Delving into the Latest Updates on Alisporivir with Synapse

Overview

Basic Info

Drug Type

Synthetic peptide

Synonyms

Alisporivir (USAN)

+ [3]

Target

CYPA

Mechanism

CYPA inhibitors(Cyclophilin A inhibitors)

Therapeutic Areas

Infectious DiseasesDigestive System DisordersNervous System Diseases+ [5]

Active Indication-

Inactive Indication

Chronic hepatitis C genotype 1Chronic hepatitis C genotype 2Chronic hepatitis C genotype 3+ [7]

Originator Organization

Debiopharm International SA

Active Organization-

Inactive Organization

Novartis Pharmaceuticals Corp.

Debiopharm International SA

Solid Biosciences, Inc.

+ [2]

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

RegulationSpecial Review Project (CN)

Login to view timeline

Structure

Molecular FormulaC63H113N11O12

InChIKeyOLROWHGDTNFZBH-XEMWPYQTSA-N

CAS Registry254435-95-5

Gene Sequence

Sequence Code 525034309

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]

EUCTR2020-002295-13-FR / Unknown statusPhase 2IIT

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. - CYCLOVID

Start Date15 Oct 2020

Sponsor / Collaborator

Assistance Publique des Hôpitaux de Paris SA

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.

100 Clinical Results associated with Alisporivir

Login to view more data

100 Translational Medicine associated with Alisporivir

Login to view more data

100 Patents (Medical) associated with Alisporivir

Login to view more data

96

Literatures (Medical) associated with Alisporivir

01 Oct 2024·Protein science : a publication of the Protein Society

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

Article

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

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: Limbach, Miranda N. ; Steren, Carlos A. ; Lindberg, Edward T. ; Martens, Jonathan ; van Tetering, Lara ; Olivos, Hernando J. ; Ngo, Van A. ; Oomens, Jos ; 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 Nov 2023·JHEP Reports

The novel cyclophilin inhibitor C105SR reduces hepatic ischaemia–reperfusion injury via mitoprotection

Article

Author: Ahnou, Nazim ; Morin, Didier ; Ahmed-Belkacem, Abdelhakim ; Hulin, Anne ; Teixeira-Clerc, Fatima ; Guichou, Jean-François ; Kheyar, Amel ; Pawlotsky, Jean-Michel ; Ghaleh, Bijan ; Pressiat, Claire

Background & AimsMitochondrial permeability transition pore (mPTP) opening is critical for mediating cell death during hepatic ischaemia-reperfusion injury (IRI). Blocking mPTP opening by inhibiting cyclophilin D (CypD) is a promising pharmacological approach for the treatment of IRI. Here, we show that diastereoisomers of a new class of small-molecule cyclophilin inhibitors (SMCypIs) have properties that make them attractive candidates for the development of therapeutic agents against liver IRI.MethodsDerivatives of the parent SMCypI were synthesised and evaluated for their ability to inhibit CypD peptidyl-prolyl cis-trans isomerase (PPIase) activity and for their mitoprotective properties, evaluated by measuring mitochondrial swelling and calcium retention capacity in liver mitochondria. The ability of the selected compounds to inhibit mPTP opening was evaluated in cells subjected to hypoxia/reoxygenation using a calcein/cobalt assay. Their ability to inhibit cell death was evaluated in cells subjected to hypoxia/reoxygenation by measuring lactate dehydrogenase (LDH) release, propidium iodide staining, and cell viability. The compound performing best in vitro was selected for in vivo efficacy evaluation in a mouse model of hepatic IRI.ResultsThe two compounds that showed the strongest inhibition of CypD PPIase activity and mPTP opening, C105 and C110, were selected. Their SR diastereoisomers carried the activity of the racemic mixture and exhibited mitoprotective properties superior to those of the known macrocyclic cyclophilin inhibitors cyclosporin A and alisporivir. C105SR was more potent than C110SR in inhibiting mPTP opening and prevented cell death in a model of hypoxia/reoxygenation. Finally, C105SR substantially protected against hepatic IRI in vivo by reducing hepatocyte necrosis and apoptosis.ConclusionsWe identified a novel cyclophilin inhibitor with strong mitoprotective properties both in vitro and in vivo that represents a promising candidate for cellular protection in hepatic IRI.Impact and ImplicationsHepatic ischaemia-reperfusion injury (IRI) is one of the main causes of morbidity and mortality during or after liver surgery. However, no effective therapies are available to prevent or treat this devastating syndrome. An attractive strategy to prevent hepatic IRI aims at reducing cell death by targeting mitochondrial permeability transition pore opening, a phenomenon regulated by cyclophilin D. Here, we identified a new small-molecule cyclophilin inhibitor, and demonstrated the enhanced mitoprotective and hepatoprotective properties of one of its diastereoisomers both in vitro and in vivo, making it an attractive lead compound for subsequent clinical development.

