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OHTUVAYRE TRIALS EVALUATED

Lung function, safety, and 
health-related quality of life

Study design

The ENHANCE studies were pivotal phase 3 trials that enrolled a broad population of symptomatic adult patients with moderate to severe COPD1

Graph Secondary Endpoints improvementThe graphic shows a bar graph of parallel-group clinical trials: ENHANCE-1 and ENHANCE-2 spanning 24 weeks. A subset of ENHANCE-1 patients was evaluated for 48 weeks. The graphic depicts a horizontal x-axis with text markers and dotted lines of 0 weeks, 12 weeks, 24 weeks, and 48 weeks. In between the 24 weeks and 48 weeks text markers is the title, “ENHANCE-1 Safety Cohort.” The vertical y-axis labels the ENHANCE-1 N=763, R 5:3, in navy blue, and ENHANCE-2 N=790, R 5:3, in purple. The top bar on the x-axis is in the ENHANCE-1 navy blue category and is navy blue in color. It is labeled “OHTUVAYRE 3 mg BID n=477b” and begins at zero weeks and ends at 48 weeks. The bar originates at 0 weeks, reaches as a solid bar to 24 weeks, then extends further as a thinner bar from 24 to 48 weeks. The second to top bar on the x-axis is in the ENHANCE-1 navy blue category and is gray in color. It is labeled “Placebo BID n=282b” and begins at zero weeks and ends at 48 weeks. The bar originates at 0 weeks, reaches as a solid bar to 24 weeks, then extends further as a thinner bar from 24 to 48 weeks. The third bar from the top on the x-axis is in the ENHANCE-2 purple category and is purple in color. It is labeled “OHTUVAYRE 3 mg BID n=498b” and begins at zero weeks and ends at 24 weeks. The fourth bar from the top on the x-axis is in the ENHANCE-2 purple category and is gray in color. It is labeled “Placebo BID n=291b” and begins at zero weeks and ends at 24 weeks.
Graph Secondary Endpoints improvementThe graphic shows a bar graph of parallel-group clinical trials: ENHANCE-1 and ENHANCE-2 spanning 24 weeks. A subset of ENHANCE-1 patients was evaluated for 48 weeks. The graphic depicts a horizontal x-axis with text markers and dotted lines of 0 weeks, 12 weeks, 24 weeks, and 48 weeks. In between the 24 weeks and 48 weeks text markers is the title, “ENHANCE-1 Safety Cohort.” The vertical y-axis labels the ENHANCE-1 N=763, R 5:3, in navy blue, and ENHANCE-2 N=790, R 5:3, in purple. The top bar on the x-axis is in the ENHANCE-1 navy blue category and is navy blue in color. It is labeled “OHTUVAYRE 3 mg BID n=477b” and begins at zero weeks and ends at 48 weeks. The bar originates at 0 weeks, reaches as a solid bar to 24 weeks, then extends further as a thinner bar from 24 to 48 weeks. The second to top bar on the x-axis is in the ENHANCE-1 navy blue category and is gray in color. It is labeled “Placebo BID n=282b” and begins at zero weeks and ends at 48 weeks. The bar originates at 0 weeks, reaches as a solid bar to 24 weeks, then extends further as a thinner bar from 24 to 48 weeks. The third bar from the top on the x-axis is in the ENHANCE-2 purple category and is purple in color. It is labeled “OHTUVAYRE 3 mg BID n=498b” and begins at zero weeks and ends at 24 weeks. The fourth bar from the top on the x-axis is in the ENHANCE-2 purple category and is gray in color. It is labeled “Placebo BID n=291b” and begins at zero weeks and ends at 24 weeks.
Graph Secondary Endpoints improvement_MobileThe graphic shows a bar graph of parallel-group clinical trials: ENHANCE-1 and ENHANCE-2 spanning 24 weeks. A subset of ENHANCE-1 patients was evaluated for 48 weeks. The graphic depicts a horizontal x-axis with text markers and dotted lines of 0 weeks, 12 weeks, 24 weeks, and 48 weeks. In between the 24 weeks and 48 weeks text markers is the title, “ENHANCE-1 Safety Cohort.” The vertical y-axis labels the ENHANCE-1 N=763, R 5:3, in navy blue, and ENHANCE-2 N=790, R 5:3, in purple. The top bar on the x-axis is in the ENHANCE-1 navy blue category and is navy blue in color. It is labeled “OHTUVAYRE 3 mg BID n=477b” and begins at zero weeks and ends at 48 weeks. The bar originates at 0 weeks, reaches as a solid bar to 24 weeks, then extends further as a thinner bar from 24 to 48 weeks. The second to top bar on the x-axis is in the ENHANCE-1 navy blue category and is gray in color. It is labeled “Placebo BID n=282b” and begins at zero weeks and ends at 48 weeks. The bar originates at 0 weeks, reaches as a solid bar to 24 weeks, then extends further as a thinner bar from 24 to 48 weeks. The third bar from the top on the x-axis is in the ENHANCE-2 purple category and is purple in color. It is labeled “OHTUVAYRE 3 mg BID n=498b” and begins at zero weeks and ends at 24 weeks. The fourth bar from the top on the x-axis is in the ENHANCE-2 purple category and is gray in color. It is labeled “Placebo BID n=291b” and begins at zero weeks and ends at 24 weeks.

aN, number of all enrolled patients.

bn, number of patients who received at least one dose of study drug and had non-missing FEV1 value.

Safety of OHTUVAYRE was based on the pooled safety population for 24 weeks in ENHANCE-1 and ENHANCE-2 and on a 48-week cohort (OHTUVAYRE, n=280; placebo, n=89) in ENHANCE-1.

Overview

The ENHANCE Trials were designed to evaluate the efficacy and safety of OHTUVAYRE in patients with moderate to severe COPD in two 24-week randomized, double-blind, placebo-controlled, parallel-group clinical studies. After a 28-day run-in to ensure stable background medication use, a total of 1553 adults (763 in ENHANCE-1, 790 in ENHANCE-2) were randomized 5:3 to receive 3 mg of OHTUVAYRE or placebo twice daily administered by oral inhalation via standard jet nebulizer.1

ENHANCE-1

The ENHANCE-1 trial enrolled a total of 763 patients randomized to receive 3 mg of OHTUVAYRE or placebo twice daily administered by oral inhalation via standard jet nebulizer. A total of 68% of patients were taking concurrent therapy: 30% taking concurrent LAMA, 18% taking concurrent LABA, and 20% taking concurrent LABA/ICS therapy throughout the trial. A subset of patients was evaluated for 48 weeks.

ENHANCE-2

The ENHANCE-2 trial enrolled a total of 790 patients randomized to receive 3 mg of OHTUVAYRE or placebo twice daily administered by oral inhalation via standard jet nebulizer. A total of 55% of patients were taking concurrent therapy: 33% taking concurrent LAMA, 7% taking concurrent LABA, and 15% taking concurrent LABA/ICS therapy throughout the trial.

Patients were allowed to remain in the trials after treatment discontinuation.1

cSelected inclusion/exclusion criteria.
BID, twice daily; COPD, chronic obstructive pulmonary disease; ENHANCE, Ensifentrine as a Novel inHAled Nebulized COPD thErapy; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; ICS, inhaled corticosteroids; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council dyspnea scale; R, randomization.

Patients1

Selected eligibility criteriac:

  • COPD diagnosis: FEV1/FVC<0.71
  • Post-bronchodilator FEV1 30-70% predicted normal1
  • mMRC dyspnea scale score ≥21
  • Current smoker or smoking history (≥10 pack-years)1
  • No asthma diagnosis1
  • No exacerbation requiring oral or parenteral steroids in the 3 months prior to screening1,2

Selected baseline characteristics:

  • Approximately 62% of patients were on maintenance background therapy, which primarily included LAMA, LABA, or LABA + ICS1
  • ~38% weren’t currently on concomitant maintenance COPD therapy1
  • In the ENHANCE-1 and ENHANCE-2 trials, 25% and 21% of patients, respectively, reported exacerbations of COPD within the 15 months prior to the studies

Primary endpoint

Change from baseline in FEV1 AUC0-12h post dose at Week 12a

Selected key secondary endpoints

The ENHANCE trials were powered to statistically test secondary endpoints in a hierarchical order, including the selected endpoints below:

  • Change from baseline in peak FEV1 at Week 121,b
  • Change from baseline in SGRQ total score at Week 241,c
  • SGRQ responder rates at Week 24c

Selected other endpoints

These endpoints were not part of the formal testing hierarchy and therefore were not evaluated for statistical significance. Therefore, no conclusions can be drawn.1

  • Change from baseline in peak FEV1 at different timepoints (Day 1, Week 6, Week 12, and Week 24)3,4,b,c
  • Change from baseline in SGRQ total score at different timepoints (Week 6, Week 12, and Week 24)3,4,c
  • TDI at different timepoints (Week 6, Week 12, and Week 24)1
  • Moderate/severe exacerbation risk over 24 weeks and 48 weeks1,d

To address multiplicity in the analysis of the endpoints, statistical testing of the primary endpoint and selected key secondary endpoints was conducted in a hierarchical order.1,5 As the pre-specified hierarchical testing criteria were not fully met in ENHANCE-2, SGRQ total score and proportion of SGRQ responders at Week 24 were not formally tested for statistical significance.1,6

aAverage FEV1 AUC0-12h is defined as the AUC over 12 hours of the FEV1, divided by 12 hours.1
bPeak FEV1 was defined as the highest post-dose FEV1 within the first 4 hours after dosing.1
cSGRQ is a patient-reported measure of symptoms, activity, and impacts on daily life and perceived well-being in patients with obstructive airway disease.7

dModerate COPD exacerbations were defined as worsening of COPD symptoms requiring 2 or more major symptoms or one major symptom and one minor symptom for 2 or more days requiring a minimum of 3 days of therapy with oral or systemic corticosteroids and/or antibiotics; severe COPD exacerbations were defined as worsening of symptoms and inpatient hospitalization.1
AUC, area under the curve; FEV1, forced expiratory volume in one second; SGRQ, St. George’s Respiratory Questionnaire; TDI, transition dyspnea index.

