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Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH)

Open AccessPublished:November 28, 2022DOI:https://doi.org/10.1016/j.rmed.2022.107065

      Highlights

      • Current PAH therapies are administered systemically resulting in extrapulmonary effects.
      • MK-5475 is an inhaled sGC stimulator under development for the treatment of PAH.
      • This Phase 1 study evaluated single-dose MK-5475 in adult PAH participants.
      • Single inhaled doses of MK-5475 had favorable effects on pulmonary vasodilation.
      • Inhaled MK-5475 had a favorable safety profile without deleterious systemic effects.

      Abstract

      Background

      Novel therapeutics for pulmonary arterial hypertension (PAH) with improved safety/tolerability profiles are needed to address continued high rates of morbidity/mortality.

      Methods

      This Phase 1 study evaluated efficacy/safety of inhaled single-dose MK-5475, an investigational, small-molecule stimulator of soluble guanylate cyclase designed for inhaled delivery via a dry-powder inhaler device, in participants with PAH (Clinicaltrials.gov: NCT03744637). Eligible participants were 18–70 years of age; body mass index ≤35 kg/m2; diagnosis of PAH (Group 1 pulmonary hypertension). In Part 1, participants received double-blind MK-5475 or placebo for safety assessment (primary outcome). In Part 2, 4 panels participated in ≤3 open-label periods. Part 2/Period 1 assessed safety/tolerability. Part 2/Periods 2 and 3, respectively, involved functional respiratory imaging for measuring pulmonary blood volume (secondary outcome) and right heart catheterization for measuring pulmonary vascular resistance (primary outcome).

      Results

      MK-5475 was generally well tolerated without systemic side effects on blood pressure or heart rate up to 24 h post dose. With respect to the primary pharmacodynamic outcome, mean reductions in pulmonary vascular resistance ranged from 21% to 30% across 120 μg and 360 μg doses.

      Conclusions

      Treatment with inhaled single-dose MK-5475 showed rapid and sustained reductions in pulmonary vascular resistance and increases in pulmonary blood volume. MK-5475 was generally well tolerated versus placebo without vasodilatory systemic side effects. The promising pulmonary selectivity and favorable safety/tolerability profile of MK-5475 seen in this study of adult participants with PAH lays the foundation for further clinical development.

      Keywords

      1. Introduction

      Pulmonary arterial hypertension (PAH) is a debilitating and potentially fatal condition characterized by elevated pulmonary arterial pressure and progressive right ventricular hypertrophy resulting in heart failure if left untreated. PAH is diagnosed via right heart catheterization (RHC), defined as mean pulmonary arterial pressure ≥25 mmHg at rest, a pulmonary arterial wedge pressure (PAWP) ≤15 mmHg and a pulmonary vascular resistance (PVR) of ≥3 Woods units [
      • Simonneau G.
      • Montani D.
      • Celermajer D.S.
      • Denton C.P.
      • Gatzoulis M.A.
      • Krowka M.
      • Williams P.G.
      • Souza R.
      Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
      ].
      Approved pharmacotherapies for PAH generally fall into 4 therapeutic classes with distinct mechanisms of action: 1) prostacyclin analogues and prostacyclin receptor antagonists, which stimulate cyclic adenosine monophosphate production; 2) endothelin receptor antagonists (ERA), which block endothelial receptors and mitigate the effects of excess endothelin; 3) phosphodiesterase type-5 inhibitors (PDE5i), which target nitric oxide and natriuretic pathways; and 4) soluble guanylate cyclase (sGC) stimulators, which also target the nitric oxide pathway. The current PAH treatment strategy is based on the severity of disease as assessed by a multiparametric risk stratification approach. The recommended initial treatment for a non-vasoreactive, treatment-naïve patient at low or intermediate risk should be initial oral combination therapy with an ERA and a PDE5i [
      • Galiè N.
      • Channick R.N.
      • Frantz R.P.
      • Grünig E.
      • Jing Z.C.
      • Moiseeva O.
      • Preston I.R.
      • Pulido T.
      • Safdar Z.
      • Tamura Y.
      • McLaughlin V.V.
      Risk stratification and medical therapy of pulmonary arterial hypertension.
      ]. In non-vasoreactive and treatment-naïve patients at high risk, initial combination therapy including intravenous prostacyclin analogues (PCAs) is recommended. Risk assessment once every 3–6 months is recommended to assess the patient's response to treatment and to initiate triple combination therapy as needed. Treatment for PAH is administered to stimulate pulmonary vasodilation and effectuate improvements in symptoms, exercise tolerance, hemodynamic measurements, right ventricular (RV) function, and outcomes.
      Despite improvements in treatment, patients with PAH have high mortality and median survival of 7 years [
      • Preston I.R.
      • Roberts K.E.
      • Miller D.P.
      • Sen G.P.
      • Selej M.
      • Benton W.W.
      • Hill N.S.
      • Farber H.W.
      Effect of warfarin treatment on survival of patients with pulmonary arterial hypertension (PAH) in the registry to evaluate early and long-term PAH disease management (REVEAL).
      ,
      • Thenappan T.
      • Shah S.J.
      • Rich S.
      • Tian L.
      • Archer S.L.
      • Gomberg-Maitland M.
      Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation.
      ]. Combination therapy with therapeutic agents of different classes has improved the therapeutic landscape, but novel therapies are still needed to optimize treatment of PAH. Most approved therapies are delivered systemically (via subcutaneous or intramuscular injection or oral administration) for a disease that is limited to the pulmonary vasculature. Due to systemic delivery, extra-pulmonary side effects are common, resulting in poor tolerability and dose-limiting toxicities that necessitate careful dose titration. Further, the ability to co-administer a novel pulmonary-selective PAH agent with PDE5i may allow treatment optimization in difficult-to-treat populations wherein differential local exposure aligned with ventilation is deemed critical. Therefore, there is an urgent unmet need for novel PAH therapies with pulmonary selectivity and improved safety/tolerability profiles enabling easier dosing without titration and expanded combination therapy options.
      Inhaled therapies offer potential advantages over systemic therapies, including optimized delivery of drug to the pulmonary arterial circulation via the lungs at lower doses, decreased systemic vasodilation, and minimization of systemic-related adverse effects. MK-5475 is an investigational, novel, dry-powder formulation of a small-molecule stimulator of sGC designed for inhaled delivery via a dry-powder inhaler device to enhance deep-lung deposition and enable direct delivery to the desired site of action. This was a 2-part, 4-panel Phase I study of MK-5475 in participants with PAH (Group 1 pulmonary hypertension [PH]). The first part of the study (i.e., Part 1) evaluated safety, tolerability, and pharmacokinetics of single ascending double-blind doses (120, 165, 240 μg) of MK-5475 versus placebo. Part 2 evaluated safety and pharmacodynamic (PD) effects of single-dose, open-label MK-5475 (120, 240, and 360 μg) on change from baseline in minimum PVR value, the primary PD outcome, as assessed via RHC. In addition, changes in pulmonary blood volume (PBV; secondary PD outcome) were assessed via a novel functional respiratory imaging (FRI) technique as well as safety and pharmacokinetics (primary safety outcome) after a single inhalation at 2 additional doses (300 and 480 μg). To date, studies examining the utility of FRI in probing pulmonary hemodynamics/vasodilation in PAH patients are limited. Hence this study also aimed to explore the relationship of the novel FRI parameter, PBV, to the validated primary endpoint of PVR reduction.

