WO2022053164A1

WO2022053164A1 - Antiviral combination for the treatment of covid-19 infection

Info

Publication number: WO2022053164A1
Application number: PCT/EP2020/075652
Authority: WO
Inventors: Sherine Hassan Abbas HELMY
Original assignee: Hc Pharma Ag
Priority date: 2020-09-14
Filing date: 2020-09-14
Publication date: 2022-03-17

Abstract

A combination of two antiviral, sofosbuvir and ravidasvir, for the treatment of COVID-19 infection is described. The combination is administered orally.

Description

Antiviral combination for the treatment of COVID-19 infection

Technical background

The present invention relates to an antiviral combination for the treatment of COVID- 19 infection, particularly a combination of sofosbuvir and ravidasvir.

The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in Wuhan, China, in December 2019, and has since spread worldwide. As of September 8, 2020, there have been more than 27 million reported cases and more than 890,000 deaths in more than 200 countries. This novel Betacoronavirus is similar to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV); based on its genetic proximity, it likely originated from bat-derived coronaviruses with spread via an unknown intermediate mammal host to humans [Zheng, SARS-CoV-2: an Emerging Coronavirus that Causes a Global Threat. Int J Biol Sci. 2020; 16(10): 1678-1685]. The viral genome of SARS-CoV-2 was rapidly sequenced to enable diagnostic testing, epidemiologic tracking, and development of preventive and therapeutic strategies. Until today, six different strains of Human coronaviruses (HCoVs) have been reported, in addition to the newly emerged COVID-19. 229E and NL63 strains of HCoVs belong to Alphacoronaviruses while OC43, HKU1 , SARS, MERS, and COVID-19 HCoVs belong to Betacoronaviruses. SARS and MERS HCoV are the most aggressive strains of coronaviruses, leaving about 800 deaths each in the years 2002 and 2012, respectively. SARS HCoV has a 10% mortality rate, while MERS HCoV has a 36% mortality rate, according to the WHO [Elfiky, A.A., Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sciences, 2020. 248: p. 117477], HCoVs generally are positive-sense and very long (30,000 bp) single-stranded RNA viruses. Two groups of protein characterize HCoVs: structural, such as Spike (S), Nucleocapsid (N) Matrix (M) and Envelope (E), and non-structural proteins such as RNA dependent RNA polymerase (RdRp) (nsp12). RdRp is a crucial enzyme in the life cycle of RNA viruses, including coronaviruses. RdRp is targeted in different RNA viruses, including Hepatitis C Virus (HCV), Zika Virus (ZIKV), and coronaviruses (CoVs) [Elfiky, A.A., Zika viral polymerase inhibition using anti-HCV drugs both in market and under clinical trials. J Med Virol, 2016. 88(12): p. 2044-2051]. The active site of RdRp is highly conserved representing two successive aspartate residues protruding from a beta-turn structure making them surface accessible through the nucleotide channel (free nucleotides can pass through) [Elfiky, A. A. and A.M. Ismail, Molecular docking revealed the binding of nucleotide/side inhibitors to Zika viral polymerase solved structures. SAR and QSAR in Environmental Research, 2018. 29(5): p. 409-418],

Currently, only remedisivir gained FDA emergency use authorization (EUA) for treatment of all hospitalized adult and pediatric patients with suspected or laboratory-confirmed COVID-19, irrespective of their severity of disease. The (EUA) authorization is granted by FDA to facilitate availability and unapproved uses of MCMs needed to prepare for and respond to CBRN emergencies. Several other drugs are under investigation in Phase II & III for treatment and prevention of COVID-19 infected patients.

