................................................................................................................................28
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`Reference ID: 3198107
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`3
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`

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`NDA 203496 – Treprostinil diolamine, PAH
`Clinical Pharmacology Review
`
`1. EXECUTIVE SUMMARY
`
`In the current submission, NDA 203496, United Therapeutics Corp. is seeking approval for an
`oral extended release (ER) formulation of treprostinil, a tricyclic analog of prostacyclin (PGI2).
`Treprostinil has shown clinical effectiveness when administered as continuous infusion via
`intravenous and subcutaneous route (Remodulin®; NDA 21272) and also as intermittent
`nebulization via the inhaled route (Tyvaso®; NDA 22387).
`
`For the current submission, 3 controlled clinical trials have been performed to demonstrate the
`effectiveness and safety of treprostinil in patients with pulmonary arterial hypertension (PAH).
`In study TDE-PH-302, the effectiveness of treprostinil as a front-line therapy was evaluated.
`Studies TDE-PH-301 and TDE-PH-308 focused on the use of treprostinil as an add-on therapy to
`other approved oral therapies [oral phosphodiesterase inhibitors (PDE5-I), and/or endothelin
`receptor antagonists (ERA)].
`
`The clinical pharmacology package for the current submission primarily comprises of a mass
`balance study, a single and multiple dose pharmacokinetic study, an absolute bioavailability
`study comparing exposures from oral ER tablet vs Remodulin®, a relative bioavailability study
`comparing the oral ER product vs an oral solution, a study each evaluating the pharmacokinetics
`of treprostinil in renal and hepatic impaired subjects, two food effect studies, and five drug-
`interaction studies. In addition, since the active moiety of the oral ER tablet is identical to that of
`the prior approved drug products, Remodulin® and Tyvaso®, data from these products were also
`used as appropriate in support of the clinical pharmacology package.
`
`1.1 Recommendations
`
`The Office of Clinical Pharmacology (OCP) recommends approval of treprostinil as extended
`release tablets for the treatment of PAH in the monotherapy and adjunctive setting, provided an
`agreement on labeling is reached with the sponsor. Further, a thrice-daily dosing regimen should
`be considered for approval. These recommendations are based on the following information:
`
`• Effectiveness of treprostinil has already been established in the prior approved products,
`Remodulin® and Tyvaso®. No significant change is observed in the metabolic profile of oral
`treprostinil compared to the prior approved products.
`
` Similar steady state exposures (plasma treprostinil concentration) are observed upon comparison
`of the oral ER product and the prior approved intravenous product (Remodulin®).
`
` A consistent dose-response relationship is observed in the monotherapy and adjunctive settings.
`
` Based on the pharmacokinetic properties of the current oral ER product, a thrice-daily dosing
`regimen will provide less peak-to-trough fluctuation in treprostinil systemic exposures.
`
`1.2 Phase 4 Commitments
`
`
`No specific post-marketing commitments or requirements are proposed by the OCP at this point
`of time.
`
` •
`
` •
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` •
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`Reference ID: 3198107
`
`4
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`