      2. Methods

      2.1 Study population

      Eligible participants were 18–70 years of age, with a body mass index ≤35 kg/m2 and Group 1 PH (i.e., Nice 2013 Clinical Classification guidelines). In all panels, participants were screened on the basis of historical RHC done within the prior 3 years. Alternatively, in Panels B/C/D only, participants were also considered for screening if an echocardiogram performed at/within 1 year showed evidence of elevated pulmonary artery systolic pressure (≥50 mmHg) in conjunction with one or more of the following: tricuspid valve regurgitation, significant right heart enlargement, or reduced right heart function.
      Eligible participants were enrolled and referred for study RHC. In the RHC period only (i.e., Period 2 for Panel A and Period 3 for Panels B, C and D), the following baseline hemodynamic measures were required for continued eligibility: mean pulmonary artery pressure of ≥25 mmHg (obtained from 3 pre-dose measurements taken 10 min apart; the mean value computed from the last 2 measurements was used to calculate PVR baseline value), PVR ≥300 dyn/s/cm5 and PAWP ≤15 mmHg (obtained from the mean of 2 values used to calculate PVR). Values from 2 consecutive PVR calculations were required to be within 15% of each other (highest PVR value defined the 15%) to confirm a stable baseline. If the PVR data from the first 2 calculations deviated by >15%, up to 2 additional measurements were collected. If a stable baseline PVR was not obtained after 4 measurements, the individual was deemed ineligible to continue dosing and was discontinued from the study. RHC measurements were collected during spontaneous respiration while the participant was in a supine position. The same procedure was employed for each patient. Using a manual level, the height of the transducer was positioned at the level of the mid-chest. The indirect Fick method was used to calculate PVR and cardiac index [
      • Fritts H.W.
      • Cournand A.
      The application of the Fick principle to the measurement of pulmonary blood flow.
      ].
      Baseline PAH therapies were determined by local clinical practice patterns and local availability of medications. Medications were not stopped for the purpose of meeting study inclusion criteria. Decisions regarding medical management were left to the patient and investigator and were not specified by the study protocol. Per protocol, participants could not receive the following medications within 24 h before RHC: calcium channel blockers, nitrates, diltiazem (within 48 h for extended-release medications), PDE5i sildenafil or vardenafil (within 7 days for tadalafil), sGC stimulators, ERAs, or inhaled prostacyclin. Certain calcium channel blockers, not being used for the treatment of PAH, were permitted, as were diuretics, angiotensin receptor blockers, or angiotensin converting enzyme inhibitors. No restrictions were placed on medication use after each dose of MK-5475, so any treatment interruptions would have been brief.
      This study was conducted according to the principles outlined in the Declaration of Helsinki and the protocol was approved by the independent ethics committee of the Republican Clinical Hospital (National Committee for Ethical Expertise of Clinical Trial, Chisinau City, Moldovia). All participants provided informed consent before the inititation of any study procedures.

      2.2 Study design and treatment

      This Phase 1, randomized, placebo-controlled, single-center study evaluated the safety/tolerability and PD of inhaled MK-5475 versus placebo (both delivered via a dry-powder inhaler device) in participants with PAH (Clinicaltrials.gov NCT03744637; Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA). The study was conducted at a single site (Republican Clinical Hospital of Moldova, Chisinau) from January 18, 2019 to December 11, 2020.
      Part 1 examined safety/tolerability and pharmacokinetics of MK-5475. In Part 1, Panel A consisted of 8 participants dosed in ≤3 periods with a ≥7-day washout between dosing. PD assessments were performed in Part 2. Panel A participants, along with 3 additional panels (Panels B, C and D), were enrolled. Participants in Panel B (N = 4), C (N = 9), and D (N = 4) participated in ≤3 dosing periods. Period 1 (Panels B, C, and D) was an open-label assessment of safety/tolerability and pharmacokinetics.
      A schematic of the study design is illustrated in Fig. 1. The two study parts represent the double-blind (Part 1) and open-label (Part 2) dosing phases of the study. The periods that represent the treatment periods assessing safety/tolerability and PK (i.e., Panel A [Part 1/Periods 1–3] was double-blind and Panels B–D [Part 2/Period 1] was open-label), RHC hemodynamics (i.e., Period 2 for Panel A [Part 2/Period 2] and Period 3 for Panels B–D [Part 2/Period 3]; note Periods 2 and 3 were open-label for all panels) and PBV FRI (i.e., Period 3 for Panel A [Part 2/Period 3] and Period 2 for Panels B–D [Part 2/Period 2]; note Periods 2 and 3 were open-label for all panels).
      Fig. 1
      Fig. 1Study design schematic showing Part 1 and Part 2 for Panel A (A) and Part 2 for Panels B, C and D (B).

