Comprehensive Pharmaceutical Asset Profile: Alisporivir (DB12139)

Executive Summary

Alisporivir (DB12139) is an investigational, orally administered small molecule that represents a pioneering effort in the field of host-targeting antiviral (HTA) therapy. A semi-synthetic derivative of cyclosporine A, Alisporivir was specifically engineered to inhibit the host protein cyclophilin A (CypA) without exerting the immunosuppressive effects of its parent compound. Its primary mechanism of action involves neutralizing the peptidyl-prolyl isomerase activity of CypA, thereby disrupting the formation of the Hepatitis C Virus (HCV) replication complex. This unique host-centric mechanism conferred several highly desirable properties, including potent, pangenotypic activity and a remarkably high barrier to the development of viral resistance, positioning it as a promising candidate for HCV treatment.

Extensive clinical development, encompassing over 2,000 patients, demonstrated significant efficacy, particularly when combined with the then-standard-of-care, pegylated interferon and ribavirin (PEG/RBV). In pivotal trials, Alisporivir-containing regimens consistently produced superior sustained virologic response (SVR) rates compared to PEG/RBV alone. However, the program's trajectory was irrevocably altered in 2012 by a partial clinical hold from the U.S. Food and Drug Administration (FDA). This regulatory action was prompted by a critical safety signal—a cluster of acute pancreatitis cases, including one fatality, observed exclusively in patients receiving Alisporivir in combination with interferon-based therapy.

Although subsequent analyses suggested that the incidence of pancreatitis was not statistically different from interferon therapy alone and that interferon-free Alisporivir regimens had a markedly better safety profile, the clinical hold, coupled with the concurrent revolution in HCV treatment brought by highly effective and safer direct-acting antivirals (DAAs), rendered the commercial and clinical path forward for Alisporivir in HCV untenable. Consequently, Novartis returned the development rights to Debiopharm in 2015.

Despite the cessation of its HCV program, the unique pharmacology of Alisporivir has sustained interest in its potential for therapeutic repurposing. Its ability to inhibit mitochondrial cyclophilin-D and modulate the mitochondrial permeability transition pore has provided a strong scientific rationale for its investigation in rare muscular dystrophies. This strategic pivot was validated in March 2022 when the European Medicines Agency (EMA) granted Alisporivir orphan drug designation for the treatment of collagen VI-related myopathies. Alisporivir's journey thus serves as a compelling case study in drug development, illustrating the profound impact of safety signals, the risks of targeting host biology, and the strategic resilience required to find value in a scientifically intriguing but commercially challenged asset.

Alisporivir: Compound Identification and Physicochemical Profile

Nomenclature and Identifiers

Alisporivir is an investigational small molecule drug that has been assigned numerous identifiers and development codes throughout its history. A comprehensive understanding of its nomenclature is essential for tracking its development and research across various scientific and regulatory databases.

• Generic Name: Alisporivir [1]
• Synonyms and Development Codes: The compound is widely known by its primary development code, DEB025 (also written as DEB 025, DEB-025, DEBIO 025, or DEBIO-025). Other codes include UNIL 025 (and UNIL-025). A chemically descriptive synonym is MeAla(3)EtVal(4)-cyclosporin, which highlights its structural relationship to cyclosporine.[1]
• Registry Numbers and Database Identifiers: To ensure unambiguous identification, Alisporivir is cataloged under several key international registries:
• CAS Number: 254435-95-5 [1]
• DrugBank Accession Number: DB12139 [1]
• PubChem Compound ID (CID): 11513676 [2]
• ChEMBL ID: CHEMBL1651956 [2]
• UNII (Unique Ingredient Identifier): VBP9099AA6 [2]
• KEGG ID: D10087 [2]

Chemical Classification and Structure

Alisporivir is a complex macrocyclic peptide with a distinct chemical heritage that defines its biological activity.

