Patent Application
20230149504
The present invention concerns the drug alisporivir for use in the treatment of a human patient suffering of COVID-19 infections and for prevention of a human patient from suffering of COVID-19 infections.
Coronaviruses are a large family of viruses that usually cause medium to moderate upper-respiratory tract illnesses, like the common cold, in people. However, three times in the 21st century coronavirus outbreaks have emerged from animal reservoirs to cause severe disease and global transmission concerns. There are hundreds of coronaviruses, most of which circulate among animals including pigs, camels, bats and cats. Sometimes those viruses jump to humans (process called a spillover event) and can cause disease. Seven coronaviruses are known to cause human disease, four of which are medium: viruses 229E, 0043, NL63 and HKU1.
Three of the coronaviruses can have more serious outcomes in people, and those diseases are SARS (severe acute respiratory syndrome), caused by coronavirus known as SARS-Cov-1, which emerged in late 2002 and disappeared by 2004; MERS (Middle East respiratory syndrome), which emerged in 2012 and remains in circulation in camels; and the new coronavirus disease 2019 (COVID-19), which emerged in December 2019 from China and a global effort is under way to contain its spread. COVID-19 is caused by the coronavirus known as SARS-CoV-2.
The WHO reports that human-to-human transmission is occurring with a preliminary RO estimate of 1.4-2.5. Current estimates of the incubation period of the virus range from 2-14 days, and the virus seems to be transmitted mainly via respiratory droplets when people sneeze, cough, or exhale.
Typical symptoms of COVID-19 include fever, cough, difficulty breathing, muscle pain and tiredness. More serious cases develop severe pneumonia, acute respiratory distress syndrome, sepsis and septic shock through bacterial superinfections. Generally, older people and those with underlying conditions (such as hypertension, heart disorders, diabetes, liver disorders, and respiratory diseases) are expected to be more at risk of developing severe symptoms. The evidence from analyses of cases to date is that COVID-19 infection causes medium disease (i.e. non-pneumonia or medium pneumonia) in about 80% of cases and most cases recover; 14% have more severe disease and 6% experience critical illness.
Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV/SARS-CoV-2 shares the highest nucleotide sequence identity with SARS-CoV-1 (79.7%). Specifically, the envelope and nucleocapsid proteins of 2019-nCoV/SARS-CoV-2 are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV.
Alisporivir (INN) ([D-MeAla]3-[EtVal]4-CsA; CAS RN 254435-95-5) is cyclic undecapeptide which is synthesized from cyclosporine A (WO 00/01715). It differs from parent cyclosporine A, with sarcosine replaced by Me-alanine at position 3, with leucine replaced by valine at position 4, and with the nitrogen being N-ethylated instead of N-methylated. These modifications enhance the binding affinity of alisporivir for cyclophilins while abolishing its binding to calcineurin and thus immunosuppressive activity.
Alisporivir clears HCV replicon cells when used alone or in combination with direct-acting antivirals, such as protease or polymerase inhibitors (Paeshuyse J et al, Hepatology 2006: 43, 761-770; Gallay et al., Drug Design, Development and Therapy 2013:7 105-115) and has been tested in more than 2000 patients suffering of chronic hepatitis C (Stanciu C et al, Exp Op Pharmacother, 2019:20 379-384). Cyclophilin A is the principal cyclophilin that is essential for HCV viral replication, and its blockade underlines the anti-HCV activity of cyclophilin inhibitors.
Alisporivir shows preclinical activities against some coronaviruses such as Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-1), Middle East Respiratory Syndrome virus (MERS-CoV), feline Coronavirus (FCoV), or Mouse Hepatitis Virus (MHV-LUC) (WO 2015/161908), or HCoV-229E (Ma-Lauer et al., Antiviral Research 173 (2020) 104620). So far, the EC50 of alisporivir in vitro against different SARS-Cov-1 ranged between 2 and 10 microM, 10.-50 fold higher than for HCV replicon (de Wilde A H et al, Virus Research, 2017:228, 7-13). The strong involvement of cyclophilin A in the replication of CoV-1 is still controversial and its possible role remains unknown for SARS-CoV-2.
Considering the rapid and global spread of SARS-CoV-2 and the severity of COVID-19 infections and theft high mortality, there is an urgent need to provide the clinician with a medication for use in the treatment of human patient suffering of COVID-19 infections.
The aim of the present invention is to provide such a medication that reduces the SARS-CoV-2 viral load, improves the clinical symptoms, reduces the need for Intensive Care Unit admission and procedures and ultimately help curing the infection and reduce the mortality associated with the COVID-19 infection.