      2.3 Assignment and blinding

      All eligible participants were allocated to treatment by a computer-generated schedule (Table 1). Eligible participants were allocated by random assignment in Panel A and by non-random assignment in Panels B through D. A central reader blinded to timing of RHC assessed RHC parameters. Participants in Panel A were randomized to receive a single dose of MK-5475 120 μg or placebo (Part 1/Period 1), 165 μg or placebo (Part 1/Period 2), 240 μg or placebo (Part 1/Period 3) and 240 μg (Part 2/Period 2 and Part 2/Period 3). Participants in Panel B were allocated to receive a single dose of MK-5475 300 μg (Part 2/Period 1) and 360 μg (Part 2/Period 2 and Part 2/Period 3). One participant in Panel B received 165 μg in Part 2/Period 2 and Part 2/Period 3. Participants in Panel C were allocated to receive a single dose of MK-5475 300 μg (Part 2/Period 1) and 360 μg (Part 2/Period 2 and Part 2/Period 3). Four participants in Panel C received 120 μg in Part 2/Period 2 and Part 2/Period 3. Participants in Panel D were allocated to receive a single dose of MK-5475 480 μg (Part 2/Period 1) and 120 μg (Part 2/Period 2 and Part 2/Period 3).
      Table 1Sample allocation schedule.
      InterventionUnit Dose and FrequencyRoute of Administration
      Placebo: Part 1(Panel A)0 μg: once in Periods 1, 2, and 3Inhalation
      Placebo: Parts 1 and 2 (Panels A, B, C, and D)0 μg: once in Screening 2
      All participants in Panels A through D received placebo at Screening 2 as part of training on use of the dry-powder inhaler device.
      Inhalation
      MK-5475: Part 1 (Panel A)120 μg, 165 μg, 240 μg: one time per dose in Periods 1, 2, and 3Inhalation
      MK-5475: Part 2 (Panel A)240 μg: one time in Periods 2 and 3Inhalation
      MK-5475: Part 2 (Panel B
      One participant in Panel B received 165 μg in Part 2/Period 2 and Period 3.
      )
      300 μg: one time in Period 1 and 360 μg: one time per dose in Periods 2 and 3Inhalation
      MK-5475: Part 2 (Panel C)300 μg: one time in Period 1; 120 μg or 360 μg: one time in Periods 2 and 3Inhalation
      MK-5475: Part 2 (Panel D)480 μg: one time in Period 1; 120 μg one time in Periods 2 and 3Inhalation
      a All participants in Panels A through D received placebo at Screening 2 as part of training on use of the dry-powder inhaler device.
      b One participant in Panel B received 165 μg in Part 2/Period 2 and Period 3.

      3. Study outcomes

      3.1 Safety and tolerability

      The primary safety endpoints were the percentages of participants with ≥1 adverse event (AE) and the percentage who discontinued due to an AE.

      3.2 PD outcomes

      The primary PD outcome measurement in Part 2 was minimum change from baseline in PVR through 4.5 h post dose. PVR was calculated from RHC variables. Values from 2 consecutive PVR measurements had to be within 15%. If PVR from the first 2 measurements deviated by >15%, up to 2 additional PVR measurements were obtained. Secondary PD outcome measurements included heart rate and blood pressure at baseline (0 h), 0.5, 1, 2, 3, 4, 4.5, 24 h. Other PD measurements included PBV at baseline (0 h), 1, 3, 8, 24 h post dose calculated using FRI methodology. Further details regarding FRI methodology can be found in the Supplementary Data.
      All patients presented fasted for at least 4 h prior to baseline RHC and FRI procedures. RHC and FRI baseline measurements were taken up to 30 min prior to dosing. FRI scans lasted ∼15 min. RHC lasted up to 4.5 h post dose. Doses were administered sitting for FRI and semi-recumbent for RHC due to location and positioning of femoral catheter.

      3.3 Statistical analyses

      For each participant, the percent change from baseline for the minimum PVR value and the time-weighted average (TWA) for the duration of the RHC procedure were calculated. TWA was calculated as the area under the curve for PVR divided by the total length of the RHC procedure. The mean change from baseline for heart rate and blood pressure were calculated at 0.5 through 24 h post dose. PBV was measured using CT scans with an intravenous iodinated contrast agent. Changes from baseline in measured PBV were calculated at 1, 3, 8, and 24 h.
      For the PBV analysis, a linear mixed-effects model was constructed with PBV as the dependent variable, and time and zones (lung lobes) as the independent variables. Heterogeneity across zones (within subject) were modelled using an unstructured variance-covariance matrix (random slope). An additional mixed effect model was constructed where dose and its interactions with the other independent variables were incorporated. Only the doses with sufficient datapoints were included in this model. Contrasts were applied to the linear mixed-effects models to extract information on the change from baseline for each of the FRI endpoints and their corresponding p-values.