• Classification: It is classified as a small molecule and, more specifically, a homodetic cyclic peptide.[1] It belongs to the well-defined chemical class of cyclosporins, which are characterized as cyclic depsipeptides containing the cyclosporin backbone.[1] Taxonomically, it falls under the superclass of organic acids and derivatives and the class of peptidomimetics.[1]
• Chemical Formula and Molecular Weight: The molecular formula for Alisporivir is .[1] This corresponds to an average molecular weight of approximately 1216.6 g/mol (or 1216.662 Da) and a monoisotopic mass of approximately 1215.857 Da.[1]
• Systematic (IUPAC) Name: The complete and unambiguous IUPAC name for the structure is (3S,6S,9S,12R,15S,18S,21S,24S,27R,30S,33S)-25,30-diethyl-33--1,4,7,10,12,15,19,27,28-nonamethyl-6,9,18-tris(2-methylpropyl)-3,21,24-tris(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2,5,8,11,14,17,20,23,26,29,32-undecone.[1] A common chemical name that describes its peptide sequence is cyclo.[3]

Physicochemical Properties

The physicochemical properties of Alisporivir are characteristic of a large, complex macrocycle derived from a natural product. These properties are critical determinants of its pharmacokinetic behavior, formulation requirements, and overall "drug-likeness."

• Physical State and Appearance: Alisporivir is typically supplied as a white to off-white solid, which may be in a powder, lyophilized powder, or film form.[3]
• Solubility: The compound exhibits very poor aqueous solubility, a key challenge for oral drug delivery. Its calculated water solubility is extremely low at 0.00917 mg/mL.[1] In contrast, it is soluble in organic solvents such as dimethyl sulfoxide (DMSO), where concentrations of 50 mg/mL can be achieved with the aid of sonication.[9]
• Lipophilicity and Polarity: Alisporivir is a highly lipophilic molecule, as indicated by its partition coefficient (logP) values, which are consistently measured and calculated to be around 4.2 to 4.28.[1] Despite its lipophilicity, the molecule possesses a large polar surface area (PSA) of 278.8 , owing to its numerous amide and hydroxyl groups. It has 12 hydrogen bond acceptors and 5 hydrogen bond donors.[1]

The combination of a high molecular weight, high lipophilicity, and a large number of rotatable bonds and polar groups places Alisporivir well outside the parameters of typical oral small molecules, as defined by heuristics like Lipinski's Rule of Five.[1] This "beyond rule of 5" profile is not uncommon for cyclic peptides and natural product derivatives but necessitates specialized drug delivery solutions. The extremely low water solubility, for instance, is a primary driver for its formulation in soft gel capsules, a strategy designed to enhance dissolution and absorption in the gastrointestinal tract.[2] This indicates that formulation science was a critical and non-trivial component of its clinical development program, aimed at overcoming the inherent biopharmaceutical limitations of the molecule itself.

A summary of key physicochemical properties is provided in Table 1.

Table 1: Physicochemical Properties of Alisporivir

Property	Value	Source(s)
Molecular Formula		1
Average Molecular Weight	1216.662 Da	1
Monoisotopic Mass	1215.857018123 Da	1
Physical Form	White to off-white powder/film	3
Water Solubility	0.00917 mg/mL	1
logP (Octanol-Water Partition Coefficient)	4.2 - 4.28	1
logS (Aqueous Solubility)	-5.1	1
Polar Surface Area (PSA)	278.8	1
Hydrogen Bond Donors	5	1
Hydrogen Bond Acceptors	12	1
Rotatable Bond Count	15	1
pKa (Strongest Acidic)	11.85	1
pKa (Strongest Basic)	-2.4	1

Mechanism of Action: A Novel Host-Targeting Antiviral Strategy

Alisporivir's mechanism of action represents a significant departure from direct-acting antivirals (DAAs), which target specific viral enzymes or proteins. Instead, Alisporivir is the most clinically advanced example of a host-targeting antiviral (HTA), a strategy that aims to disrupt the viral life cycle by inhibiting host cellular factors that are essential for viral replication.[11]