It has been surprisingly found that alisporivir can be used for the treatment of a human patient suffering of COVID-19 infections.
The present invention concerns the drug alisporivir for use in treatment of a human patient suffering of COVID-19 infections, initially known as Coronavirus disease 2019 and for prevention of a human patient from suffering of COVID-19 infections. These infections are due to SARS-CoV-2, formerly called 2019-nCoV.
The present invention further concerns the drug alisporivir for use in prevention of a human patient from suffering of COVID-19 infections once a positive test for SARS-CoV has been performed.
The present invention concerns also alisporivir for use in the treatment of human patients suffering of COVID-19 infections for reducing SARS-CoV-2 viral load. Said SARS-CoV-2 is located in the airways, mainly in the lower airways, in particular in lung.
According to the present invention, alisporivir is administered at a total dose comprised between 200 mg and 1500 mg per day. For example, alisporivir is administered at a total dose of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg or 1500 mg per day. Preferably alisporivir is administered at a total dose comprised between 400 mg and 1200 mg per day. More preferably alisporivir is administered at a daily dose comprised between 800 mg and 1200 mg per day. For example, alisporivir is administered at a daily dose of 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg or 1200 mg.
Alisporivir is administered once a day (Quaque Die, QD), or twice a day (Bis In Die, BID), or three times a day (Ter In Die, TID), or four times a day (Quater In Die, QID).
Preferably, alisporivir is administered at a daily regimen of 800 mg to 1200 mg as total dose per day, administered one or two times a day (i.e. 400 mg to 600 mg Bis In Die (BID)).
Alisporivir is administered through oral route or naso-gastric intubation route for patients not able to swallow voluntarily due to their medical condition.
When alisporivir is administered through oral route, the following pharmaceutical formulations may be used:
According to the present invention, alisporivir is administered daily for up to 21 days, preferably up to 14 days.
According to the present invention, the patients are patients suffering from medium to severe COVID-19 infections. Definitions of different degrees of severity of illness can be found in WHO Interim guidance, Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected, dated Mar. 13, 2020.
In particular, to be eligible for the treatment, patients with medium/severe COVID-19 infections should meet the following criteria:
and at least one of the following criteria:
As evident, prevention of a human patient from suffering of COVID-19 infections includes reducing the risk of the patient suffering from medium to severe COVID-19 infections.
The present invention will be explained in more detail with the following figures and examples.
VeroE6 cells were infected with SARS-Cov-2 (isolate from patient infected in Paris), alisporivir diluted in culture medium was added at different concentrations and the cells were incubated for five days in a humidified incubator at 37° C. and 5% Co2.
The antiviral effect was assessed by measuring the SARS-Cov-2 RNA relative quantities in the cell supernatant. For cytotoxicity, cells were incubated with serial alisporivir dilutions in the absence of virus challenge. Data analysis and statistics were performed with Prims and SigmaPlot software.
The Half Maximal Effective Concentration (EC50) of alisporivir on the percentage of SARS-Cov-2 RNA production in cell culture supernatant was 0.54+/−0.06 microM. The compound was not cytotoxic at 20 microM. The index of selectivity (CC50/EC50) of alisporivir was >37.
In
The goal of this study was to assess the antiviral properties of alisporivir against SARS-CoV-2, with the objective of generating the preclinical proof of concept of antiviral effectiveness required to start a clinical trial in patients with COVID-19.
The antiviral effectiveness of increasing concentrations of alisporivir was measured in Vero E6 cells infected for 2 h with a clinical isolate of SARS-CoV-2 at a multiplicity of infection (MOI) of 0.02 (
Alisporivir reduced SARS-CoV-2 RNA production in a dose-dependent manner: the 50% effective concentration (EC50) was 0.46+/−0.04 μM, and the EC90 was 3.10+/−1.40 μM. The maximum viral RNA reduction was 2 log 10 at 5 μM. Alisporivir was not cytotoxic at the effective concentration, with a 50% cytotoxic concentration (CC50s) of more than 20 μM and a therapeutic index of more than 43.