      4. Results

      In total, 31 individuals were screened for eligibility and 25 participants were enrolled with 23 completing study medication dosing as per protocol and 2 study medication discontinuations due to physician decision (Fig. 2). The characteristics of study participants are shown in Table 2. The mean age was 56 ± 10 years (range 28–69 years) and 72% were female. All participants were Caucasian and not of Hispanic or Latino descent. Demographic characteristics were generally well balanced across the panels. In terms of functional class, 18/25 (72%) participants had New York Heart Association Functional Class 2–4. In addition, 18 participants had some degree of tricuspid valve regurgitation; most noted as either Grade 2 or 3. Most participants were not receiving PAH treatment at baseline. No participants on baseline ERA therapy were included in the RHC population. One participant who was receiving baseline bosentan was enrolled and participated in Part 1 of the study but did not progress to Part 2 RHC.
      Table 2Participant characteristics and right heart catheterization
      As measured prior to dosing in the right heart catheterization period (i.e., pre-dose Period 2 for Panel A and pre-dose Period 3 for Panels B, C and D).
      (RHC) data.
      Panel A
      Participants in Panel A were randomized to receive a single dose of MK-5475 120 μg or Placebo (Part 1/Period 1), 165 μg or Placebo (Part 1/Period 2), 240 μg or Placebo (Part 1/Period 3), and 240 μg (Part 2/Period 2 and Part 2/Period 3).
      Panel B
      Participants in Panel B were allocated to receive a single dose of MK-5475 300 μg (Part 2/Period 1) and 360 μg (Part 2/Period 2 and Part 2/Period 3). One participant in Panel B received 165 μg in Part 2/Period 2 and Part 2/Period 3.
      Panel C
      Participants in Panel C were allocated to receive a single dose of MK-5475 300 μg (Part 2/Period 1) and 360 μg (Part 2/Period 2 and Part 2/Period 3). Four participants in Panel C received 120 μg in Part 2/Period 2 and Part 2/Period 3.
      Panel D
      Participants in Panel D were allocated to receive a single dose of MK-5475 480 μg (Part 2/Period 1) and 120 μg (Part 2/Period 2 and Part 2/Period 3).
      Total
      n(%)N(%)n(%)n(%)n(%)
      Participants in population849425
      Sex, no. (%)
       Female6(75.0)3(75.0)6(66.7)3(75.0)18(72.0)
      Age (Years)
       18 to 708(100.0)4(100.0)9(100.0)4(100.0)25(100.0)
       Median56.050.560.066.059.0
       Range48 to 6444 to 6428 to 6456 to 6928 to 69
      Race, no. (%)
       White8(100.0)4(100.0)9(100.0)4(100.0)25(100.0)
      Ethnicity, no. (%)
       Not Hispanic or Latino8(100.0)4(100.0)9(100.0)8(100.0)25(100.0)
      Hemoglobin g/dL: Mean (SD)13.92(1.61)13.92(1.94)13.89(2.49)13.38(1.49)13.82(1.90)
      PAH medications, no. (%)
      ERA1(12.5)0(0)0(0)0(0)1(4)
      Prostanoids(0)0(0)0(0)(0)0(0)0(0)
      PDE5i3(37.5)2(50)4(44.4)1(25)10(45.5)
      sGC stimulators(0)0(0)0(0)(0)0(0)0(0)
      Classification of PAH, no. (%)
      Idiopathic3(37.5)2(50)3(33.3)0(0)8(32)
      Associated with connective-tissue disease1(12.5)1(25)3(33.3)0(0)5(20)
      Associated with corrected congenital shunts4(50)1(25)3(33.3)3(75)11(44)
      Unknown0(0)0(0)0(0)1(25)1(4)
      Time since diagnosis (years): Mean (SD)13.12(14.32)8(9.24)3.56(4.72)12.67
      Missing one participant.
      (11.24)8.62
      Missing one participant.
      (10.56)
      RHC Endpoints: Mean (SD)
      mPAP-, mmHg39.40(15.99)47.75(22.90)34.92(11.38)30(3.33)37.88(14.83)
      PVR using indirect Fick- dynes*sec/cm5415.18(293.75)816.05(741.69)458.49(478.46)196.59(64.51)473.33(463.82)
      PAWP- mmHg14.68(2.04)10.08(4.95)11.74(2.11)18.08(3.29)13.38(3.81)
      Cardiac index using indirect Fick- L·min−1·m−22.52(0.38)2.84(1.25)2.64(0.72)2.77(0.17)2.66(0.66)
      RAP- mmHg10(2.71)8(2.45)10(3.08)14.5(2.08)10.42(3.26)
      ERA = endothelin receptor antagonists, sGC = soluble guanylate cyclase, SD = standard deviation, mPAP = mean pulmonary arterial pressure, PAWP = pulmonary arterial wedge pressure, PDE5i = phosphodiesterase 5 inhibitors, PVR = pulmonary vascular resistance, RAP = right atrial pressure.
      a As measured prior to dosing in the right heart catheterization period (i.e., pre-dose Period 2 for Panel A and pre-dose Period 3 for Panels B, C and D).
      b Missing one participant.
      c Participants in Panel A were randomized to receive a single dose of MK-5475 120 μg or Placebo (Part 1/Period 1), 165 μg or Placebo (Part 1/Period 2), 240 μg or Placebo (Part 1/Period 3), and 240 μg (Part 2/Period 2 and Part 2/Period 3).
      d Participants in Panel B were allocated to receive a single dose of MK-5475 300 μg (Part 2/Period 1) and 360 μg (Part 2/Period 2 and Part 2/Period 3). One participant in Panel B received 165 μg in Part 2/Period 2 and Part 2/Period 3.
      e Participants in Panel C were allocated to receive a single dose of MK-5475 300 μg (Part 2/Period 1) and 360 μg (Part 2/Period 2 and Part 2/Period 3). Four participants in Panel C received 120 μg in Part 2/Period 2 and Part 2/Period 3.
      f Participants in Panel D were allocated to receive a single dose of MK-5475 480 μg (Part 2/Period 1) and 120 μg (Part 2/Period 2 and Part 2/Period 3).
      Overall, 23/25 (92%) enrolled participants completed the study medication per protocol (Fig. 2). Two participants, 1 during Panel A and another during Panel D, were discontinued at the physician's decision. One participant in Panel A was discontinued after the completion of Part 1 at the investigator's discretion based on the individual's inability to adhere to the study protocol. The participant in Panel D was discontinued prior to dosing in Period 3 due to pulmonary hemodynamic measurements during the baseline pre-dose RHC that did not meet the criteria for continued dosing.

