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Ohtuvayre trials evaluated lung function, health-related quality of life, and long-term safety1

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Study Design
Primary Endpoint
Secondary Endpoints
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STUDY DESIGN1,2

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

More than 1,500 patients were treated for 24 weeks.

Overview of the ENHANCE clinical trials Overview of the ENHANCE clinical trials

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In the ENHANCE Trials, ~ 60% of patients were on maintenance background bronchodilator therapy, with ~20% also taking ICS

Overview

The ENHANCE Trials were designed to evaluate the efficacy and safety of Ohtuvayre in patients with COPD in two 24-week randomized, double-blind, placebo-controlled, parallel-group clinical trials (ENHANCE-1 and ENHANCE-2).1 The two trials enrolled a total of 1553 adults with moderate to severe COPD.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.1 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.1

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 a standard jet nebulizer.1 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.1

The modified intention-to-treat population (mITT) was defined as all randomized patients that received at least one dose of Ohtuvayre.2

*Randomized set: N=763; mITT population: N=7601,2
†Randomized set: N=790; mITT population: N=7891,2
‡Selected inclusion/exclusion criteria.
BID = twice daily; 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; R = randomization.

Patients2

Selected Eligibility Criteria‡:

  • COPD diagnosis: FEV1/FVC<0.7
  • Post-bronchodilator FEV1
    30-70% predicted normal
  • Modified Medical Research Council dyspnea scale ≥2
  • Current or former smoker (>10 pack-years)
  • No asthma diagnosis
  • No exacerbation history requirement (other than no steroid-treated exacerbation in past 12 weeks)

*Randomized set: N=763; mITT population: N=7601,2
†Randomized set: N=790; mITT population: N=7891,2
‡Selected inclusion/exclusion criteria.
BID = twice daily; 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; R = randomization.

Primary Endpoint*

Change from baseline in average FEV1 AUC0-12h post dose at Week 122†

Selected Secondary Endpoints

Key*

  • Change from baseline in Peak FEV1 at Week 122‡
  • Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) total score at Week 242§
  • Proportion of SGRQ responders at Week 241,3§

Additional

  • Change from baseline in Peak FEV1 and SGRQ total score at different timepoints3

*To address multiplicity in the analysis of the endpoints, statistical testing of the primary endpoint and key secondary endpoints was done in a hierarchical order.2,3 Formal testing stopped with the first nonsignificant result.2,3
†Average FEV1 AUC0-12h is defined as the AUC over 12 hours of the FEV1, divided by 12 hours.2
‡Peak FEV1 was defined as the highest post-dose FEV1 within the first 4 hours after dosing.2
§SGRQ is a questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease.4
These endpoints were not part of the formal testing hierarchy and therefore not controlled for multiplicity.3
AUC = area under the curve; FEV1 = forced expiratory volume in one second; SGRQ = St. George’s Respiratory Questionnaire.

Ohtuvayre demonstrated significant improvement in lung function1,2

Ohtuvayre’s impact on lung function in the ENHANCE clinical trials Ohtuvayre’s impact on lung function in the ENHANCE clinical trials Ohtuvayre’s impact on lung function in the ENHANCE clinical trials

*Average FEV1AUC0-12h is defined as the AUC over 12 hours of the FEV1, divided by 12 hours.2
†One patient was randomized to placebo and treated but was not included in the endpoint analysis due to missing baseline FEV1.3

Ohtuvayre demonstrated early and sustained lung function improvement2,3

Secondary Endpoints: Peak FEV1 Improvement from Baseline

Early

Sustained

Peak FEV1 evaluated at Week 12 was included in the statistical testing hierarchy. Peak FEV1 at other timepoints were not included in the statistical hierarchy and therefore not controlled for multiplicity.2,3

Peak FEV1 evaluated at Week 12 was included in the statistical testing hierarchy. Peak FEV1 at other timepoints were not included in the statistical hierarchy and therefore not controlled for multiplicity.2,3

