GB2594480A - New treatment - Google Patents

Abstract

Ensifentrine, or a pharmaceutically acceptable acid addition salt thereof, for use in treating coronavirus disease 2019 (COVID-19) in a subject. Ensifentrine may be used to alleviate or ameliorate the respiratory symptoms of COVID-19. Ensifentrine may increase forced expiratory volume in 1 second in the subject. Ensifentrine may be administered by inhalation, particularly via the use of a nebuliser or a pressurised meter dose inhaler. Ensifentrine, or a pharmaceutically acceptable acid addition salt thereof, for use in reducing shortness of breath in a subject with COVID-19 is also disclosed. Methods of treating COVID-19 using ensifentrine and use of ensifentrine in the manufacture of a medicament for the treatment of COVID-19 are also disclosed. A composition comprising ensifentrine, or a pharmaceutically acceptable acid addition salt thereof, and a second active agent selected from antiviral agents of anti-malarial agents is disclosed. An antiviral agent of anti-malarial agent in the treatment for use in the treatment of COVID-19 in a subject in combination with ensifentrine, or a pharmaceutically acceptable acid addition salt thereof is also disclosed.

Description

NEW TREATMENT

FIELD OF THE INVENTION

The present invention relates to the treatment of coronavirus disease 2019 (COVID- 19). The invention also relates to a combination of ensifentrine and an antiviral or anti-malarial agent.

BACKGROUND OF THE INVENTION

COVID-19 is a highly infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-00V-2) and characterised by a number of symptoms, most notably cough, shortness of breath and fever. The lungs are the organ most affected by COVID-19 and severe cases can progress to viral pneumonia and even death.

No cure for COVID-19 has been identified and there is no available vaccine. There is therefore a significant need to develop effective treatments for the symptoms of COVID-19 and reduce the severity of the illness and associated mortality. It is particularly important to develop treatments for the symptoms of COVID-19 which affect the pulmonary system.

Ensifentrine (N-(2-{(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,64rimethylphenyl)imino]-6, 7-dihydro-2H-pyrimido[6,1-a]isoguinolin-3(4H)-yl}ethyOurea; also known as RPL554) is 20 a dual P DE3/PDE4 inhibitor and is described in WO 00/58308 Al. The structure of ensifentrine is shown below.

N

N N H 2

N

As a combined PDE3/PDE4 inhibitor, ensifentrine has both bronchodilatory and anti-inflammatory activity, and has shown to increase ciliary beat frequency via stimulation of CFTR. Ensifentrine is known to be effective in the treatment of chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis (Franciosi et al, Lancet Respir Med. 2013,1:714-27; Turner et a/, Am J Physiol Lung Cell Mol Physiol 310: L59-L70, 2016; Singh eta!, Eur Respir J. 2018, 52: 1801074; and Singh et al, Respir Res. 2020, 10; 21(1); 47).

Some commonly used bronchodilators have been found to be ineffective in patients with lung diseases who are exposed to viral infections. Salbutamol is commonly used as a bronchodilator in the treatment of asthma. Donovan eta!, Clin Sci (Lond), 2016 May 1; 130(10): 829-837 reports that the relaxant effect of salbutamol in mouse lung tissue infected with influenza was transient and not well-maintained. However, ensifentrine is effective in treating COVID-19 symptoms.

SUMMARY OF THE INVENTION

It is a finding of the present invention that ensifentrine is effective in treating COVID- 19, and in particular in treating the symptoms of ensifentrine affecting the lower respiratory tract.

The invention accordingly provides a compound for use in treating coronavirus disease 2019 (COVID-19) in a subject, wherein the compound is ensifentrine or a pharmaceutically acceptable acid addition salt thereof.

Ensifentrine is effective in reducing shortness of breath in patients. The invention also provides a compound for use in reducing shortness of breath in a subject with coronavirus disease 2019 (COVID-19), wherein the compound is ensifentrine or a pharmaceutically acceptable acid addition salt thereof.

The treatment of COVID-19 by ensifentrine can be enhanced by adjunct therapy with an antiviral or anti-malarial agent. The invention therefore further provides a composition comprising (i) a compound which is ensifentrine or a pharmaceutically acceptable acid addition salt thereof and (ii) a second active agent which is an antiviral agent or an anti-malarial agent.

