Research Article
`
`Pharmacokinetics and tolerability of LIQ861, a novel
`dry-powder formulation of treprostinil
`
`Robert Roscigno1, Toby Vaughn1, Stephanie Anderson1, William Wargin2, Thomas Hunt3 and
`Nicholas S. Hill4
`1Liquidia Technologies, Research Triangle Park, NC, USA; 2Nuventra, Inc., Durham, NC, USA; 3PPD Development, LLC, Austin, TX, USA; 4Tufts Medical Center,
`Boston, MA, USA
`
`Abstract
`A dry-powder inhaled formulation of treprostinil (LIQ861) produced using PRINTVR technology offers a substantial advantage
`over current nebulized therapy. Treprostinil is a synthetic prostacyclin analogue that is currently approved for inhalation admin-
`istration to patients with pulmonary arterial hypertension via nebulized TyvasoVR
`inhalation solution. LTI-101 was a phase 1,
`placebo-controlled, double-blind, randomized, single-center study that evaluated the ascending single-dose pharmacokinetics
`of LIQ861 in healthy subjects. Six sequential, escalating doses (25, 50, 75, 100, 125, and 150 mcg) were studied to investigate
`
`treprostinil exposure from LIQ861 inhalation. Subjects (n ¼ 57) were randomly assigned in a 3:1 ratio to receive a single dose of
`either LIQ861 (n ¼ 43) or placebo (n ¼ 14); 56 subjects completed all protocol-defined assessments. Following single-
`
`dose administration, treprostinil exposure from LIQ861 increased proportionally across the dose range studied, and the phar-
`macokinetics profile of treprostinil administered as LIQ861 was similar to prior reports of inhaled treprostinil. All doses of
`LIQ861 were generally well-tolerated with no deaths, serious adverse events, or dose-limiting toxicities. The most frequently
`reported treatment-emergent adverse events related to study drug administration were coughing and throat irritation, which are
`common to dry-powder formulations. Treatment-related treatment-emergent adverse events were reported more frequently at
`higher dose levels; however, all were assessed as mild in severity. We conclude that the pharmacokinetics profile of treprostinil
`using a dry-powder inhaled formulation increased in proportion to dose as anticipated and was similar to earlier reports of
`inhaled, nebulized treprostinil (TyvasoVR ). Based on these results, a phase 3 study (INSPIRE; Clinicaltrials.gov Identifier
`NCT03399604) evaluating the long-term safety and tolerability of LIQ861 in patients with pulmonary arterial hypertension
`was initiated.
`
`Keywords
`inhaled prostacyclin, pharmacokinetics, pulmonary arterial hypertension
`
`Date received: 20 March 2020; accepted: 20 September 2020
`
`Pulmonary Circulation 2020; 10(4) 1–9
`DOI: 10.1177/2045894020971509
`
`Introduction
`
`The current management of pulmonary arterial hyperten-
`sion (PAH) relies on targeted therapies to address the path-
`ophysiologic abnormalities that damage the pulmonary
`vasculature and result in elevated pulmonary artery pres-
`sures, dyspnea, diminished exercise capacity, right heart
`failure, and, ultimately, death.1–3 The synthesis and release
`of prostacyclin are impaired in PAH,4,5 and the prostacyclin
`(prostaglandin I2 (PGI2)) pathway is a critical therapeutic
`target in the disease.6–8 Prostacyclin therapy provokes vaso-
`dilation and also has anti-proliferative, anti-thrombotic,
`and anti-inflammatory effects.2,3,9
`
`Despite offering significant clinical benefits to patients
`with PAH, PGI2 therapies are underutilized in clinical prac-
`tice,10–12 with only 34.1% of patients enrolled in the
`REVEAL RegistryTM (Registry to Evaluate Early And
`Long-term PAH Disease Management) treated with a pros-
`tacyclin analogue.13 Lower rates of prostacyclin therapy are
`
`Corresponding author:
`Nicholas S. Hill, Tufts Medical Center, Pulmonary Division, 800 Washington
`Street, Suite 257, Boston, MA 02111, USA.
`Email: nhill@tuftsmedicalcenter.org
`
`Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative
`Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which
`permits non-commercial use, reproduction and distribution of the work without further permission provided the original work
`is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
`
`! The Author(s) 2020
`Article reuse guidelines:
`sagepub.com/journals-permissions
`journals.sagepub.com/home/pul
`
`IPR2021-00406
`United Therapeutics EX2084
`
`

`

`2
`
`| Pharmacokinetics and tolerability of LIQ861 Roscigno et al.