Primary endpoint

Change from baseline in FEV1 AUC0-12h at Week 12a

Significantly improved lung function as demonstrated by average FEV1 AUC0-12h

Graph Primary EndpointThe vertical y-axis of this graph is labeled, “LS Mean Change from Baseline FEV1 AUCo-12h(mL).” The y-axis numbers begin at -60 from the bottom of the graph and end at 80 at the top of the graph, counting up from -60 to 80 in increments of ten. The horizontal x-axis label of the graph gives two different title labels to four bar graphs, two of which are grouped under the title “ENHANCE-1” on a navy blue background with white text, and two of which are grouped under the title “ENHANCE-2” on a purple background with white text. Underneath the graph is a color label. Solid gray color indicates Placebo bars, and a light blue to dark blue gradient color indicates OHTUVAYRE bars. The first bar under the ENHANCE-1 grouping is labeled, “Placebo (n=282)b”. This placebo bar is colored in solid gray. Within the solid gray placebo bar illustration is the number “-26” in white text on the gray color of the bar. The ENHANCE-1 gray placebo bar begins at zero (of the y-axis) and extends downward to slightly more than halfway between -20 and -30 positions on the y-axis, illustrating its -26 position. The second bar, to its right, within the ENHANCE-1 grouping, is a light blue to dark blue gradient colored bar labeled, “OHTUVAYRE (n=477)b”. Within the blue gradient OHTUVAYRE bar illustration is the number “61” in white text on the gradient blue color of the bar. The ENHANCE-1 blue OHTUVAYRE bar begins at zero and extends upwards to just above the 60 position on the y-axis, illustrating its 61 position. In between the placebo bar and the OHTUVAYRE bar is a dotted line, extending from the -26 position upwards to the 61 position. Toward the top portion of this dotted line is a callout bubble, with a light purple background and dark purple text. The text reads, “+87 mL LS Mean Difference from Placebo p<0.0001.” The third bar on this graph, which is underneath the ENHANCE-2 grouping is labeled, “Placebo (n=291)b.” This placebo bar is colored in solid gray. Within the solid gray placebo bar illustration is the number “-46” in white text on the gray color of the bar. The ENHANCE-2 placebo bar begins at zero (of the y-axis) and extends downward to slightly more than halfway between -40 and -50 positions on the y-axis, illustrating its -46 position. The fourth bar on this graph, to its right, within the ENHANCE-2 grouping, is a light blue to dark blue gradient colored bar labeled, “OHTUVAYRE (n=498)b”. Within the blue gradient OHTUVAYRE bar illustration is the number “48” in white text on the gradient blue color of the bar. The ENHANCE-2 OHTUVAYRE bar begins at zero and extends upwards to just below the 50 position on the y-axis, illustrating its 48 position. In between the placebo bar and the OHTUVAYRE bar is a dotted line, extended from the -46 position upwards to the 48 position. Toward the top portion of this dotted line is a callout bubble, with a light purple background and dark purple text. The text reads, “+94 mL LS Mean Difference from Placebo p<0.0001.”
Graph Primary EndpointThe vertical y-axis of this graph is labeled, “LS Mean Change from Baseline FEV1 AUCo-12h(mL).” The y-axis numbers begin at -60 from the bottom of the graph and end at 80 at the top of the graph, counting up from -60 to 80 in increments of ten. The horizontal x-axis label of the graph gives two different title labels to four bar graphs, two of which are grouped under the title “ENHANCE-1” on a navy blue background with white text, and two of which are grouped under the title “ENHANCE-2” on a purple background with white text. Underneath the graph is a color label. Solid gray color indicates Placebo bars, and a light blue to dark blue gradient color indicates OHTUVAYRE bars. The first bar under the ENHANCE-1 grouping is labeled, “Placebo (n=282)b”. This placebo bar is colored in solid gray. Within the solid gray placebo bar illustration is the number “-26” in white text on the gray color of the bar. The ENHANCE-1 gray placebo bar begins at zero (of the y-axis) and extends downward to slightly more than halfway between -20 and -30 positions on the y-axis, illustrating its -26 position. The second bar, to its right, within the ENHANCE-1 grouping, is a light blue to dark blue gradient colored bar labeled, “OHTUVAYRE (n=477)b”. Within the blue gradient OHTUVAYRE bar illustration is the number “61” in white text on the gradient blue color of the bar. The ENHANCE-1 blue OHTUVAYRE bar begins at zero and extends upwards to just above the 60 position on the y-axis, illustrating its 61 position. In between the placebo bar and the OHTUVAYRE bar is a dotted line, extending from the -26 position upwards to the 61 position. Toward the top portion of this dotted line is a callout bubble, with a light purple background and dark purple text. The text reads, “+87 mL LS Mean Difference from Placebo p<0.0001.” The third bar on this graph, which is underneath the ENHANCE-2 grouping is labeled, “Placebo (n=291)b.” This placebo bar is colored in solid gray. Within the solid gray placebo bar illustration is the number “-46” in white text on the gray color of the bar. The ENHANCE-2 placebo bar begins at zero (of the y-axis) and extends downward to slightly more than halfway between -40 and -50 positions on the y-axis, illustrating its -46 position. The fourth bar on this graph, to its right, within the ENHANCE-2 grouping, is a light blue to dark blue gradient colored bar labeled, “OHTUVAYRE (n=498)b”. Within the blue gradient OHTUVAYRE bar illustration is the number “48” in white text on the gradient blue color of the bar. The ENHANCE-2 OHTUVAYRE bar begins at zero and extends upwards to just below the 50 position on the y-axis, illustrating its 48 position. In between the placebo bar and the OHTUVAYRE bar is a dotted line, extended from the -46 position upwards to the 48 position. Toward the top portion of this dotted line is a callout bubble, with a light purple background and dark purple text. The text reads, “+94 mL LS Mean Difference from Placebo p<0.0001.”
Graph Primary Endpoint_MobileThe vertical y-axis of this graph is labeled, “LS Mean Change from Baseline FEV1 AUCo-12h(mL).” The y-axis numbers begin at -60 from the bottom of the graph and end at 80 at the top of the graph, counting up from -60 to 80 in increments of ten. The horizontal x-axis label of the graph gives two different title labels to four bar graphs, two of which are grouped under the title “ENHANCE-1” on a navy blue background with white text, and two of which are grouped under the title “ENHANCE-2” on a purple background with white text. Underneath the graph is a color label. Solid gray color indicates Placebo bars, and a light blue to dark blue gradient color indicates OHTUVAYRE bars. The first bar under the ENHANCE-1 grouping is labeled, “Placebo (n=282)b”. This placebo bar is colored in solid gray. Within the solid gray placebo bar illustration is the number “-26” in white text on the gray color of the bar. The ENHANCE-1 gray placebo bar begins at zero (of the y-axis) and extends downward to slightly more than halfway between -20 and -30 positions on the y-axis, illustrating its -26 position. The second bar, to its right, within the ENHANCE-1 grouping, is a light blue to dark blue gradient colored bar labeled, “OHTUVAYRE (n=477)b”. Within the blue gradient OHTUVAYRE bar illustration is the number “61” in white text on the gradient blue color of the bar. The ENHANCE-1 blue OHTUVAYRE bar begins at zero and extends upwards to just above the 60 position on the y-axis, illustrating its 61 position. In between the placebo bar and the OHTUVAYRE bar is a dotted line, extending from the -26 position upwards to the 61 position. Toward the top portion of this dotted line is a callout bubble, with a light purple background and dark purple text. The text reads, “+87 mL LS Mean Difference from Placebo p<0.0001.” The third bar on this graph, which is underneath the ENHANCE-2 grouping is labeled, “Placebo (n=291)b.” This placebo bar is colored in solid gray. Within the solid gray placebo bar illustration is the number “-46” in white text on the gray color of the bar. The ENHANCE-2 placebo bar begins at zero (of the y-axis) and extends downward to slightly more than halfway between -40 and -50 positions on the y-axis, illustrating its -46 position. The fourth bar on this graph, to its right, within the ENHANCE-2 grouping, is a light blue to dark blue gradient colored bar labeled, “OHTUVAYRE (n=498)b”. Within the blue gradient OHTUVAYRE bar illustration is the number “48” in white text on the gradient blue color of the bar. The ENHANCE-2 OHTUVAYRE bar begins at zero and extends upwards to just below the 50 position on the y-axis, illustrating its 48 position. In between the placebo bar and the OHTUVAYRE bar is a dotted line, extended from the -46 position upwards to the 48 position. Toward the top portion of this dotted line is a callout bubble, with a light purple background and dark purple text. The text reads, “+94 mL LS Mean Difference from Placebo p<0.0001.”

aAverage FEV1 AUC0-12h is defined as the AUC over 12 hours of the FEV1, divided by 12 hours.1
bn, number of patients who received at least one dose of study drug and had non-missing baseline FEV1 value.

AUC, area under the curve; ENHANCE, Ensifentrlne as a Novel inHAled Nebulized COPD thErapy; FEV1, forced expiratory volume in one second; mL, milliliter.

Selected key secondary endpoints

Peak FEV1 at Week 121,3,4,8

Key secondary endpoint: Peak FEV1 evaluated at Week 12 was included in the statistical testing hierarchy.1

Limitations: Peak FEV1 at Day 1, Week 6, and Week 24 were not included in the statistical hierarchy for ENHANCE-1 and ENHANCE-2 and therefore not controlled for multiplicity. Therefore, no conclusions can be drawn.1

Mean peak FEV1 change from baseline at Day 1, Week 6, Week 12, and Week 241,3,4,8