The invention also provides a product comprising (i) a compound which is ensifentrine or a pharmaceutically acceptable acid addition salt thereof and (ii) a second active agent which is an antiviral agent or an anti-malarial agent, for simultaneous, sequential or separate use in the treatment of COVID-19.

Also provided by the invention is a compound which is ensifentrine or a pharmaceutically acceptable acid addition salt thereof for use in the treatment of COVID-19 in a subject in combination with a second active agent which is an antiviral agent or an anti-malarial agent.

The invention further provides a second active agent which is an antiviral agent or an anti-malarial agent for use in the treatment of COVID-19 in a subject in combination with a compound which is ensifentrine or a pharmaceutically acceptable acid addition salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compound is ensifentrine or a pharmaceutically acceptable acid addition salt thereof. Typically, the compound is ensifentrine ensifentrine free base).

The subject to be treated is typically a mammal. Preferably, the subject is a human.

The compound is for use in treating coronavirus disease 2019 (COVID-19). As used herein, treating COVID-19 includes alleviating, ameliorating or preventing aggravation of the symptoms of COVID-19. Typically treating COVID-19 comprises alleviating or ameliorating the symptoms of COVID-19. Treating COVID-19 may also include prolonging survival, increasing survival rates, shortening the time to recovery, or preventing deterioration, in subjects with COVID-19.

Ensifentrine is an effective bronchodilator and agent for reducing bronchial inflammation. Treating COVID-19 typically comprises treating the respiratory symptoms of COVID-19 in the subject. Respiratory symptoms are those associated with the respiratory and pulmonary system and include shortness of breath, difficulty breathing, breathlessness, cough, sputum and mucous production, bronchial inflammation (bronchitis), hypoxia and pneumonia. Typically, the respiratory symptom treated is shortness of breath. The respiratory symptoms of COVID-19 are typically the symptoms of COVID-19 affecting the lower respiratory tract.

The compound typically increases forced expiratory volume in 1 second (FEVi) in the subject. For instance, administration of the compound may increase FEVi in the subject by at least 5%, by at least 10% or by at least 15% compared with the FEVi of the subject prior to treatment. For instance, the mean FEVi of the patient in the hour following treatment with the compound may be increased compared with the mean FEVi of the patient in the hour preceding the treatment with the compound.

The compound may reduce viral-induced inflammation in the subject. The compound may reduce viral load in the patient.

The subject has COVID-19 and as such experiences one or more symptoms of COVID-19. Typically, the subject is suffering from shortness of breath, cough, hypoxia or pneumonia. More typically, the subject is suffering from shortness of breath. Shortness of breath (dyspnea) is typically characterised by one or more of difficulty breathing, disordered breathing, short or inadequate breaths, and uncomfortable awareness of breathing. The subject may be fitted to a ventilator at the time the compound is administered.

Treating COVID-19 may comprise reducing hypoxia in the subject, for instance by improving dyspnea in the subject. Treating COVID-19 may comprise improving clearance of the viral infection from the lungs in the subject, for instance by increased mucociliary clearance or by directly decreasing viral load. Treating COVID-19 may comprising reducing or delaying the need for mechanical ventilation in the subject.

The symptoms of COVID-19 and mortality of COVID-19 are typically worsened in those subjects with a pre-existing health condition or an underlying illness. The subject with COVID-19 may have a pre-existing condition. The pre-existing condition is typically hypertension, ischaemic heart disease, chronic lower respiratory disease (for instance COPD or asthma), obesity or diabetes. The subject may have a body mass index (BMI) of greater than or equal to 40 kg/m2, where the BMI is calculated as the body mass in kilogrammes divided by the square of the body height in metres.

Increased mortality is seen for COVID-19 in older patient groups. The subject is typically at least 50 years old, at least 60 years old or at least 70 years old. The subject may alternatively be a younger patient, for instance 40 years old or less.

COVID-19 affects both male and female patients. However, survival rates are typically lower in male patients. The subject may therefore be male.

It has been found that COVID-19 in some cases disproportionately affects subjects of different ethnicities. The subject may self-identify as an ethnicity which is Black, African, Caribbean, Asian (including Indian, Pakistani, Bangladeshi and Chinese), Arab, American Indian or a mixed or multiple ethnic group.

The compound is typically administered by inhalation. This means that the compound is delivered directly to the lungs. The compound can alternatively be administered orally or parenterally, for instance if the subject is unable to inhale a formulation comprising the compound.