Agents previously used to treat SARS and MERS are potential candidates to treat COVID-19. Various agents with apparent in vitro activity against SARS-CoV and MERS-CoV were used during the SARS and MERS outbreaks, with inconsistent efficacy. Meta-analyses of SARS and MERS treatment studies found no clear benefit of any specific regimen. Broad-spectrum anti-viral agents (BSAAs) that have been deemed “safe-in-man” through testing on early phase clinical trials have been touted as good drug repurposing candidates. Andersen et al. [DrugVirus. Broadspectrum antiviral agents (BSAAs) and viruses they inhibit (2020). https://drugvirus.info/] have recently summarized 31 potential candidates for COVID- 19 in a highly accessible database of 120 experimental, investigational and approved agents. Conceptually, BSAAs take advantage of the promiscuity of viral replicative mechanisms and host interactions to target two or more viral families. Following the COVID-19 outbreak in December 2019, a few existing BSAAs have been rapidly introduced into clinical trials, spanning Phases II through IV [Senanayake, S.L., Drug repurposing strategies for COVID-19. Future Drug Discovery, 2020. 0(0): p. fdd-2020-0010].

Different directly acting antiviral drugs are approved against other viruses, by the Food and Drugs Administration (FDA) in the USA, against RdRp of Hepatitis C Virus (HCV). These drugs are nucleotide derivatives competing with physiological nucleotide for RdPd active site [Ezat, A.A., et al., Novel inhibitors against wild-type and mutated HCV NS3 serine protease: an in silico study. VirusDisease, 2019. 30(2): p. 207-213]. Additionally, a huge number of attempts to develop anti-RdRp compounds are under clinical testing against different viruses. Recent in vitro molecular docking study showed that sofosbuvir can tightly bind to the newly emerged coronavirus RdRp and hence contradict the function of the protein leading to viral eradication. Data suggests that sofosbuvir can be repurposed as a potent inhibitor against the newly emerged COVID-19 strain of HCoV [Elfiky, A.A., Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life sciences, 2020. 253: p. 117592-117592; Elfiky, A.A., SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective. J Biomol Struct Dyn, 2020: p. 1-9],

Based on the available data regarding the genotype of SARS-CoV-2, the 5’ end of the genome, a single Orf encodes a polyprotein that auto-proteolytically cleaves into 16 non-structural proteins (Nsp1 -16) that form the replicase-transcriptase complex. The 16 protein replicase-transcriptase consists of multiple enzymes essential to viral genome replication, including the viral RNA-dependent RNA polymerase and other enzymes such as endo- and exonucleases essential to nucleic acid metabolism [Mousavizadeh, L. and S. Ghasemi, Genotype and phenotype of COVID-19: Their roles in pathogenesis. Journal of Microbiology, Immunology and Infection, 2020]. On the other hand, non-structural proteins may play a role in the pathogenesis of SARS-CoV-2. Sofosbuvir was found to be more potent than Chloroquine & LPV/RTV to inhibit SARS-CoV-2 replication in Huh-7 then in Calu-3 cells [Sacramento, C. et al., The in vitro antiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2. 2020, bioRxiv.]. Based on these data, inhibitors of non-structural proteins NS5A, a protein essential for viral replication assembly seems to be promising drugs against covid-19.

In a computational target-based drug repurposing investigation published in April 2020, Elbasivir (NS5A inhibitor) was predicted to bind stably and preferentially to three proteins necessary for viral replication of SARS-CoV-2, the human coronavirus responsible for the COVID-19 pandemic. In another study, the NS5A inhibitors antivirals ledipasvir and velpatasvir were found to be particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache [Chen, Y.W., C.B. Yiu, and K.Y. Wong, Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL^pro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates. FIOOORes, 2020. 9: p. 129],

Ravidasvir is a promising treatment for Hepatitis C [Esmat et aL, Effectiveness of ravidasvir plus sofosbuvir in interferon-naive and treated patients with chronic hepatitis C genotype-4. J Hepatol. 2017. doi:10.1016/j.jhep.2O17.09.006 ] are of the same class of elbasvir which could be promising agents against COVID-19 virus.

In-silico studies found that ravidasvir could be a potential treatment for COVID-19 due to its activity against 5R81 viral enzyme [Shah, B., P. Modi, and S.R. Sagar, In silico studies on therapeutic agents for COVID-19: Drug repurposing approach. Life sciences, 2020. 252: p. 117652-117652.].