Primary Mechanism: Inhibition of Cyclophilin A and Disruption of the HCV Replisome

The central mechanism of Alisporivir's anti-HCV activity is its potent and specific inhibition of a host protein called cyclophilin A (CypA).[2] Cyclophilins are a family of ubiquitous intracellular proteins that possess peptidyl-prolyl cis-trans isomerase (PPIase) activity, an enzymatic function that catalyzes the slow isomerization of peptide bonds preceding proline residues, thereby acting as critical chaperones in protein folding and regulation.[15]

The replication of the Hepatitis C virus is critically dependent on CypA.[11] The virus co-opts this host factor to ensure the correct conformation and function of its own nonstructural protein 5A (NS5A), a key component of the viral replication complex, often referred to as the replisome.[15] Alisporivir functions by binding with high affinity directly to the hydrophobic enzymatic pocket of CypA, which competitively inhibits and neutralizes its PPIase activity.[11] This blockade prevents the crucial interaction between CypA and specific proline residues within domain II of the HCV NS5A protein.[9] Without the chaperoning activity of CypA, NS5A is unable to achieve its correct functional conformation, leading to a dysfunctional replication complex and a potent inhibition of viral RNA synthesis.[3]

Molecular Basis for Pangenotypic Activity and High Barrier to Resistance

The decision to target a host factor rather than a viral one confers two profound and highly advantageous therapeutic properties: broad genotypic coverage and a high barrier to resistance.

• Pangenotypic Activity: Because CypA is a highly conserved human protein, its structure and function do not vary between individuals infected with different HCV genotypes. Consequently, Alisporivir's ability to inhibit CypA is independent of the viral genotype, making it a pangenotypic agent with demonstrated potent activity against HCV genotypes 1, 2, 3, and 4.[12] This contrasts sharply with many early-generation DAAs, which often had a narrow spectrum of activity limited to specific genotypes.
• High Barrier to Resistance: Viruses, particularly RNA viruses like HCV, have high mutation rates, allowing them to rapidly develop resistance to drugs that target viral proteins. By targeting a host protein, Alisporivir presents the virus with a formidable challenge. For the virus to become resistant, it would need to evolve in a way that it no longer depends on CypA for replication—a significant evolutionary hurdle. In vitro resistance selection experiments have validated this high genetic barrier; while resistance to DAAs can typically be generated in under two weeks, it required an average of 20 weeks of continuous culture to select for Alisporivir-resistant HCV replicons.[15] Furthermore, the primary mutation identified, D320E in NS5A, conferred only a low level of resistance, suggesting that the virus cannot easily circumvent its dependency on CypA.[19]
• Lack of Cross-Resistance: The mechanism of Alisporivir is orthogonal to that of all major DAA classes. DAAs target distinct viral proteins like the NS3/4A protease, the NS5B polymerase, or domain I of the NS5A protein.[12] Because Alisporivir targets a host protein, viral mutations that confer resistance to DAAs have no impact on Alisporivir's activity, and vice versa. This lack of cross-resistance makes Alisporivir, in principle, an ideal partner for combination therapy, capable of suppressing DAA-resistant variants.[12]

Non-immunosuppressive Profile: Structural Modifications from Cyclosporine A

Alisporivir is a semi-synthetic derivative of Cyclosporine A (CsA), a well-known immunosuppressant drug.[6] The immunosuppressive action of CsA is not due to CypA inhibition itself, but rather to the formation of a ternary molecular complex consisting of CsA, CypA, and a calcium-dependent phosphatase called calcineurin. This complex inhibits calcineurin's activity, which is a key step in the T-cell activation pathway.[23]

