Evaluation of the Efficacy, Safety and Tolerability of Alisporivir for the Treatment of Hospitalised Patients With Infections Due to SARS-CoV-2 (COVID-19). A Randomised, Open-label, Proof of Concept, Phase 2 Study

COVID-19 is a viral respiratory and systemic disease that has been rapidly spreading globally since the first cases were reported in December 2019 and has now become pandemic. The causative agent of COVID-19 was identified as a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, first designated as 2019-nCoV).
The disease manifestations of COVID-19 can range from mild, self-resolving respiratory disease to severe pneumonia, ARDS, multiorgan failure, and ultimately death. In early reports, the mortality rate among patients admitted to hospital and with confirmed SARS-CoV-2 infection was reported to be between 4 and 15%. Although the disease can afflict all age groups, elderly patients and patients with underlying comorbidities such as high body mass index, hypertension, diabetes, cardiovascular disease, or cerebrovascular disease are at risk of developing severe disease and dying.
There are currently no etiologic treatments for COVID-19, and efforts are underway to identify therapeutics that could be effective in controlling this disease.

Start Date08 Jan 2021

Sponsor / Collaborator

Assistance Publique des Hôpitaux de Paris SA

[+1]

NCT02173574

/ CompletedPhase 1

An Open-label, Two Part Investigation of the Pharmacokinetics, Safety, and Tolerability of Alisporivir and EDP239 When Co-administered to Healthy Adult Subjects

The purpose of Part 1 is to inform dose selection for use of alisporivir and EDP239 in combination and obtain initial safety data for co-administration of alisporivir and EDP239 to support future treatment studies in patients. The purpose of Part 2 is to inform the drug-drug interaction potential of EDP239 more broadly and possibly facilitate the interpretation of lower than expected alisporivir concentrations in Part 1, if observed.

Start Date01 Aug 2014

Sponsor / Collaborator

Enanta Pharmaceuticals, Inc.

NCT02094443

/ CompletedPhase 2

A Multicenter, Open-label, Randomized, 2-arm, Phase II Trial of Pharmacodynamics, Pharmacokinetics and Safety of Two Dose Regimens of DEB025/Alisporivir in Combination With Ribavirin Therapy in Chronic Hepatitis C Genotype 2 and 3 Patients Who Have Previously Failed Interferon Therapy or Are Intolerant or Unable to Take Interferon.

The primary purpose of this study is to evaluate the pharmacodynamic (i.e. hepatitis C virus (HCV) viral load), pharmacokinetic and safety profiles between two treatment groups receiving different doses of DEB025 in combination with ribavirin (RBV) during the first 12 weeks treatment in chronic hepatitis C genotype (GT)-2 and GT-3 patients who had previously failed interferon therapy or were intolerant or unable to take interferon.

Start Date01 Mar 2014

Sponsor / Collaborator

Debiopharm International SA

100 Clinical Results associated with Alisporivir

100 Translational Medicine associated with Alisporivir

100 Patents (Medical) associated with Alisporivir

147

Literatures (Medical) associated with Alisporivir

01 Oct 2024·PROTEIN SCIENCE

Evaluating the potential of non‐immunosuppressive cyclosporin analogs for targeting Toxoplasma gondii cyclophilin: Insights from structural studies

Article

Author: Sadeghi, Sheila J. ; Di Matteo, Adele ; Dominici, Paola ; Astegno, Alessandra ; Hermoso, Juan A. ; Jiménez‐Faraco, Eva ; Favretto, Filippo ; Travaglini‐Allocatelli, Carlo ; Catucci, Gianluca

Abstract:

Toxoplasmosis persists as a prevalent disease, facing challenges from parasite resistance and treatment side effects. Consequently, identifying new drugs by exploring novel protein targets is essential for effective intervention. Cyclosporin A (CsA) possesses antiparasitic activity against Toxoplasma gondii, with cyclophilins identified as possible targets. However, CsA immunosuppressive nature hinders its use as an antitoxoplasmosis agent. Here, we evaluate the potential of three CsA derivatives devoid of immunosuppressive activity, namely, NIM811, Alisporivir, and dihydrocyclosporin A to target a previously characterized cyclophilin from Toxoplasma gondii (TgCyp23). We determined the X‐ray crystal structures of TgCyp23 in complex with the three analogs and elucidated their binding and inhibitory properties. The high resolution of the structures revealed the precise positioning of ligands within the TgCyp23 binding site and the details of protein–ligand interactions. A comparison with the established ternary structure involving calcineurin indicates that substitutions at position 4 in CsA derivatives prevent calcineurin binding. This finding provides a molecular explanation for why CsA analogs can target Toxoplasma cyclophilins without compromising the human immune response.

22 Apr 2024·JACS Au

Taming Conformational Heterogeneity on Ion Racetrack to Unveil Principles that Drive Membrane Permeation of Cyclosporines

Article

Author: Lindberg, Edward T. ; Steren, Carlos A. ; Oomens, Jos ; Olivos, Hernando J. ; van Tetering, Lara ; Ngo, Van A. ; Limbach, Miranda N. ; Martens, Jonathan ; Do, Thanh D.

Our study reveals the underlying principles governing the passive membrane permeability in three large N-methylated macrocyclic peptides (N-MeMPs): cyclosporine A (CycA), Alisporivir (ALI), and cyclosporine H (CycH). We determine a series of conformers required for robust passive membrane diffusion and those relevant to other functions, such as binding to protein targets or intermediates, in the presence of solvent additives. We investigate the conformational interconversions and establish correlations with the membrane permeability. Nuclear magnetic resonance (NMR) and cyclic ion-mobility spectrometry-mass spectrometry (cIMS-MS) are employed to characterize conformational heterogeneity and identify cis-amides relevant for good membrane permeability. In addition, ion mobility selected cIMS-MS and infrared (IR) multiple-photon dissociation (IRMPD) spectroscopy experiments are conducted to evaluate the energy barriers between conformations. We observe that CycA and ALI, both cyclosporines with favorable membrane permeabilities, display multiple stable and well-defined conformers. In contrast, CycH, an epimer of CycA with limited permeability, exhibits fewer and fewer stable conformers. We demonstrate the essential role of the conformational shift from the aqueous cis MeVal11-MeBmt1 state (A1) to the closed conformation featuring cis MeLeu9-MeLeu10 (C1) in facilitating membrane permeation. Additionally, we highlight that the transition from A1 to the all-trans open conformation (O1) is specifically triggered by the presence of CaCl₂. We also capture a set of conformers with cis Sar3-MeLeu4, MeLeu9-MeLeu10, denoted as I. Conformationally selected cIMS-MS and IRMPD data of [CycA+Ca]²⁺ show immediate repopulation of the original population distribution, suggesting that CaCl₂ smooths out the energy barriers. Finally, our work presents an improved sampling molecular dynamics approach based on a refined force field that not only consistently and accurately captures established conformers of cyclosporines but also exhibits strong predictive capabilities for novel conformers.

01 Dec 2023·Molecular pharmacology

Targeting Cyclophilin A and CD147 to Inhibit Replication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and SARS-CoV-2–Induced Inflammation

Article

Author: Ma-Lauer, Yue ; Wu, Aihua ; Yang, Fan ; Li, Pengyuan ; Zhu, Di ; Liu, Chenglong ; Zhang, Hao ; Su, Zhuang ; Lu, Wei ; von Brunn, Albrecht