Secondary Endpoints: Mean Peak FEV1 Over 24 Weeks2,3

Chart showing mean peak FEV1 in the ENHANCE-1 trial Chart showing mean peak FEV1 in the ENHANCE-2 trial Chart showing mean peak FEV1 in the ENHANCE-1 trial Chart showing mean peak FEV1 in the ENHANCE-2 trial

Peak FEV1 evaluated at Week 12 was included in the statistical testing hierarchy. Peak FEV1 at other timepoints were not included in the statistical hierarchy and therefore not controlled for multiplicity.2,3
Peak FEV1 was defined as the highest post-dose FEV1 within the first 4 hours after dosing.2
*One patient was randomized to placebo and treated but was not included in the endpoint analysis due to missing baseline FEV1.3

St. George’s Respiratory Questionnaire (SGRQ)

SGRQ is a questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease4

  • During clinical visits, patients had their HRQoL assessed by a physician using the St. George’s Respiratory Questionnaire2

HRQoL = health-related quality of life.

Part 1: One Component

Symptoms

Evaluates symptomatology, including frequency of cough, sputum production, wheezing, breathlessness, and the duration and frequency of attacks of breathlessness or wheezing5

HRQoL = health-related quality of life.

Part 2: Two Components

Activity

Evaluates activities that cause breathlessness or are limited because of breathlessness5

Impact

Evaluates a range of factors, including influence on employment, being in control of health, panic, stigmatization, the need for medication, side effects of prescribed therapies, expectations for health, and disturbances of daily life5

SGRQ score was assessed in the ENHANCE trials

Mean Change from Baseline in the SGRQ Total Score at Weeks 6, 12, and 242,3,6

SGRQ score assessment in the ENHANCE-1 clinical trial SGRQ score assessment in the ENHANCE-2 clinical trial SGRQ score assessment in the ENHANCE-1 clinical trial SGRQ score assessment in the ENHANCE-2 clinical trial

Ohtuvayre SGRQ Responder Rate vs placebo§

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; p=0.019].1,3

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; p=NS].1,3

SGRQ total score at Week 24 was included in the statistical testing hierarchy. SGRQ total score at other timepoints were not included in the statistical hierarchy and therefore not controlled for multiplicity.2,3

SGRQ responder rate at Week 24 was included in the statistical hierarchy.3

*Minimal clinically important difference (MCID) for SGRQ is defined as a reduction from baseline of at least 4 units.1,2
§Responder rate is defined as the proportion of patients who achieved MCID.1,2
CFB = change from baseline; LS = least-squares; NS = not significant.

Learn about the delivery
system of Ohtuvayre.

Take a look at the safety
profile of Ohtuvayre.

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. 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 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.

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.

Adverse Reactions: The most common adverse reactions ≥1% in Ohtuvayre and greater than placebo in the pooled population were back pain 1.8%, hypertension 1.7%, urinary tract infection 1.3%, and diarrhea 1.0%.

These are not all of the possible risks associated with Ohtuvayre. Please see Full Prescribing Information for Ohtuvayre.

To report suspected adverse reactions, contact Verona Pharma, Inc. at
1-888-672-0371 or FDA at
1-800-FDA-1088 or
www.fda.gov/medwatch.

References:
1. Ohtuvayre™ (ensifentrine). Prescribing Information. Raleigh, NC: Verona Pharma plc; 2024. 2. 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. 3. Data on File. Raleigh, NC: Verona Pharma plc. 4. St. George's Respiratory Questionnaire (SGRQ). American Thoracic Society. Accessed July 3, 2024. https://www.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php 5. Jones PW, Quirk FH, Baveystcok C, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis. 1992;145(6):1321-1327. 6. 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 Ill trials (the ENHANCE Trials). Online Data Supplement. Am J Respir Crit Care Med. 2023:208(4):1-29.