Key Secondary Endpoint Graph_Mobile (1)The first graph is labeled, “Peak FEV1: ENHANCE-1” written in white text on a navy blue background. The vertical y-axis of the graph is labeled, “LS Mean Change From Baseline FEV1 (mL).” The y-axis numbers begin at 0 from the bottom of the graph and end at 300 at the top of the graph, counting up from 0 in increments of fifty, from 0, 50, 100, 150, 200, 250, to 300. The horizontal x-axis is labeled “Time” and the numerical markers of the x-axis has markers from Day 1, Week 6, Week 12 (p<0.0001) and Week 24. To the right-hand side of the graph title is a color label. Solid gray colored circle markers indicate Placebo, and light blue colored squares indicate OHTUVAYRE. The markers for Day 1, Week 6, Week 12, and Week 24 are marked on a line graph. The placebo markers in dark gray circles are illustrated as circular dots placed along Day 1, Week 6, Week 12, and Week 24 on a plain white background between the 50 and 100 markers of the y-axis, with a slight downward trend of the line graph as it spans from Day 1 to Week 24. The OHTUVAYRE markers in light blue squares are illustrated as square dots placed along Day 1, Week 6, Week 12, and Week 24 on a plain white background between the 200 and 250 markers of the y-axis, with a slight downward trend of the line graph as it spans from Day 1 to Week 24. In between the Day 1 placebo marker dot and the Day 1 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “152.” In between the Week 6 placebo marker dot and the Week 6 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the vertical dotted line is the number, “136.” In between the Week 12 placebo marker dot and the Week 12 OHTUVAYRE marker dot is a light purple vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “147b.” In between the Week 24 placebo marker dot and the Week 24 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “116.” — The second graph is labeled, “Peak FEV1: ENHANCE-2” written in white text on a purple background. The vertical y-axis of the graph is labeled, “LS Mean Change From Baseline FEV1 (mL).” The y-axis numbers begin at 0 from the bottom of the graph and ends at 300 at the end top of the graph, counting up from 0 in increments of fifty, from 0, 50, 100, 150, 200, 250, to 300. The horizontal x-axis is labeled “Time” and the numerical markers on the x-axis are labeled from Day 1, Week 6, Week 12 (p<0.0001) and Week 24. To the right-hand side of the graph title is a color label. Solid gray colored circle markers indicate Placebo, and light blue colored squares indicate OHTUVAYRE. The markers for Day 1, Week 6, Week 12, and Week 24 are marked on a line graph. The placebo markers in dark gray circles are illustrated as circular dots placed along Day 1, Week 6, Week 12, and Week 24 on a plain white background between the 50 and 100 markers of the y-axis, with a slight downward trend of the line graph as it spans from Day 1 to Week 24. The OHTUVAYRE markers in light blue squares are illustrated as square dots placed along Day 1, Week 6, Week 12, and Week 24 on a plain white background between the 200 and 250 markers of the y-axis, with a slight downward trend of the line graph as it spans from Day 1 to Week 24. In between the Day 1 placebo marker dot and the Day 1 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “157.” In between the Week 6 placebo marker dot and the Week 6 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “152.” In between the Week 12 placebo marker dot and the Week 12 OHTUVAYRE marker dot is a light purple vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the vertical dotted line is the number, “146b.” In between the Week 24 placebo marker dot and the Week 24 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “152.”
Key Secondary Endpoint Graph_Mobile (1)The first graph is labeled, “Peak FEV1: ENHANCE-1” written in white text on a navy blue background. The vertical y-axis of the graph is labeled, “LS Mean Change From Baseline FEV1 (mL).” The y-axis numbers begin at 0 from the bottom of the graph and end at 300 at the top of the graph, counting up from 0 in increments of fifty, from 0, 50, 100, 150, 200, 250, to 300. The horizontal x-axis is labeled “Time” and the numerical markers of the x-axis has markers from Day 1, Week 6, Week 12 (p<0.0001) and Week 24. To the right-hand side of the graph title is a color label. Solid gray colored circle markers indicate Placebo, and light blue colored squares indicate OHTUVAYRE. The markers for Day 1, Week 6, Week 12, and Week 24 are marked on a line graph. The placebo markers in dark gray circles are illustrated as circular dots placed along Day 1, Week 6, Week 12, and Week 24 on a plain white background between the 50 and 100 markers of the y-axis, with a slight downward trend of the line graph as it spans from Day 1 to Week 24. The OHTUVAYRE markers in light blue squares are illustrated as square dots placed along Day 1, Week 6, Week 12, and Week 24 on a plain white background between the 200 and 250 markers of the y-axis, with a slight downward trend of the line graph as it spans from Day 1 to Week 24. In between the Day 1 placebo marker dot and the Day 1 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “152.” In between the Week 6 placebo marker dot and the Week 6 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the vertical dotted line is the number, “136.” In between the Week 12 placebo marker dot and the Week 12 OHTUVAYRE marker dot is a light purple vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “147b.” In between the Week 24 placebo marker dot and the Week 24 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “116.” — The second graph is labeled, “Peak FEV1: ENHANCE-2” written in white text on a purple background. The vertical y-axis of the graph is labeled, “LS Mean Change From Baseline FEV1 (mL).” The y-axis numbers begin at 0 from the bottom of the graph and ends at 300 at the end top of the graph, counting up from 0 in increments of fifty, from 0, 50, 100, 150, 200, 250, to 300. The horizontal x-axis is labeled “Time” and the numerical markers on the x-axis are labeled from Day 1, Week 6, Week 12 (p<0.0001) and Week 24. To the right-hand side of the graph title is a color label. Solid gray colored circle markers indicate Placebo, and light blue colored squares indicate OHTUVAYRE. The markers for Day 1, Week 6, Week 12, and Week 24 are marked on a line graph. The placebo markers in dark gray circles are illustrated as circular dots placed along Day 1, Week 6, Week 12, and Week 24 on a plain white background between the 50 and 100 markers of the y-axis, with a slight downward trend of the line graph as it spans from Day 1 to Week 24. The OHTUVAYRE markers in light blue squares are illustrated as square dots placed along Day 1, Week 6, Week 12, and Week 24 on a plain white background between the 200 and 250 markers of the y-axis, with a slight downward trend of the line graph as it spans from Day 1 to Week 24. In between the Day 1 placebo marker dot and the Day 1 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “157.” In between the Week 6 placebo marker dot and the Week 6 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “152.” In between the Week 12 placebo marker dot and the Week 12 OHTUVAYRE marker dot is a light purple vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the vertical dotted line is the number, “146b.” In between the Week 24 placebo marker dot and the Week 24 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “152.”
Key Secondary Endpoint Graph_Mobile (1)The first graph is labeled, “Peak FEV1: ENHANCE-1” written in white text on a navy blue background. The vertical y-axis of the graph is labeled, “LS Mean Change From Baseline FEV1 (mL).” The y-axis numbers begin at 0 from the bottom of the graph and end at 300 at the top of the graph, counting up from 0 in increments of fifty, from 0, 50, 100, 150, 200, 250, to 300. The horizontal x-axis is labeled “Time” and the numerical markers of the x-axis has markers from Day 1, Week 6, Week 12 (p<0.0001) and Week 24. To the right-hand side of the graph title is a color label. Solid gray colored circle markers indicate Placebo, and light blue colored squares indicate OHTUVAYRE. The markers for Day 1, Week 6, Week 12, and Week 24 are marked on a line graph. The placebo markers in dark gray circles are illustrated as circular dots placed along Day 1, Week 6, Week 12, and Week 24 on a plain white background between the 50 and 100 markers of the y-axis, with a slight downward trend of the line graph as it spans from Day 1 to Week 24. The OHTUVAYRE markers in light blue squares are illustrated as square dots placed along Day 1, Week 6, Week 12, and Week 24 on a plain white background between the 200 and 250 markers of the y-axis, with a slight downward trend of the line graph as it spans from Day 1 to Week 24. In between the Day 1 placebo marker dot and the Day 1 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “152.” In between the Week 6 placebo marker dot and the Week 6 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the vertical dotted line is the number, “136.” In between the Week 12 placebo marker dot and the Week 12 OHTUVAYRE marker dot is a light purple vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “147b.” In between the Week 24 placebo marker dot and the Week 24 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “116.” — The second graph is labeled, “Peak FEV1: ENHANCE-2” written in white text on a purple background. The vertical y-axis of the graph is labeled, “LS Mean Change From Baseline FEV1 (mL).” The y-axis numbers begin at 0 from the bottom of the graph and ends at 300 at the end top of the graph, counting up from 0 in increments of fifty, from 0, 50, 100, 150, 200, 250, to 300. The horizontal x-axis is labeled “Time” and the numerical markers on the x-axis are labeled from Day 1, Week 6, Week 12 (p<0.0001) and Week 24. To the right-hand side of the graph title is a color label. Solid gray colored circle markers indicate Placebo, and light blue colored squares indicate OHTUVAYRE. The markers for Day 1, Week 6, Week 12, and Week 24 are marked on a line graph. The placebo markers in dark gray circles are illustrated as circular dots placed along Day 1, Week 6, Week 12, and Week 24 on a plain white background between the 50 and 100 markers of the y-axis, with a slight downward trend of the line graph as it spans from Day 1 to Week 24. The OHTUVAYRE markers in light blue squares are illustrated as square dots placed along Day 1, Week 6, Week 12, and Week 24 on a plain white background between the 200 and 250 markers of the y-axis, with a slight downward trend of the line graph as it spans from Day 1 to Week 24. In between the Day 1 placebo marker dot and the Day 1 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “157.” In between the Week 6 placebo marker dot and the Week 6 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “152.” In between the Week 12 placebo marker dot and the Week 12 OHTUVAYRE marker dot is a light purple vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the vertical dotted line is the number, “146b.” In between the Week 24 placebo marker dot and the Week 24 OHTUVAYRE marker dot is a light gray vertical dotted line with a downward facing arrow at the bottom and upward facing arrow at the top, and in the middle of the dotted line is the number, “152.”

Peak FEV1 was defined as the highest post-dose FEV1 within the first 4 hours after dosing.1
aOne patient was randomized to placebo and treated but was not included in the endpoint analysis due to missing baseline FEV1.3

Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phosphodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE Trials). Am J Respir Crit Care Med. 2023;208(4):406-416 by permission of the American Thoracic Society.

The St. George’s Respiratory Questionnaire (SGRQ)

The SGRQ is designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease.7

  • During clinical visits, patients had their HRQoL assessed by a physician using the St. George’s Respiratory Questionnaire1

Part 1: One component

Symptoms (frequency and severity)

Covers the patients’ recollection of their symptoms (eg, cough, sputum production, shortness of breath, and wheezing) over a preceding period that may range from 1 month to 1 year9

Part 2: Two components

Activity

Evaluates activities that cause breathlessness or are limited because of breathlessness9

Impact

Covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease9

HRQoL, Health-Related Quality of Life.

SGRQ responder rates in the ENHANCE trials

Selected key secondary endpoint: OHTUVAYRE SGRQ responder rate vs placeboa,b

Key secondary endpoint: SGRQ responder rate at Week 24 was included in the statistical testing hierarchy.1,5,6

  • As the pre-specified hierarchical testing criteria were not fully met in ENHANCE-2, SGRQ responder proportion at Week 24 was not formally tested for statistical significance.1,6

Limitations: SGRQ responder rates at Week 6 and Week 12 were not included in the statistical hierarchy for ENHANCE-1 and ENHANCE-2 and therefore not controlled for multiplicity. Therefore, no conclusions can be drawn.1,5,6

ENHANCE-1: The SGRQ responder rate for patients on OHTUVAYRE was 58.2% compared to 45.9% on placebo at Week 24 [Odds Ratio: 1.49; 95% CI: 1.07, 2.07].4

ENHANCE-2: The SGRQ responder rate for patients on OHTUVAYRE was 45.4% compared to 50.3% on placebo at Week 24 [Odds Ratio: 0.92; 95% CI: 0.66, 1.29].3

aResponder rate is defined as the proportion of patients who achieved minimal clinically important difference (MCID).1,3,4
bMCID for SGRQ is defined as an improvement from baseline of at least 4 units.7
CI, confidence interval; ENHANCE, Ensifentrine as a Novel inHAled Nebulized COPD thErapy; LS, least-squares; NS, not significant.