      4.1 Primary outcome: Safety

      There were no serious AEs, events of clinical interest, or deaths in the study (Table 3). Of the 25 participants included in the safety analyses, 13 (52.0%) experienced ≥1 AEs during Part 1 (Periods 1 to 3) and Part 2 (Period 1) of the study. All AEs were mild-to-moderate in intensity and resolved or were resolving by study end. Six participants (24.0%) reported ≥1 AE that the investigator considered drug-related. One participant experienced 2 AEs of blood bilirubin increased. One event (1.02 x ULN), which occurred ∼24 h after administration of MK-5475 240 μg in Part 1/Period 3, was deemed drug related by the investigator and resolved after ∼3 weeks. A second AE of blood bilirubin increased (2.13 x ULN), which was reported prior to administration of MK-5475 240 μg in Part 2/Period 2, was deemed not related to study drug and was resolving at the poststudy visit. A second participant experienced 1 AE of blood bilirubin increased (1.15 x ULN) prior to dosing of MK-5475 120 μg in Part 2/Period 2; this was deemed not related to study drug and was resolving at the poststudy visit. There were no dose-related increases in the incidences of AEs, either overall or by type, across the treatment groups (Table 3; Table 4).
      Table 3Summary of adverse events (AEs) in Part 1 and Part 2/Period 1.
      120 μg165 μg240 μg300 μg480 μgPlaceboTotal
      n(%)n(%)n(%)n(%)n(%)n(%)N(%)
      Participants in population666134625
       with ≥1 AE2(33.3)1(16.7)3(50.0)5(38.5)2(50.0)4(66.7)13(52.0)
       with no AE4(66.7)5(83.3)3(50.0)8(61.5)2(50.0)2(33.3)12(48.0)
       with drug-related
      Determined by the investigator to be related to the study drug.
      AE
      1(16.7)1(16.7)1(16.7)1(7.7)0(0.0)3(50.0)6(24.0)
       with non-serious AE2(33.3)1(16.7)3(50.0)5(38.5)2(50.0)4(66.7)13(52.0)
       with serious AE0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)
       with serious drug-related
      Determined by the investigator to be related to the study drug.
      AE
      0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)
       who died0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)
       who died due to a drug-related
      Determined by the investigator to be related to the study drug.
      AE
      0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)
       discontinued drug due to an AE0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)
       discontinued drug due to a drug-related
      Determined by the investigator to be related to the study drug.
      AE
      0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)
       discontinued drug due to a serious AE0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)
       discontinued drug due to a serious drug-related
      Determined by the investigator to be related to the study drug.
      AE
      0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)
      Part 1 includes participants in Panel A randomized to receive a single dose of MK-5475 120 μg or placebo (Part 1/Period 1), 165 μg or placebo (Part 1/Period 2), and 240 μg or placebo (Part 1/Period 3).
      Part 2/Period 1 includes participants allocated to receive a single dose of MK-5475 300 μg (Panels B and C) or 480 μg (Panel D).
      a Determined by the investigator to be related to the study drug.
      Table 4Participants with adverse events (AEs) in Part 1 and Part 2/Period 1 (incidence rate >0% in ≥1 treatment group).
      120 μg165 μg240 μg300 μg480 μgPlaceboTotal
      N(%)n(%)n(%)n(%)n(%)n(%)N(%)
      Participants in population666134625
       with ≥1 AE2(33.3)1(16.7)3(50.0)5(38.5)2(50.0)4(66.7)13(52.0)
       with no AE4(66.7)5(83.3)3(50.0)8(61.5)2(50.0)2(33.3)12(48.0)
      Infections and infestations1(16.7)0(0.0)0(0.0)1(7.7)0(0.0)1(16.7)3(12.0)
       Rhinitis0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)1(16.7)1(4.0)
       Urinary tract infection1(16.7)0(0.0)0(0.0)1(7.7)0(0.0)0(0.0)2(8.0)
      Investigations1(16.7)0(0.0)1(16.7)1(7.7)2(50.0)3(50.0)7(28.0)
       Alanine aminotransferase increased1(16.7)0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)1(4.0)
       Blood alkaline phosphatase increased0(0.0)0(0.0)0(0.0)1(7.7)0(0.0)0(0.0)1(4.0)
       Blood bilirubin increased0(0.0)0(0.0)1(16.7)0(0.0)1(25.0)2(33.3)4(16.0)
       Blood creatinine increased0(0.0)0(0.0)0(0.0)0(0.0)1(25.0)1(16.7)2(8.0)
      Metabolism and nutrition disorders0(0.0)1(16.7)1(16.7)1(7.7)0(0.0)0(0.0)2(8.0)
       Hyperkalaemia0(0.0)1(16.7)1(16.7)1(7.7)0(0.0)0(0.0)2(8.0)
      Musculoskeletal and connective tissue disorders0(0.0)0(0.0)2(33.3)0(0.0)0(0.0)0(0.0)2(8.0)
       Back pain0(0.0)0(0.0)2(33.3)0(0.0)0(0.0)0(0.0)2(8.0)
      Neoplasms benign, malignant and unspecified (incl cysts and polyps)0(0.0)0(0.0)0(0.0)1(7.7)0(0.0)0(0.0)1(4.0)
       Haemangioma of bone0(0.0)0(0.0)0(0.0)1(7.7)0(0.0)0(0.0)1(4.0)
       Lung neoplasm0(0.0)0(0.0)0(0.0)1(7.7)0(0.0)0(0.0)1(4.0)
      Nervous system disorders0(0.0)0(0.0)0(0.0)1(7.7)0(0.0)1(16.7)2(8.0)
       Dizziness0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)1(16.7)1(4.0)
       Headache0(0.0)0(0.0)0(0.0)1(7.7)0(0.0)0(0.0)1(4.0)
      Respiratory, thoracic and mediastinal disorders0(0.0)0(0.0)0(0.0)1(7.7)0(0.0)1(16.7)2(8.0)
       Bronchitis chronic0(0.0)0(0.0)0(0.0)0(0.0)0(0.0)1(16.7)1(4.0)
      Respiratory, thoracic and mediastinal disorders0(0.0)0(0.0)0(0.0)1(7.7)0(0.0)1(16.7)2(8.0)
       Pulmonary embolism0(0.0)0(0.0)0(0.0)1(7.7)0(0.0)0(0.0)1(4.0)
      Every participant is counted a single time for each applicable row and column.
      A system organ class or specific AE appears on this report only if its incidence in ≥1 of the columns meets the incidence criterion in the report title, after rounding.
      AE terms are from MedDRA Version 23.1.
      Part 1 includes participants in Panel A randomized to receive a single dose of MK-5475 120 μg or placebo (Part 1/Period 1), 165 μg or placebo (Part 1/Period 2) and 240 μg or placebo (Part 1/Period 3).
      Part 2/Period 1 includes participants allocated to receive a single dose of MK-5475 300 μg (Panels B and C) or 480 μg (Panel D).
      The safety findings from the RHC and FRI treatment periods are presented in the supplementary appendix. There was no evidence of dose-related increases in the incidences of AEs, either overall or by type, across the treatment groups (Tables S1–S4). No clinically meaningful effects on systolic blood pressure, diastolic blood pressure, or heart rate were seen during the RHC treatment period either within or across the doses (Tables S5–S7).The most frequent AEs reported with MK-5475 treatment across study parts and periods included back pain (13/25; 52%), blood bilirubin increased (5/25; 20%), hyperkalemia (3/25; 12%), abdominal pain (2/25; 8%), blood creatinine increased (2/25; 8%), dizziness (2/25; 8%), fatigue (2/25; 8%) and urinary tract infection (2/25; 8%). All AEs were mild-to-moderate in severity and resolved spontaneously, no severe AEs occurred. Back pain was most often attributed to positioning during the RHC procedure.