Alisporivir was rationally designed to abrogate this immunosuppressive effect while retaining its high-affinity binding to cyclophilins.[2] This was achieved through specific chemical modifications to the parent CsA structure. The key changes are the substitution of sarcosine at amino acid position 3 with N-methyl-D-alanine, and the substitution of N-methyl-leucine at position 4 with N-ethyl-valine.[10] These modifications, particularly the change at position 4, sterically hinder the binding of the Alisporivir-CypA complex to calcineurin.[16] As a result, Alisporivir does not inhibit calcineurin and is devoid of clinically significant immunosuppressive activity, allowing it to be developed as a dedicated antiviral agent.[23]

Ancillary Mechanisms: Mitochondrial Protection and Broader Antiviral Potential

While developed for HCV, Alisporivir's mechanism of inhibiting cyclophilins has broader biological implications that form the basis for its potential use in other diseases.

• Mitochondrial Protection: In addition to the cytosolic CypA, Alisporivir also inhibits cyclophilin-D (CypD), a cyclophilin isoform located in the mitochondrial matrix.[2] CypD is a key regulatory component of the mitochondrial permeability transition pore (mPTP), a large, non-selective channel in the inner mitochondrial membrane. Under conditions of cellular stress (such as oxidative stress or calcium overload), the opening of the mPTP can lead to mitochondrial depolarization, cessation of ATP synthesis, and ultimately, cell death.[2] By inhibiting CypD, Alisporivir desensitizes the mPTP to these triggers, preventing its inappropriate opening and thereby protecting mitochondrial function and preventing cell death.[2] This mitochondrial-protective mechanism is the primary rationale for investigating Alisporivir in diseases characterized by mitochondrial dysfunction, such as Duchenne muscular dystrophy.[3]
• Broader Antiviral Spectrum: The replication cycles of numerous other viruses are also dependent on host cyclophilins. Consequently, Alisporivir has demonstrated a broad spectrum of antiviral activity in preclinical models. This includes in vitro activity against human immunodeficiency virus-1 (HIV-1), Hepatitis B Virus (HBV), and several coronaviruses, including MERS-CoV and SARS-CoV-2, the causative agent of COVID-19.[2]
• Immune Modulation: Separate from its antiviral and mitochondrial effects, Alisporivir has been shown to have immunomodulatory properties that are distinct from immunosuppression. Studies have demonstrated that it can stimulate antigen presentation by upregulating the surface expression of Major Histocompatibility Complex class I (MHC-I) molecules on cells. This enhancement of antigen presentation can, in turn, promote more robust activation of antigen-specific CD8+ T cells, a key component of the adaptive immune response against viral infections and tumors.[9]

The host-targeting strategy of Alisporivir is the source of its most compelling therapeutic attributes, but it also carries inherent risks. While targeting a viral protein offers high specificity, targeting a ubiquitous and multifunctional host protein like cyclophilin creates a greater potential for on-target but physiologically undesirable side effects. The clinical experience with Alisporivir, particularly the emergence of hyperbilirubinemia due to the inhibition of host bilirubin transporters, serves as a clear example of this principle.[12] This dynamic illustrates that the development of any HTA requires a careful balancing of the benefits of a high resistance barrier against the intrinsic risk of interfering with normal host cell biology.

Pharmacokinetic Profile and Metabolic Interactions

The clinical utility of Alisporivir is governed by its pharmacokinetic (PK) profile, which describes its absorption, distribution, metabolism, and excretion (ADME). As a large, lipophilic cyclic peptide, its PK properties are complex and present significant potential for drug-drug interactions (DDIs).