Identification and development of effective therapeutics for coronavirus disease 2019 (COVID-19) are still urgently needed. The CD147-spike interaction is involved in the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 invasion process in addition to angiotensin-converting enzyme 2 (ACE2). Cyclophilin A (CyPA), the extracellular ligand of CD147, has been found to play a role in the infection and replication of coronaviruses. In this study, our results show that CyPA inhibitors such as cyclosporine A (CsA) and STG-175 can suppress the intracellular replication of SARS-CoV-2 by inhibiting the binding of CyPA to the SARS-CoV-2 nucleocapsid C-terminal domain (N-CTD), and the IC₅₀ is 0.23 μM and 0.17 μM, respectively. Due to high homology, CsA also had inhibitory effects on SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), and the IC₅₀ is 3.2 μM and 2.8 μM, respectively. Finally, we generated a formulation of phosphatidylserine (PS)-liposome-CsA for pulmonary drug delivery. These findings provide a scientific basis for identifying CyPA as a potential drug target for the treatment of COVID-19 as well as for the development of broad-spectrum inhibitors for coronavirus via targeting CyPA. Highlights: 1) SARS-CoV-2 infects cells via the binding of its S protein and CD147; 2) binding of SARS-CoV-2 N protein and CyPA is essential for viral replication; 3) CD147 and CyPA are potential therapeutic targets for SARS-CoV-2; and 4) CsA is a potential therapeutic strategy by interrupting CD147/CyPA interactions. SIGNIFICANCE STATEMENT: New severe acute respiratory syndrome coronavirus (SARS-CoV)-2 variants and other pathogenic coronaviruses (CoVs) are continually emerging, and new broad-spectrum anti-CoV therapy is urgently needed. We found that binding sites of cyclophilin A/cyclosporin A (CyPA/CsA) overlap with CyPA/N-CTD (nucleocapsid C-terminal domain), which shows the potential to target CyPA during SARS-CoV-2 infection. Here, we provide new evidence for targeting CyPA in the treatment of coronavirus disease 2019 (COVID-19) as well as the potential of developing CyPA inhibitors for broad-spectrum inhibition of CoVs.

News (Medical) associated with Alisporivir

18 Jan 2021

·www.biospace.com

Phase II Research Against Covid-19 Launched in France With Debiopharm's Antiviral Alisporivir

