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Ensifentrine

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{{Drugbox | verifiedrevid = 461481983 | IUPAC_name = N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea | image = RPL554.png | width = 240

| tradename = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = | routes_of_administration =

| bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion =

| CAS_number_Ref =  checkY | CAS_number = | ATC_prefix = | ATC_suffix = | PubChem = 9934746 | DrugBank_Ref =  checkY | DrugBank = | ChemSpiderID_Ref =  checkY | ChemSpiderID = 8110374 | InChI = 1/C26H31N5O4/c1-15-10-16(2)24(17(3)11-15)29-23-14-20-19-13-22(35-5)21(34-4)12-18(19)6-8-30(20)26(33)31(23)9-7-28-25(27)32/h10-14H,6-9H2,1-5H3,(H3,27,28,32)/b29-23+ | InChIKey = CSOBIBXVIYAXFM-BYNJWEBRBJ | StdInChI_Ref =  checkY | StdInChI = 1S/C26H31N5O4/c1-15-10-16(2)24(17(3)11-15)29-23-14-20-19-13-22(35-5)21(34-4)12-18(19)6-8-30(20)26(33)31(23)9-7-28-25(27)32/h10-14H,6-9H2,1-5H3,(H3,27,28,32)/b29-23+ | StdInChIKey_Ref =  checkY | StdInChIKey = CSOBIBXVIYAXFM-BYNJWEBRSA-N

| C=26 | H=31 | N=5 | O=4 | molecular_weight = 477.554 g/mol | smiles = Cc3cc(C)cc(C)c3N=c2cc1-c(cc4OC)c(cc4OC)CCn1c(=O)n2CCNC(N)=O | synonyms = 9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one }}

RPL-554 (LS-193,855) is a drug which acts as a long-acting inhibitor of the phosphodiesterase enzymes PDE-3 and PDE-4, producing both bronchodilator and anti-inflammatory effects.[1]

RPL554 was originally developed at The Sackler Institute of Pulmonary Pharmacology, King’s College, London, as a result of extensive work led by Professor Clive Page, Sir David Jack and Dr Alec Oxford.[2] [3]

RPL554 is now being developed by Verona Pharma plc as a potential treatment for :-

RPL554 is currently in Phase II clinical trials for asthma[4] and COPD.[5]

Verona Pharma has recently received a Venture and Innovation Award from the Cystic Fibrosis Trust.[6]


Background

Unmet medical needs

There are unmet medical needs for the therapy of respiratory disease, such as COPD, asthma and cystic fibrosis.

COPD

It is recognised that there are many different grades of disease severity for COPD and also many sub types which requires a broader spectrum of therapy than is currently available.[7]

ASTHMA

The most common treatment for asthma is an inhaled short-acting beta2-adrenergic agonist (such as salbutamol), which is only effective for 4–6 hours.

The treatment for more severe asthma is similar to that for COPD and usually involves a combination of the following :-

  1. Long-acting beta2-adrenergic agonist (LABA) (bronchodilator) (E.g. salmeterol)
  2. Long-acting muscarinic antagonist (LAMA) (E.g. ipratropium bromide)
  3. Inhaled corticosteroid (ICS) (anti-inflammatory) (E.g. fluticasone)

The most powerful drugs use a triple LABA-LAMA-ICS therapy.[7]

However these drugs can carry potential health risks :-

There are health warnings for the following commonly used LABA:-

CYSTIC FIBROSIS

There is urgent need for more effective and affordable treatments for the control and management of cystic fibrosis.

For this reason the Cystic Fibrosis Trust has initiated a Venture and Innovation Award to encourage the development of novel new treatments.[6]

King's College, London

The creation and discovery of the unique properties of the molecule RPL554 is the result of extensive work carried out at The Sackler Institute of Pulmonary Pharmacology, King’s College London.[2][3]

Notable people involved include :-

  • Professor Clive Page
  • Sir David Jack
  • Dr Alec Oxford

The team made around 200 molecules before hitting on RPL554 as the molecule with the desired properties.