The anti-SARS-CoV-2 effectiveness of alisporivir was confirmed by immunofluorescence. Vero E6 cells were infected by SARS-CoV-2 at an MOI of 0.4 for 2 h in the presence of increasing concentrations of alisporivir (1, 5 and 10 μM). After virus removal, infected cells were incubated for 24 h in the presence of alisporivir and immunostained with an anti-double-stranded-RNA (dsRNA) antibody. Infected cells were quantified using ImageJ software. Alisporivir reduced the number of SARS-CoV-2-infected cells in a dose-dependent manner, and complete inhibition was attained at 10 μM (
The aim of this study is to evaluate the efficacy, safety, tolerability, of alisporivir in combination of Standard of Care (SOC) as compare to SOC alone for the treatment of hospitalized patients with medium to severe infections due to SARS-CoV-2 (COVID-19 infections), excluding patients with Acute Respiratory Distress Syndrome and/or need for mechanical ventilation. The study objectives are a) to evaluate the reduction in SARS-CoV-2 viral load in naso-pharyngeal swabs at Day7 in patients treated with alisporivir in combination with SOC compared to patients treated with SOC alone in patients hospitalized for medium to severe COVID-19 infections, b) to compare the percentage of patients on mechanical ventilation at Day 14.
The study population is hospitalized adults with a diagnosis of COVID-19 infection in its early stage (symptoms onset and COVID-19 RT-PCR test positive in naso-pharyngeal swab within the last 48 hours. A total of 81 subjects are enrolled and randomized 2:1 in one of the two treatment arms (54 subjects in the alisporivir combination with SOC treatment arm and 27 subjects in the SOC treatment arm).
Alisporivir is administered at a dose of 600 mg p.o. BID from Day 1 to Day 14 with the possibility to make dose adjustments, the dosing regimen for alisporivir of 600 mg twice daily for 14 days being selected based on available PK and safety results in healthy volunteers and patients infected with Hepatitis C Virus (HCV), lung penetration data obtained in rat studies and in vitro activity of alisporivir against Sars-CoV-2.
During a weekly Safety Monitoring Committee meeting, decision is taken on early stopping for futility or safety. If a significant beneficial effect of alisporivir is observed, patients on SOC alone could be switched to the alisporivir+SOC arm.
Eligible patients have the onset of symptoms AND a laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) in a naso-pharyngeal swab collected 48 hours prior to randomization. All patients have the RT-PCR COVID19 test based on the same validated method for the whole duration of study in order to ensure consistency and reliability. Sample collection and processing for determining the viral load are done in a standardized and consistent manner in order to decrease variability between samples that might influence the viral load. It is envisaged to use a quantitative method assessing the average viral load/infected host cell, accounting the number of cells from each swabbing sample and the viral RNA copies/cell (“Droplet Digital PCR”).
While it has been shown that alisporivir can be administered safely up to 48 weeks according to previous studies in Chronic Hepatitis C, alisporivir is administered up to 14 days with the possibility to increase the duration of administration to 21 days or more, as required by the clinical and safety parameters.
Participants will be randomized 2:1 into one of the following treatment arms:
For the SOC, the investigator chooses the treatment based on locally accepted regimen protocols for patients care and select agents based on the underlying diagnosis and the severity of Covid-19 infection. Additions or changes to SOC are allowed during the patient participation in the study based on patient status and evolution, including antibiotics (excepting Azithromycin due to drug-drug interaction with Alisporivir). Prohibited medications are all anti-viral agents, immunomodulators including Interferons and corticosteroids, Azithromycin, mABs (e.g. tocilizumab), ACE inhibitors, immunoglobulins as well as any experimental drugs.
De-escalation (discontinuing a SOC agent if no longer needed—e.g. administration of oxygen) is allowed and is not considered a failure. Treatment beyond 14 days is considered a treatment failure.
SARS-CoV-2 viral load assessments and Clinical Assessments will occur daily from Day 1 to Day 14 and then until discharge from hospital.
Participants are screened within 48 hours prior to dosing. All participants are treated with alisporivir+SOC or SOC alone up to 14 days. The maximum duration of participation for each participant is approximately 32 days (2-day screening period, 14-day treatment period, and 16-day follow-up period). The patients remain hospitalized for the whole duration of treatment and discharged from hospital based on the investigator's assessment of their status.
The inclusion criteria are, in particular, the followings:
The exclusion criteria are, in particular, the followings:
Assessment of clinical status change based on Percentage of subjects reporting each severity rating on an 8-point ordinal scale [Time Frame: daily from Day1 to Hospital Discharge and then at FUP visits]
The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows:
To be eligible for study enrolment and randomization, a subject must have at least one prior test positive for SARS-CoV-2 within 48 h. Viral load in nasopharyngeal swabs is performed daily until discharge from the hospital/withdrawal from the study and at the FUP visits. All patients have the RT-PCR COVID19 test based on the same validated method for the whole duration of study in order to ensure consistency and reliability. Sample collection and processing for determining the viral load are done in a standardized and consistent manner in order to decrease variability between samples that might influence the viral load. It is envisaged to use a quantitative method assessing the average viral load/infected host cell, accounting the number of cells from each swabbing sample and the viral RNA copies/cell.