`

`NDA 203496 – Treprostinil diolamine, PAH
`Clinical Pharmacology Review
`
`1.3. Major Clinical Pharmacology Findings
`
`The important clinical pharmacology and biopharmaceutics findings were,
`
`• The absolute bioavailability of treprostinil oral ER tablet is 17%. This dosage form exhibits
`extended release characteristics compared to treprostinil administered as an oral solution.
`
` •
`
` The dose-normalized steady-state peak and trough concentrations following the administration of
`treprostinil oral ER tablet spans the average steady-state exposures obtained following the
`administration of an intravenous infusion. However, the oral ER tablet exhibits a high peak to
`trough ratio (ranges from 7 to 10 across studies).
`
`
`
` •
`
` The inter-subject variability of treprostinil for the pharmacokinetic metrics, Cmax and AUC, is in
`the range of 40-65%, expressed as percent coefficient of variation (CV%), across various Phase 1
`studies. However, the intra-subject variability (25-30%), does not contribute to more than 50% of
`the overall variability.
`
`
`• A high calorie, high fat meal delayed the absorption of treprostinil when compared to the fasted
`state. The systemic exposure to treprostinil, as seen by area under the plasma concentration-time
`curve (AUC), was increased by 1.5-fold with no significant change in the maximum
`concentration (Cmax). Furthermore, the between subject variability in AUC decreased from 50%
`to 20%, expressed as CV%. No discernible change in the exposures was noted when compared
`among meals of varying fat and caloric content.
`
`• The systemic exposure to treprostinil is increased in subjects with hepatic impairment. Increases
`of 2-, 5- and 8-fold were observed in subjects with mild, moderate and severe hepatic
`impairment respectively compared to otherwise healthy controls. No significant change in
`exposure to treprostinil was observed in patients with renal impairment.
`
` •
`
`•
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` Treprostinil is a metabolized predominantly by CYP2C8. Gemfibrozil, a strong inhibitor of
`CYP2C8 increases the systemic exposure to treprostinil by 2-fold.
`
`In Study TDE-PH-302 (front-line therapy trial), a trend for dose-dependent increase in percent
`change from baseline peak 6-minute walk distance (corresponding to the peak treprostinil
`exposures) at week 12 was observed as a function of the last stabilized dose (body weight
`normalized) in patients who completed the study. This relationship was consistent for the 6-
`minute walk distance data at week 11, which corresponds to the trough exposures of treprostinil.
`
`• Similar dose-dependent relationship for the percent change from baseline in peak 6-minute walk
`distance at week 16 as a function of the last stabilized dose (body weight normalized) was
`observed for studies TDE-PH-301 and TDE-PH-308 (add-on therapy trials) in completers.
`
`• The relationship is consistent with a trend for dose-dependent increase in percent change from
`baseline in 6-minute walk distance as a function of cumulative treprostinil dose across all the
`patients randomized in the study (Study TDE-PH-302, ITT population).
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`Reference ID: 3198107
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`5
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`

`

`NDA 203496 — Treprostinii dio amine. PAH
`Ciinical Pharmacology Reviex.
`
`2. QUESTION BASED REVIEW
`
`The clinical pharmacology of treprostinil has been previously reviewed for Remodulin® (NDA
`21272, DARRTS date: 03/12/2003) and Tyvaso® (NDA 22387, DARRTS date: 03/04/2009) by
`Drs. Beasley, Gobburu and Kumi. In the current review, an abbreviated question based review
`describing the clinical pharmacology aspects pertinent to the oral ER product is presented.
`
`2.1. General Attributes of the Drug
`
`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?
`
`Treprostinil is a tricyclic analog of prostacyclin (PGIZ). It is synthesized as a diolamine salt
`which exists as a white to cream colored powder with a molecular weight of 495.6 g/mol. The
`diolamine salt of treprostinil is freely soluble in water with a solubility of 453 mg/mL. The
`chemical structure is shown in Fig. 1.
`
`OH
`
`H
`////\\ //\\ /\/\\‘v/
`[
`H
`> -
`-
`| IOH
`
`-
`
`\\\ / \V/ \/
`H
`OCHZCOg ,
`
`\v,/
`
`A»
`
`\V/
`
`A
`
`\\
`
`H3N(CH3CHZOH)2
`+
`
`.
`Figure 1: Chemical structure
`of treprostinil diolamine
`
`Treprostinil diolamine is formulated as an oral extended release (ER) tablet using an osmotic
`release mechanism. The tablet core
`
`is coated by a semi—permeable membrane with a laser drilled aperture. Upon contact with water,
`the water soluble osmotic excipients swell up, creating hydrostatic pressure within the membrane
`and force the solubilized drug through the aperture.
`
`2.1.2. What are the proposed mechanism(s) of action and therapeutic indication(s)?
`
`Treprostinil is a tricyclic analog of prostacyclin (PGIZ), which is a potent vasodilator. The
`pharmacological action of treprostinil pertinent to puhnonary arterial hypertension (PAH) is
`direct vasodilation of puhnonary and systemic arterial vascular beds.
`
`Treprostinil is indicated for the treatment of puhnonary arterial hypertension (PAH) (WHO
`Group 1) by improving the exercise capacity.
`
`2.1.3. What are the proposed dosage(s) and route(s) of administration?
`
`The proposed dosage form is a ER tablet for oral use to be administered twice-daily. The ER
`tablet is available in @mdifferent strength for the ease of titration i.e., 0.125, 0.25, we 1.0 and
`2.5 mg.
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`Reference ID: 3198107
`
`

