Effective Date

Date of Origin 

01-01-2025            

01-01-2025

Ohtuvayre™

(ensifentrine)

Inhalation Suspension

Maintenance treatment of chronic obstructive pulmonary disease (COPD) in adult patients

1

Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a common lung disease characterized by chronic respiratory symptoms caused by abnormalities of the airways and/or alveoli that cause persistent, and often progressive, airway obstruction. Symptoms include dyspnea, cough, sputum production, and/or exacerbations. COPD is one of the top causes of death in the United States, and prior to Covid 19, was the third leading cause of death in the world.(2)

COPD develops due to a combination of environmental exposures and patient characteristics. Smoking and air pollution are the two leading environmental exposures leading to the development of COPD.(2) These toxins cause chronic inflammation, an increase in the number of goblet cells, mucus gland hyperplasia, fibrosis, and narrowing of the small airways.(4) Structural changes in the distal to terminal bronchiole lead to the development of emphysema. The structural changes also cause changes in normal ventilation-perfusion distributions.(2)

Diagnosis of COPD is dependent on the presence of pulmonary symptoms (i.e., dyspnea, chronic cough, sputum production), patient’s exposure history (e.g., current/previous smoker, history of recurrent lower respiratory tract infections), and evidence of airflow limitation. Diagnosis is confirmed by spirometry. A post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) less than 0.7 is indicative of the diagnosis. Once diagnosis is confirmed it is important to determine severity of airflow obstruction to appropriately guide treatment options.(2)

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) ABE Assessment tool is recommended for determining initial pharmacotherapy for the management of COPD. The tool takes into account spirometry measures, disease severity, and frequency of exacerbations. The first portion of the assessment includes the GOLD grades, which determine airflow obstruction severity based on specific spirometry cut points.(2)

The tool also takes exacerbation history into account. Exacerbation history is broken into two sections. Patients then fall into one of three groups E, A, or B. For patients with 0 to 1 moderate exacerbations in the past year, the GOLD guideline recommends two symptom questionnaires to further establish initial therapy. The modified Medical Research Council (mMRC) dyspnea scale, assesses breathlessness, which is a key symptom for many patients with COPD. A more comprehensive questionnaire is the COPD Assessment Test.(2)

Treatment recommendations based on GOLD ABE grouping are as follows(2):

• Group E:
  • Long-acting beta agonist (LABA) + long-acting muscarinic antagonist (LAMA)
  • Consider LABA + LAMA + inhaled corticosteroid (ICS) if blood eosinophil levels are 300 or greater
• Group A
  • A bronchodilator
• Group B
  • LABA + LAMA

The GOLD guideline has a separate algorithm for follow up therapy, based on persistence of dyspnea and occurrence of exacerbations. Patients not responding to initial therapy should have inhaler technique, adherence, and other interfering comorbidities addressed prior to intitiating additional or changing therapies.(2) 

• Dyspnea:
  • Initial therapy LABA or LAMA: switch to dual therapy (LABA/LAMA)
  • Initial therapy dual therapy: consider switching inhaler devices, implement or escalate non-pharmacologic therapies, or investigate other causes of dyspnea
• Exacerbations:
  • Initial therapy LABA or LAMA: 
    • Blood eosinophils less than 300, swith to dual therapy (LABA/LAMA) 
    • Blood eosinophils greater than or equal to 300, switch to triple therapy (LABA/LAMA/ICS) 
  • Initial dual therapy: 
    • Blood eosinophils less than 100, add roflumilast
    • Blood eosinophils greater than or equal to 100, switch to triple therapy (LABA/LAMA/ICS)
  • Exacerbations on triple therapy:
    • Add roflumilast (a phosphodiesterase-4 inhibitor)
    • Add a macrolide (i.e., azithromycin)

Efficacy

The efficacy of Ohtuvayre was evaluated in two 24-week randomized, double-blind, placebo controlled, parallel-group clinical trials (ENHANCE-1 [NCT04535986] and ENHANCE-2 [NCT04542057]). The two trials enrolled a total of 1553 adults with moderate to severe COPD. Eligible patients were aged 40–80 years, had a COPD diagnosis, had post-bronchodilator FEV1 30 to 70% predicted normal, had FEV1/FVC less than 0.7, had greater than or equal to 2 modified Medical Research Council dyspnea scale score, and had a smoking history greater than or equal to10 pack-years.(3) The primary endpoint for ENHANCE-1 and ENHANCE-2 was the change from baseline in FEV1 AUC0-12h post dose at Week 12. In both trials, Ohtuvayre demonstrated a statistically significant improvement in FEV1 AUC0-12h compared to placebo.(1)