`
`attributed, in part, to the complexities of dose up-titration
`coupled with challenges associated with diverse routes of
`administration.6,7 PGI2 therapies, currently approved for
`use in the United States, can be delivered by intravenous
`inhaled,16,17
`(SC),14,15
`and oral
`(IV),
`subcutaneous
`routes.18,19 IV and SC therapies place patients at increased
`risk of catheter occlusion, thrombosis, thromboembolism,
`infections, sepsis, and infusion site pain.7,12,14,20–27
`Dosing errors due to variations in breathing patterns and
`the inability to up-titrate, as well as the number, frequency,
`and duration of inhalations, are limitations of currently-
`available inhaled prostacyclin therapies.7,22,28,29 Oral pros-
`tacyclins are associated with systemic side effects that may
`prompt treatment noncompliance or discontinuation.7,26,30
`Novel drugs that target the PGI2 pathway and overcome the
`recognized limitations of the IV, SC,
`inhaled, and oral
`routes are needed to ensure that patients with PAH obtain
`the clinical benefits of prostacyclin therapy while reducing
`the risk of serious, dose-limiting, and systemic side effects.
`LIQ861 is an investigational, inhaled, dry-powder formu-
`lation of treprostinil designed using Liquidia’s PRINTVR
`technology
`(Particle
`Replication
`in Nonwetting
`Templates), aiming to enhance deep-lung delivery using a
`convenient, palm-sized dry-powder
`inhaler
`(DPI),
`the
`Plastiape RS00 Model 8 Device, for the treatment of PAH
`(Fig. 1). PRINTVR is a proprietary particle engineering plat-
`form that enables precise production of highly uniform drug
`particles with independent control over their size, shape,
`and chemical
`composition. Through this
`approach,
`PRINTVR enables the development of drug particles that
`are engineered for optimal deposition in the lung following
`oral inhalation (Fig. 1).31–33 LIQ861 has the potential to
`overcome the limitations of current inhaled therapies and
`to maximize the therapeutic benefits of treprostinil for the
`treatment of PAH by safely delivering high doses into the
`lungs in one to two breaths. LTI-101 was a phase 1,
`placebo-controlled,
`double-blind,
`randomized,
`single-
`center, first-in-human study to evaluate the ascending
`single-dose pharmacokinetics (PK) of LIQ861 in healthy
`subjects.
`
`Methods
`
`Study design
`
`This was a phase 1, placebo-controlled, double-blind, ran-
`domized, single-center study that evaluated the ascending
`single-dose PK of LIQ861 in healthy male and female sub-
`jects. Six sequential, escalating dose levels (25, 50, 75, 100,
`125, and 150 mcg capsule strength) were investigated.
`Subjects were screened within the 28 days (Days –28 to
`–1) prior to admission to the clinical research unit (CRU;
`PPD Development, Austin, TX) on Day 0 (the day prior to
`dosing) for baseline assessments. On Day 1, following the
`pre-dose collection of blood for PK, subjects were random-
`ized in a 3:1, active-to-placebo ratio to receive a single dose
`of either LIQ861 or placebo at time zero. Placebo capsules
`contained a nearly identical preparation of excipient matrix
`compared with active LIQ861, with an equivalent mass of
`trehalose (the most abundant excipient) instead of trepros-
`tinil. In vitro aerosol performance testing was performed in
`accordance with General Chapter: <601> USP-29-NF-24,
`“Aerosol, Nasal Sprays, Metered Dose Inhalers and Dry
`Powder Inhalers” with a fine particle fraction of approxi-
`mately 86% of emitted dose.34
`All inhalations were conducted using the Plastiape RS00
`Model 8 DPI and 2 inhalation breaths per capsule.
`Inhalations were made in immediate succession to minimize
`the amount of time needed to administer the complete dose.
`Variations in breathing patterns and skills were minimized
`by providing all subjects with in-depth training on the use of
`the device. An additional cohort of subjects at the 150-mcg
`dose was investigated due to capsule seating interference in
`the DPI device that occurred during drug administration for
`approximately half of the subjects in the original cohort.
`This cohort was repeated while the study remained blinded.
`Treatment administration by dose cohort
`is shown in
`Table 1.
`Subjects remained in the CRU from admission (Day 0)
`until discharge by the Investigator on the day after dosing
`(Day 2). Subjects returned to the CRU approximately two
`
`Fig. 1. LIQ861 particles and dry-powder inhaler.
`
`

`

`Table 1. Treatment administration by cohort.