Absorption, Distribution, Metabolism, and Excretion (ADME) Overview

• Absorption: Alisporivir is formulated for oral administration in soft gel capsules to overcome its poor aqueous solubility.[10] In vitro studies using Caco-2 cell monolayers, a model of the intestinal barrier, show that Alisporivir has good passive permeability ( cm/s).[10] Following oral administration, it is rapidly absorbed, with the time to reach maximum plasma concentration () occurring at approximately 2 hours.[10] Pharmacokinetic modeling has suggested that its bioavailability is not constant but increases over the first few days of dosing, reaching a maximal relative bioavailability approximately 3-fold higher than baseline after about 4 days of treatment.[30] This phenomenon necessitates the use of a higher, twice-daily loading dose for the first week of therapy to rapidly achieve therapeutic concentrations, followed by a once-daily maintenance dose.[23]
• Distribution: The distribution of Alisporivir in the body is best described by a two-compartment PK model.[30] Its lipophilic nature suggests wide distribution into tissues. This property has been cited as part of the rationale for its investigation in COVID-19, with the hypothesis that the drug accumulates in lung tissue, the primary site of infection.[32]
• Metabolism: Alisporivir undergoes extensive hepatic metabolism. The primary enzyme responsible for its biotransformation is cytochrome P450 3A4 (CYP3A4), a major drug-metabolizing enzyme in the liver.[10]
• Excretion: Following metabolism, the metabolites of Alisporivir are primarily eliminated from the body via the bile.[23] The drug exhibits a very long terminal elimination half-life (), estimated to be approximately 100 hours. This long half-life is what allows for a convenient once-daily dosing schedule during maintenance therapy.[23]

Role of CYP3A4 and Clinically Significant Drug-Drug Interactions (DDI)

The central role of CYP3A4 in Alisporivir's clearance makes it highly susceptible to clinically significant DDIs. Furthermore, Alisporivir itself is not merely a passive substrate but also acts as a time-dependent inhibitor (TDI) of CYP3A4, meaning its inhibitory effect increases with duration of exposure.[10] This dual role as both a "victim" and a "perpetrator" of CYP3A4-mediated interactions is a critical clinical pharmacology consideration.

• Alisporivir as a Victim Drug: The co-administration of drugs that strongly modulate CYP3A4 activity can dramatically alter Alisporivir exposure, with potentially severe consequences for efficacy and safety.
• CYP3A4 Inhibition: When co-administered with a strong CYP3A4 inhibitor like ketoconazole, the metabolism of Alisporivir is blocked, leading to a massive increase in its plasma concentration. PBPK modeling predicted that ketoconazole would increase the Alisporivir area-under-the-curve (AUC), a measure of total drug exposure, by 9.4-fold.[10] Such an increase would almost certainly lead to toxicity.
• CYP3A4 Induction: Conversely, when co-administered with a strong CYP3A4 inducer like rifampin, the metabolic clearance of Alisporivir is greatly accelerated. The same PBPK model predicted that rifampin would cause a profound 86% decrease in Alisporivir AUC, which would likely result in sub-therapeutic concentrations and loss of antiviral efficacy.[10]
• Alisporivir as a Perpetrator Drug: As a TDI of CYP3A4, Alisporivir can inhibit the metabolism of other co-administered drugs that are also CYP3A4 substrates. This could lead to increased concentrations and potential toxicity of the companion drug.
• Interaction with Pegylated Interferon (Peg-IFN): An interesting interaction was identified through PK modeling of clinical trial data. The analysis suggested that peg-IFN may reduce the elimination of Alisporivir, particularly at the higher 1000 mg dose. The model indicated this effect was mediated by a decrease in the maximal velocity () and Michaelis constant () of Alisporivir's metabolism.[30] This finding is particularly salient as it provides a potential pharmacokinetic explanation for the observed safety profile of Alisporivir. The pancreatitis cases that led to the clinical hold occurred exclusively in patients receiving combination therapy with peg-IFN and ribavirin.[35] A reduction in Alisporivir clearance by peg-IFN would lead to higher-than-anticipated drug exposure, which could in turn increase the risk of concentration-dependent adverse events. This suggests a plausible causal link between the PK interaction and the pharmacodynamic toxicity observed in the clinical program.