SGRQ total score data

Secondary endpoints: Mean change from baseline in the SGRQ total scores at Week 6, Week 12, and Week 241,3,4,8

Key secondary endpoint: SGRQ total score at Week 24 was included in the statistical testing hierarchy.

  • As the pre-specified hierarchical testing criteria were not fully met in ENHANCE-2, SGRQ total score at Week 24 was not formally tested for statistical significance.1

Limitations: SGRQ total scores at Week 6 and Week 12 were not included in the statistical hierarchy for ENHANCE-1 and ENHANCE-2 and therefore not controlled for multiplicity. Therefore, no conclusions can be drawn.1

Graph Secondary Endpoint SGRQ DeskThis graphic contains two separate bar charts, one for ENHANCE-1 and one for ENHANCE-2. The first graphic is a vertical stacked-bar chart titled, “ENHANCE-1” on a navy blue background in white text. The format of the graph is bar graphs that run left to right vertically, indicating Week 6, Week 12, and Week 24 on the x-axis. Week 6 and Week 12 are in standard text and Week 24 is in bold text. The y-axis label is “LS Mean Change from Baseline” in navy blue text. The y-axis numbers begin at -7.0 at the bottom and mark upwards in increments of one (-6.0, -5.0, -4.0, -3.0, -2.0, -1.0, and 0) ending at zero. Underneath the graph is a color label. The light blue gradient color indicates OHTUVAYRE (n=474) and the solid gray indicates Placebo (n=281). The first bar on this graph under the “Week 6” x-axis marker is a light blue gradient colored OHTUVAYRE bar. It has “-6.2” written in white text on it. This OHTUVAYRE bar extends from zero to just beyond the -6.0 mark on the y-axis, illustrating its -6.2 position. The second bar to the right on this graph under the “Week 6” x-axis marker is a gray colored Placebo bar. It has “-4.0” written in white text on it. This Placebo bar extends from zero to exactly at the -4.0 mark on the y-axis, illustrating its -4.0 position. The third bar to the right on this graph under the “Week 12” x-axis marker is a light blue gradient colored OHTUVAYRE bar. It has “-5.7” written in white text on it. This OHTUVAYRE bar extends from zero to just before the -6.0 mark on the y-axis, illustrating its -5.7 position. The fourth bar to the right on this graph under the “Week 12” x-axis marker is a gray colored Placebo bar. It has “-2.7” written in white text on it. This Placebo bar extends from zero just before the -3.0 mark on the y-axis, illustrating its -2.7 position. The fifth bar to the right on this graph under the “Week 24” x-axis marker is a dark blue gradient colored OHTUVAYRE bar. It has “-6.2” written in white text on it. This OHTUVAYRE bar extends from zero to just beyond the -6.0 mark on the y-axis, illustrating its -6.2 position. The sixth bar to the right on this graph under the “Week 24” x-axis marker is a dark gray colored Placebo bar. It has “-3.9” written in white text on it. This Placebo bar extends from zero just before the -4.0 mark on the y-axis, illustrating its -3.9 position. In small navy blue text, “LS mean difference -2.3 (95% CI: -4.3, -0.3; p=0.025)” is written near the sixth bar of the graph but just outside the bar graph area. — The second graphic is a vertical stacked-bar chart titled, “ENHANCE-2” on a purple background in white text. The format of the graph is bar graphs that run left to right vertically, indicating Week 6, Week 12, and Week 24 on the x-axis. The y-axis label is “LS Mean Change from Baseline” in navy blue text. The y-axis numbers begin at -7.0 at the bottom and mark upwards in increments of one (-6.0, -5.0, -4.0, -3.0, -2.0, -1.0, and 0) ending at zero. Underneath the graph is a color label. The light blue gradient color indicates OHTUVAYRE (n=489) and the light gray indicates Placebo (n=286). The first bar on this graph under the “Week 6” x-axis marker is a light blue gradient colored OHTUVAYRE bar. It has “-3.6” written in white text on it. This OHTUVAYRE bar extends from zero to just beyond the midpoint between the -3.0 and -4.0 marks on the y-axis, illustrating its -3.6 position. The second bar to the right on this graph under the “Week 6” x-axis marker is a gray colored Placebo bar. It has “-1.9” written in white text on it. This Placebo bar extends from zero to just before the -2.0 mark on the y-axis, illustrating its -1.9 position. The third bar to the right on this graph under the “Week 12” x-axis marker is a light blue gradient colored OHTUVAYRE bar. It has “-4.0” written in white text on it. This OHTUVAYRE bar extends from zero to the -4.0 mark on the y-axis, illustrating its -4.0 position. The fourth bar to the right on this graph under the “Week 12” x-axis marker is a gray colored Placebo bar. It has “-2.9” written in white text on it. This Placebo bar extends from zero to just before the -3.0 mark on the y-axis, illustrating its -2.9 position. The fifth bar to the right on this graph under the “Week 24” x-axis marker is a dark blue gradient colored OHTUVAYRE bar. It has “-4.5” written in white text on it. This OHTUVAYRE bar extends from zero to exactly between -4.0 mark and the -5.0 mark on the y-axis, illustrating its -4.5 position. The sixth bar to the right on this graph under the “Week 24” x-axis marker is a dark gray colored Placebo bar. It has “-4.1” written in white text on it. This Placebo bar extends from zero to just beyond the -4.0 mark on the y-axis, illustrating its -4.1 position. A text note that reads, “LS mean difference -0.5 (95% CI: -2.7, 1.7; p=NS)” in small navy blue text is written near the sixth bar of the graph but just outside the bar graph area.
Graph Secondary Endpoint SGRQ DeskThis graphic contains two separate bar charts, one for ENHANCE-1 and one for ENHANCE-2. The first graphic is a vertical stacked-bar chart titled, “ENHANCE-1” on a navy blue background in white text. The format of the graph is bar graphs that run left to right vertically, indicating Week 6, Week 12, and Week 24 on the x-axis. Week 6 and Week 12 are in standard text and Week 24 is in bold text. The y-axis label is “LS Mean Change from Baseline” in navy blue text. The y-axis numbers begin at -7.0 at the bottom and mark upwards in increments of one (-6.0, -5.0, -4.0, -3.0, -2.0, -1.0, and 0) ending at zero. Underneath the graph is a color label. The light blue gradient color indicates OHTUVAYRE (n=474) and the solid gray indicates Placebo (n=281). The first bar on this graph under the “Week 6” x-axis marker is a light blue gradient colored OHTUVAYRE bar. It has “-6.2” written in white text on it. This OHTUVAYRE bar extends from zero to just beyond the -6.0 mark on the y-axis, illustrating its -6.2 position. The second bar to the right on this graph under the “Week 6” x-axis marker is a gray colored Placebo bar. It has “-4.0” written in white text on it. This Placebo bar extends from zero to exactly at the -4.0 mark on the y-axis, illustrating its -4.0 position. The third bar to the right on this graph under the “Week 12” x-axis marker is a light blue gradient colored OHTUVAYRE bar. It has “-5.7” written in white text on it. This OHTUVAYRE bar extends from zero to just before the -6.0 mark on the y-axis, illustrating its -5.7 position. The fourth bar to the right on this graph under the “Week 12” x-axis marker is a gray colored Placebo bar. It has “-2.7” written in white text on it. This Placebo bar extends from zero just before the -3.0 mark on the y-axis, illustrating its -2.7 position. The fifth bar to the right on this graph under the “Week 24” x-axis marker is a dark blue gradient colored OHTUVAYRE bar. It has “-6.2” written in white text on it. This OHTUVAYRE bar extends from zero to just beyond the -6.0 mark on the y-axis, illustrating its -6.2 position. The sixth bar to the right on this graph under