`

`NDA 203—196 — Treprostimi dio amine. PAH
`C mica Pharmaco og, Rams;
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`2.1.4. What is the proposed dose and dosing regimen of treprostinil for the oral ER tablet?
`
`The recommended initial starting dose is 0.25 mg administered twice-daily taken along with
`food. Doses should be increased over time in a given patient based on tolerability until a
`beneficial effect is achieved. The recommended titration increment is 0.25 mg twice-daily every
`3-4 days as tolerated. If 0.25 mg dose increments are not tolerated, an increment ofO. 125 mg is
`recommended.
`
`2.1.5. What are the previous approved products of treprostinil? What are their recommended
`doses and dosing regimen?
`
`The two approved products of treprostinil are Remodulin® and Tyvaso®. Remodulin® is an
`injection for infusion which is administered at a starting dose of 1.25 ng/kg/min (or 0.625
`ng/kg/min if not tolerated), further titrated based on tolerability in increments of 1.25 ng/kg/min
`per week for the first 4 weeks and later by 2.5 ng/kg/min per week.
`
`Tyvaso® is a solution for inhalation which is administered as 3 breaths per session for a total of 4
`treatment session per day. Each breath of Tyvaso® delivers approximately 6 ug of treprostinil.
`Tyvaso® is further titrated to a target maintenance dose of 9 breaths per session administered 4
`times daily (54 pg x 4 times daily).
`
`2.2. General Clinical Pharmacology
`
`2.2.1. What are the design features of the clinical and clinical pharmacology studies used to
`support dosing or claims?
`
`Design features of clinical and clinical pharmacology studies are shown in Table 1 and 2,
`respectively.
`
`Table 1: List and design features of clinical studies supporting this application
`
`
`Study No.
`
`Description
`
`N
`
`Dose
`
`Duration
`
`Randomized. multi-center.
`placebo-controlled study in subjects
`_,
`_
`TDE PH 302 with PAH NOT receiving approved
`background therapy
`
`_
`_
`TDE PH 301
`
`Randomized multi—center.
`placebo-controlled study in subjects
`with PAH on approved backgromld
`therapy
`
`3
`‘ 49
`
`354
`
`0.25-l mg BID
`starting dose with
`dose increasing
`over time
`
`0.25-l mg BID
`starting dose with
`dose increasing
`over time
`
`_
`12 Weeks
`
`_
`16 Weeks
`
`0.25 mg BID
`Randomized multi—center.
`_
`starting dose with
`placebo-controlled study in subjects
`_
`_
`16 Weeks
`dose increasing
`310
`with PAH on approved backgromld
`TDE PH 308
`
`therapy over time
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`Reference ID: 3198107
`
`

