Ensifentrine as a Novel, Inhaled Treatment for Patients with COPD

Figures & data

Figure 1 Ensifentrine mechanism of action. Ensifentrine is a novel inhaled, single molecule that is a potent and selective inhibitor of PDE3 and PDE4 in late-stage clinical development for treatment of patients with COPD. PDE3 and PDE4 are expressed on airway smooth muscle, inflammatory cells and bronchial epithelial cells. The dual inhibition of PDE3 and PDE4 by ensifentrine produces additive or synergistic effects compared with inhibition of either PDE3 or PDE4 alone, which results in enhanced effects on bronchodilation, airway inflammation, and mucociliary clearance.

Abbreviations: CFTR, Cystic Fibrosis Transmembrane Conductance Regulator; PDE, phosphodiesterase.

Table 1 Summary of Clinical Study Designs of Nebulized Ensifentrine in Healthy Volunteers and in Subjects with COPD

Study	Public Registry ID	Trial Design	Primary Endpoint	Subjects	Ensifentrine Dose
Healthy volunteers
VRP120120^Citation16	EudraCT: 2012–000742-34	Phase 1 6-days dosed QD (nebulized solution) R, DB, PC, XO	Percentage change in neutrophil counts in induced sputum 6 hours after LPS challenge	Full analysis set = 22 Healthy volunteers at a single site in the UK	0.018 mg/kg (approx. 1.5 mg) Placebo
RPL554-CV-101^Citation30	N/A	Phase 1 Single dose (nebulized suspension) R, DB, Placebo- and Active-controlled, XO	Concentration-QTc analysis with placebo- corrected change from baseline QTcF (ΔΔQTcF)	Full analysis set = 32 Healthy volunteers at a single site in the US	3 mg 9 mg Placebo Moxifloxacin (400 µg, open-label)
Subjects with COPD
Ensifentrine monotherapy
RPL554-CO-203^Citation18,Citation31,Citation32	NCT03443414 EudraCT: 2016–005205-40	Phase 2 28-day dosed BID R, DB, PC, PG, dose-ranging	Change from baseline to Week 4 Peak FEV1 (0–3h)	Full analysis set = 403 Moderate-to-severe COPD, 47 sites (UK and Europe) 40–75 years old; ≥10 pack-year current or former smoking history; post-bronchodilator FEV1 ≥40% and ≤80% of predicted; FEV1/FVC <0.70 Background ICS use permitted	6 mg 3 mg 1.5 mg 0.75 mg Placebo
Ensifentrine in combination with standard of care β2-agonist or muscarinic antagonist bronchodilators
RPL554-009-2015^Citation17	NCT02542254 EudraCT: 2015–002536-41	Phase 2 single-dose R, DB, PC, albuterol- and ipratropium-controlled, 6-way XO	Peak FEV1 (0–8h) after single dose Average AUC (0–8h) FEV1 after single dose	Full analysis set = 33 Moderate COPD, single site (UK) 40–70 years old; ≥10 pack-year current or former smoking history; post-bronchodilator FEV1 ≥40% and ≤80% of predicted; FEV1/FVC <0.70; ≥150 mL increase from pre-bronchodilator FEV1 Background ICS use permitted	6 mg Placebo
RPL554-CO-202^Citation17	NCT03028142 EudraCT: 2016–004450-15	Phase 2 3-day dosed BID R, DB, PC, 3-way XO added on to open-label tiotropium	Day 3 Peak FEV1 (0–4h) Day 3 Average AUC (0–12h) FEV1	Full analysis set = 28 Moderate-to-severe COPD, single site (UK) 40–75 years old; ≥10 pack-year current or former smoking history; post-bronchodilator FEV1 ≥40% and ≤80% of predicted; FEV1/FVC <0.70; ≥150 mL increase from pre-bronchodilator FEV1 Background ICS use permitted	6 mg 1.5 mg Placebo
RPL554-CO-205^Citation19,Citation32	NCT03937479	Phase 2 28-day dosed BID R, DB, PC, PG, dose-ranging added to open-label tiotropium	Change from baseline to Week 4 Peak FEV1 (0–3h)	Full analysis set = 413 Moderate-to-severe COPD, 46 sites (US) 40–80 years old; ≥10 pack-year current or former smoking history; post-bronchodilator FEV1 ≥30 and ≤70% of predicted; FEV1/FVC <0.70; symptomatic (mMRC ≥ 2) at randomization No ICS use permitted; Stratified 1:1 by screening reversibility stratus: pre- to post-albuterol change in FEV1 ≥200 mL and ≥12%; 2-week run-in on TIO QD	3 mg 1.5 mg 0.75 mg 0.375 mg Placebo
Ensifentrine Phase 3 Trials
ENHANCE 1^Citation21 [RPL554-CO-301]	NCT04535986 EudraCT: 2020–002086-34	Phase 3 24-week dosed BID (+48-week safety sub-set) R, DB, PC, PG	Change from baseline to Week 12 Average FEV1 AUC0-12h	Modified intent-to-treat population = 760 Moderate-to-severe COPD; 120 sites (US, UK, Europe, Russian Federation, South Korea) 40–80 years old; ≥10 pack-year current or former smoking history; post-bronchodilator FEV1 ≥30 and ≤70% of predicted; FEV1/FVC <0.70; symptomatic (mMRC ≥ 2) at screening Background concomitant LAMA ± ICS or LABA ± ICS in 69% (including 21% on ICS)	3 mg Placebo
ENHANCE-2^Citation21 [RPL554-CO-302]	NCT04542057 EudraCT: 2020–002069-32	Phase 3 24-week dosed BID R, DB, PC, PG	Change from baseline to Week 12 Average FEV1 AUC0-12h	Modified intent-to-treat population= 789 Moderate-to-severe COPD; 130 sites (US, Canada, Europe) 40–80 years old; ≥10 pack-year current or former smoking history; post-bronchodilator FEV1 ≥30 and ≤70% of predicted; FEV1/FVC <0.70; symptomatic (mMRC ≥ 2) at screening Background concomitant LAMA ± ICS or LABA ± ICS in 55% (including 15% on ICS)	3 mg Placebo