When administered by inhalation, the compound may be administered by a nebuliser, a pressurised metered dose inhaler or a dry powder inhaler. Typically, the compound is administered by a nebuliser or a pressurised metered dose inhaler (pMDI). The pMDI may be used with a spacer.

Nebulisers aerosolise a liquid pharmaceutical composition into an aerosol that is inhaled into a subject's respiratory tract. It can be advantageous to administer the compound to the subject using a nebuliser because the nebulised formulation may be passively inhaled during respiration without requiring forceful inhalation by a subject with compromised breathing.

Examples of nebulisers include a soft mist nebuliser, a vibrating mesh nebuliser, a jet nebuliser and an ultrasonic wave nebuliser. Suitable nebuliser devices include the Philips lnebTM (Philips), the Philips SideStream (Philips), the AeroNeb® (Philips), the Philips Inn°Spire Go (Philips), the Pan i LC Sprint (Pan GmbH), the AERxRTM Pulmonary Delivery System (Aradigm Corp) and the Pan LC Plus Reusable Nebuliser (Pan i GmbH).

The compound is typically formulated in a formulation suitable for administration by inhalation. For instance, a formulation comprising the compound and a diluent may be administered to the subject. The formulation typically comprises a suspension of particles of ensifentrine or a pharmaceutically acceptable acid addition salt thereof and a diluent. The diluent may be water or a hydrofluoroalkane propellant. The particles of ensifentrine or a pharmaceutically acceptable acid addition salt thereof typically have a Dv50 (median particle size by volume) of from 0.5 pm to 5.0 pm, for instance as measured by laser diffraction.

The compound is administered in an amount which treats COVID-19, for instance by alleviating or ameliorating the respiratory symptoms of COVID-19. An effective amount of ensifentrine is typically from about 0.001 mg/kg to 50 mg/kg for a single dose, for instance from 0.01 mg/kg to 1 mg/kg for a single dose. An effective amount of ensifentrine may be a dose of from about 0.1 mg to about 500 mg, or from about 0.1 mg to about 100 mg, or from about 0.1 mg to about 6 mg. A single dose of ensifentrine may be from 0.3 mg to 3 mg.

Typically, from 0.1 mg to 100 mg of the compound is administered once, twice or three times daily. The compound may be administered twice daily, once in the morning and once in the evening.

The compound may be for use in reducing shortness of breath in a subject with coronavirus disease 2019 (COVID-19). Reduction in shortness of breath may be measured by any suitable technique, for instance by carrying out a subject questionnaire before and after treatment or by measuring a change in respiration in the subject by spirometry or another technique. The compound typically increases forced expiratory volume in 1 second (FEV1) in the subject.

The invention relates to a method of treating coronavirus disease 2019 (COVID-19) in a subject, wherein the method comprises administering a therapeutically effective amount of a compound which is ensifentrine or a pharmaceutically acceptable acid addition salt thereof to the subject.

The invention also relates to use of a compound for the manufacture of a medicament for the treatment of coronavirus disease 2019 (COVID-19), wherein the compound is ensifentrine or a pharmaceutically acceptable acid addition salt thereof.

Ensifentrine may be used in combination with a second active agent which is useful in the treatment of respiratory disorders, for instance a beta2-agonist or a muscarinic antagonist. The beta2-agonist or muscarinic antagonist may be short-acting or long-acting. For instance, ensifentrine may be used in combination with a short-acting beta-agonist (SABA), a long-acting beta-agonist (LABA), a short-acting muscarinic antagonist (SAMA), a long-acting muscarinic antagonist (LAMA), a SABA/SAMA combination or a LABA/LAMA combination.

Ensifentrine has been found to be effective in treating COVID-19, a viral infection caused by the SARS-CoV-2 virus. Ensifentrine can accordingly be advantageously be administered in combination with an agent which treats the viral cause of COVID- 19. As such, the compound which is ensifentrine or a pharmaceutically acceptable acid addition salt thereof may be used in combination with a second active agent which is an antiviral agent or an anti-malarial agent.