`

`NDA 203496 — Treprostinil diolamine. PAH
`Clinical Pharmacology Reviev.
`
`Table 2: List and design features of relevant clinical pharmacology & biopharmaceutics studies
`
`N
`Description
`Study type
`Study NO-
`Treplrostrml
`ose
`
`
`TDE-PH-107 Mass Balance
`
`OL. mass balance. metabolite profiling and
`safety study ot‘[“c1.[3H] TDE
`
`TDE—PH-104
`
`Singlet' Multiple
`dose PK
`
`TDE-PH—l l4
`
`Absolute
`
`.
`.
`.
`.
`.
`Broavarlabrlrt)
`
`_
`_
`TDE PH 123
`
`Relative
`Bioavailability
`
`TDE—PH—103
`
`Food Effect
`
`0L. R, DB. placebo controlled, parallel
`group. PK and safety study with TDE oral
`SR tablet administered over 13 days in
`.
`escalatma doses
`
`0L. two-sequence CO study to evaluate the
`
`absolute bioavailability oftreprostinil
`
`administered as a oral SR tablet as
`.
`.
`.
`.
`compared to an IV infusron of treprostrml
`‘
`.
`sodium
`
`0L. two-sequence. C0 study to evaluate the
`comparative bioavailability of treprostinil
`administered as a single SR tablet or as a
`oral solution
`OL‘ two period. (‘0, PK and safety study
`‘5’".11 $913“ (“5“ 0f “emsm‘l
`administer ed as tln ee tablet prototypes
`(12 h formulations) in fasted and fed states
`
`8
`
`36
`
`24
`
`24
`
`30
`
`fi
`0" mg
`
`1 mo BID
`.—
`2 mg BID
`3 ma BID
`‘
`
`(SI: fitnlilet)
`
`0.2 1119,
`a
`(Remodulm®)
`
`1 mg
`and
`0.25 mg
`q2 b X 4 doses
`
`1mg
`
`0L, R, single-dose. four-period, C‘O
`1 m2
`32
`PK‘an‘d safety study evaluating the effect of
`Food Effect
`TDE-PH—l 15
`different meal composrtrons on treprostrml
`*
`
`PK
`
`TDE-PH-l 12
`
`TDE-PH-lZO
`
`Hepatic
`Impaument
`
`Renal
`Impairment
`
`0L, single-dose, PK and safety study in
`three cohorts ofsubjects with varying
`degrees of hepatrc nnpanment and one
`cohort of healthy vollmteers
`0L. single-dose. two-period. C0. PK. safety
`and tolerability study in healthy volunteers
`and patients with ESRD
`1 111g
`01., R, three-period. tln‘ee sequence CO
`Drug
`TDE-PH-IOS.
`Interaction
`study to evaluate the effect of bosentan on
`24
`
`steady state treprostinil PK
`Dru
`01., R, three-period, three-sequence. CO
`1
`mg
`18
`TDE-PH—lO6
`Interacitzion
`study to evaluate the effect ofsildenafrl on
`
`steady state treprostinrl PK
`OL‘ R. single-sequence. C0 study to
`evaluate the effect of repeated
`.
`nfampin dosing on a single dose of TDE
`0L, R, two-period. two-sequence. C0 study
`to evaluate the effect of repeated
`Drug
`1 mg
`gemfibrozil or fluconazole dosing on the PK 40
`Interaction
`TDE-PH-l 10
`
`of a single dose of treprostinil
`0L, single-sequence CO study to evaluate
`the effect of repeated esomeprazole dosrng
`on the PK of a single dose of TDE
`TDE = Trepr'ostinil diethanolamine: OL = Open label: R = Randomized. DB = Double-blind: (‘O = Crossover
`
`30
`
`1 ma
`‘
`
`16
`
`1 mg
`
`20
`
`1 111g
`
`30
`
`1 mg
`
`TDE-PH-109
`
`Drug
`Interaction
`
`TDE-PH-l l6
`
`Drug
`Interaction
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`Reference ID: 3198107
`
`8
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`