A BBC news report was generated as a result of the excitement of the discovery of the unique properties of RPL554.[12]

PDE inhibiters

For some time there has been excitement about the possibility of developing novel new drugs which act as selected phosphodiesterase inhibitor's.

The molecule RPL554 is a selective, long-acting dual inhibitor of the enzymes PDE3 / PDE4.

Existing and approved drugs which act as PDE3 inhibitor's are mostly used for the therapy of acute heart failure. These drugs are designed to have a strong positive inotropic effect which makes them very powerful and for this reason have to be applied under close observation.

RPL554 has a minimal inotropic effect, it only has the desired bronchodilator and anti-inflammatory properties that are essential to treat respiratory disease, such as COPD, asthma and cystic fibrosis.

A phase I clinical trial [13] study in 50 healthy volunteers showed that there were no changes in subjects’ cardiovascular parameters.[14]

Caffeine is an example of a non selective phosphodiesterase inhibitor.

A study has investigated the possibility that caffeine may reduce asthma symptoms.[15]

Indications

Chronic obstructive pulmonary disease

RPL554 is currently in development as a nebulised treatment for acute exacerbations in COPD patients in a hospital or home-care setting.[16]

Professor Dave Singh of the Medicines Evaluation Unit, University of Manchester, commented:- 

"I am very encouraged by the headline results of this study using the new suspension formulation of RPL554. The marked improvement in lung function seen in this initial small study shows that this product has potential to be a meaningful addition to existing treatment options for COPD."[16]

RPL554 is currently in Phase II clinical trials for COPD.[5]

Asthma

RPL554 has the potential to be used as a treatment for asthma and is currently in Phase II clinical trials.[4]

Cystic fibrosis

A paper demonstrating that RPL554 enhances CTFR activation in cystic fibrosis airway epithelia has been published in the American Journal of Physiology.[17]

Verona Pharma has recently received a Venture and Innovation Award from the Cystic Fibrosis Trust.[6]

Mechanism of action

An effective treatment for respiratory disease, such as COPD, asthma or cystic fibrosis (CF), needs to remedy the problems of bronchoconstriction.

Air flow in air passages can get restricted due to 3 factors :-

  1. A spasmodic state of the smooth muscles in bronchi and bronchioles
  2. Inflammation of the airways
  3. Excessive production of mucus

An effective remedy for these 3 factors can be achieved by :-

  1. Bronchodilation by regulating the smooth muscle of the bronchi and bronchioles
  2. Anti-inflammatory effect to reduce the inflammation of the airways
  3. Mucociliary clearance - especially for cystic fibrosis (CF)

Bronchodilation

The molecule RPL554 is a selective, long-acting dual inhibitor of the enzymes PDE3 / PDE4.

The PDE3 inhibitor helps to reduce bronchoconstriction by regulating the smooth muscle of the bronchi and bronchioles (lungs).

RPL554 has a much lower positive inotropic effect than those PDE3 inhibitor drugs used for the therapy of acute heart failure.

A phase I clinical trial [13] study in 50 healthy volunteers showed that there were no changes in subjects’ cardiovascular parameters.[14]

Anti-inflammatory effect

The PDE4 inhibitor has an anti-inflammatory effect to reduce the inflammation of the airways.

Clinical trials have shown that RPL554 can inhibit the bacterial component lipopolysaccharides (LPS) and therefore has a significant anti-inflammatory effect.[3]

Mucociliary clearance for cystic fibrosis

By inhibiting cAMP breakdown, PDE inhibitors stimulate cystic fibrosis transmembrane conductance regulator (CFTR).[17]

RPL554 may increase mucociliary clearance through stimulation of CFTR and increasing ciliary beat frequency and thus could provide a novel therapeutic option for CF.[17]

Clinical trials 2016

Phase IIa Comparison of RPL554 With Placebo and Salbutamol in Asthmatic Patients

This study is ongoing, but not recruiting participants. NCT02427165[4]