`
`LIQ861
`
`Capsules
`administered,
`
`#  mcg
`1  25
`1  50
`1  75
`2  50
`1  75 þ 1 50
`2  75
`
`Cohort
`
`Treprostinil
`dose, mcg
`
`1
`2
`3
`4
`5
`6
`
`25
`50
`75
`100
`125
`150
`
`mcg: micrograms; n: number of subjects.
`
`Pulmonary Circulation Volume 10 Number 4
`
`|
`
`3
`
`Powder
`weight, mg
`
`5
`10
`15
`20
`25
`30
`
`n
`
`6
`7
`6
`6
`6
`12
`
`Placebo
`
`Capsules
`administered,
`
`#  mcg
`1  0
`1  0
`1  0
`2  0
`2  0
`2  0
`
`Powder
`weight, mg
`
`15
`15
`15
`30
`30
`30
`
`n
`
`2
`2
`2
`2
`2
`4
`
`days after discharge (Day 4)
`assessments.
`
`for completion of final
`
`Study participants
`
`Healthy male and female volunteers between 18 and
`45 years of age (inclusive), with a body mass index (BMI)
`of 18–32 kg/m2, who abstained from tobacco and nicotine
`use for at least two months prior to screening were eligible
`for enrollment. Eligible subjects were instructed not to take
`any prescription medication for 14 days or any dietary sup-
`plements or over-the-counter drugs for at least three days
`prior to CRU admission through completion of the study.
`Subjects provided written informed consent before partici-
`pating in any study procedure.
`Subjects were excluded if they had a history of asthma or
`other respiratory condition; a history of illicit drug or alco-
`hol abuse or positive urine drug screen; were positive for
`human immunodeficiency virus, hepatitis B, and/or hepati-
`tis C; in pregnant or lactating females; had donated plasma
`or blood within 7 or 30 days prior to CRU admission,
`respectively; had participated in another investigational
`drug study within the 30 days prior to CRU admission; or
`had surgery within six months of screening.
`
`Pharmacokinetic analysis
`
`Approximately 4 mL of whole blood was collected for each
`PK sample, yielding approximately 2 mL of plasma for
`analysis of treprostinil concentrations. Blood samples were
`collected via IV catheters implanted in peripheral arm veins
`and stored with VacutainerVR tubes with potassium EDTA
`(BD #367861 or equivalent) approximately one hour before
`dosing and at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 150, 180,
`and 210 min and at 4, 6, and 8 h after study drug
`administration.
`Treprostinil plasma concentrations were measured at
`PPD Laboratories (Middleton, WI) using a validated
`ultra-performance liquid chromatography-tandem mass
`spectrometry bioanalytical method (Bioanalytical Method
`P1313).35 The lower limit of quantification in the assay
`was 0.025 ng/mL and the upper limit of quantification was
`
`10 ng/mL. Treprostinil concentrations were summarized
`using descriptive statistics.
`Individual treprostinil PK parameters were calculated
`using PhoenixVR WinNonlinVR v6.3 (Certara, Princeton, NJ)
`and summarized with descriptive statistics. Plasma concen-
`trations below the limit of quantification (BLQ) were set to
`zero, unless they fell between two quantifiable samples, in
`which case they were treated as missing. Figures were pre-
`pared using R version 3.3.1 (R Foundation for Statistical
`Computing, Vienna, Austria).
`Dose proportionality assessments were conducted with
`Cmax and AUCinf using the confidence interval equivalence
`criterion with a power model.36 Given the exploratory
`nature of the study and the corresponding wide dose
`range with small sample sizes, a wider acceptance interval
`of 0.5–2.0 was applied to establish conclusion of propor-
`tionality within the tested dosing range.37 For both param-
`eters,
`the estimate for
`the ratio of dose-normalized
`geometric mean, 90% confidence intervals, maximal pro-
`portional dose range, and threshold dose ratio to reject pro-
`portionality were calculated.
`
`Safety assessments
`
`Safety monitoring included an evaluation of adverse events
`(AEs) and assessments of electrocardiograms (ECG), respi-
`ratory signs, vital signs, clinical
`laboratory parameters
`(pre-dose and through 6–8 h post-dose), physical examina-
`tions, urinalysis, and concomitant medications. In addition,
`subjects in the 125-mcg and 150-mcg dose cohorts (cohorts
`5 and 6) underwent continuous cardiac telemetry and were
`monitored by Advanced Cardiac Life Support-certified staff
`from 30 min prior to dosing through three hours after dose
`administration. This extra safety precaution was imple-
`mented due to the evidence of QTc prolongation in healthy
`subjects after administration of maintenance and suprather-
`apeutic doses (54 and 84 mcg, respectively) of treprostinil
`(inhaled TyvasoVR ).16
`Following each dosing, and prior to each dose escalation,
`the Safety Review Committee (SRC), which consisted of the
`Principal Investigator, the Study Medical Monitor, and a
`
`

`

`4
`
`| Pharmacokinetics and tolerability of LIQ861 Roscigno et al.