      5. Pharmacodynamics

      5.1 Right heart catheterization treatment periods

      Descriptive statistics for the primary PD outcome of minimum and TWA percent change from baseline in PVR over the time course are shown in Table 5. A mean minimum percent change from baseline of at least −20% was observed for the 120 μg, 240 μg, and 360 μg doses. The corresponding decreases from baseline in mean TWA values ranged from −8% to −14% across the doses. One participant in Panel B received a single 165 μg dose, rather than the planned 240 μg dose, for the PD assessments; this participant had much higher systemic exposures after a single 300 μg dose in the pharmacokinetics period compared to other participants receiving the same dose and a decision was made to reduce the dose during PD assessments. For this participant, increases from baseline in both the minimum and TWA PVR of 13% and 23% were seen.
      Table 5Statistical analysis of percent change from baseline in pulmonary vascular resistance (PVR) as measured during right heart catheterization (RHC).
      EndpointDoseParameter
      Minimum corresponds to the smallest post-dose value during the RHC procedure (up to 4.5 h post dose).
      N% Change from baseline
      MeanSDMedianMinimumMaximum
      PVR using indirect Fick (dynes*sec/cm5)120 μgTWA7−8.1016.62−10.54−28.5626.01
      Minimum7−20.7713.88−20.15−39.551.04
      165 μgTWA122.71.22.7122.7122.71
      Minimum113.01.13.0113.0113.01
      240 μgTWA7−11.0415.45−11.44−33.8313.15
      Minimum7−29.4613.72−32.29−47.62−12.35
      360 μgTWA8−14.2714.97−16.67−36.5610.17
      Minimum8−29.2517.58−33.35−52.183.45
      SD = standard deviation.
      One participant in Panel B received 165 μg during the RHC period.
      TWA is the Time Weighted Average from the first post-dose to last post-dose RHC timepoint (∼4.5 h post dose).
      a Minimum corresponds to the smallest post-dose value during the RHC procedure (up to 4.5 h post dose).

      5.2 Functional respiratory imaging treatment periods

      Descriptive and inferential statistics for the secondary PD outcome of percent change from baseline in PBV during the FRI procedure are shown in Table 6. Significant mean percent increases from baseline in PBV were observed at 3, 8, and 24 h post dose for the 360 μg dose as well as when combined in the pooled analysis. Representative images from one participant showing changes from baseline in PBV as measured by FRI at 1, 3, 8, and 24 h after inhalation of 360 μg MK-5475 are shown in Fig. 3. Increases in PBV versus baseline were generally consistent across lobes and reached a maximum at 8 h post dose in this participant.
      Table 6Statistical analysis of percent change from baseline in pulmonary blood volume (PBV) as measured by functional respiratory imaging (FRI).
      Time Point (hour)All Doses120 μg240 μg360 μg
      % Change from baseline (N = 22)p-value
      No formal hypothesis testing was performed for PBV. P-values are presented for illustrative purposes only and were not adjusted for multiplicity hence the p-values would not be used to infer a definitive treatment effect on PBV.
      % Change from baseline (N = 8)p-value
      No formal hypothesis testing was performed for PBV. P-values are presented for illustrative purposes only and were not adjusted for multiplicity hence the p-values would not be used to infer a definitive treatment effect on PBV.
      % Change from baseline (N = 6)
      Data from 1 participant receiving 240 μg were excluded from the summary as contrast was administered to this participant only at baseline and not at post-dose time points.
      p-value
      No formal hypothesis testing was performed for PBV. P-values are presented for illustrative purposes only and were not adjusted for multiplicity hence the p-values would not be used to infer a definitive treatment effect on PBV.
      % Change from baseline (N = 7)
      Data from one participant receiving 360 μg were excluded from the summary as the scans for this participant showed a radiological state not observed in other participants, suggesting a condition in addition to PAH.
      p-value
      No formal hypothesis testing was performed for PBV. P-values are presented for illustrative purposes only and were not adjusted for multiplicity hence the p-values would not be used to infer a definitive treatment effect on PBV.
      100.760−20.14520.35930.124
      34<0.00120.25420.1929<0.001
      86<0.00130.07411<0.0019<0.001
      2420.051−20.15530.08960.004
      PAH = pulmonary arterial hypertension.
      a No formal hypothesis testing was performed for PBV. P-values are presented for illustrative purposes only and were not adjusted for multiplicity hence the p-values would not be used to infer a definitive treatment effect on PBV.
      b Data from 1 participant receiving 240 μg were excluded from the summary as contrast was administered to this participant only at baseline and not at post-dose time points.
      c Data from one participant receiving 360 μg were excluded from the summary as the scans for this participant showed a radiological state not observed in other participants, suggesting a condition in addition to PAH.
      Fig. 3
      Fig. 3Percent change of pulmonary blood vessel volume (PBV) after a single inhaled MK-5475 administration versus baseline constructed from functional respiratory imaging (FRI) computed tomography scans in 1 study participant. Percent PBV change (see scale) at A) 1 h post dose; B) 3 h post dose; C) 8 h post dose; and D) 24 h post dose versus baseline.