Abbreviations: AUC, area under the curve; BID, twice daily; COPD, chronic obstructive pulmonary disease; DB, double-blind; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; h, hours; ICS, inhaled corticosteroid; LPS, lipo-polysaccharide; mg, milligram; μg, microgram; LABA, long-acting beta2 agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified medical research council score; PC, placebo-controlled; PG, parallel-group; placebo, ensifentrine matched nebulized placebo; QD, once daily; R, randomized; TIO, tiotropium; UK, United Kingdom; US, United States; XO, crossover.

Table 2 Summary of Phase 2 Clinical Study Efficacy Data of Nebulized Ensifentrine by Dose in Subjects with COPD

Study	Primary Endpoint	Ensifentrine Dose (n FAS)	Placebo Dose (n FAS)	Placebo-Corrected Change, FAS (95% CI)	p-value^a
Nebulized ensifentrine as a monotherapy
RPL554-CO-203^Citation18	Change from baseline to Week 4 Peak FEV1 (0–3h)	6 mg (n = 80) 3 mg (n = 82) 1.5 mg (n = 81) 0.75 mg (n = 81)	Placebo (n = 79)	139 mL (69, 210) 200 mL (131, 270) 153 mL (83, 222) 146 mL (75, 216)	p < 0.001 p < 0.001 p < 0.001 p < 0.001
Nebulized ensifentrine in combination with standard of care β2-agonist or muscarinic antagonist bronchodilators
RPL554-009-2015^Citation17	Peak FEV1 (0–8h) post-single dose	6 mg (n = 30)	Placebo (n = 31)	223 mL (178, 269)	p < 0.001
	Average AUC (0–8h) FEV1 post-single dose			165 mL (133, 206)	p < 0.001
RPL554-CO-202^Citation17	Day 3 Peak FEV1 (0–4h)	6 mg+tiotropium (n = 27)	Placebo + tiotropium (n = 27)	127 mL (LSMR: 1.09 L [1.05, 1.12])	p < 0.001
	Day 3 Average AUC (0–12h) FEV1			65 mL (LSMR: 1.06 L [1.02, 1.09])	p < 0.001
	Day 3 Peak FEV1 (0–4h)	1.5 mg+tiotropium (n = 28)		104 mL (LSMR: 1.05 L [1.02, 1.09])	p = 0.002
	Day 3 Average AUC (0–12h) FEV1			51 mL (LSMR: 1.03 L [0.99, 1.06])	p = 0.099
RPL554-CO-205^Citation19	Change from baseline Week 4 Peak FEV1 (0–3h)	3 mg+tiotropium (n = 82) 1.5 mg+tiotropium (n = 81) 0.75 mg+tiotropium (n = 83) 0.375 mg+tiotropium (n = 83)	Placebo + tiotropium (n = 84)	124 mL (52, 197) 107 mL (34, 180) 91 mL (18, 164) 78 mL (5, 150)	p < 0.001 p = 0.004 p = 0.015 p = 0.037

Note: ^ap < 0.05 is statistically significant. Refer to Table 2 for study descriptions.

Abbreviations: AUC, area under the curve; COPD, chronic obstructive pulmonary disease; FAS, full analysis set, participants randomized and received at least one dose of blinded ensifentrine or placebo; FEV₁, forced expiratory volume in 1 second; GMR, geometric mean ratio; h, hours; LSMR, least-squares mean ratio; mg, milligram; μg, microgram; mL, milliliter; placebo, ensifentrine matched nebulized placebo.

Table 3 The Most-Commonly Reported AEs (by More Than One Subject) with Nebulized Ensifentrine (3 mg) Twice Daily in Subjects with COPD from Two 4-Week Phase 2 Dose-Ranging Studies RPL554-CO-203 and RPL554-CO-205^a,³²

Adverse Event (Preferred Term)	Subjects Treated with Ensifentrine 3 mg BID, n (%) [N Treated = 165 in Safety Analysis]	Subjects Treated with Placebo BID, n (%) [N Treated = 163 in Safety Analysis]
Headache	9 (5.5)	4 (2.5)
COPD (worsening)^b	6 (3.6)	6 (3.7)
Cough	7 (4.2)	2 (1.2)
Dyspnea	3 (1.8)	5 (3.1)
Nasopharyngitis	5 (3.0)	9 (5.5)
Hypertension	4 (2.4)	1 (0.6)
Nausea	3 (1.8)	2 (1.2)
Diarrhea	3 (1.8)	1 (0.6)
Dry mouth	2 (1.2)	0
Arthralgia	2 (1.2)	0

Notes: ^aPooled for subjects with COPD received nebulized ensifentrine (3 mg) or nebulized placebo BID in RPL554-CO-203 and RPL554-CO-205. Refer to Table 1 for study descriptions. ^bWorsening of COPD symptoms or COPD exacerbation.

Abbreviations: BID, twice daily; COPD, chronic obstructive pulmonary disease; N, number pooled subjects treated; n, number subjects reporting adverse event.

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