the “Week 24” x-axis marker is a dark gray colored Placebo bar. It has “-3.9” written in white text on it. This Placebo bar extends from zero just before the -4.0 mark on the y-axis, illustrating its -3.9 position. In small navy blue text, “LS mean difference -2.3 (95% CI: -4.3, -0.3; p=0.025)” is written near the sixth bar of the graph but just outside the bar graph area. — The second graphic is a vertical stacked-bar chart titled, “ENHANCE-2” on a purple background in white text. The format of the graph is bar graphs that run left to right vertically, indicating Week 6, Week 12, and Week 24 on the x-axis. The y-axis label is “LS Mean Change from Baseline” in navy blue text. The y-axis numbers begin at -7.0 at the bottom and mark upwards in increments of one (-6.0, -5.0, -4.0, -3.0, -2.0, -1.0, and 0) ending at zero. Underneath the graph is a color label. The light blue gradient color indicates OHTUVAYRE (n=489) and the light gray indicates Placebo (n=286). The first bar on this graph under the “Week 6” x-axis marker is a light blue gradient colored OHTUVAYRE bar. It has “-3.6” written in white text on it. This OHTUVAYRE bar extends from zero to just beyond the midpoint between the -3.0 and -4.0 marks on the y-axis, illustrating its -3.6 position. The second bar to the right on this graph under the “Week 6” x-axis marker is a gray colored Placebo bar. It has “-1.9” written in white text on it. This Placebo bar extends from zero to just before the -2.0 mark on the y-axis, illustrating its -1.9 position. The third bar to the right on this graph under the “Week 12” x-axis marker is a light blue gradient colored OHTUVAYRE bar. It has “-4.0” written in white text on it. This OHTUVAYRE bar extends from zero to the -4.0 mark on the y-axis, illustrating its -4.0 position. The fourth bar to the right on this graph under the “Week 12” x-axis marker is a gray colored Placebo bar. It has “-2.9” written in white text on it. This Placebo bar extends from zero to just before the -3.0 mark on the y-axis, illustrating its -2.9 position. The fifth bar to the right on this graph under the “Week 24” x-axis marker is a dark blue gradient colored OHTUVAYRE bar. It has “-4.5” written in white text on it. This OHTUVAYRE bar extends from zero to exactly between -4.0 mark and the -5.0 mark on the y-axis, illustrating its -4.5 position. The sixth bar to the right on this graph under the “Week 24” x-axis marker is a dark gray colored Placebo bar. It has “-4.1” written in white text on it. This Placebo bar extends from zero to just beyond the -4.0 mark on the y-axis, illustrating its -4.1 position. A text note that reads, “LS mean difference -0.5 (95% CI: -2.7, 1.7; p=NS)” in small navy blue text is written near the sixth bar of the graph but just outside the bar graph area.
Graph Secondary Endpoint SGRQ MobThis graphic contains two separate bar charts, one for ENHANCE-1 and one for ENHANCE-2. The first graphic is a vertical stacked-bar chart titled, “ENHANCE-1” on a navy blue background in white text. The format of the graph is bar graphs that run left to right vertically, indicating Week 6, Week 12, and Week 24 on the x-axis. Week 6 and Week 12 are in standard text and Week 24 is in bold text. The y-axis label is “LS Mean Change from Baseline” in navy blue text. The y-axis numbers begin at -7.0 at the bottom and mark upwards in increments of one (-6.0, -5.0, -4.0, -3.0, -2.0, -1.0, and 0) ending at zero. Underneath the graph is a color label. The light blue gradient color indicates OHTUVAYRE (n=474) and the solid gray indicates Placebo (n=281). The first bar on this graph under the “Week 6” x-axis marker is a light blue gradient colored OHTUVAYRE bar. It has “-6.2” written in white text on it. This OHTUVAYRE bar extends from zero to just beyond the -6.0 mark on the y-axis, illustrating its -6.2 position. The second bar to the right on this graph under the “Week 6” x-axis marker is a gray colored Placebo bar. It has “-4.0” written in white text on it. This Placebo bar extends from zero to exactly at the -4.0 mark on the y-axis, illustrating its -4.0 position. The third bar to the right on this graph under the “Week 12” x-axis marker is a light blue gradient colored OHTUVAYRE bar. It has “-5.7” written in white text on it. This OHTUVAYRE bar extends from zero to just before the -6.0 mark on the y-axis, illustrating its -5.7 position. The fourth bar to the right on this graph under the “Week 12” x-axis marker is a gray colored Placebo bar. It has “-2.7” written in white text on it. This Placebo bar extends from zero just before the -3.0 mark on the y-axis, illustrating its -2.7 position. The fifth bar to the right on this graph under the “Week 24” x-axis marker is a dark blue gradient colored OHTUVAYRE bar. It has “-6.2” written in white text on it. This OHTUVAYRE bar extends from zero to just beyond the -6.0 mark on the y-axis, illustrating its -6.2 position. The sixth bar to the right on this graph under the “Week 24” x-axis marker is a dark gray colored Placebo bar. It has “-3.9” written in white text on it. This Placebo bar extends from zero just before the -4.0 mark on the y-axis, illustrating its -3.9 position. In small navy blue text, “LS mean difference -2.3 (95% CI: -4.3, -0.3; p=0.025)” is written near the sixth bar of the graph but just outside the bar graph area. — The second graphic is a vertical stacked-bar chart titled, “ENHANCE-2” on a purple background in white text. The format of the graph is bar graphs that run left to right vertically, indicating Week 6, Week 12, and Week 24 on the x-axis. The y-axis label is “LS Mean Change from Baseline” in navy blue text. The y-axis numbers begin at -7.0 at the bottom and mark upwards in increments of one (-6.0, -5.0, -4.0, -3.0, -2.0, -1.0, and 0) ending at zero. Underneath the graph is a color label. The light blue gradient color indicates OHTUVAYRE (n=489) and the light gray indicates Placebo (n=286). The first bar on this graph under the “Week 6” x-axis marker is a light blue gradient colored OHTUVAYRE bar. It has “-3.6” written in white text on it. This OHTUVAYRE bar extends from zero to just beyond the midpoint between the -3.0 and -4.0 marks on the y-axis, illustrating its -3.6 position. The second bar to the right on this graph under the “Week 6” x-axis marker is a gray colored Placebo bar. It has “-1.9” written in white text on it. This Placebo bar extends from zero to just before the -2.0 mark on the y-axis, illustrating its -1.9 position. The third bar to the right on this graph under the “Week 12” x-axis marker is a light blue gradient colored OHTUVAYRE bar. It has “-4.0” written in white text on it. This OHTUVAYRE bar extends from zero to the -4.0 mark on the y-axis, illustrating its -4.0 position. The fourth bar to the right on this graph under the “Week 12” x-axis marker is a gray colored Placebo bar. It has “-2.9” written in white text on it. This Placebo bar extends from zero to just before the -3.0 mark on the y-axis, illustrating its -2.9 position. The fifth bar to the right on this graph under the “Week 24” x-axis marker is a dark blue gradient colored OHTUVAYRE bar. It has “-4.5” written in white text on it. This OHTUVAYRE bar extends from zero to exactly between -4.0 mark and the -5.0 mark on the y-axis, illustrating its -4.5 position. The sixth bar to the right on this graph under the “Week 24” x-axis marker is a dark gray colored Placebo bar. It has “-4.1” written in white text on it. This Placebo bar extends from zero to just beyond the -4.0 mark on the y-axis, illustrating its -4.1 position. A text note that reads, “LS mean difference -0.5 (95% CI: -2.7, 1.7; p=NS)” in small navy blue text is written near the sixth bar of the graph but just outside the bar graph area.