      6. Discussion

      Despite currently available therapies, the morbidity and mortality associated with PAH remains high, underscoring the urgency for novel therapies to address this unmet need. Current PAH therapies are administered systemically, thus resulting in non-selective extrapulmonary vasodilatory effects, poor overall tolerability profiles and undesirable dose-limiting toxicities. MK-5475 is a novel, highly potent, small molecule sGC stimulator under development for the treatment of PAH. MK-5475 is designed to be administered as a dry powder via a dry-powder inhaler device to enable deep-lung disposition and targeted lung activity. Inhaled PAH therapies like MK-5475 may provide selectivity of hemodynamic effects to the lung vasculature thus offering significant advantages over current systemic therapies, including optimized drug delivery to the lungs at a lower overall dose with a more favorable tolerability profile. Novel inhaled PAH compounds with targeted pulmonary selectivity also hold promise in enabling easier dosing without the need for titration, higher exposures without safety limitations and the ability to co-administer with PDE5i including in populations with heterogenous lung disease in which vasodilation in poorly ventilated regions of the lung might lead to clinically significant mismatches in distribution of ventilation and perfusion. The current study evaluated the safety, tolerability, and ascending single-dose PD of MK-5475 delivered by inhalation in participants with Group 1 PH.
      In this study, single inhaled doses of MK-5475 ranging from 120 to 480 μg were generally well tolerated in both male and female participants. Mild-to-moderate treatment-emergent AEs were seen across the individual dose groups with no dose-limiting side effects. There were no serious AEs, events of clinical interest, or deaths reported at any doses. The most frequently reported AEs included hyperkalemia, blood bilirubin increased, fatigue, and back pain; none were clearly linked causally to MK-5475. Unintended side effects common with PAH therapies due to their vasodilatory effects, such as headache, hypotension, and edema, were not frequently reported with MK-5475 in this single-dose study [
      • Burks M.
      • Stickel S.
      • Galiè N.
      Pulmonary arterial hypertension: combination therapy in practice.
      ]. Of note, characteristic AEs associated with other inhaled PAH therapeutic formulations, such as cough and throat irritation, also were not observed in this study [
      ,
      ]. Two AEs of small subsegmental pulmonary emboli were noted as pre-existing incidental findings in 2 participants during the baseline CT scan procedure. There were no signs or symptoms associated with these pulmonary embolisms in either participant. Further, no clinically meaningful effects on systemic blood pressure and heart rate were seen across the dose range, supporting that inhaled single doses of MK-5475 do not elicit unintended vasodilatory side effects commonly seen with systemic PAH therapies.
      The primary PD outcome in this study was percent change from baseline for the minimum PVR value as measured by RHC though 4.5 h post dose. The mean percent reductions from baseline in minimum PVR following single-dose treatment with MK-5475 ranged from 21% to 30% across the 120 μg and 360 μg doses. The magnitude of the reductions in PVR seen in this study following single inhaled doses of MK-5475 are similar to those reported with single-dose orally-administered riociguat, a marketed sGC stimulator [
      • Grimminger F.
      • Weimann G.
      • Frey R.
      • Voswinckel R.
      • Thamm M.
      • Bölkow D.
      • Weissmann N.
      • Mück W.
      • Unger S.
      • Wensing G.
      • Schermuly R.T.
      • Ghofrani H.A.
      First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension.
      ]. MK-5475 also led to reductions from baseline in TWA PVR ranging from 8% to 14% across the 120 μg–360 μg dose groups. An increase from baseline in minimum and TWA PVR (13% and 23%, respectively) was seen in the one participant in the MK-5475 165 μg group. Upon review of the clinical information by the team of investigators, it appeared that the participant suffered from pulmonary veno-occlusive disease which caused elevation of left atrial pressure after pulmonary arterial vasodilation was induced by MK-5475.
      FRI assessment of PBV was prespecified as a secondary PD outcome to compare against the primary outcome of PVR as derived by RHC in participants with PAH. Treatment with single inhaled doses of MK-5475 produced rapid and sustained effects on PBV out to 24 h post dose. Significant increases from baseline in PBV were observed at 3, 8, and 24 h post dose across the entire dose range studied. The magnitudes of the changes in PBV seen in this study were comparable to those previously observed in participants with secondary PH due to chronic obstructive pulmonary disease after the administration of inhaled nitrous oxide [
      • Hajian B.
      • De Backer J.
      • Vos W.
      • Van Holsbeke C.
      • Ferreira F.
      • Quinn D.A.
      • Hufkens A.
      • Claes R.
      • De Backer W.
      Pulmonary vascular effects of pulsed inhaled nitric oxide in COPD patients with pulmonary hypertension.
      ].
      Taken together, the PD findings in this study suggest single inhaled doses of MK-5475 have favorable effects on pulmonary vasodilation as assessed by both RHC and FRI. Future studies are needed to conclusively demonstrate the potential utility of the non-validated FRI-derived imaging measurement, PBV, in PAH research. Nevertheless, preliminary findings suggest that PBV may provide a useful quantitative measurement of pulmonary arterial perfusion that may be complementary to those derived from the conventional PVR outcome as measured by the more invasive RHC methodology.
      This study has several limitations including the small sample size (common for studies for PAH due to the small number of individuals with this rare disease), the short duration of treatment, and the potential reporting bias of AEs during the open-label portion of the study. The study population was entirely composed of Caucasians not of Hispanic or Latino ethnicity with the majority naïve to PAH medications at baseline thus it is not clear if the results reported herein are generalizable to other races and ethnic groups, use and types of prior/co-administered PAH therapies and/or patients with more pronounced PAH disease severity. The results also may not be generalizable to PAH patients with an altered hemodynamic profile relative to the RHC entry criteria used in this study (i.e., mPAP ≥25 mmHg and PVR ≥3.75 dyn/s/cm5 and PAWP ≤15 mmHg). It should be noted that the thermodilution method (i.e., based on cold temperature saline bolus measurement) in this study yielded cardiac output (CO) values that were consistently lower than the measurements obtained by the indirect Fick method (i.e., based on assumed rather than directly measured oxygen consumption). Thus, given that PVR is derived from CO, the reductions from baseline in PVR seen with MK-5475 treatment may be a consequence of the technique used to measured cardiac function and/or variability in the CO measurement rather than a true reflection of a treatment effect. However, we would note that in this study, reduction of mPAP was the dominant driver of reduction in PVR, suggesting that the PVR findings should be robust to errors in CO measurement. Placebo was not included in the open-label portion of the study because it was not deemed necessary for the change-from-baseline design of the assessments. Thus, this study is underpowered to definitively make conclusions regarding the safety/tolerability profile of inhaled MK-5475 and its effects on potential biomarkers. In some participants, systemic blood pressure appeared to minimally increase throughout the duration of the RHC procedure, likely due to discomfort, stress and fatigue associated with the procedure. The within-group changes from baseline in blood pressure were not clinically significant; however, the absence of a placebo group limits this assessment. Another important limitation is the lack of an active comparator control arm which hampered a thorough understanding of the PD effects of MK-5475. Finally, no formal hypothesis testing was performed in this study and any p-values provided were for illustrative purposes only; hence, p-values should not be used to infer definitive treatment effects in this small study. Therefore, while compelling, the results of this study should be considered preliminary. Further evaluation is currently ongoing in a larger, multi-center Phase 2/3 trial that is now enrolling (INSIGNIA-PAH MK-5475-007; Clinicaltrials.gov: NCT04732221).
      In conclusion, treatment with MK-5475 showed significant improvements in pulmonary circulation as assessed by both PVR and PBV outcomes. The post-treatment improvements in the validated RHC-derived PVR primary outcome observed across the dose range was both confirmed and corroborated by improvements in the empirical FRI-derived PBV secondary outcome, suggesting PBV may serve as a useful surrogate clinical endpoint for arterial perfusion in PAH research. Future research is needed to conclusively demonstrate the potential value of FRI technology and the relative clinical utility of PBV versus PVR in an adequately powered study conducted in a larger population of participants with PAH. Further, the overall favorable safety/tolerability profile of inhaled MK-5475 was similar across the dose groups without evidence of dose-limiting toxicities or deleterious systemic side effects typically seen with systemic PAH therapies. Taken together, these findings suggest that inhaled MK-5475 holds promise as a selective pulmonary vasodilator (i.e., reducing PVR and increasing PBV) with targeted lung delivery thereby enabling the avoidance of systemic toxicities. Thus, this study lays the foundation for further clinical investigation of a dry-powder inhaler formulation of the novel small-molecule sGC stimulator, MK-5475, in patients with pulmonary hypertension.