A Phase II, Randomised, Double Blind, Placebo Controlled, Seven Way Crossover Study to Assess the Effect of Single Doses of RPL554 Compared to Salbutamol and Placebo Administered by Nebuliser on Lung Function of Patients With Chronic Asthma[4]

In this study 29 patients with mild to moderate persistent asthma will each receive single doses of nebulised RPL554, from the very low dose to the highest dose previously tested in the Phase Ib studies of the same drug in healthy subjects.[18]

The study is being performed at Celerion (Belfast, Ireland) and Skane University Hospital (Lund, Sweden).

Phase IIa The Effects of RPL554 on Top of Standard COPD Reliever Medications

This study is ongoing, but not recruiting participants. NCT02542254[5]

The purpose of this study is to investigate if RPL554 has an additive bronchodilator effect when administered in combination with standard of care bronchodilators in patients with COPD. This study investigates the pharmacodynamic effect of RPL554 using spirometry and whole body plethysmography compared to placebo, when administered in addition to a beta2 agonist (salbutamol), a muscarinic antagonist (ipratropium) or placebo. [5]

All patients will receive the same six treatments in a randomised sequence:

  1. salbutamol,
  2. ipratropium,
  3. salbutamol + RPL554,
  4. ipratropium + RPL554,
  5. RPL554
  6. Placebo

Thirty patients have been enrolled in this double-blind, placebo-controlled, six way crossover study, which will investigate the pharmacodynamic effect of nebulised RPL554 in a commercially scalable suspension formulation. [18]

The trial is being performed at the Medicines Evaluation Unit in Manchester by lead investigator Professor Dave Singh.

Clinical trials 2015

Phase Ib SAD/MAD Study of RPL554 in Healthy Subjects and COPD Subjects

This study has been completed (July 2015). NCT02307162[13]

A Phase I, Randomised, Double Blind, Placebo Controlled, 3-part Study to Assess the Safety, Tolerability and Pharmacokinetics of Single and Multiple Inhaled Doses of RPL554 Administered by Nebuliser to Healthy Male Subjects and Stable COPD Subjects.[13]

  • Part A. Single Ascending Dose Study in Healthy Male Subjects[14]
  • Part B. Multiple Ascending Dose Study in Healthy Male Subjects[19]
  • Part C. Multiple Ascending Dose in moderate, stable COPD Subjects[16]

The result from Part A of the study in 50 healthy volunteers showed that the drug was well tolerated across all doses and no maximum tolerated dose could be defined. Importantly, there were no changes in subjects’ cardiovascular parameters and there was complete absence of nausea or vomiting at all doses.[14]

The result from Part B showed consistent safety and tolerability with the result from Part A.[19]

The result from Part C showed that RPL554 caused pronounced improvement in lung function in moderate, stable COPD Subjects[16]

Chronology

2016

Q2 expected Phase IIa The Effects of RPL554 on Top of Standard COPD Reliever Medications[5]
Q1 expected Phase IIa Comparison of RPL554 With Placebo and Salbutamol in Asthmatic Patients[4]

2015

6 November The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia

published in American Journal of Physiology - Lung Cellular and Molecular Physiology[17]

29 September Part C. Multiple Ascending Dose in moderate, stable COPD Subjects[16]
8 June Part B. Multiple Ascending Dose Study in Healthy Male Subjects[19]
23 March Part A. Single Ascending Dose Study in Healthy Male Subjects[14]
Phase Ib SAD/MAD Study of Nebulised RPL554 in Healthy Subjects and COPD Subjects(Part A, B, C).