Recently and according to the Iranian clinical trial registry, a randomized clinical trial is being conducted in Iran to evaluate efficacy and safety of sofosbuvir and daclatasvir in patients with COVID-19 infection [seehttps://en.irct.ir/trial/46463]. However, as reported in the paper, in spite of encouraging initial results, larger, well- designed studies are required to confirm these preliminary results. In fact, conducting research and clinical trials in a pandemic situation with overwhelmed hospitals is a challenge and there could be no certainty of success. Sometimes treatments look promising in early trials but then fail later on.

Moreover, any therapeutic approaches to COVID-19 infections with BSAAs need to properly address the low potency of these drugs for the new indication, as their maximal tolerated dose is often sub therapeutic.

Therefore, in spite of all the efforts of the scientific community to find a therapy for COVID-19 infection using known antiviral drugs, the clinical efficacy of any antiviral treatments is very far to be predictable and expected even if the pharmacological rationale is well founded.

There is still a high urgent need for a safe and effective therapy against COVID-19 infection.

Summary of the invention

In one aspect, the present invention relates to the use of a combination of two known antiviral drugs, sofosbuvir and ravidasvir, for the treatment of COVID-19 infection.

In a preferred aspect, the present invention relates to the use of a combination of sofosbuvir and ravidasvir, for the treatment of COVID-19 infection wherein sofosbuvir is orally administered at the daily dose of 400 mg and ravidasvir is orally administered at the daily dose of 200 mg.

In another preferred aspect, the present invention relates to the use of a combination of sofosbuvir and ravidasvir, for the treatment of COVID-19 infection wherein sofosbuvir is orally administered at the daily dose of 400 mg in the form of a tablet and ravidasvir is orally administered at the daily dose of 200 mg in the form of a tablet.

In another preferred aspect, the present invention relates to the use of a combination of sofosbuvir and ravidasvir, for the treatment of COVID-19 infection wherein sofosbuvir is orally administered at the daily dose of 400 mg and ravidasvir is orally administered at the daily dose of 200 mg, for a time period of at least 10 days.

To the best of our knowledge, the combination of sofosbuvir and ravidasvir has been never disclosed for the treatment of COVID-19 infection and its safety and efficacy for this new indication could not be predicted from the known data about these drugs.

A more complete understanding of the present invention will be apparent to the skilled in the art from the following detailed description.

Detailed description

Sofosbuvir is a direct acting antiviral medication used as part of a combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). As a prodrug nucleotide analog, sofosbuvir is metabolized into its active form as the antiviral agent 2’-deoxy-2’-a-fluoro-p-C- methyluridine-5’-triphosphate (also known as GS-461203), which acts as a defective substrate for NS5B (non-structural protein 5B) synthesis. Ns5B, an RNA-dependent RNA polymerase, is essential for the transcription of Hepatitis C viral RNA and its high replicative rate and genetic diversity. Sofosbuvir and other direct acting antivirals are therefore very potent options for the treatment of Hepatitis C, as they exhibit a high barrier to the development of resistance. This is an important advantage relative to HCV drugs that target other viral enzymes such as protease, for which rapid development of resistance has proven to be an important cause of therapeutic failure [Buggisch, P., et al., Real-world effectiveness and safety of sofosbuvir/velpatasvir and ledipasvir/sofosbuvir hepatitis C treatment in a single centre in Germany. PLoS One, 2019. 14(4): p. e0214795; Osinusi, A., et al., Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA, 2013. 310(8): p. 804- 811 ; Koff, R.S., Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatits C virus infection. Aliment Pharmacol Ther, 2014. 39(5): p. 478-87],