Antiviral agents are compounds which treat or prevent viral infection, for instance by interfering with the lifecycle of a virus. Examples of antiviral agents include abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, baloxavir marboxil, boceprevir, cidofovir, cobicistat, daclatasvir, darunavir, delavirdine, descovy, didanosine, dolutegravir, doravirine, ecoliever, edoxudine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, fomivirsen, fosamprenavir, foscarnet, ganciclovir, ibacitabine, ibalizumab, idoxuridine, imunovir, indinavir, inosine, interferon type I, interferon type II, interferon type III, lamivudine, letermovir, lopinavir, loviride, maraviroc, methisazone, moroxydine, nelfinavir, nevirapine, nitazoxanide, oseltamivir, peginterferon, penciclovir, peramivir, pleconaril, podophyllotoxin, pyramidine, raltegravir, remdesivir, ribavirin, rilpivirine, rimantadine, ritonavir, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, telbivudine, tenofovir alafenamide, tenofovir disoproxil, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, umifenovir, valaciclovir, valganciclovin vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir and zidovudine.

Anti-malarial agents are those agents which are used to prevent or treat malaria.

Examples of anti-malarial agents include ailanthone, 8-aminoquinoline, amodiaquine, aplasmomycin, artelinic acid, artemether, artemisinin, artemotil, arterolane, artesunate, atovaquone, azithromycin, chloroquine, chlorproguanil, cipargamin, codinaeopsin, cotrifazid, cryptolepine, cycloguanil, dihydroartemisinin, doxycycline, halofantrine, hydroxychloroquine, lumefantrine, mefloquine, mepacrine, neurolenin b, nitidine, olivacine, oroidin, pamaquine, piperaquine, primaquine, proguanil, pyrimethamine, pyronaridine, quinine, semapimod, spiroindolone, sulfadoxine, sulfalene, tafenoquine and voacamine.

Typically, the second active agent is an antiviral agent which is favipiravir, lopinavir, ritonavir or remdesivir. The second active agent may be an anti-malarial agent which is chloroquine, hydroxychloroquine or mefloquine, preferably hydroxychloroquine.

The combination of the compound and the second active agent may be a fixed combination where the compound and the second active agent are formulated in a single composition in fixed proportions. The combination may alternatively be a free combination where the compound and the second active agent are separately formulated.

Typically, the composition of the invention is a free combination in which the compound ensifentrine and the second active agent are separately formulated. For instance, the ensifentrine or a pharmaceutically acceptable acid addition salt thereof may be in a formulation suitable for administration by inhalation and the second active agent may be in a formulation suitable for parenteral or oral administration.

The compound and the second active agent may be adminsitered simultaneously or separately. For instance, the second active agent may be adminstered orally or parenterally at one time and at a later time the compound may be adminstered by inhalation.

The invention is described in more detail by the following Examples.

EXAMPLES

The following protocol is carried out to conduct the efficacy of ensifentrine in treating COVID-19. It is found that ensifentrine is effective in treating the symptoms of COVID-19 such as shortness of breath.

Objectives Primary Objective * To evaluate the effect of ensifentrine on lung function in patients with COVID19 Secondary Objectives * To evaluate the effect of ensifentrine on oxygen saturation in hospitalized patients with COVID-19.

* To evaluate the effect of ensifentrine on COVID-19 signs and symptoms.

* To evaluate the effect of ensifentrine on use of supplemental oxygen, mechanical ventilation and time to hospital discharge.

Safety Objective To evaluate the safety and tolerability of ensifentrine in patients with COVID-19. Endpoints Primary Endpoint * Change from baseline in lung function [FEVi 1-hour post-morning dose]. 20 Secondary Endpoints * Time to normalization of oxygen saturation [Sp02/Fi02 >94% for 24h].

* Time to improvement in oxygenation for at least 48 hours [Increase in Sp02/Fi02 of 10% or greater compared to the nadir Sp02/Fi02].

* Change from baseline in Pa02/Fi02 ratio.

* Change from baseline in COVID-19 signs and symptoms [time to normalization of fever, resolution of breathlessness (E-RS), resolution of cough (E-RS), chest symptoms (E-RS)].

* Time to hospital discharge.

* Time to mechanical ventilation.

* Time to ICU admission.

* Incidence of mechanical ventilation or ICU admission.

* Incidence and time to hypercapnic respiratory failure.

* Time to discontinuation of supplemental oxygen.

* Respiratory mechanics on the ventilator -ventilator settings, Fi02, PEEP, peak pressure, static compliance, plateau pressure, auto-PEEP.

Safety Endpoints * Incidence of Adverse Events (AEs).

* Vital Signs.