1

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.

100 Deals associated with Alisporivir

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
D10087	Alisporivir	-	DB12139

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Chronic hepatitis C genotype 1	Phase 3	AU	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	US	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	KR	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	MX	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	AU	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	ES	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	US	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	MX	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Phase 3	KR	Debiopharm International SA	01 Mar 2011
Chronic hepatitis C genotype 1	Discovery	ES	Debiopharm International SA	01 Mar 2011

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

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)	pjozburdvi(zjlcecstei) = ebuboetspy aoxaroxnil (pqjhffguxf, rehenwsuvz - jnzkolmdlg) View more	-	13 Oct 2016
				Alisporivir+Ribavirin (Alisporivir 400 mg BID)	pjozburdvi(zjlcecstei) = massbcngxm aoxaroxnil (pqjhffguxf, bytzhfbzgk - oagijvseht) View more
NCT01318694 (CTgov)	Phase 3	Chronic hepatitis C genotype 1	1,081	Peginterferon alfa-2a+Alisporivir+Ribavirin (Treatment Arm A)	abjzwxiyid(enkdghltmu) = riajatsefo xhovbjefsl (zskymqspey, jquiqcorjv - mnjirmxjxd) View more	-	30 Sep 2016
				Peginterferon alfa-2a+Alisporivir+Ribavirin (Treatment Arm B)	abjzwxiyid(enkdghltmu) = bdagkmwtwn xhovbjefsl (zskymqspey, asfrutlypo - syqzvvhuml) View more
NCT02753699 (CTgov)	Phase 3	Hepatitis C, Chronic	723	Alisporivir (From Study 2210)	lpdrxykdjl(cvadrjgcow) = ukqusfpyhi pcysibzlzt (vnpmmbwamp, qmswocthcn - nilgnjxvhr) View more	-	26 Aug 2016
				Alisporivir (From Study 2301)	lpdrxykdjl(cvadrjgcow) = pkqparqgkt pcysibzlzt (vnpmmbwamp, icpjahtfvw - dkwczekwzg) View more
NCT01500772 (CTgov)	Phase 3	Chronic hepatitis C genotype 1	6	Peginterferon alfa-2a+Alisporivir+Ribavirin	cmfpmkfvbo(qoevqmgwzh) = zqyyhsppfp ofepwwoiud (nvzstonioe, iclpsqgejm - zqxrucxfiv) View more	-	27 Jun 2016
NCT00537407 (CTgov)	Phase 2	Chronic hepatitis C genotype 1	50	Debio 025+Peg-IFNα2a+Ribavirin (Treatment Arm A)	ooiaskavtl(dergqmwqzc) = qdvsbycpde qtvhvqfumc (oponwszblc, xbjnxezmnd - gmlfptriid) View more	-	07 May 2015
				Debio 025+Peg-IFNα2a+Ribavirin (Treatment Arm D)	ooiaskavtl(dergqmwqzc) = mpegwdhhcf qtvhvqfumc (oponwszblc, ohfhkofhfq - toseomkxnl) View more