The primary efficacy endpoints are the proportion of patients achieving Viral Load Response Rate (VLRR) response at Day 7, Viral Load Response being defined as an intra patient decrease of 1.5 in log10 viral load compared to baseline.
The secondary efficacy endpoints are:
This is a randomised, open-label, proof of-concept, Phase 2 study to evaluate the efficacy, safety and tolerability of alisporivir plus Standard of Care (SOC) as compared to SOC for the treatment of hospitalised patients with infections due to SARS-CoV-2 (COVID-19), excluding patients with acute respiratory distress syndrome (ARDS) and/or need for mechanical ventilation. All participants are treated with alisporivir+SOC or SOC alone for 14 days.
The study population consists in adults (18-80 years old) hospitalised for 4E3 hours prior to randomisation with a diagnosis of COVID-19 based on symptoms onset and SARS-CoV-2 RT-PCR test positive from nasopharyngeal swab.
In this study, a laboratory-confirmed SARS-CoV-2 infection is determined by reverse transcription polymerase chain reaction (RT-PCR) in a nasopharyngeal swab. All patients have the RT-PCR COVID-19 test based on the same validated method for the duration of the study in order to ensure data consistency and reliability. Sample collection and processing for determining the viral load is done in a standardised and consistent manner in order to decrease variability between samples that might influence the viral load. Droplet digital PCR is used to quantify the average viral load per infected host cell, accounting for the number of cells from each swabbing sample and the viral RNA copies/cell.
The duration of treatment is 14 days (D1-D14). Treatment may be administered on an inpatient (patient hospitalized, at least until D4) or outpatient (patient discharged from hospital) basis. Patients are screened and, if eligible, randomised 2:1 to one of the two treatment arms:
During this Phase 2 study, alisporivir (oral solution) is administered either orally or via a nasogastric tube, if necessary after beginning of treatment (condition of patient does not require the use of a nasogastric tube in enrolment), at the dose of 600 mg p.o. BID from D1 to D14 to patients in Arm 1. The total duration of treatment is 14 days.
The investigator should choose the SOC based on locally accepted regimen protocols for patient care and select agents based on the underlying diagnosis and the severity of COVID-19. Additions or changes to SOC are allowed during the patient participation in the study based on patient status and evolution, including antibiotics, excepting e.g. azithromycin and other antibiotics listed as prohibited medications per protocol. Changes in SOC are allowed and are not considered a treatment failure.
The main objective of this study is to evaluate the reduction in SARS-CoV-2 viral load in nasopharyngeal swabs at Day 7 (D7) in patients hospitalised for COVID-19 and treated either with alisporivir and standard of care (SOC) or SOC alone.
The primary endpoint of this study is Viral Load Response Rate (VLRR), defined as the proportion of patients with an intra patient decrease of 1.5 log 10 viral load, at D7 compared to baseline. Thus the primary outcome measure is the change in SARS-CoV-2 viral load in nasopharyngeal swabs [Time Frame: at Day 1 and Day 7].
The secondary objective of this study is to evaluate the clinical and radiological efficacy, safety and tolerability of alisporivir plus SOC compared to SOC alone in patients with COVID-19. For such evaluation, the secondary outcome measures are as follows:
There are daily treatment visits from D1-D4, and at D7. The visits on D5, D6 and D8 to D13 take place only if the patient remains hospitalized. Information may still be collected by telephone if the patient is no longer hospitalized at the time of visit. There is an EOT visit upon completion of the therapy (D14), and three FUP visits at approximately 7 days (FUP7) [i.e. D21 of study+/−2 days], 14 days (FUP14) [i.e. D28 of study+/−2 days] and 76 days (End of Study, EOS) after the completion of therapy [i.e. D90 of study+/−2 days]. SARS-CoV-2 viral load assessment occurs at each visit except EOS and pulmonary clinical assessment occurs at each visit. Other clinical and laboratory assessments are defined per protocol.
Inclusion criteria include:
SARS-CoV-2 RT-PCR test from nasopharyngeal swab.
Exclusion criteria include:
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/IB2020/053266 | Apr 2020 | WO | international |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2021/052846 | 4/6/2021 | WO |