The Transition Dyspnea Index (TDI)10,11

Designed to quantify breathlessness based on activities of daily living, the TDI is an evaluative instrument that measures how dyspnea changes over time relative to the patient’s baseline.

The TDI focuses on the change over time in three components: functional impairment, magnitude of task, and magnitude of effort.

  • Functional impairment: effect of dyspnea on ability to perform daily activities and to work
  • Magnitude of task: range of various physical tasks that provoke dyspnea (e.g., walking on a level surface, climbing stairs, etc.)
  • Magnitude of effort: degree of effort required to perform activities and tasks (e.g., need to pause or rest)

Transition Dyspnea Index (TDI) in ENHANCE program

Secondary endpoint: TDI was evaluated for OHTUVAYRE compared with placebo in ENHANCE-1 and ENHANCE-2 as prespecified secondary endpoints.1,3,4

Limitations: These observations are descriptive only, as they are not included in the statistical hierarchy and therefore not controlled for multiplicity. Therefore, no conclusions can be drawn.1

Transition Dyspnea Index (TDI) scores at Week 6, Week 12, and Week 241,3,4

TDI GraphsThis graphic contains two separate bar charts, one for TDI: ENHANCE-1 and one for TDI: ENHANCE-2. The first graphic is a vertical stacked-bar chart titled, “TDI: ENHANCE-1” on a navy blue background in white text. The format of the graph is bar graphs that run left to right vertically, indicating Week 6, Week 12, and Week 24 on the x-axis. The y-axis label is “LS Mean TDI Total Score” in navy blue text. The y-axis numbers begin at 0.0 at the bottom and mark upwards in increments of .5 (0.0, 0.5, 1.0, 1.5, 2.0, 2.5) ending at 2.5. Underneath the graph is a color label. The dark blue gradient color indicates OHTUVAYRE (n=471) and the solid gray indicates Placebo (n=277). The first bar on this graph under the “Week 6” x-axis marker is a dark blue gradient colored OHTUVAYRE bar. It has “1.3” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just past the 1.0 mark on the y-axis, illustrating its 1.3 position. The second bar on this graph under the “Week 6” x-axis marker is a gray colored Placebo bar. It has “0.6” written in white text on it. This placebo bar extends from the 0.0 mark and just past the 0.5 mark on the y-axis, illustrating its 0.6 position. The third bar on this graph is under the “Week 12” x-axis marker and is a dark blue gradient colored OHTUVAYRE bar. It has “1.6” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just past the 1.5 mark on the y-axis, illustrating its 1.6 position. The fourth bar on this graph is under the “Week 12” x-axis marker is a gray colored Placebo bar. It has “0.4” written in white text on it. This placebo bar extends from the 0.0 mark and just before the 0.5 mark on the y-axis, illustrating its 0.4 position. The fifth bar on this graph is under the “Week 24” x-axis marker and is a dark blue gradient colored OHTUVAYRE bar. It has “1.9” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just before the 2.0 mark on the y-axis, illustrating its 1.9 position. The sixth bar on this graph is under the “Week 24” x-axis marker is a gray colored Placebo bar. It has “0.8” written in white text on it. This placebo bar extends from the 0.0 mark and just before the 1.0 mark on the y-axis, illustrating its 0.8 position. A text note that reads, “LS mean difference 1.0 (95% CI: 0.6, 1.5)” in small navy blue text is written near the sixth bar of the graph just outside the bar graph area. — The second graphic is a vertical stacked-bar chart titled, “TDI: ENHANCE-2” on a purple background in white text. The format of the graph is bar graphs that run left to right vertically, indicating Week 6, Week 12, and Week 24 on the x-axis. The y-axis label is “LS Mean TDI Total Score” in navy blue text. The y-axis numbers begin at 0.0 at the bottom and mark upwards in increments of .5 (0.0, 0.5, 1.0, 1.5, 2.0, 2.5) ending at 2.5. Underneath the graph is a color label. The dark blue gradient color indicates OHTUVAYRE (n=484) and the solid gray indicates Placebo (n=286). The first bar on this graph under the “Week 6” x-axis marker is a dark blue gradient colored OHTUVAYRE bar. It has “1.6” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just past the 1.5 mark on the y-axis, illustrating its 1.6 position. The second bar on this graph under the “Week 6” x-axis marker is a gray colored Placebo bar. It has “0.9” written in white text on it. This placebo bar extends from the 0.0 mark and just before 1.0 mark on the y-axis, illustrating its 0.9 position. The third bar on this graph is under the “Week 12” x-axis marker and is a dark blue gradient colored OHTUVAYRE bar. It has “1.8” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and past the 1.5 mark on the y-axis, illustrating its 1.8 position. The fourth bar on this graph is under the “Week 12” x-axis marker is a gray colored Placebo bar. It has “1.2” written in white text on it. This placebo bar extends from the 0.0 mark and just past the 1.0 mark on the y-axis, illustrating its 1.2 position. The fifth bar on this graph is under the “Week 24” x-axis marker and is a dark blue gradient colored OHTUVAYRE bar. It has “2.2” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just past the 2.0 mark on the y-axis, illustrating its 2.2 position. The sixth bar on this graph is under the “Week 24” x-axis marker is a gray colored Placebo bar. It has “1.3” written in white text on it. This placebo bar extends from the 0.0 mark and just past the 1.0 mark on the y-axis, illustrating its 1.3 position. A text note that reads, “LS mean difference 0.9 (95% CI: 0.4, 1.4)” in small navy blue text is written near the sixth bar of the graph just outside the bar graph area.
TDI GraphsThis graphic contains two separate bar charts, one for TDI: ENHANCE-1 and one for TDI: ENHANCE-2. The first graphic is a vertical stacked-bar chart titled, “TDI: ENHANCE-1” on a navy blue background in white text. The format of the graph is bar graphs that run left to right vertically, indicating Week 6, Week 12, and Week 24 on the x-axis. The y-axis label is “LS Mean TDI Total Score” in navy blue text. The y-axis numbers begin at 0.0 at the bottom and mark upwards in increments of .5 (0.0, 0.5, 1.0, 1.5, 2.0, 2.5) ending at 2.5. Underneath the graph is a color label. The dark blue gradient color indicates OHTUVAYRE (n=471) and the solid gray indicates Placebo (n=277). The first bar on this graph under the “Week 6” x-axis marker is a dark blue gradient colored OHTUVAYRE bar. It has “1.3” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just past the 1.0 mark on the y-axis, illustrating its 1.3 position. The second bar on this graph under the “Week 6” x-axis marker is a gray colored Placebo bar. It has “0.6” written in white text on it. This placebo bar extends from the 0.0 mark and just past the 0.5 mark on the y-axis, illustrating its 0.6 position. The third bar on this graph is under the “Week 12” x-axis marker and is a dark blue gradient colored OHTUVAYRE bar. It has “1.6” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just past the 1.5 mark on the y-axis, illustrating its 1.6 position. The fourth bar on this graph is under the “Week 12” x-axis marker is a gray colored Placebo bar. It has “0.4” written in white text on it. This placebo bar extends from the 0.0 mark and just before the 0.5 mark on the y-axis, illustrating its 0.4 position. The fifth bar on this graph is under the “Week 24” x-axis marker and is a dark blue gradient colored OHTUVAYRE bar. It has “1.9” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just before the 2.0 mark on the y-axis, illustrating its 1.9 position. The sixth bar on this graph is under the “Week 24” x-axis marker is a gray colored Placebo bar. It has “0.8” written in white text on it. This placebo bar extends from the 0.0 mark and just before the 1.0 mark on the y-axis, illustrating its 0.8 position. A text note that reads, “LS mean difference 1.0 (95% CI: 0.6, 1.5)” in small navy blue text is written near the sixth bar of the graph just outside the bar graph area. — The second graphic is a vertical stacked-bar chart titled, “TDI: ENHANCE-2” on a purple background in white text. The format of the graph is bar graphs that run left to right vertically, indicating Week 6, Week 12, and Week 24 on the x-axis. The y-axis label is “LS Mean TDI Total Score” in navy blue text. The y-axis numbers begin at 0.0 at the bottom and mark upwards in increments of .5 (0.0, 0.5, 1.0, 1.5, 2.0, 2.5) ending at 2.5. Underneath the graph is a color label. The dark blue gradient color indicates OHTUVAYRE (n=484) and the solid gray indicates Placebo (n=286). The first bar on this graph under the “Week 6” x-axis marker is a dark blue gradient colored OHTUVAYRE bar. It has “1.6” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just past the 1.5 mark on the y-axis, illustrating its 1.6 position. The second bar on this graph under the “Week 6” x-axis marker is a gray colored Placebo bar. It has “0.9” written in white text on it. This placebo bar extends from the 0.0 mark and just before 1.0 mark on the y-axis, illustrating its 0.9 position. The third bar on this graph is under the “Week 12” x-axis marker and is a dark blue gradient colored OHTUVAYRE bar. It has “1.8” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and past the 1.5 mark on the y-axis, illustrating its 1.8 position. The fourth bar on this graph is under the “Week 12” x-axis marker is a gray colored Placebo bar. It has “1.2” written in white text on it. This placebo bar extends from the 0.0 mark and just past the 1.0 mark on the y-axis, illustrating its 1.2 position. The fifth bar on this graph is under the “Week 24” x-axis marker and is a dark blue gradient colored OHTUVAYRE bar. It has “2.2” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just past the 2.0 mark on the y-axis, illustrating its 2.2 position. The sixth bar on this graph is under the “Week 24” x-axis marker is a gray colored Placebo bar. It has “1.3” written in white text on it. This placebo bar extends from the 0.0 mark and just past the 1.0 mark on the y-axis, illustrating its 1.3 position. A text note that reads, “LS mean difference 0.9 (95% CI: 0.4, 1.4)” in small navy blue text is written near the sixth bar of the graph just outside the bar graph area.
TDI Graphs MobThis graphic contains two separate bar charts, one for TDI: ENHANCE-1 and one for TDI: ENHANCE-2. The first graphic is a vertical stacked-bar chart titled, “TDI: ENHANCE-1” on a navy blue background in white text. The format of the graph is bar graphs that run left to right vertically, indicating Week 6, Week 12, and Week 24 on the x-axis. The y-axis label is “LS Mean TDI Total Score” in navy blue text. The y-axis numbers begin at 0.0 at the bottom and mark upwards in increments of .5 (0.0, 0.5, 1.0, 1.5, 2.0, 2.5) ending at 2.5. Underneath the graph is a color label. The dark blue gradient color indicates OHTUVAYRE (n=471) and the solid gray indicates Placebo (n=277). The first bar on this graph under the “Week 6” x-axis marker is a dark blue gradient colored OHTUVAYRE bar. It has “1.3” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just past the 1.0 mark on the y-axis, illustrating its 1.3 position. The second bar on this graph under the “Week 6” x-axis marker is a gray colored Placebo bar. It has “0.6” written in white text on it. This placebo bar extends from the 0.0 mark and just past the 0.5 mark on the y-axis, illustrating its 0.6 position. The third bar on this graph is under the “Week 12” x-axis marker and is a dark blue gradient colored OHTUVAYRE bar. It has “1.6” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just past the 1.5 mark on the y-axis, illustrating its 1.6 position. The fourth bar on this graph is under the “Week 12” x-axis marker is a gray colored Placebo bar. It has “0.4” written in white text on it. This placebo bar extends from the 0.0 mark and just before the 0.5 mark on the y-axis, illustrating its 0.4 position. The fifth bar on this graph is under the “Week 24” x-axis marker and is a dark blue gradient colored OHTUVAYRE bar. It has “1.9” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just before the 2.0 mark on the y-axis, illustrating its 1.9 position. The sixth bar on this graph is under the “Week 24” x-axis marker is a gray colored Placebo bar. It has “0.8” written in white text on it. This placebo bar extends from the 0.0 mark and just before the 1.0 mark on the y-axis, illustrating its 0.8 position. A text note that reads, “LS mean difference 1.0 (95% CI: 0.6, 1.5)” in small navy blue text is written near the sixth bar of the graph just outside the bar graph area. — The second graphic is a vertical stacked-bar chart titled, “TDI: ENHANCE-2” on a purple background in white text. The format of the graph is bar graphs that run left to right vertically, indicating Week 6, Week 12, and Week 24 on the x-axis. The y-axis label is “LS Mean TDI Total Score” in navy blue text. The y-axis numbers begin at 0.0 at the bottom and mark upwards in increments of .5 (0.0, 0.5, 1.0, 1.5, 2.0, 2.5) ending at 2.5. Underneath the graph is a color label. The dark blue gradient color indicates OHTUVAYRE (n=484) and the solid gray indicates Placebo (n=286). The first bar on this graph under the “Week 6” x-axis marker is a dark blue gradient colored OHTUVAYRE bar. It has “1.6” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just past the 1.5 mark on the y-axis, illustrating its 1.6 position. The second bar on this graph under the “Week 6” x-axis marker is a gray colored Placebo bar. It has “0.9” written in white text on it. This placebo bar extends from the 0.0 mark and just before 1.0 mark on the y-axis, illustrating its 0.9 position. The third bar on this graph is under the “Week 12” x-axis marker and is a dark blue gradient colored OHTUVAYRE bar. It has “1.8” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and past the 1.5 mark on the y-axis, illustrating its 1.8 position. The fourth bar on this graph is under the “Week 12” x-axis marker is a gray colored Placebo bar. It has “1.2” written in white text on it. This placebo bar extends from the 0.0 mark and just past the 1.0 mark on the y-axis, illustrating its 1.2 position. The fifth bar on this graph is under the “Week 24” x-axis marker and is a dark blue gradient colored OHTUVAYRE bar. It has “2.2” written in white text on it. This OHTUVAYRE bar extends from the 0.0 mark and just past the 2.0 mark on the y-axis, illustrating its 2.2 position. The sixth bar on this graph is under the “Week 24” x-axis marker is a gray colored Placebo bar. It has “1.3” written in white text on it. This placebo bar extends from the 0.0 mark and just past the 1.0 mark on the y-axis, illustrating its 1.3 position. A text note that reads, “LS mean difference 0.9 (95% CI: 0.4, 1.4)” in small navy blue text is written near the sixth bar of the graph just outside the bar graph area.

Time to first moderate/severe COPD exacerbation over 24 and 48 weeks1,12,13

The time to first moderate or severe COPD exacerbation was evaluated for OHTUVAYRE compared with placebo in ENHANCE-1 and ENHANCE-2 as a prespecified exploratory analysis.1,a

Limitations: These observations are descriptive only, as they are not included in the statistical hierarchy and therefore not controlled for multiplicity.1

Time to first Moderate or Severe COPD Exacerbation Over 24 Weeks; Pooled Analysis From ENHANCE-1 and ENHANCE-212

Limitations: These observations are descriptive only, as they are not included in the statistical hierarchy and therefore not controlled for multiplicity.1