      Funding

      Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD). MSD provided MK-5475 and financial support for the study.

      Ethical approval

      This study (ClinicalTrials.gov NCT03744637 [A Study of Single Doses of MK-5475 on Pulmonary Vascular Resistance (MK-5475-002)]) was approved by the Health Authority and Central Ethics Committee of Moldova.

      Author declaration of interest

      Ednan K. Bajwa, Dawn Cislak, John Palcza, Hwa-ping Feng, Eric J. Messina, Tom Reynders, Jean-François Denef, Eseng Lai, and S. Aubrey Stoch are current or former employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may hold stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. Vasile Corcea received material support and investigational medical products from MSD during the clinical trial.

      Data availability

      The data sharing policy, including restrictions, of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA is available at http://engagezone.msd.com/ds_documentation.php. Requests for access to the study data can be submitted through the Engage Zone site or via email to [email protected]

      CRediT authorship contribution statement

      Ednan K. Bajwa: Conceptualization, Methodology, Formal analysis, Writing – original draft, Writing – review & editing. Dawn Cislak: Conceptualization, Methodology, Formal analysis, Writing – review & editing. John Palcza: Conceptualization, Methodology, Formal analysis, Writing – review & editing. Hwa-ping Feng: Formal analysis, Writing – review & editing. Eric J. Messina: Conceptualization, Methodology, Formal analysis, Writing – original draft, Writing – review & editing. Tom Reynders: Conceptualization, Methodology, Writing – review & editing. Jean-François Denef: Conceptualization, Methodology, Writing – review & editing. Vasile Corcea: Data curation, Writing – review & editing. Eseng Lai: Conceptualization, Methodology, Formal analysis, Writing – review & editing. S. Aubrey Stoch: Conceptualization, Methodology, Formal analysis, Writing – review & editing.

      Acknowledgments

      The authors gratefully acknowledge Maxim Bogus MD, and Nelea Ghicavîi MD, of PMSI Republican Clinical Hospital “T. Mosneaga”, ARENSIA EM Unit, Chisinau, Republic of Moldova, for their assistance with clinical site set-up including patient recruitment and clinical/procedure follow-up of dosed patients with their dedicated team. The authors also wish to thank Mahesh J. Patel MD for his guidance and support of this manuscript, and Amy O. Johnson Levonas PhD for writing and editorial assistance, as well as Jennifer Rotonda PhD and Michele McColgan BA for administrative assistance. They are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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