key: cord-0919724-ho89o8mj
authors: Pawlotsky, Jean-Michel
title: SARS-CoV-2 pandemic : Time to revive the cyclophilin inhibitor alisporivir
date: 2020-05-15
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa587
sha: d0377511f1dd35ce0fb773d54d07a6ce8203d922
doc_id: 919724
cord_uid: ho89o8mj

December 2019 saw the emergence of a new epidemic of pneumonia of varying severity, called COVID-19, caused by a newly identified coronavirus, SARS-CoV-2. No therapeutic option is available to treat this infection that has already killed more than 235,000 people worldwide. This Viewpoint summarizes the strong scientific arguments supporting the use of alisporivir, a non-immunosuppressive analogue of cyclosporine A with potent cyclophilin inhibition properties that has reached Phase 3 clinical development, for the treatment of COVID-19. They include the strong cyclophilin dependency of the lifecycle of many coronaviruses, including SARS-CoV and MERS-CoV, and preclinical data showing strong antiviral and cytoprotective properties of alisporivir in various models of coronavirus infection, including SARS-CoV-2. Alisporivir should be tested without delay on both virological and clinical endpoints in patients with or at-risk of severe forms of SARS-CoV-2 infection.

A c c e p t e d M a n u s c r i p t 3 December 2019 saw the emergence of a new epidemic of pneumonia of varying severity that started in the Chinese city of Wuhan [1] . The agent responsible for the epidemic was very rapidly identified [2] . It is a coronavirus, hitherto unknown member of the Orthocoronavirinae subfamily, genus beta-coronavirus, forming a separate clade within the sarbecovirus subgenus (lineage B) to which also belongs the virus responsible for the Despite initial measures aimed at preventing its spread, the disease is now pandemic, with active hotspots of infection in Western Europe and North America. The typical clinical presentation of COVID-19 is an acute respiratory illness with fever and respiratory symptoms, including cough and shortness of breath. The disease may aggravate and necessitate oxygen therapy and, especially in patients with risk factors (such as overweight, hypertension, diabetes or cardiac disease), transfer to an intensive care unit and mechanical ventilation. Milder forms may be limited to runny nose or sore throat, while an unknown proportion of patients remains asymptomatic. Non-respiratory, sometimes severe manifestations have also been described, including taste and/or olfactory disorders, as well as gastrointestinal, neurological, cardiovascular and/or ocular symptoms [1, 3] . At the time of writing this Viewpoint, more than 3. Several mechanisms have been identified as potential targets for direct-acting antivirals and host-targeted agents against SARS and the Middle-East Respiratory Syndrome coronavirus (MERS-CoV) [5] . However, these hypotheses could not be clinically evaluated, because these two epidemics spontaneously stopped their progression.

Empirical attempts have been made in the context of the COVID-19 epidemic to repurpose drugs that are approved or have reached late clinical developmental stages in other indications. The combination of the antiretroviral drug lopinavir with ritonavir failed to demonstrate antiviral efficacy in patients with severe COVID-19 disease [6] . Chloroquine, an anti-malarial drug, bears significant antiviral properties against SARS-CoV-2 in vitro [7] .

Chloroquine has been tested in patients with COVID-19, alone or in combination with the anti-bacterial drug azithromycin, with thus far contradictory results, probably due to the heterogeneity of the populations studied (mild to severe, early to late disease) and methodological flaws [8] . Camostat mesylate was also recently suggested to act as a SARS-CoV, MERS-CoV and SARS-CoV-2 entry inhibitor in vitro [9] , but no clinical data are available.

The nucleotide analogue remdesivir showed antiviral efficacy against SARS-CoV and MERS-CoV viruses in both in vitro and animal models [10] [11] [12] [13] . Remdesivir was recently reported to inhibit the SARS-CoV-2 lifecycle in vitro [7] . Modest but significant results from a randomized clinical trial were recently released: the administration of remdesivir was associated with a significantly shortened median time to recovery (11 vs 15 days) and a trend towards less frequent death (8.0% vs 11.6%, p=0.059) [14] . However, a yet unpublished Chinese study reported negative results with this compound. Overall, the antiviral treatment of COVID-19 remains to be found.

A c c e p t e d M a n u s c r i p t 5 A very credible therapeutic option for SARS-CoV-2 is the use of cyclophilin inhibitors.

Cyclophilins are host peptidyl-prolyl cis-trans isomerases. They catalyze the interconversion of the two energetically preferred conformers (cis and trans) of the planar peptide bond preceding an internal proline residue [15, 16] [17] .

Cyclophilins also play a very important role in the lifecycle of many coronaviruses.

It has indeed been shown that the lifecycles of human coronaviruses 229E (HCoV-229E) and NL-63 (HCoV-NL63), responsible for mild respiratory infections in humans, of feline infectious peritonitis coronavirus (FPIV), responsible for a fatal disease in cats, and of SARS-CoV were highly dependent on cyclophilin A (and possibly also cyclophilin B for FPIV) [18] [19] [20] [21] [22] .