The participants included :-

  • 50 healthy people
  • 32 stable COPD patients with moderate disease severity

2014

3 November The Cystic Fibrosis Trust announced its first Venture and Innovation Award for a specific company, a £65,000 grant to support further research by Verona Pharma into its lead pipeline drug RPL554; a new inhaled treatment for cystic fibrosis.[6]

2013

25 October Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials

published in The Lancet Respiratory Medicine[20]

2009

February Between February 2009 and January 2013, four small proof-of-concept clinical trials were carried out in the Netherlands, Italy, and the UK to assess the safety and efficacy of inhaled RPL554, and for its ability to act as a bronchodilator and anti-inflammatory drug.[3]

The participants included :-

  • 39 healthy people
  • 28 people with mild-to-moderate asthma
  • 12 people with COPD

2006

4 May The Pharmacology of Two Novel Long-Acting Phosphodiesterase 3/4 Inhibitors, RPL554 and RPL565

published in Journal of Pharmacology and Experimental Therapeutics.[1]

References

  1. ^ a b Boswell-Smith V, Spina D, Oxford AW, Comer MB, Seeds EA, Page CP. The Pharmacology of Two Novel Long-Acting Phosphodiesterase 3/4 Inhibitors, RPL554 (9,10-Dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl) -3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)isoquinolin-4-one) and RPL565 (6,7-Dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido(6,1-a)isoquinolin-4-one). Journal of Pharmacology and Experimental Therapeutics 2006; 318(2):840-848.
  2. ^ a b "Revolutionary asthma treatment". King's College London. Retrieved 25 January 2016.
  3. ^ a b c d e "New class of drug shows promise for treating asthma and COPD". King's College London. Retrieved 25 January 2016.
  4. ^ a b c d e "Comparison of RPL554 With Placebo and Salbutamol in Asthmatic Patients". U.S. National Institutes of Health. Retrieved 25 January 2016.
  5. ^ a b c d e "The Effects of RPL554 on Top of Standard COPD Reliever Medications". U.S. National Institutes of Health. Retrieved 25 January 2016.
  6. ^ a b c d "Trust award for further research into pipeline drug". Cystic Fibrosis Trust (Charity). Retrieved 25 January 2016.
  7. ^ a b Barjaktarevic, Igor. "Positioning new pharmacotherapies for COPD". National Center for Biotechnology Information. Retrieved 25 January 2016.
  8. ^ Zhang, Linjie. "Inhaled corticosteroids in children with persistent asthma: effects on growth". Cochrane Airways Group. Retrieved 25 January 2016.
  9. ^ a b "Search results for: salmeterol". DAILYMED. Retrieved 25 January 2016.
  10. ^ a b "Search results for: formoterol". DAILYMED. Retrieved 25 January 2016.
  11. ^ a b "Search results for: vilanterol". DAILYMED. Retrieved 25 January 2016.
  12. ^ "Asthma and hay fever drug tested". BBC News Report. Retrieved 25 January 2016.
  13. ^ a b c d "SAD/MAD Study of Nebulised RPL554 in Healthy Subjects and COPD Subjects". U.S. National Institutes of Health. Retrieved 31 January 2016.
  14. ^ a b c d e "Part A. Single Ascending Dose Study in Healthy Male Subjects" (PDF). Verona Pharma plc. Retrieved 25 January 2016.
  15. ^ Welsh, Emma. "Caffeine for asthma". Cochrane Airways Group. Retrieved 25 January 2016.
  16. ^ a b c d e "Part C. Multiple Ascending Dose in moderate, stable COPD Subjects" (PDF). Verona Pharma plc. Retrieved 25 January 2016.
  17. ^ a b c d "The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia". American Journal of Physiology - Lung Cellular and Molecular Physiology (Published 6 November 2015). Retrieved 25 January 2016.
  18. ^ a b "Completion of patient enrolment in two RPL554 Phase IIa studies" (PDF). Verona Pharma plc. Retrieved 25 January 2016.
  19. ^ a b c "Part B. Multiple Ascending Dose Study in Healthy Male Subjects" (PDF). Verona Pharma plc. Retrieved 25 January 2016.
  20. ^ "Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials". The Lancet Respiratory Medicine. Retrieved 25 January 2016.
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