`
`representative from the Sponsor, convened by teleconfer-
`ence to review safety findings and interim PK results from
`each cohort. Treatment assignments remained blinded
`during these reviews and an unanimous agreement from
`voting members of the SRC was required prior to proceed-
`ing with the next sequential dose cohort. Stopping criteria
`were also prospectively defined in the study protocol. If a
`severe AE or serious adverse event (SAE) was observed in
`2 subjects within a dose cohort, the SRC was required to
`stop escalation of the dose levels.
`
`Table 2. Demographic and clinical characteristics by treatment
`group.
`
`Characteristic
`
`Age at screening, years
`Mean (SD)
`Min, max
`
`Sex, n (%)
`Female
`Male
`Race, n (%)
`American Indian or Alaska Native
`Asian
`Black or African American
`White
`Ethnicity, n (%)
`Hispanic or Latino
`Not Hispanic or Latino
`BMI, kg/m2
`Mean (SD)
`Min, max
`
`Treatment group, n (%)
`
`LIQ861
`
`(n¼ 43)
`
`30.3 (6.7)
`18, 44
`
`Placebo
`
`(n ¼ 14)
`
`26.1 (5.4)
`19, 36
`
`21 (48.8)
`22 (51.2)
`
`1 (2.3)
`1 (2.3)
`13 (30.2)
`28 (65.1)
`
`18 (41.9)
`25 (58.1)
`
`7 (50.0)
`7 (50.0)
`
`0 (0.0)
`0 (0.0)
`4 (28.6)
`10 (71.4)
`
`8 (57.1)
`6 (42.9)
`
`25.8 (3.3)
`19.2, 30.6
`
`25.9 (2.8)
`22.1, 29.7
`
`BMI: body mass index; max: maximum; min: minimum; n: number of subjects;
`SD: standard deviation.
`
`Results
`
`Subject characteristics
`
`Fifty-seven subjects were enrolled in the study, and 56
`subjects completed all protocol-defined assessments. One
`subject in cohort 2 (50 mcg) withdrew consent from PK
`sample collections after the 10-min post-dose timepoint
`complaining of painful venipuncture and was replaced,
`which resulted in a total of seven subjects on active treat-
`ment in this cohort. The subject who was withdrawn con-
`sented to continued observation and safety assessments and
`was included in the safety population.
`Demographic characteristics were well-balanced between
`the LIQ861 and placebo groups (Table 2). Similar propor-
`tions of male and female subjects were enrolled and subjects
`in both treatment groups were predominantly White. Mean
`age and BMI were similar in both treatment groups.
`
`PK of LIQ861
`
`Plasma treprostinil concentrations in subjects who received
`LIQ861 were quantifiable by five minutes after dosing
`(time of first post-dose sample collection) in all but one
`subject. Absorption of treprostinil was rapid, with median
`Tmax ranging from 0.18 to 0.31 h across all dose levels
`(Table 3). Following peak concentrations,
`treprostinil
`plasma levels declined in a monophasic manner. Plasma
`concentrations of treprostinil were BLQ in the 25-, 50-,
`and 75-mcg dose cohorts by 3.5 h post-dose and in the
`100-, 125-, and 150-mcg cohorts by six hours post-dose.
`Treprostinil plasma concentrations over time by dose are
`shown in Fig. 2.
`ranged from 0.31 to
`for Cmax
`Geometric means
`1.25 ng/mL across the dose cohorts. Geometric means for
`AUCinf ranged from 0.28 h*ng/mL in cohort 1 (25 mcg) to
`1.36 h*ng/mL in cohort 6 (150 mcg).
`Dose proportionality was assessed based on Cmax and
`AUCinf over the tested dose range of 25–150 mcg treprosti-
`nil administered as LIQ861. The apparent clearance (CL/F)
`
`Table 3. Treprostinil pharmacokinetic parameters following inhalation administration of LIQ861.