`

`NDA 203496 – Treprostinil diolamine, PAH
`Clinical Pharmacology Review
`
`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?
`
`The efficacy measures included in the clinical development program are widely used and
`accepted as clinically meaningful indices for patients with PAH. In studies TDE-PH-301, -302
`and -308, the primary efficacy endpoint was change in 6-minute walk distance from baseline to
`the end of the study i.e., week 12 for study TDE-PH-302 and week 16 for study TDE-PH-301
`and -308. Secondary efficacy assessments included changes in 6-minute walk distance at weeks
`4, 8, 11 (trough), WHO functional class, Borg dyspnea score, dyspnea-fatigue index, signs and
`symptoms of PAH and clinical worsening.
`
`2.2.3. What are the key results from the pivotal efficacy trial(s)?
`
`In study TDE-PH-302, where efficacy of treprostinil was evaluated as a monotherapy, the
`primary endpoint i.e., change in 6-minute walk distance between treatment and placebo groups at
`week 12 for the entire study population was significant, with a median placebo-corrected
`treatment effect of +25.5 meters, as reported by the sponsor. The treatment effects at week 4 and
`8 were +14 and +20 meters, respectively, and were statistically significant. Additionally, the
`placebo-corrected treatment effect on 6-minute walk distance at week 11, which was assessed at
`a time expected to correlate with trough treprostinil concentrations, was also statistically
`significant with a treatment effect of +17 meters, as reported by the sponsor (Table 3).
`
`In the other two add-on therapy trials, a scenario how treprostinil will be most used if approved,
`the treatment effect was not statistically significant at week 16 when evaluated as independent
`trials (Table 3). However, the sponsor reported a statistically significant treatment effect upon
`pooling both studies (Table 3).
`
`Table 3: Display of Hodges-Lehmann estimates of treatment effect for the ITT population across
`studies TDE-PH-302, -301 and -308
`
`
`
`
`
`
`Study
`Study 302
`
`Period
`
`Median 6MWD (meters)
`Active
`Placebo
`
`Hodges-Lehmann
`estimate of treatment
`effect (95% CIs)
`17 (3, 33)
`25.5 (10, 41)
`11 (0, 22)
`10 (-2, 22)
`
`p-value
`
`0.0025
`0.0001
`0.072
`0.089
`
`10 (3, 19)
`
`0.00397
`
`Week 11
`(trough)
`Week 12
`Week 16
`Week 16
`
`Week 16
`
`351
`370
`381
`370
`
`375
`
`327
`330
`367
`365
`
`366
`
`Study 301
`Study 308
`Pooled
`Studies
`301 & 308
` Source: Sponsor submitted study reports of TDE-PH-301, -302 and -308
`
`
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`Reference ID: 3198107
`
`9
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`