LAUSANNE, Switzerland, Jan. 18, 2021 /PRNewswire/ -- Debiopharm ( ), a Swiss biopharmaceutical company, announced today the first patient dosed in an investigator-initiated, randomized phase II, open-label clinical trial for its antiviral alisporivir (Debio 025). The study will be conducted by the AP-HP to assess the efficacy and safety of the cyclophilin inhibitor in the treatment of early stage, hospitalized COVID-19 patients not requiring medical ventilation nor exhibiting signs of acute respiratory distress syndrome. The primary objective of this "proof-of-concept" trial is to evaluate the reduction in COVID-19 viral load in alisporivir treated patients. The secondary objective involves the analysis of clinical & radiological efficacy, safety and tolerability of the compound plus Standard of Care (SOC) compared to SOC alone. Patients in the investigational arm will receive alisporivir either orally or via a nasogastric tube, at the dose of 600mg twice daily for 14 days during the trial led by Prof. Jean-Michel Pawlotsky, virologist, Head of the Biology and Pathology Department of the Henri Mondor Hospital Group, Greater Paris University Hospitals. The trial, supported by both the hospital group and Debiopharm, will be carried out in multiple centers in France including the Henri Mondor Hospital Group. Medical observations have shown that viral infections such as COVID-19 can be life-threatening due to an overreaction of the body's immune defense system. Part of the cyclophilin inhibitor class of antivirals, this macrocyclic cyclophilin inhibitor could prove to be a valuable additional therapy to SOC due to its non-immunosuppressive nature. "New evidence generated by our research group suggests that alisporivir's antiviral activity could work by decreasing the viral load in the cells and reducing the risk of pulmonary damage caused by an excessive immune response from infected patients. The treatment is expected to be most effective in the early stages of infection by inhibiting the virus' capacity to replicate and multiply, potentially due to the drug's capacity to accumulate in the lungs and strong distribution throughout the body overall," explained Prof. Jean-Michel Pawlotsky, Head of the Biology and Pathology Department at the Henri Mondor Hospital Group. "The preliminary evidence provide a scientific rational for this Phase II trial, with hopes that treatment will help patients to avoid advancing to more life-threatening phase of the COVID-19 infection. We are thrilled that this compound will be tested for its ability to fight this pandemic and save lives," expressed Bertrand Ducrey, CEO, Debiopharm. Involved in anti-viral research for over 20 years, Debiopharm has maintained its commitment to fighting cancer and infectious diseases. In addition to its anti-infective alisporivir, the company focuses on developing novel antibiotics to help battle highly-resistant "super-bugs" fueling the growing crisis in antibiotic resistance. Despite the substantial financial responsibility that this COVID-19 trial represents – expected to reach several millions in clinical research and product supply costs - the company has committed to donating all potential commercial revenue to fund research against infectious diseases. If phase II results show the results required to advance to phase III, Debiopharm will seek to partner with a larger global pharmaceutical company or public healthcare organization for rapid patient access. Debiopharm's commitment to patients Debiopharm, awarded the Swiss Biotech Success Story 2020, develops innovative therapies targeting high unmet medical needs in oncology and infectious diseases. Bridging the gap between disruptive discovery products and real-world patient reach, we identify high-potential compounds and technologies for in-licensing, clinically demonstrate their safety and efficacy and then select large pharmaceutical commercialization partners to maximize patient access globally. Visit us Follow us @DebiopharmNews at Debiopharm Contact Dawn Haughton - Communication Manager 289393@email4pr.com Tel: +41 (0)21 321 01 11 1. Softic L et al. Inhibition of SARS-CoV-2 infection by the non-immunosuppressive macrocyclic cyclophilin inhibitor Alisporivir (Debio025); Antimicrob Agents Chemother. 2020 Jul; 64(7): e00876-20.

01 Oct 2014

·www.biospace.com

Novartis AG Ditches Hepatitis C Drug Dreams, Breaks $440 Million Enanta Pharmaceuticals, Inc. Deal

October 1, 2014 By Krystle Vermes , BioSpace.com Breaking News Staff Swiss bipharma behemoth Novartis AG has announced that it will give full rights of its hepatitis C inhibitor to Enanta Pharmaceuticals, Inc. just as the drug, EDP-239, is currently in phase 1 development for the hepatitis C virus. Enanta Pharmaceuticals works on small molecule drugs in the infectious disease industry. Enanta and Novartis entered a collaboration to advance EDP-239 in February 2012 but now appear to be parting ways as Novartis revamps its portfolio. “Novartis notified Enanta that as part of an ongoing portfolio transformation, HCV research would no longer be a strategic focus for Novartis,” said Jay Luly, president and chief executive of Enanta Pharmaceuticals. “We appreciate Novartis’ contributions to the clinical development of EDP-239 and its ready agreement to return the NS5A program to us. Enanta is now positioned with three wholly-owned HCV programs from which future drug combinations can be explored.” EDP-239 inhibits the NS5A non-structural viral protein that is essential to the replication of hepatitis C within the body. The inhibitor has shown that it has additive or synergistic antiviral activity when use in combination with other anti-hepatitis C virus therapeutics. This new agreement assists with the completion of specified proof-of-concept clinical studies underway involving the inhibitor, a combination study with Alisporivir, and a cyclophilin inhibitor licensed by Novartis. The Fight Against Hepatitis C On Sept. 15, Gilead Sciences, Inc. announced that it had entered a entered a non-exclusive licensing agreement with seven Indian-based pharmaceutical companies to expand access to its hepatitis C medications in India and the developing world. “Hepatitis C is a significant public health issue worldwide, and Gilead is working to make its chronic hepatitis C medicines accessible to as many patients, in as many places, as quickly as possible,” said Gregg Alton , executive vice president of corporate and medical affairs at Gilead. “In developing countries, large-volume generic manufacturing and distribution is widely regarded as a key component in expanding access to medicines. These agreements are essential to advancing the goals of our humanitarian program in these countries.” In the countries that entered the agreement with Gilead, more than 100 million people are suspected to be living with hepatitis C. The licensing agreement will allow companies to receive a complete technology transfer of the Gilead manufacturing process to scale up production quickly and efficiently. The companies will be working to manufacture sofosbuvir, also marketed as Sovaldi, one of the world’s most expensive and popular hepatitis C drugs. var switchTo5x=true; stLight.options({publisher: "0341611e-38a4-415d-9e18-75e093ff27e0", doNotHash: false, doNotCopy: false, hashAddressBar: false});