Exacerbation Over 24 WeeksThere is a line graph illustrating both the OHTUVAYRE and Placebo fraction of patients without event. The vertical y-axis of the graph is labeled, “Fraction of patients without event”. The y-axis numbers begin at 0.60 from the bottom of the graph and end at 1.00 at the top of the graph, counting up from 0.60 in increments .05. The horizontal x-axis is labeled “Time (Days)” and the numerical markers of the x-axis 0 to 175, counting up in increments of 25. To the bottom right-hand side of the graph is a color label. Light blue circles indicate OHTUVAYRE (N=975) and gray squares indicate Placebo (N=574). The OHTUVAYRE line graph extends from the 1.00 y-axis area starting at 0 days in a slightly downward trend ending at 175 days, with small blue circles along the line. The blue line ends near the 0.90 to 0.95 y-axis marks. The Placebo graph is a dark gray line that also extends from the 1.00 y-axis area in a downward trend ending at 175 days, with small gray squares along the line. This dark gray line ends near the 0.85 and 0.90 marks on the y-axis marks. Underneath the line graph is a table. The label of the table is “Number at risk”. The first row of the table is labeled “OHTUVAYRE” in blue. The columns align with the Time (Days) of the numerical markers of the x-axis of the graph above it. It has markers from 0 to 175, counting up in increments of 25. The OHTUVAYRE row lists the numbers 975, 952, 914, 867, 832, 816, 792, 714. The second row of the table is labeled “Placebo” in gray. The columns align with the Time (Days) of the numerical markers of the x-axis of the graph above it. It has markers from 0 to 175, counting up in increments of 25. The Placebo row lists the numbers 574, 550, 520, 492, 466, 450, 429, 392. At the bottom of this illustration, there is a text box with a light peach background, with the words “HAZARD RATIO: 0.59” in blue text and “(95% CI: 0.44, 0.81)” written in black text.
Exacerbation Over 24 WeeksThere is a line graph illustrating both the OHTUVAYRE and Placebo fraction of patients without event. The vertical y-axis of the graph is labeled, “Fraction of patients without event”. The y-axis numbers begin at 0.60 from the bottom of the graph and end at 1.00 at the top of the graph, counting up from 0.60 in increments .05. The horizontal x-axis is labeled “Time (Days)” and the numerical markers of the x-axis 0 to 175, counting up in increments of 25. To the bottom right-hand side of the graph is a color label. Light blue circles indicate OHTUVAYRE (N=975) and gray squares indicate Placebo (N=574). The OHTUVAYRE line graph extends from the 1.00 y-axis area starting at 0 days in a slightly downward trend ending at 175 days, with small blue circles along the line. The blue line ends near the 0.90 to 0.95 y-axis marks. The Placebo graph is a dark gray line that also extends from the 1.00 y-axis area in a downward trend ending at 175 days, with small gray squares along the line. This dark gray line ends near the 0.85 and 0.90 marks on the y-axis marks. Underneath the line graph is a table. The label of the table is “Number at risk”. The first row of the table is labeled “OHTUVAYRE” in blue. The columns align with the Time (Days) of the numerical markers of the x-axis of the graph above it. It has markers from 0 to 175, counting up in increments of 25. The OHTUVAYRE row lists the numbers 975, 952, 914, 867, 832, 816, 792, 714. The second row of the table is labeled “Placebo” in gray. The columns align with the Time (Days) of the numerical markers of the x-axis of the graph above it. It has markers from 0 to 175, counting up in increments of 25. The Placebo row lists the numbers 574, 550, 520, 492, 466, 450, 429, 392. At the bottom of this illustration, there is a text box with a light peach background, with the words “HAZARD RATIO: 0.59” in blue text and “(95% CI: 0.44, 0.81)” written in black text.
Exacerbation Over 24 Weeks MobileThere is a line graph illustrating both the OHTUVAYRE and Placebo fraction of patients without event. The vertical y-axis of the graph is labeled, “Fraction of patients without event”. The y-axis numbers begin at 0.60 from the bottom of the graph and end at 1.00 at the top of the graph, counting up from 0.60 in increments .05. The horizontal x-axis is labeled “Time (Days)” and the numerical markers of the x-axis 0 to 175, counting up in increments of 25. To the bottom right-hand side of the graph is a color label. Light blue circles indicate OHTUVAYRE (N=975) and gray squares indicate Placebo (N=574). The OHTUVAYRE line graph extends from the 1.00 y-axis area starting at 0 days in a slightly downward trend ending at 175 days, with small blue circles along the line. The blue line ends near the 0.90 to 0.95 y-axis marks. The Placebo graph is a dark gray line that also extends from the 1.00 y-axis area in a downward trend ending at 175 days, with small gray squares along the line. This dark gray line ends near the 0.85 and 0.90 marks on the y-axis marks. Underneath the line graph is a table. The label of the table is “Number at risk”. The first row of the table is labeled “OHTUVAYRE” in blue. The columns align with the Time (Days) of the numerical markers of the x-axis of the graph above it. It has markers from 0 to 175, counting up in increments of 25. The OHTUVAYRE row lists the numbers 975, 952, 914, 867, 832, 816, 792, 714. The second row of the table is labeled “Placebo” in gray. The columns align with the Time (Days) of the numerical markers of the x-axis of the graph above it. It has markers from 0 to 175, counting up in increments of 25. The Placebo row lists the numbers 574, 550, 520, 492, 466, 450, 429, 392. At the bottom of this illustration, there is a text box with a light peach background, with the words “HAZARD RATIO: 0.59” in blue text and “(95% CI: 0.44, 0.81)” written in black text.

Time to first moderate/severe COPD exacerbation over the full study length for patients in the 48-week stratum in ENHANCE-1–Kaplan-Meier Plot (mITT Populationb)13

Limitations: These observations are descriptive only, as they are not included in the statistical hierarchy and therefore not controlled for multiplicity.1

Exacerbation Over 48 WeeksThere is a line graph illustrating OHTUVAYRE and Placebo probability of not having the event. The vertical y-axis of the graph is labeled, “Probability of not having an event”. The y-axis numbers begin at 0.60 from the bottom of the graph and end at 1.00 at the top of the graph, counting up from 0.60 in increments .05. The horizontal x-axis is labeled “Number of weeks” and the numerical markers of the x-axis has markers from 0 to 48, counting up in increments of 4. To the bottom right-hand side of the graph is a color label. Light blue circles indicate OHTUVAYRE (N=280) and gray squares indicate Placebo (N=89). The OHTUVAYRE line graph is blue and extends from the 1.00 y-axis area starting at 0 weeks in a slightly downward trend ending at 48 weeks, with small blue circles along the line. This blue line ends between the .80 and .90 marks on the y-axis. The Placebo graph is a dark gray line that also extends from the 1.00 y-axis area in a downward trend ending at 48 weeks, with small gray squares along the line. This dark gray line ends between the 0.70 and 0.80 marks on the y-axis. Underneath the line graph is a table. The label of the table is “Number at risk of having an event at the timepoint”. The first row of the table is labeled “OHTUVAYRE” in blue. The columns align with the Number of weeks of the numerical markers of the x-axis of the graph above it. It has markers from from 0 to 48, counting up in increments of 4. The OHTUVAYRE row lists the numbers 280, 275, 270, 256, 249, 242, 235, 220, 212, 209, 205, 201, 124. The second row of the table is labeled “Placebo” in gray. The columns align with the Number of weeks of the numerical markers of the x-axis of the graph above it. It has markers from from 0 to 48, counting up in increments of 4. The Placebo row lists the numbers 89, 83, 78, 74, 73, 71, 68, 64, 62, 59, 58, 56, 42. At the bottom of this illustration, there is a text box with a light peach background, with the words “HAZARD RATIO: 0.48” in blue text and “(95% CI: 0.28, 0.82)” written in black text.
Exacerbation Over 48 WeeksThere is a line graph illustrating OHTUVAYRE and Placebo probability of not having the event. The vertical y-axis of the graph is labeled, “Probability of not having an event”. The y-axis numbers begin at 0.60 from the bottom of the graph and end at 1.00 at the top of the graph, counting up from 0.60 in increments .05. The horizontal x-axis is labeled “Number of weeks” and the numerical markers of the x-axis has markers from 0 to 48, counting up in increments of 4. To the bottom right-hand side of the graph is a color label. Light blue circles indicate OHTUVAYRE (N=280) and gray squares indicate Placebo (N=89). The OHTUVAYRE line graph is blue and extends from the 1.00 y-axis area starting at 0 weeks in a slightly downward trend ending at 48 weeks, with small blue circles along the line. This blue line ends between the .80 and .90 marks on the y-axis. The Placebo graph is a dark gray line that also extends from the 1.00 y-axis area in a downward trend ending at 48 weeks, with small gray squares along the line. This dark gray line ends between the 0.70 and 0.80 marks on the y-axis. Underneath the line graph is a table. The label of the table is “Number at risk of having an event at the timepoint”. The first row of the table is labeled “OHTUVAYRE” in blue. The columns align with the Number of weeks of the numerical markers of the x-axis of the graph above it. It has markers from from 0 to 48, counting up in increments of 4. The OHTUVAYRE row lists the numbers 280, 275, 270, 256, 249, 242, 235, 220, 212, 209, 205, 201, 124. The second row of the table is labeled “Placebo” in gray. The columns align with the Number of weeks of the numerical markers of the x-axis of the graph above it. It has markers from from 0 to 48, counting up in increments of 4. The Placebo row lists the numbers 89, 83, 78, 74, 73, 71, 68, 64, 62, 59, 58, 56, 42. At the bottom of this illustration, there is a text box with a light peach background, with the words “HAZARD RATIO: 0.48” in blue text and “(95% CI: 0.28, 0.82)” written in black text.
Exacerbation Over 48 Weeks MobileThere is a line graph illustrating OHTUVAYRE and Placebo probability of not having the event. The vertical y-axis of the graph is labeled, “Probability of not having an event”. The y-axis numbers begin at 0.60 from the bottom of the graph and end at 1.00 at the top of the graph, counting up from 0.60 in increments .05. The horizontal x-axis is labeled “Number of weeks” and the numerical markers of the x-axis has markers from 0 to 48, counting up in increments of 4. To the bottom right-hand side of the graph is a color label. Light blue circles indicate OHTUVAYRE (N=280) and gray squares indicate Placebo (N=89). The OHTUVAYRE line graph is blue and extends from the 1.00 y-axis area starting at 0 weeks in a slightly downward trend ending at 48 weeks, with small blue circles along the line. This blue line ends between the .80 and .90 marks on the y-axis. The Placebo graph is a dark gray line that also extends from the 1.00 y-axis area in a downward trend ending at 48 weeks, with small gray squares along the line. This dark gray line ends between the 0.70 and 0.80 marks on the y-axis. Underneath the line graph is a table. The label of the table is “Number at risk of having an event at the timepoint”. The first row of the table is labeled “OHTUVAYRE” in blue. The columns align with the Number of weeks of the numerical markers of the x-axis of the graph above it. It has markers from from 0 to 48, counting up in increments of 4. The OHTUVAYRE row lists the numbers 280, 275, 270, 256, 249, 242, 235, 220, 212, 209, 205, 201, 124. The second row of the table is labeled “Placebo” in gray. The columns align with the Number of weeks of the numerical markers of the x-axis of the graph above it. It has markers from from 0 to 48, counting up in increments of 4. The Placebo row lists the numbers 89, 83, 78, 74, 73, 71, 68, 64, 62, 59, 58, 56, 42. At the bottom of this illustration, there is a text box with a light peach background, with the words “HAZARD RATIO: 0.48” in blue text and “(95% CI: 0.28, 0.82)” written in black text.

COPD exacerbations were defined as worsening of two or more major symptoms or one major and one minor symptom for at least 2 consecutive days that were treated with a minimum of 3 days of treatment with oral/systemic corticosteroids and/or antibiotics (moderate exacerbation) or resulted in in-patient hospitalization (severe exacerbation).13

Major symptoms were defined as dyspnea, sputum volume, or sputum purulence (color). Minor symptoms were defined as sore throat, colds (nasal discharge and/or nasal congestion), fever (oral temperature >37.5°C) without other cause, increased cough, or increased wheeze.13

aIn the ENHANCE-1 and ENHANCE-2 trials, 25% and 21% of patients, respectively, reported exacerbations of COPD within the 15 months prior to the studies.

bPatients were allowed to remain in the trials after treatment discontinuation.1

Learn about the delivery system of OHTUVAYRE.