The N protein of SARS-CoV binds strongly to cyclophilin A and this binding could facilitate cell invasion [19, 23] . Interestingly, the SARS-CoV and MERS-CoV virions bring with them quantities of cyclophilin A sufficient for the achievement of their lifecycle, allowing them to compensate for a defect in cell production in their target cells [24] . In this context, it is not Because of its strong immunosuppressive properties, CsA cannot be considered as a therapeutic option for SARS-CoV-2 infections. There are, however, alternative molecules capable of strongly inhibiting the functional activity of cyclophilins without exerting any immunosuppressive effects. This is the case for the non-immunosuppressive analogue of CsA alisporivir (Debio 025). Alisporivir was developed by the Swiss company Debiopharm, initially for the treatment of chronic HCV infection, as the HCV lifecycle is strongly dependent on cyclophilin A. Alisporivir induced a decrease of HCV replication of the order of 3 to 4 logs in patients infected with all HCV genotypes, with a very high barrier to resistance since the drug target is a host protein [27, 28] . Administered for 14 days to 24 weeks as a monotherapy, alisporivir was well tolerated. Headache, nausea, fatigue and a few cases of reversible hyperbilirubinemia were the most common adverse events in patients treated with the highest dose of the drug [28] [29] [30] [31] . Hyperbilirubinemia was not observed in previous studies with alisporivir at oral dosages up to 1,200 mg/day for 10 days [28] . We have shown that the combination of alisporivir and ribavirin is also very well tolerated for several weeks in HCV-infected patients [31] .

Alisporivir has entered Phase 3 clinical evaluation for the treatment of chronic hepatitis C, in combination with pegylated interferon alpha and ribavirin, under license with Novartis. However, in April 2012, this Phase 3 program was interrupted due to the occurrence of 3 cases of acute pancreatitis, including one fatal case, occurring several weeks after the onset of treatment in a trial. Overall, there were 7 cases of acute pancreatitis among over 2,000 patients included in the alisporivir clinical development program, with equal frequency in patients receiving pegylated interferon alpha with or without alisporivir (0.35% vs 0.41%, respectively) [32] . Pancreatitis is a classic complication of interferon alpha and the direct responsibility of alisporivir in the reported cases has not been formally A c c e p t e d M a n u s c r i p t 7 established, especially since no case has occurred with alisporivir alone or with alisporivir and ribavirin in other studies [28, 31] .

The current situation is that a non-immunosuppressive CsA analogue endowed with powerful cyclophilin inhibitory properties and having reached Phase 3 clinical development, which is well tolerated for several weeks of administration alone or in combination with ribavirin, exists. Strong arguments suggest that alisporivir will have antiviral efficacy against SARS-CoV-2 infections. First, the lifecycles of many coronaviruses, including SARS-CoV, are strongly dependent on cyclophilins. Secondly, experimental results, including findings from our laboratory, indicate that alisporivir inhibits the replication of HCoV-229E, HCoV-NL63 and MHV at low micromolar concentrations and without cytotoxic effect in vitro [18, 33, 34] . Thirdly, we observed that alisporivir fully abolishes the cytopathic effect of HCoV-229E in cell culture (unpublished data). A recent study showed that alisporivir blocks the lifecycle of SARS-CoV and MERS-CoV in different cellular models of infection [34] .

However, treatment of a mouse model of SARS-CoV infection with alisporivir and ribavirin did not lead to a reduction in infection-related mortality or weight loss compared to untreated mice [34] , emphasizing the importance of a careful design of clinical trials to maximize the clinical effect of the antiviral treatment. Alisporivir inhibits all cyclophilins, including cyclophilin D, an essential component of the mitochondrial permeability transition pore (mPTP). Cyclophilin D inhibition has been shown to be beneficial in heart, kidney and hepatic disorders in which abnormal mPTP opening plays a major pathogenic role [36, 37] . Whether similar protection of lung tissues will be achieved by alisporivir in order to improve the clinical course of COVID-19, in the presence or in the absence of a significant antiviral effect, must be assessed. Therefore Over 235,000 patients already died from SARS-CoV-2 infection on the day of writing this Viewpoint. If alisporivir proves to have an antiviral and/or clinical effect, we will, finally, have a first-line therapeutic solution to the current pandemic, as well as, possibly, a weapon against the future emergence of other coronaviruses. In the absence of an effect, we will have advanced scientific knowledge and, most importantly, we will have no regrets.

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

A novel coronavirus from patients with pneumonia in China

Clinical features of COVID-19

Coronaviruses: drug discovery and therapeutic options

A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Rethinking the role of hydroxychloroquine in the treatment of COVID-19

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases

The cyclophilins

The role of immunophilins in viral infection

Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by non-immunosuppressive cyclosporine Aderivatives including alisporivir

Nucleocapsid protein of SARS coronavirus tightly binds to human cyclophilin A

Genetic deficiency and polymorphisms of cyclophilin A reveal its essential role for human coronavirus 229E replication

Feline coronavirus replication is affected by both cyclophilin A and cyclophilin B

The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors

Function of HAb18G/CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus

Cyclophilins and cyclophilin inhibitors in nidovirus replication

Suppression of feline coronavirus replication in vitro by cyclosporin A

Cyclosporin A inhibits the replication of diverse coronaviruses

The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro

The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus

The cyclophilin inhibitor Debio 025 combined with PEG IFN alpha-2a significantly reduces viral load in treatment-naive hepatitis C patients

Alisporivir plus ribavirin, interferon free or in combination with pegylated interferon, for hepatitis C virus genotype 2 or 3 infection

Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment-naive patients with chronic HCV genotype 1 infection (ESSENTIAL II)

Influences of cyclosporin A and non-immunosuppressive derivatives on cellular cyclophilins and viral nucleocapsid protein during human coronavirus 229E replication

Alisporivir inhibits MERS-and SARS-coronavirus replication in cell culture, but not SARS-coronavirus infection in a mouse model

Inhibition of SARS-CoV-2 infection by the cyclophilin inhibitor Alisporivir (Debio 025)

Mitochondrial permeability transition: a molecular lesion with multiple drug targets

The author is grateful to Drs Abdelhakim Ahmed-Belkacem and Slim Fourati for helpful comments.Conflict of interest disclosure: The author has served as an advisor for Abbvie, Gilead, GlaxoSmithKline, Merck, Regulus and Siemens Healthcare.

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