Insights from Physiologically Based Pharmacokinetic (PBPK) Modeling

Given the complex PK and high DDI potential, PBPK modeling was a crucial tool in the development of Alisporivir. A comprehensive PBPK model was developed using the Simcyp platform, integrating in vitro data (e.g., permeability, metabolism kinetics) with in vivo clinical data from human studies.[10]

The model demonstrated strong predictive performance, accurately simulating the observed clinical PK parameters (AUC, , ) after both single and multiple doses, with prediction deviations generally within 32% of actual values.[10] Most importantly, the model's predictions for the magnitude of the critical DDIs with ketoconazole and rifampin were highly accurate, falling within 20% of the clinically observed changes.[10] This validation confirmed the model's utility as a powerful tool for simulating different dosing scenarios, predicting un-tested DDIs, and informing clinical trial design to mitigate risks associated with its complex pharmacology.

Table 3: Summary of Predicted Drug-Drug Interactions with Alisporivir as a Victim Drug

Co-administered Drug	Mechanism of Interaction	Predicted Effect on Alisporivir AUC	Source(s)
Ketoconazole	Strong CYP3A4 Inhibitor	9.4-fold Increase	10
Rifampin	Strong CYP3A4 Inducer	86% Decrease	10

Clinical Development in Hepatitis C Virus (HCV) Infection

Alisporivir underwent an extensive clinical development program for the treatment of chronic HCV infection, progressing from early proof-of-concept studies to large-scale, pivotal Phase 3 trials. The program demonstrated substantial efficacy but was ultimately halted due to a critical safety concern. A summary of the key clinical trials is presented in Table 2.

Early Phase Studies: Establishing Proof-of-Concept and Dose-Finding

The initial clinical studies were designed to confirm Alisporivir's antiviral activity in humans and to identify an appropriate dose range for further development.

• Phase Ib Study in HIV/HCV Co-infection: Proof-of-concept was first established in a 14-day, double-blind, placebo-controlled study in patients co-infected with HIV and HCV. In this challenging population, Alisporivir administered as monotherapy at a dose of 1200 mg twice daily (BID) produced a profound and rapid decline in HCV RNA levels, with a maximal drop of 3.63  copies/mL. In several patients, the virus became undetectable within 8 to 15 days of treatment. Importantly, this study showed activity across HCV genotypes 1, 3, and 4, and no patients developed viral breakthrough during treatment, providing the first clinical evidence of its high barrier to resistance.[15]
• Phase IIa Study (DEB-025-HCV-203): This 29-day study in 90 treatment-naïve patients with HCV genotypes 1, 2, 3, or 4 was a critical dose-ranging trial. It evaluated Alisporivir at doses of 200, 600, and 1000 mg daily, both as monotherapy and in combination with pegylated interferon alfa-2a (peg-IFN). The results showed a clear dose-dependent antiviral effect when combined with peg-IFN, achieving mean viral load reductions of over 4  IU/mL in genotype 1 patients and over 5  IU/mL in genotype 2/3 patients by week 4.[30] This study also identified the first safety signal of interest: the 1000 mg dose was associated with isolated and transient hyperbilirubinemia.[15]

Phase II Investigations: Efficacy in Diverse Genotypes and Patient Populations

Following the promising early results, a series of robust Phase IIb studies were launched to explore Alisporivir's efficacy in different patient populations and as part of interferon-free regimens.

• NCT01215643: This large Phase IIb study enrolled 340 treatment-naïve patients with HCV genotypes 2 and 3, who are generally considered easier to treat than genotype 1. The trial was designed to evaluate the potential of interferon-sparing and interferon-free regimens. It compared Alisporivir monotherapy, Alisporivir plus ribavirin (RBV), and Alisporivir plus peg-IFN against the standard of care (peg-IFN plus RBV).[4] The study was a success, with the Alisporivir-containing arms achieving sustained virologic response at 24 weeks (SVR24) rates of 80% to 85%, significantly higher than the 58% SVR24 rate in the standard of care arm.[13] These results provided strong evidence that an effective interferon-free regimen with Alisporivir was achievable.
• NCT01183169 (FUNDAMENTAL): This Phase II study targeted a difficult-to-treat population: patients with chronic HCV genotype 1 who had previously failed to respond to (non-responders) or relapsed after a prior course of interferon-based therapy. The study evaluated the efficacy of adding Alisporivir to a retreatment course of peg-IFN and RBV, demonstrating its utility in a treatment-experienced setting.[4]
• NCT02094443: This Phase II trial further advanced the interferon-free concept by evaluating two dose regimens of Alisporivir in combination with only ribavirin in patients with HCV genotypes 2 and 3 for whom interferon was not a viable option (due to prior failure, intolerance, or contraindication).[4]