Go to dosage and administration

Take a look at the safety profile of OHTUVAYRE.

Go to safety

References

  1. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phosphodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE trials). Am J Respir Crit Care Med. 2023;208(4):406-416. doi:10.1164/rccm.202306-0944OC
  2. Identifier: NCT04542057. A phase 3 trial to evaluate the safety and efficacy of ensifentrine in patients with COPD. ClinicalTrials.gov. Last update posted October 16, 2023. Accessed April 27, 2026. https://clinicaltrials.gov/study/NCT004542057
  3. Identifier: NCT04542057. Results for: a phase 3 trial to evaluate the safety and efficacy of ensifentrine in patients with COPD. ClinicalTrials.gov. Last update posted October 16, 2023. Accessed March 11, 2026. https://clinicaltrials.gov/study/NCT004542057?tab=results
  4. Identifier: NCT04535986. Results for: a phase 3 clinical trial to evaluate the safety and efficacy of ensifentrine in patients with COPD. ClinicalTrials.gov. Last update posted November 13, 2023. Accessed March 11, 2026. https://clinicaltrials.gov/study/NCT04535986?tab=results
  5. Verona Pharma protocol RPL554-CO-301: A phase III randomized, double-blind, placebo­ controlled study to evaluate the efficacy and safety of Ensifentrine over 24 weeks (with a 48-week safety subset) in patients with moderate to severe chronic obstructive pulmonary disease. NCT04535986. ClinicalTrials.com. February 18, 2022. Accessed May 26, 2026. https://cdn.clinicaltrials.gov/large-docs/86/NCT04535986/Prot_000.pdf
  6. Verona Pharma protocol RPL554-CO-302: RPL554-CO-302. A phase III randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of Ensifentrine over 24 weeks in patients with moderate to severe chronic obstructive pulmonary disease. NCT04542057. ClinicalTrials.com. April 30, 2021. Accessed May 26, 2026. https://cdn.clinicaltrials.gov/large-docs/57/NCT04542057/Prot_000.pdf
  7. St. George’s Respiratory Questionnaire (SGRQ). American Thoracic Society. Accessed March 11, 2026. https://www.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php
  8. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Supplement to: Ensifentrine, a novel phosphodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE trials). Am J Respir Crit Care Med. 2023;208(4):406-416. doi:10.1164/rccm.202306-0944OC
  9. Jones P. St. George’s respiratory questionnaire manual. City of St. George’s, University of London. March 2022. Accessed February 18, 2026. https://www.citystgeorges.ac.uk/__data/assets/pdf_file/0009/899631/SGRQ-Manual-March-2022.pdf
  10. Mahler DA, Witek TJ Jr. The MCID of the transition dyspnea index is a total score of one unit. COPD. 2005;2(1):99-103. doi:10.1081/copd-200050666
  11. Mahler DA, Bhatt SP, Rheault T, et al. Effect of ensifentrine on dyspnea in patients with moderate-to-severe chronic obstructive pulmonary disease: pooled analysis of ENHANCE trials. Expert Rev Respir Med. 2024;18(8):645-654. doi:10.1080/17476348.2024.2389960
  12. Sciurba FC, Christenson SA, Rheault T, Bengtsson T, Rickard K, Barjaktarevic IZ. Effect of dual phosphodiesterase 3 and 4 inhibitor ensifentrine on exacerbation rate and risk in patients with moderate to severe COPD. Chest. 2025;167(2):425-435. doi:10.1016/j.chest.2024.07.168
  13. Data available on request from Merck National Service Center via email at daprequests@merck.com. Please specify information package US-OHT-01715.

INDICATION

OHTUVAYRE® (ensifentrine) is indicated for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adult patients.

SELECT SAFETY INFORMATION

CONTRAINDICATIONS

OHTUVAYRE is contraindicated in patients with hypersensitivity to ensifentrine or any component of this product.

WARNINGS AND PRECAUTIONS

Acute Episodes of Bronchospasm
OHTUVAYRE should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. OHTUVAYRE has not been studied in the relief of acute symptoms and extra doses of OHTUVAYRE should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting bronchodilator.

 

Paradoxical Bronchospasm
As with other inhaled medicines, OHTUVAYRE may produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with OHTUVAYRE, it should be treated immediately with an inhaled, short-acting bronchodilator. OHTUVAYRE should be discontinued immediately and alternative therapy should be instituted.

 

Psychiatric Events Including Suicidality
Treatment with OHTUVAYRE is associated with an increase in psychiatric adverse reactions. Psychiatric events including suicide-related adverse reactions were reported in clinical studies in patients who received OHTUVAYRE (1 suicide attempt and 1 suicide). Additionally, the most commonly reported psychiatric adverse reactions in the pooled 24-week safety population were insomnia (6 patients [0.6%] OHTUVAYRE 3 mg; 2 patients [0.3%] placebo), and anxiety (2 patients [0.2%] OHTUVAYRE 3 mg; 1 patient [0.2%] placebo). Depression-related reactions including depression, major depression, and adjustment disorder with depressed mood occurred in 4 patients (0.4%) receiving OHTUVAYRE and no patients receiving placebo.

 

Before initiating treatment with OHTUVAYRE, healthcare providers should carefully weigh the risk and benefits of treatment with OHTUVAYRE in patients with a history of depression and/or suicidal thoughts or behavior. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts, or other mood changes, and if such changes occur to contact their healthcare provider. Healthcare providers should carefully evaluate the risks and benefits of continuing treatment with OHTUVAYRE if such events occur.

ADVERSE REACTIONS

The most common adverse reactions ≥1% in OHTUVAYRE and greater than placebo in the pooled population in the ENHANCE-1 and ENHANCE-2 clinical trials were back pain (1.8% vs 1.0%), hypertension (1.7% vs 0.9%), urinary tract infection (1.3% vs 1.0%), and diarrhea (1.0% vs 0.7%).

 

These are not all of the possible risks associated with OHTUVAYRE.

DOSAGE AND ADMINISTRATION

The recommended dosage of OHTUVAYRE is 3 mg (one unit-dose ampule) twice daily, once in the morning and once in the evening, administered by oral inhalation using a standard jet nebulizer with a mouthpiece.

SPECIAL POPULATIONS

Pediatric Use
The safety and effectiveness of OHTUVAYRE have not been established in pediatric patients.

 

Lactation
There are no data on the presence of ensifentrine in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OHTUVAYRE and any potential adverse effects on the breastfed child from OHTUVAYRE or from the underlying maternal condition.

 

Geriatric Use
In clinical trials, patients aged 65 and older showed no overall differences in the safety or effectiveness of OHTUVAYRE compared with younger adults, but greater sensitivity in some older individuals cannot be ruled out.

 

Hepatic Impairment
Ensifentrine systemic exposure increased by 2.3-fold in subjects with moderate or severe hepatic impairment compared with healthy subjects. Use OHTUVAYRE with caution in patients with hepatic impairment.

 

Before prescribing OHTUVAYRE® (ensifentrine), please read the accompanying Prescribing Information. The Patient Information and Instructions for Use also are available.

 

INDICATION
SELECT SAFETY INFORMATION

OHTUVAYRE® (ensifentrine) is indicated for the maintenance treatment of chronic obstructive pulmonary disease (COPD) in adult patients.

SELECT SAFETY INFORMATION

CONTRAINDICATIONS

OHTUVAYRE is contraindicated in patients with hypersensitivity to ensifentrine or any component of this product.

WARNINGS AND PRECAUTIONS

Acute Episodes of Bronchospasm
OHTUVAYRE should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. OHTUVAYRE has not been studied in the relief of acute symptoms and extra doses of OHTUVAYRE should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting bronchodilator.

 

Paradoxical Bronchospasm
As with other inhaled medicines, OHTUVAYRE may produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with OHTUVAYRE, it should be treated immediately with an inhaled, short-acting bronchodilator. OHTUVAYRE should be discontinued immediately and alternative therapy should be instituted.

 

Psychiatric Events Including Suicidality
Treatment with OHTUVAYRE is associated with an increase in psychiatric adverse reactions. Psychiatric events including suicide-related adverse reactions were reported in clinical studies in patients who received OHTUVAYRE (1 suicide attempt and 1 suicide). Additionally, the most commonly reported psychiatric adverse reactions in the pooled 24-week safety population were insomnia (6 patients [0.6%] OHTUVAYRE 3 mg; 2 patients [0.3%] placebo), and anxiety (2 patients [0.2%] OHTUVAYRE 3 mg; 1 patient [0.2%] placebo). Depression-related reactions including depression, major depression, and adjustment disorder with depressed mood occurred in 4 patients (0.4%) receiving OHTUVAYRE and no patients receiving placebo.

 

Before initiating treatment with OHTUVAYRE, healthcare providers should carefully weigh the risk and benefits of treatment with OHTUVAYRE in patients with a history of depression and/or suicidal thoughts or behavior. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts, or other mood changes, and if such changes occur to contact their healthcare provider. Healthcare providers should carefully evaluate the risks and benefits of continuing treatment with OHTUVAYRE if such events occur.

ADVERSE REACTIONS

The most common adverse reactions ≥1% in OHTUVAYRE and greater than placebo in the pooled population in the ENHANCE-1 and ENHANCE-2 clinical trials were back pain (1.8% vs 1.0%), hypertension (1.7% vs 0.9%), urinary tract infection (1.3% vs 1.0%), and diarrhea (1.0% vs 0.7%).

 

These are not all of the possible risks associated with OHTUVAYRE.

DOSAGE AND ADMINISTRATION

The recommended dosage of OHTUVAYRE is 3 mg (one unit-dose ampule) twice daily, once in the morning and once in the evening, administered by oral inhalation using a standard jet nebulizer with a mouthpiece.

SPECIAL POPULATIONS

Pediatric Use
The safety and effectiveness of OHTUVAYRE have not been established in pediatric patients.

 

Lactation
There are no data on the presence of ensifentrine in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OHTUVAYRE and any potential adverse effects on the breastfed child from OHTUVAYRE or from the underlying maternal condition.

 

Geriatric Use
In clinical trials, patients aged 65 and older showed no overall differences in the safety or effectiveness of OHTUVAYRE compared with younger adults, but greater sensitivity in some older individuals cannot be ruled out.

 

Hepatic Impairment
Ensifentrine systemic exposure increased by 2.3-fold in subjects with moderate or severe hepatic impairment compared with healthy subjects. Use OHTUVAYRE with caution in patients with hepatic impairment.

 

Before prescribing OHTUVAYRE® (ensifentrine), please read the accompanying Prescribing Information. The Patient Information and Instructions for Use also are available.