Study Design and Methodology A single center, randomized, open-label, parallel group, controlled study is carried out to determine the efficacy and safety of ensifentrine 3.0 mg twice daily (BID) administered via pMDI added on to standard of care compared to subjects receiving standard of care alone in patients up to 80-years of age hospitalized with COVID-19.

Patients randomized to ensifentrine receive this medication twice daily in the morning and evening for up to 19 days or until discharge, whichever is first. Lung function is assessed approximately 1-hour post dose for patients who are capable of performing the manoeuvre. Daytime pulse oximetry is recorded every 4 hours on assessment days. Arterial blood gas is assessed in patients who require an A-line.

Study assessments is performed every other day between randomization (Day 1) and Day 19 or discharge.

Patients have a confirmed diagnosis of Severe Acute Respiratory Syndrome Coronavirus (SARS-00V-2) infection confirmed by polymerase chain reaction (PCR) test 4 days before randomization.

Treatment Period Approximately 45 patients meeting the criteria for inclusion and none of the criteria for exclusion at randomization are enrolled until to hospital discharge or up to 19 days of treatment, whichever comes first.

During the treatment period, patients complete all assessments and procedures as outlined in the Schedule of Assessments for up to 19 days or hospital discharge, whichever is first. Patients completing treatment complete a Follow-Up contact (telephone or visit as required) within 4 to 10 days of the last scheduled study visit.

Schedule of Assessments Procedures for Patients Completing the Study Tests and Procedures Screening/baseline Day 1 (Rand) Day 3 Day 5 Day 7 Day 9 Days 11,13, 15, 17 and 19 Follow up 0 to 4 days prior to Day 1 +/-1 day +/-1 day +/-1 day +/-1 day +/-1 day 4 to 10 Days after Day 19 or Discharge VO V1 V2 V3 V4 V5 V6 to V10 Written Informed Consent X Demographics X Medical History X Physical Exam X Inclusion/Exclusion Criteria X Chest X-ray X Screening Spirometry x Register Visit in IVRS X X X X X X X X Randomization x Study Medication Dosing (morning and evening) * P. pMDI Observation & Training X X Pulse oximetry (collected every 4 hours) X X X X X X X Arterial oxygen (in patients with A-line) x x x x x x x Spirometry 1 hour post dose2 X X X X X X Vital Signs (blood pressure, heart rate, temperature) X X X X X X X Concomitant Medication Assessment X' X X X X X X AE Assessment x * ^ Safety Laboratory Tests Haematology, Chemistry (non-fasting), Urine Analysis, Serum Pregnancy Test (as applicable) X Questionnaires x x x x x x Dispense Study Medication x x x x Collect Study Medication x x x x x Assess Study Medication Compliance X x x x x Main Criteria for Eligibility Inclusion Criteria * * * * Informed Consent Capable of giving informed consent indicating that they understand the purpose of the study and study procedures and agree to comply with the requirements and restrictions listed in the informed consent form and in this protocol.

Age: Patient must be less than or equal to 80 years of age at the time of informed consent.

Sex: Males are eligible to participate or females of non-childbearing potential or who have a negative pregnancy test at screening are eligible to participate. SARS-CoV-2 Diagnosis and Symptoms: o Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test 4 days before randomization.

o Currently hospitalized with fever defined as temperature 36.6 °C armpit, 37.2 °C oral, or a. 37.8 °C rectal at some time during the prior 72 hours.

o Peripheral capillary oxygen saturation (5p02) 94% on room air at screening.

Exclusion Criteria Current Condition or Medical History: * Participation in any other clinical trial of an experimental treatment for COVID19.

* Evidence of multiorgan failure.

* Requiring mechanical ventilation at screening.

* Alanine Aminotransferase (ALT) or aspartate am inotransferase (AST) > 5 X upper limit of normal (ULN).

* Creatinine clearance < 30 mL/min.

* Pregnancy or lactation.

Duration of Treatment Approximately 30 patients receive treatment for up to 19 days. An additional 15 patients will receive standard of care over for up to 19 days.

Study Treatments and Administration Patients are randomized 2:1 to receive the following study arms: * Treatment Arm 1: Ensifentrine MDI; 3.0 mg BID * Treatment Arm 2: Standard of care Dosing Patients self-administer 6 actuations (puffs) pMDI (0.5 mg per actuation) with a commercially available spacer device for a total dose of 3 mg at each dosing event.