`
`Parameter
`
`LIQ861, mcg
`
`25
`
`50
`
`75
`
`100
`
`125
`
`150
`
`6
`
`12
`6
`6
`6
`n
`Cmax (ng/mL)
`1.25 (0.70–2.34)
`1.08 (0.51–1.96)
`1.04(0.73–1.54)
`0.68 (0.43–1.11)
`0.45 (0.12–1.03)
`0.31(0.19–0.54)
`0.31 (0.08–0.47)
`0.24 (0.16–0.41)
`0.29 (0.17–0.50)
`0.25 (0.08–0.42)
`0.18 (0.08–0.42)
`0.21 (0.16–0.45)
`Tmax (h)
`AUClast (h*ng/mL) 0.25 (0.16–0.36)
`1.32 (0.58–2.84)
`1.01 (0.36–1.87)
`1.16 (0.78–1.44)
`0.68 (0.40–1.26)
`0.31 (0.07–0.73)
`AUCinf (h*ng/mL)
`1.36 (0.62–2.94)
`1.04 (0.38–1.91)
`1.20 (0.82–1.47)
`0.72 (0.45–1.29)
`0.34 (0.08–0.75)
`0.28 (0.18–0.39)
`t1/2 (h)
`0.64 (0.46–0.95)
`0.52 (0.44–0.65)
`0.70 (0.47–0.97)
`0.60 (0.52–0.98)
`0.42 (0.25–0.52)
`0.50 (0.41–0.72)
`CL/F (L/h)
`90.9 (64.8–136.0) 149.0 (66.6–624.0) 105.0 (58.0–169.0) 83.4 (67.9–122.0) 120.0 (65.6–329.0) 110.0 (51.0–243.0)
`
`6
`
`Note: Data are geometric mean and range or median and range for Tmax.
`AUCinf: area under the plasma concentration–time curve from 0 to infinity; AUClast: area under the plasma concentration–time curve from time 0 to time of last
`measurable plasma concentration; CL/F: clearance; Cmax: maximum plasma concentration; max: maximum; min: minimum; n: number of subjects; t1/2: terminal
`elimination half-life; Tmax: time to reach Cmax.
`
`

`

`Pulmonary Circulation Volume 10 Number 4
`
`|
`
`5
`
`Fig. 2. Mean plasma treprostinil concentration over time.
`
`of treprostinil was observed to be independent of adminis-
`tered dose (geometric means ranged from 83.4 to 149.0 L/h).
`
`Safety and tolerability
`
`Overall, treprostinil administered by inhalation as LIQ861
`was well-tolerated by study subjects. There were no deaths,
`SAEs, dose-limiting toxicities, or
`treatment-emergent
`adverse events (TEAEs) that led to study withdrawal.
`Approximately half of the subjects who received active
`treatment (55.8%) experienced a TEAE compared with
`14.3% on placebo (Table 4). The majority of subjects on
`active treatment who reported a TEAE had an event that
`was
`considered related to study treatment by the
`Investigator (19/24 subjects; 79.2%).
`The most common TEAEs related to study drug admin-
`istration were cough (25.6%) and throat irritation (20.9%)
`(Table 5). Painful respiration and dizziness were both expe-
`rienced by 14% of subjects on active treatment. Treatment-
`related TEAEs were reported more frequently at higher
`dose levels (Table 4). All treatment-related events were
`reported as mild in severity. TEAEs considered unrelated
`to study treatment that were reported during the study were
`associated with vasovagal symptoms that occurred during
`or around the time of PK venipuncture and included pre-
`syncope (n¼ 5), dizziness (n¼ 1), feeling hot (n¼ 1), and
`headache (n ¼ 1) in subjects who received LIQ861 and rhi-
`norrhea (n ¼ 1) and vessel puncture site pain (n ¼ 1) in sub-
`jects who received placebo.
`There were no clinically significant changes in laboratory
`parameters, vital signs, physical examination findings, or
`ECG parameters observed during the study in either treat-
`ment group. A slight prolongation in QTc interval, which is
`consistent with the known pharmacodynamic effects of tre-
`prostinil, was observed in subjects administered more than
`100 mcg, but no subjects had a prolongation of more
`than 60 msec from baseline or a QTc interval that exceeded
`450 msec.