`

`NDA 203496 – Treprostinil diolamine, PAH
`Clinical Pharmacology Review
`
`2.2.4. Are the active moieties in the plasma appropriately identified and measured to assess
`pharmacokinetic parameters and exposure response relationships?
`
`Treprostinil is the only active moiety and its pharmacokinetics is characterized across various
`Phase 1 studies. Pharmacokinetics of treprostinil was not measured during the Phase 3 trials.
`However, the PK of treprostinil were assessed in a small subset of patients (N=74) during the
`open-label safety extension study. For details on bioanalytical method validation, refer to Q
`2.8.1.
`
`
` 2.3. Exposure-Response Relationship
`
`
`
`
`
`
`2.3.1. How do the exposures compare against the previously approved products?
`
`The average steady state exposures of the oral ER tablet and the currently approved intravenous
`product of treprostinil are reasonably similar. Fig. 2 shows the dose-normalized mean steady
`state treprostinil plasma concentrations as box plots for (i) oral ER tablet (Cmax,ss and Cmin,ss) and
`(ii) intravenous infusion (Cavg,ss). Dose-normalization was performed corresponding to the mean
`dose achieved in the respective pivotal trials (3.4 mg for the oral ER formulation and 9.3
`ng/kg/min, for Remodulin®). It can be seen that the average steady state maximum and minimum
`concentration from the oral ER product spans the average steady state concentration of
`treprostinil from the previously approved intravenous product, indicative of matching systemic
`exposures between the two products. It should be noted that the exposures from Tyvaso®
`(another prior approved product of treprostinil administered via the inhalation route) cannot be
`used as reference, since, treprostinil is delivered locally and the PK/PD relationship could be
`different.
`
`
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`Reference ID: 3198107
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`:iio amine. PAH
`NBA; 333—196 — Treprostini
`C mica Phan‘nco og, ReJc—x.
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`Mean Remodulin dose = 9.3 ng/kglmin
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`Mean oral dose = 3.4 mg BID
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`O
`Treprostinildose-normalizedconcentration(ng/mL) Aon
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`.x N
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`OIaLCmax
`N = 72
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`lrfusion_SS
`N = 183
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`Ola|_Cmin
`N = 72
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`Figure 2: Mean steady state treprostinil concentrations from the oral ER tablet and RemodulinO
`corresponding to the mean dose achieved in their respective pivotal Phase 3 trial.
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`2.3.2. What are the characteristics of the dose-response relationship for efficacy?
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`The phase 3 trials of treprostinil incorporated a titration to tolerability design. Analysis of dose—
`response, in situations such as these, presents its own challenges and may not be representative
`of the cleanest form of dose-response such as those resulting out of a parallel fixed-dose study.
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`Nevertheless, in the current review, the relationship between the last stabilized dose (body
`weight normalized) and the corresponding percent change from baseline in 6-minute walk
`distance was explored as the primary analysis. As the trial design employed a titration to
`tolerability, the last stabilized dose was deemed a relevant metric for this exploration. For the
`response metric, percent change from baseline in 6-minute walk distance at the end of the study
`was considered more robust than the absolute change from baseline, since, the former takes into
`account baseline 6—minute walk distance. This relationship is constructed using the data from
`patients who completed the study, since a completer analysis is not confounded with imputation
`methodologies used to account for missing data in the trial. Completers of the study with
`corresponding peak 6—minute walk distance at week 12 represent about 70% and 75% of the total
`randomized patients in the treatment and placebo arms, respectively. However, it is important to
`note that the analysis presented cannot rule out time dependent effects and an interaction
`between tolerability and the ability to exercise.
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`Reference ID: 3198107
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`1 1
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`NDA 203496 – Treprostinil diolamine, PAH
`Clinical Pharmacology Review
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`As shown in Fig. 3, in Study TDE-PH-302, a trend for dose-dependent increase in the percent
`change from baseline in peak 6-minute walk distance (corresponding to the peak treprostinil
`exposures) at week 12 was observed as a function of the last stabilized dose (body weight
`normalized), upon anchoring to the placebo response. A significant non-zero slope for this
`relationship was obtained upon assuming a linear trend. The slope for this relationship denotes
`1.23% change from baseline in peak 6-minute walk distance per 0.01 mg/kg dose.
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` similar relationship (1.35% change from baseline in trough 6-minute walk distance per 0.01
`mg/kg dose) was also observed between last stabilized dose (body weight normalized) and
`percent change in baseline in trough 6-minute walk distance at week 11 as shown in the Fig. 4.