The St. George’s Respiratory Questionnaire (SGRQ) was assessed in ENHANCE-1 and ENHANCE2. In ENHANCE-1, the SGRQ responder rate (defined as an improvement in score of 4 or more as threshold) for Ohtuvayre at Week 24 was 58.2% compared to 45.9% for placebo [Odds Ratio: 1.49; 95% CI: 1.07, 2.07]. In ENHANCE-2, the SGRQ responder rate for Ohtuvayre at Week 24 was 45.4% compared to 50.3% for placebo [Odds Ratio: 0.92; 95% CI: 0.66, 1.29].(1)

Safety

Ohtuvayre is contraindicated in patients with hypersensitivity to ensifentrine or any component of this product.(1)

1

Ohtuvayre prescribing information. Verona Pharma. June 2024. 

2

GLOBAL STRATEGY FOR PREVENTION, DIAGNOSIS AND MANAGEMENT OF COPD: 2024 Report. https://goldcopd.org/2024-gold-report/

3

Anzueto A, Barjaktarevic IZ, Siler TM, Rheault T, Bengtsson T, Rickard K, Sciurba F. 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 Aug 15;208(4):406-416. doi: 10.1164/rccm.202306-0944OC. PMID: 37364283; PMCID: PMC10449067.

4

McDonough JE, Yuan R, Suzuki M, et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. New England Journal of Medicine 2011; 365:1567.

Ohtuvayre

ensifentrine inhalation susp

3 MG/2.5ML

M ; N ; O ; Y

N

Ohtuvayre

ensifentrine inhalation susp

3 MG/2.5ML

60

Ampules

30

DAYS

Ohtuvayre

ensifentrine inhalation susp

3 MG/2.5ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Ohtuvayre

ensifentrine inhalation susp

3 MG/2.5ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. ONE of the following:
   1. The requested agent is eligible for continuation of therapy AND ONE of the following:

1. 1. 1. The patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days OR
      2. The prescriber states the patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days AND is at risk if therapy is changed OR
   2. BOTH of the following:
      1. ONE of the following:
         1. The patient has a diagnosis of chronic obstructive pulmonary disease (COPD) AND ALL of the following:
            1. The patient's diagnosis was confirmed by spirometry with a post-bronchodilator FEV1/FVC ratio less than 0.7 AND
            2. The patient has a post-bronchodilator FEV1 between 30% to 70% predicted AND 
            3. ONE of the following:
               1. The patient has a Medical Research Council dyspnea (mMRC) score of 2 or greater OR
               2. The patient has a COPD Assessment Test (CAT) score greater than or equal to 10 AND
            4. ONE of the following:
               1. The patient is currently being treated with a long-acting beta-2 agonist (LABA) + long-acting muscarinic antagonist (LAMA) combination with or without an inhaled corticosteroid (ICS) OR 
               2. The patient has an intolerance or hypersensitivity to a LABA + LAMA combination OR 
               3. The patient has an FDA labeled contraindication to ALL LABA + LAMA combinations OR
         2. The patient has another FDA labeled indication for the requested agent AND
      2. If the patient has an FDA labeled indication, then ONE of the following:
         1. The patient's age is within FDA labeling for the requested indication OR
         2. There is support for using the requested agent for the patient's age for the requested indication AND
2. If the patient has a diagnosis of COPD, the patient will continue COPD control therapy (e.g., LABA, LAMA, ICS) in combination with the requested agent AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., allergist, immunologist, pulmonologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 6 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. 

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. ONE of the following:
   1. The patient has a diagnosis of COPD AND BOTH of the following:
      1. The patient has had a decrease in exacerbations and/or dyspnea with the requested agent AND
      2. The patient will continue COPD control therapy (e.g., LABA, LAMA, ICS) in combination with the requested agent OR
   2. The patient has a diagnosis other than COPD AND has had clinical benefit with the requested agent AND 
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., allergist, immunologist, pulmonologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. 

Universal QL

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met: 

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
   3. BOTH of the following:
      1. ​​​​​​​The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication​​​​​​​

Length of Approval: up to 12 months