`
`Discussion
`
`Study LTI-101 is the first clinical trial to evaluate the safety
`and PK of treprostinil administered as LIQ861, a novel dry-
`powder
`formulation,
`to healthy subjects. Our
`results
`showed that administration of single doses of LIQ861
`resulted in rapid absorption of treprostinil (Tmax 0.18–
`0.31 h) and median values for Tmax that were consistent
`across the dose range. Approximately 50% of subjects in
`the higher dose cohorts (100, 125, and 150 mcg) continued
`to show measurable concentrations of treprostinil at 4 h
`post-dosing with all doses well-tolerated. Observed expo-
`sures of treprostinil after inhalation of LIQ861 increased
`proportionally with doses between 25 and 150 mcg. Mean
`maximum observed plasma concentration (Cmax) and area
`under the plasma concentration versus time curve from time
`0 (pre-dose) to infinity (AUCinf) values from this study were
`compared with mean exposure levels reported in the pub-
`lished literature and in the Drug Approval Reviews from the
`US Food and Drug Administration for TyvasoVR .16,38,39
`Commonalities between the exposures observed in study
`LTI-101 and those reported for TyvasoVR were used to proj-
`ect a TyvasoVR transition dose for LIQ861 for patients par-
`ticipating in phase 3 clinical trials.
`A systemic exposure was achieved with fewer inhalations
`than required for TyvasoVR and no unexpected safety issues,
`with subjects experiencing only mild, class-related AEs.
`LIQ861 may improve the therapeutic profile of treprostinil
`by enhancing deep-lung delivery and achieving higher dose
`levels than current inhaled therapies while overcoming some
`of the limitations of prostacyclin therapies delivered by the
`IV, SC, and oral routes.
`There is a clear need for new, more convenient PAH
`therapies
`that offer
`sustained long-term benefits and
`improved safety and tolerability profiles while increasing
`the utilization of drugs that target the prostacyclin path-
`way.40 Oral agents may overcome some of the limitations
`therapy.
`associated with IV, SC, and inhaled PGI2
`Treprostinil18 and selexipag19 are oral prostacyclin agonists
`
`

`

`6
`
`| Pharmacokinetics and tolerability of LIQ861 Roscigno et al.
`
`Table 4. Overall incidence of treatment-emergent adverse events by cohort and treatment.
`
`Cohort
`
`Cohort 1
`LIQ861
`Placebo
`Cohort 2
`LIQ861
`Placebo
`Cohort 3
`LIQ861
`Placebo
`Cohort 4
`LIQ861
`Placebo
`Cohort 5
`LIQ861
`Placebo
`Cohort 6a
`LIQ861
`Placebo
`Cohort 6b
`LIQ861
`Placebo
`Total
`LIQ861
`Placebo
`
`n
`
`6
`6
`2
`
`7
`2
`
`6
`2
`
`6
`2
`
`6
`2
`
`6
`2
`
`6
`2
`
`43
`14
`
`Related to treatment
`
`Unrelated to treatment
`
`Overall
`
`Treprostinil
`dose, mcg
`
`No. (%) of
`subjects
`
`No. of
`events
`
`No. (%) of
`subjects
`
`No. of
`events
`
`No. (%) of
`subjects
`
`No. of
`events
`
`25
`0
`
`50
`0
`
`75
`0
`
`100
`0
`
`125
`0
`
`150
`0
`
`150
`0
`
`1 (16.7)
`0 (0.0)
`
`2 (28.6)
`0 (0.0)
`
`2 (33.3)
`0 (0.0)
`
`2 (33.3)
`0 (0.0)
`
`4 (66.7)
`0 (0.0)
`
`4 (66.7)
`0 (0.0)
`
`4 (66.7)
`0 (0.0)
`
`19 (44.2)
`0 (0.0)
`
`1
`0
`
`2
`0
`
`3
`0
`
`3
`0
`
`12
`0
`
`9
`0
`
`10
`0
`
`40
`0
`
`2 (33.3)
`0 (0.0)
`
`1 (14.3)
`1 (50.0)
`
`0 (0.0)
`0 (0.0)
`
`1 (16.7)
`1 (50.0)
`
`0 (0.0)
`0 (0.0)
`
`0 (0.0)
`0 (0.0)
`
`1 (16.7)
`0 (0.0)
`
`5 (11.6)
`2 (14.3)
`
`3
`0
`
`2
`1
`
`0
`0
`
`2
`1
`
`0
`0
`
`0
`0
`
`1
`0
`
`8
`2
`
`3 (50.0)
`0 (0.0)
`
`3 (42.9)
`1 (50.0)
`
`2 (33.3)
`0 (0.0)
`
`3 (50.0)
`1 (50.0)
`
`4 (66.7)
`0 (0.0)
`
`4 (66.7)
`0 (0.0)
`
`5 (83.3)
`0 (0.0)
`
`24 (55.8)
`2 (14.3)
`
`4
`0
`
`4
`1
`
`3
`0
`
`5
`1
`
`12
`0
`
`9
`0
`
`11
`0
`
`48
`2
`
`Note: Percentages are based on the number of subjects in each respective cohort.