`Regardless of the analysis of dose-response corresponding to peak (week 12) or trough (week
`11) treprostinil concentration, a significant relationship exists which is suggestive of that fact that
`the effect or the ability to exercise is preserved during the inter-dosing interval.
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`Figure 3: Relationship between last stabilized dose (body weight normalized) and
`corresponding percent change from baseline in peak 6-minute walk distance at week 12 from
`Study TDE-PH-302 in completers [N = 246; active=160 (40 per bin), placebo=86]. A positive
`slope for the relationship was observed [Mean and 95% CIs: 1.23 (0.418 – 2.04) as percent
`change from baseline-per-0.01 mg/kg of treprostinil].
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`Note: For exposure-response, the gray open circles represent the individual patient data. The blue
`closed circles and error bars represent the corresponding mean and 95% CIs of percent change
`from baseline in 6-minute walk distance for each median dose quartile. The solid line represents
`the linear fit modeled through the entire dataset with 95% CIs represented by dotted lines. Y-axis
`is truncated to provide an optimum view for the readers to understand this relationship.
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`Reference ID: 3198107
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`12
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`NDA 203496 – Treprostinil diolamine, PAH
`Clinical Pharmacology Review
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`Figure 4: Relationship between last stabilized dose (body weight normalized) and
`corresponding percent change from baseline in trough 6-minute walk distance at week 11 from
`Study TDE-PH-302 in completers [N = 243; active=159 (~40 per bin), placebo=84]. A positive
`slope for the relationship was observed [Mean and 95% CIs: 1.35 (0.548 – 2.15) as percent
`change from baseline-per-0.01 mg/kg of treprostinil].
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`Assuming a linear relationship, similar dose-dependent trend for the relationship between peak
`6-minute walk distance at week 16 as a function of the last stabilized dose (body weight
`normalized) was also observed for studies TDE-PH-301 and TDE-PH-308 in completers where
`treprostinil was evaluated in the background of other oral PAH therapies. A non-zero slope for
`the relationship is shown in Fig. 5 as mean and 95% CIs.
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`Slope
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`(% Change from baseline 6MWD per mg/kg dose)
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`Figure 5: Relationship between last stabilized dose (body weight normalized) and corresponding
`percent change from baseline in peak 6-minute walk distance at week 16 from studies TDE-PH-
`301 [N=246; active=118, placebo=128] and TDE-PH-308 [N=249; active=120, placebo=129] in
`patients who completed the study. Data is represented as slope [mean and 95% CIs].
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`Reference ID: 3198107
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`13
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`NDA 203496 – Treprostinil diolamine, PAH
`Clinical Pharmacology Review
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`One of the drawbacks of evaluating the relationship between last stabilized dose (body weight
`normalized) and corresponding percent change from baseline in 6-minute walk distance is that it
`ignores the time-course of dose titration. It is possible for patients to have the same last stabilized
`dose but differing in the duration at that dose. In order to further evaluate the exposure-response
`relationship, percent change from baseline in 6-minute walk distance as a function of cumulative
`treprostinil dose was constructed in all randomized patients i.e., the intent-to-treat (ITT)
`population as a sensitivity analysis. The last observed 6-minute walk distance data was used in
`patients who dropped out during the trial with their cumulative doses truncated until the day of
`the last observed response data. Baseline 6-minute walk distance data was carried forward for
`patients who dropped prior to week 4. As shown in Fig. 6, upon anchoring to placebo response,
`the relationship was consistent with a significant non-zero slope (2.5% change from baseline in
`6-minute walk distance per 100 mg cumulative treprostinil dose). Moreover, as expected, it can
`be observed that the non-completers with lower cumulative exposures have correspondingly
`lower percent change from baseline 6-minute walk distance.
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`Figure 6: Relationship between cumulative treprostinil dose and corresponding percent change
`from baseline from Study TDE-PH-302 in all randomized patients (ITT population) [N = 349;
`active=233 (~40 per bin), placebo=116]. A positive slope for the relationship was observed
`[Mean and 95% CIs: 2.50 (1.50 – 3.50) as percent change from baseline-per-100 mg of
`cumulative treprostinil dose]. The green open circles represent individual patient data from
`completers and the orange open squares represent the individual patient data from non-
`completers.
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`Reference ID: 3198107
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`14
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`NDA 203496 – Treprostinil diolamine, PAH
`Clinical Pharmacology Review
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`2.3.3. What are the characteristics of the dose-response relationships for safety?
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` Since treprostinil is titrated to tolerabili