Ravidasvir (RVD) is a pan-genotypic anti-HIV NS5A inhibitor with a favorable pharmacokinetic profile, rapid plasma concentrations, and high 24-hr trough concentrations, allowing for continuous HCV inhibitory drug concentrations with once daily oral dosing [Xu, X., et al., Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naive Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China. Journal of clinical and translational hepatology, 2019. 7(3): p. 213-220]. RVD achieves steady-state with the first dose, and from day-2 onward, peak and trough levels remain constant without evidence for either subsequent drug accumulation or drug induced clearance. In phasel trials, RDV proved to be well tolerated and efficacious with no appreciable pattern of treatment-related adverse events. Observed resistance substitution did not subsequently increase during continued RDV monotherapy (days 2-3), suggesting that its concentrations were sufficient to suppress single substitution variants during early treatment. RDV was studied in combination with deleobuvir (nonnucleoside NS5B polymerase inhibitor) and faldaprevir (NS3-NS4 protease inhibitor) to treat HCV gt-1 patients. A sustained virologic response was achieved in 92% of patients [Xu, X., et al. - supra; Esmat, G., et al., Effectiveness of ravidasvir plus sofosbuvir in interferon-naive and treated patients with chronic hepatitis C genotype-4. J Hepatol, 2017.]. Phase III trial performed on Egyptian patients proved its efficacy and safety in treatment of HCV infection.

The combination of sofosbuvir and ravidasvir has already proved to be safe when administered for treating HCV infection in patients.

For the use in the treatment of COVID-19 infection, sofosbuvir and ravidasvir are orally administered. The administration of the actives may be simultaneous or subsequent. When the administration is simultaneous, both actives may be in a single dosage form or in separated dosage forms.

For the use of according to the present invention, the simultaneous administration of both actives is preferred and still more preferred is the simultaneous administration of both actives in either a single dosage form or separated dosage forms.

Any dosage form suitable for oral use may be used according to the present invention. Non limitative examples of suitable oral dosage forms are solid dosage forms, such as tablets, capsules, and granulates, and liquid dosage forms, such as solutions, suspensions, emulsions. Tablets are the preferred oral dosage form.

A suitable oral dosage form contains an amount of active(s) in admixture with a pharmaceutically acceptable carrier.

The amount of active(s) may be at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg or at least 1000 mg.

In a preferred embodiment of the present invention, the amount of active(s) may be in the range of, e.g. from about 10 mg to about 100 mg, from about 50 mg to about 150 mg, from about 100 mg to about 250 mg, from about 150 mg to about 300 mg, from about 200 mg to about 400 mg, from about 300 mg to about 500 mg, from about 400 mg to about 600 mg, from about 500 mg to 800 mg.

In a still more preferred embodiment, the amount of active(s) may be in the range from 100 mg to about 250 mg, from about 150 mg to about 300 mg, from about 200 mg to about 400 mg, from about 300 mg to about 500 mg, from about 400 mg to about 600 mg, from about 500 mg to 800 mg.

Preferably the amount of sofosbuvir is from about 100 mg to about 800 mg, from about 200 mg to about 600 mg, from about 300 mg to about 500 mg, more preferably about 400 mg.

Preferably the amount of ravidasvir is from about 50 mg to about 400 mg, from about 100 mg to about 300 mg, from about 150 mg to about 250 mg, more preferably about 200 mg.

The amount of active(s) may be administered once a day or more times a day.

A once a day administration is preferred.

The schedule of treatment may vary depending on several factors including the severity of the infections and the age, weight and physical conditions of the patient to be treated.

Generally, according to the invention, the antiviral combination is administered to a patient for at least 10 days, for at least 11 days, for at least 12 days, for at least 13 days, for at least 14 days, for at least 15 days, for at least 16 days, for at least 17 days, for at least 18 days, for at least 19 days, for at least 20 days, for at least 21 days or even more.

Preferably the antiviral combination is administered to a patient for a period from 10 days to 14 days, to achieve the desired therapeutic benefit.

The combination of sofosbuvir plus ravidasvir is effective in the treatment of COVID- 19 infection and significantly decreases the mortality rate compared with the standard of care therapy.

Claims

1. A combination of sofosbuvir and ravidasvir for use in treating COVID-19 infection.

2. A combination according to claim 1 for oral administration.

3. A combination according to claim 1 wherein sofosbuvir is administered at the daily dose of 400 mg.

4. A combination according to claim 1 wherein ravidasvir is administered at the daily dose of 200 mg.

5. A combination according to claim 1 wherein sofosbuvir is administered in the form of a tablet.

6. A combination according to claim 1 wherein ravidasvir is administered in the form of tablet.

7. A combination according to claim 1 wherein sofosbuvir and ravidasvir are simultaneously administered.