`aOriginal cohort at 150 mcg treprostinil.
`bRepeated cohort at 150 mcg treprostinil with six additional patients.
`n: number of subjects per treatment group.
`
`that are approved in the US and recommended for the treat-
`ment of Group 1 PAH World Health Organization/
`Functional class II and III patients.8 They offer the advan-
`tages of oral therapy, but side effects such as headaches and
`nausea limit the ability of patients to reach therapeutic
`doses and contribute to treatment discontinuation in
`14.3% and 19.0% of patients taking selexipag41 and inhaled
`treprostinil, respectively.42
`Improvement in devices for inhaled therapies has the
`potential to enhance and maintain treatment adherence as
`well as clinical response. Inhaled therapy may also reduce
`the risk of systemic vasodilation and ventilation-perfusion
`mismatch.28,43,44 However, variations in breathing patterns
`between patients make it difficult to control dosing, and
`delivery systems that are difficult to operate or cumbersome
`may increase the likelihood of errors in dosing.7,28 Inhaled
`therapies are not administered during sleep, which can place
`patients at risk of sub-therapeutic plasma levels.7 In addi-
`tion, the number, frequency, and length of inhalations com-
`bined with the time required for drug preparation and
`maintenance of inhaler devices impose considerable burdens
`on patients and their caregivers and may reduce treatment
`compliance and persistence.7,22,29 However, a recent
`
`the
`examined
`review and meta-analysis
`systematic
`efficacy and safety profiles of prostacyclin mimetics with
`regard to their route of administration. All agents improved
`six-minute walk distance, although the authors suggested
`that the modest gains in exercise capacity for some of the
`agents might have been due to underdosing. Of note,
`inhaled therapies were associated with a more favorable
`impact on patient quality of life when compared with oral
`agents.26
`Currently available inhaled prostacyclins include iloprost
`(VentavisVR ) and treprostinil (TyvasoVR ). VentavisVR has a
`half-life of approximately 20 min and requires at least six
`administrations/day consisting of 35 mcg of
`iloprost.
`VentavisVR is delivered using an inhaler device that must be
`assembled each morning, with 10 parts listed in the patient
`the TyvasoVR
`user guide.17 TyvasoVR
`requires use of
`Inhalation System, an ultrasonic, pulsed delivery device
`that consists of 13 parts as reported in the patient starter
`kit. TyvasoVR has a half-life of three to four hours and
`requires four separate, equally spaced treatment sessions
`per day. The maximum recommended target dose is nine
`breaths per treatment, four times daily for an approximate
`total dose of 54 mcg.16
`
`

`

`Table 5. Summary of related and unrelated treatment-emergent adverse events by system organ class and preferred term.
`
`Pulmonary Circulation Volume 10 Number 4
`
`|
`
`7
`
`System organ class and preferred term
`
`Related events
`Gastrointestinal disorders
`Nausea
`Nervous system disorders
`Dizziness
`Headache
`Respiratory, thoracic, and mediastinal disorders
`Cough
`Painful respiration
`Throat irritation
`
`Vascular disorders
`Hot flush
`Unrelated events
`General disorders and administration site conditions
`Feeling hot
`Vessel puncture site pain
`
`Nervous system disorders
`Dizziness
`Headache
`Presyncopea
`Respiratory, thoracic, and mediastinal disorders
`Rhinorrhea
`
`Group
`
`LIQ861 (n ¼ 43)
`
`Placebo (n¼ 14)
`
`Overall (n ¼ 57)
`
`No. (%) of
`subjects
`
`No. of
`events
`
`No. (%) of
`subjects
`
`No. of
`events
`
`No. (%) of
`subjects
`
`No. of
`events
`
`3 (7.0)
`
`6 (14.0)
`4 (9.3)
`
`11 (25.6)
`6 (14.0)
`9 (20.9)
`
`1 (2.3)
`
`1 (2.3)
`0 (0.0)
`
`1 (2.3)
`1 (2.3)
`5 (11.6)
`
`0 (0.0)
`
`3
`
`6
`4
`
`11
`6
`9
`
`1
`
`1
`0
`
`1
`1
`5
`
`0
`
`0 (0.0)
`
`0 (0.0)
`0 (0.0)
`
`0 (0.0)
`0 (0.0)
`0 (0.0)
`
`0
`
`0
`0
`
`3 (5.3)
`
`6 (10.5)
`4 (7.0)
`
`0 (0.0)
`0 (0.0)
`0 (0.0)
`
`11 (19.3)
`6 (10.5)
`9 (15.8)
`
`0 (0.0)
`
`0 (0.0)
`
`1 (1.8)
`
`0
`1 (7.1)
`
`0 (0.0)
`0 (0.0)
`0 (0.0)
`
`1 (7.1)
`
`0
`1
`
`0
`0
`0
`
`1
`
`1 (1.8)
`1 (1.8)
`
`1 (1.8)
`1 (1.8)
`5 (8.8)
`
`1 (1.8)
`
`3
`
`6
`4
`
`11
`6
`9
`
`1
`
`1
`1
`
`1
`1
`5
`
`1
`
`aFive subjects reported vasovagal symptoms that were coded as presyncope and were all attributed by the Investigator as related to venipuncture for PK collection
`and not related to the study drug.