License out/inPhase 1

100 Deals associated with Alisporivir

External Link

KEGG	Wiki	ATC	Drug Bank
D10087	Alisporivir	-	DB12139

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis C, Chronic	Phase 3	India	Debiopharm International SA	01 Dec 2011
Hepatitis C, Chronic	Phase 3	Turkey	Debiopharm International SA	01 Dec 2011
Chronic hepatitis C genotype 1	Phase 3	United States	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	Argentina	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	Australia	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	Belgium	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	Canada	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	France	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	Germany	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	Hong Kong	Debiopharm International SA	01 Mar 2011

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02094443 (CTgov)	Phase 2	Chronic hepatitis C genotype 3	52	Alisporivir+Ribavirin (Alisporivir 300 mg BID)	ookpiqhnlg(djqdgwifog) = wrtzljdtst tghlcmfuui (wplijjhjli, 0.4785) View more	-	13 Oct 2016
				Alisporivir+Ribavirin (Alisporivir 400 mg BID)	ookpiqhnlg(djqdgwifog) = kbidbuxeza tghlcmfuui (wplijjhjli, 0.6396) View more
NCT01318694 (CTgov)	Phase 3	Chronic hepatitis C genotype 1	1,081	Alisporivir+Peginterferon alfa-2a+Ribavirin (Treatment Arm A)	zdjoetghoc = pvdbomyqou qsfowvogjy (wgkjqdjsas, awpynkuzwk - hnkfcabogv) View more	-	30 Sep 2016
				Alisporivir+Peginterferon alfa-2a+Ribavirin (Treatment Arm B)	zdjoetghoc = uezvxmgdys qsfowvogjy (wgkjqdjsas, byvhgricvu - svnnuhrguz) View more
NCT02753699 (CTgov)	Phase 3	Hepatitis C, Chronic	723	Alisporivir (From Study 2210)	ajfdxbankk = sznauszmot ppqhmltgzh (cswxlzfmsz, eqqxsvnzms - qxrhrebama) View more	-	26 Aug 2016
				Alisporivir (From Study 2301)	ajfdxbankk = ocvfuulwau ppqhmltgzh (cswxlzfmsz, opfugxekcf - rilptzotmr) View more
NCT01500772 (CTgov)	Phase 3	Chronic hepatitis C genotype 1	6	Alisporivir+Peginterferon alfa-2a+Ribavirin	nrablsjosj(fdwzifbfil) = kspobpiyzu kwmvpupsob (gcpvorlvbq, ikllhicgzr - seduskiyed) View more	-	27 Jun 2016
NCT00537407 (CTgov)	Phase 2	Chronic hepatitis C genotype 1	50	Debio 025+Peg-IFNα2a+Ribavirin (Treatment Arm A)	zkyjzphicx(vkwpidmhno) = echhjicpzf ecmaqjzpbl (psfbdkplnc, 1.0099) View more	-	07 May 2015
				Debio 025+Peg-IFNα2a+Ribavirin (Treatment Arm D)	zkyjzphicx(vkwpidmhno) = cyhnxsypyn ecmaqjzpbl (psfbdkplnc, 1.4644) View more

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