Dosing with the pMDI study medication will be performed twice daily approximately 12 hours apart in the morning and evening.

Ensifentrine Ensifentrine pMDI is supplied as a pressurised canister with a plastic actuator.

Ensifentrine is formulated with the propellant HFA-134a. Each inhaler will be packed and labelled in kits as three inhalers in a carton and labelled with a unique medication identification (ID) number. Appropriate study centre personnel will dispense the appropriate kit medication ID number according to the randomisation schedule and kit list.

Claims (23)

1. CLAIMS1. A compound for use in treating coronavirus disease 2019 (COVID-19) in a subject, wherein the compound is ensifentrine or a pharmaceutically acceptable acid addition salt thereof.
2. 2. A compound for use according to claim 1, wherein treating COVID-19 in the subject comprises alleviating or ameliorating the respiratory symptoms of COVID-19 in the subject.
3. 3. A compound for use according to claim 1 or claim 2, wherein the compound increases forced expiratory volume in 1 second (FEV-1) in the subject.
4. 4. A compound according to any one of the preceding claims, wherein the subject is suffering from shortness of breath, cough or pneumonia.
5. 5. A compound for use according to any one of the preceding claims, wherein the subject is suffering from shortness of breath.
6. 6. A compound for use according to any one of the preceding claims, wherein the subject has a pre-existing condition.
7. 7. A compound for use according to claim 6, wherein the pre-existing condition is hypertension, ischaemic heart disease, chronic lower respiratory disease, obesity or 25 diabetes.
8. 8. A compound for use according to any one of the preceding claims, wherein the subject has a body mass index (BMI) of greater than or equal to 40 kg/m2
9. 9. A compound for use according to any one of the preceding claims, wherein the subject is at least 70 years old.
10. 10. A compound for use according to any one of the preceding claims, wherein the subject is male.
11. 11. A compound for use according to any one of the preceding claims, wherein the subject self-identifies as an ethnicity which is Black, African, Caribbean, Asian, Arab, American Indian or a mixed or multiple ethnic group.
12. 12. A compound for use according to any one of the preceding claims, wherein the compound is administered by inhalation.
13. 13. A compound for use according to claim 12, wherein the compound is administered by a nebuliser or a pressurised metered dose inhaler
14. 14. A compound for use according to any one of the preceding claims, wherein 15 from 0.1 mg to 100 mg of the compound is administered once, twice or three times daily.
15. 15. A compound for use in reducing shortness of breath in a subject with coronavirus disease 2019 (COVID-19), wherein the compound is ensifentrine or a pharmaceutically acceptable acid addition salt thereof.
16. 16. A compound for use according to claim 15, wherein the compound increases forced expiratory volume in 1 second (FEVi) in the subject.
17. 17. A method of treating coronavirus disease 2019 (COVID-19) in a subject, wherein the method comprises administering a therapeutically effective amount of a compound which is ensifentrine or a pharmaceutically acceptable acid addition salt thereof to the subject.
18. 18. Use of a compound for the manufacture of a medicament for the treatment of coronavirus disease 2019 (COVID-19), wherein the compound is ensifentrine or a pharmaceutically acceptable acid addition salt thereof.
19. 19. A composition comprising (i) a compound which is ensifentrine or a pharmaceutically acceptable acid addition salt thereof and (ii) a second active agent which is an antiviral agent or an anti-malarial agent.
20. 20. A composition according to claim 19 wherein the second active agent is: an antiviral agent which is favipiravir, lopinavir, ritonavir or remdesivir; or an anti-malarial agent which is chloroquine, hydroxychloroquine or mefloquine.
21. 21. A product comprising (i) a compound which is ensifentrine or a pharmaceutically acceptable acid addition salt thereof and (ii) a second active agent as defined in claim 19 or claim 20, for simultaneous, sequential or separate use in the treatment of COVID-19.
22. 22. A compound which is ensifentrine or a pharmaceutically acceptable acid addition salt thereof for use in the treatment of COVID-19 in a subject as defined in any one of 1 and 4 to 11 in combination with a second active agent as defined in claim 19 or claim 20.
23. 23. A second active agent as defined in claim 19 or claim 20 for use in the treatment of COVID-19 in a subject as defined in any one of 1 and 4 to 11 in combination with a compound which is ensifentrine or a pharmaceutically acceptable acid addition salt thereof.