`
`Prostacyclin analogues must reach the lungs in order to
`be effective. Therefore,
`localized dosing to the lungs
`through inhalation allows more drug to be delivered directly
`to the site of action, while limiting the occurrence of sys-
`temic side effects that are typically associated with oral and
`parenteral therapies. Results from in vitro studies31 suggest
`that the precise size, trefoil-like shape, and uniformity of
`each dry-powder particle of LIQ861 may provide deep-
`lung delivery of treprostinil and may reduce deposition in
`the upper airway where cough, throat irritation, pharyngo-
`laryngeal pain, and bronchospasm have been reported for
`inhaled prostacyclins.16,17
`In this study, LIQ861 doses ranging from 25 to 150 mcg
`capsule strength were well-tolerated by subjects and resulted
`in the occurrence of only mild TEAEs with no dose-limiting
`side effects. Cough and throat irritation were the most fre-
`quently reported TEAEs and are characteristic of other
`inhaled prostacyclin formulations.16,17 Each of the five
`events of presyncope were attributed by the Investigator
`to the venipunctures for the PK collection and not related
`to the study drug. These results suggest that patients may
`tolerate higher inhaled doses of treprostinil when delivered
`
`as a PRINTVR dry powder. Consequently, doses above
`150 mcg of LIQ861, which represent treprostinil plasma lev-
`els > 85 mcg, the maximum tolerated dose for TyvasoVR , may
`be achievable. A phase 3 study45 (INSPIRE; Clinicaltrials.
`gov Identifier NCT03399604) to evaluate the long-term
`safety and tolerability of LIQ861 in patients with PAH is
`under way. Interim safety and tolerability results are con-
`sistent with those reported for this phase 1 PK trial.46
`
`Conclusions
`
`LIQ861 demonstrates a dose proportionality based on Cmax
`and AUCinf over the tested dose range of 25–150 mcg, and
`all doses were well-tolerated by subjects. LIQ861 achieved
`higher dose levels than currently approved inhaled therapies
`while overcoming some of the limitations of prostacyclin
`therapies delivered by the IV, SC, and oral routes.
`
`Conflict of interest
`
`The author(s) declared the following potential conflicts of interest
`with respect to the research, authorship, and/or publication of this
`article: Robert Roscigno, Toby Vaughn, and Stephanie Anderson
`
`

`

`8
`
`| Pharmacokinetics and tolerability of LIQ861 Roscigno et al.
`
`are employees of Liquidia Technologies. William Wargin declares
`that there is no conflict of interest. Thomas Hunt is an employee of
`PPD, a contract research organization for Liquidia Technologies.
`Nicholas S. Hill is a consultant and scientific medical advisor, and
`has received grant/research support payments to his institution
`from Liquidia Technologies.
`
`Ethical approval
`
`Salus IRB. IRB Registration #: 00006833. Chair: John C. Lewis,
`DVM.
`
`Guarantor
`
`Nicholas S. Hill
`
`Contributorship
`
`All authors contributed to the conception and design of the study;
`the acquisition, analysis, and interpretation of data; reviewed and
`revised the manuscript; gave final approval for submission; and
`agreed to be accountable of all aspects of the work in ensuring
`that questions related to the accuracy or integrity of any part of the
`work are appropriately investigated and resolved.
`
`Funding
`
`The author(s) disclosed receipt of the following financial support
`for the research, authorship, and/or publication of this article:
`Support for this study and development of this manuscript was
`provided by Liquidia Technologies. Authors were not compensat-
`ed for the development of the manuscript.
`
`Acknowledgements
`
`Carole Alison Chrvala, PhD, and Philippe Brudi, MD, are
`acknowledged for their assistance with the preparation of this
`manuscript.
`
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