Pivotal Phase III Trials and Terminated Studies

Based on the strength of the Phase II data, Alisporivir advanced into a large-scale Phase 3 program, primarily focused on the most common and difficult-to-treat HCV genotype 1. However, this program was ultimately cut short.

• ESSENTIAL I: This was a large, randomized, placebo-controlled Phase 3 study involving 1,081 treatment-naïve patients with HCV genotype 1. It evaluated two Alisporivir regimens (600 mg once daily or 400 mg BID) added to peg-IFN and RBV, compared to placebo plus peg-IFN/RBV. The addition of Alisporivir led to a significant improvement in efficacy. The overall sustained virologic response at 12 weeks (SVR12), the primary endpoint, was 69% across all Alisporivir groups, compared to just 53% in the control arm. The most effective regimen was Alisporivir 400 mg BID, which achieved an SVR12 rate of 90% in patients who were able to complete more than 24 weeks of therapy.[13]
• ESSENTIAL II (NCT01446250): This pivotal Phase 3 trial was designed to assess the safety and efficacy of Alisporivir and the protease inhibitor boceprevir, each in combination with peg-IFN/RBV, specifically in African American patients with HCV genotype 1, a population historically known to have lower response rates to interferon-based therapy.[44] The study was terminated prematurely following the FDA's partial clinical hold in 2012. All participants randomized to the Alisporivir arms were immediately taken off the investigational drug.[44]
• NCT01500772: This Phase 3 trial was also terminated. It was designed to evaluate Alisporivir plus peg-IFN/RBV in patients with genotype 1 who had already failed a prior, more advanced therapy containing a first-generation protease inhibitor (e.g., boceprevir or telaprevir), representing a population with very high unmet medical need at the time.[4]

Long-Term Follow-up

To assess the durability of the cure achieved with Alisporivir, a long-term follow-up study was conducted.

• NCT02753699: This was a completed Phase 3 study designed to follow patients who had been treated with Alisporivir in previous trials to assess the long-term durability of their sustained virologic response.[4]

Table 2: Summary of Key Alisporivir Clinical Trials in Hepatitis C

NCT Identifier	Trial Name/Acronym	Phase	Patient Population (Genotype, Treatment Status)	Key Intervention Arms	Primary Endpoint	Status
N/A	Phase Ib Co-infection Study	Ib	HIV/HCV Co-infected (GT 1, 3, 4)	Alisporivir 1200 mg BID Monotherapy	HCV RNA reduction	Completed
N/A	DEB-025-HCV-203	IIa	Treatment-Naïve (GT 1-4)	Alisporivir (200, 600, 1000 mg) +/- PEG	HCV RNA reduction	Completed
NCT01215643	N/A	IIb	Treatment-Naïve (GT 2, 3)	ALV Monotherapy; ALV + RBV; ALV + PEG vs. PEG + RBV	SVR24	Completed
NCT01183169	FUNDAMENTAL	II	Treatment-Experienced (GT 1)	Alisporivir + PEG + RBV	SVR	Completed
N/A	ESSENTIAL I	III	Treatment-Naïve (GT 1)	ALV (600 mg QD or 400 mg BID) + PEG + RBV vs. Placebo + PEG + RBV	SVR12	Terminated
NCT01446250	ESSENTIAL II	III	Treatment-Naïve African American (GT 1)	Alisporivir + PEG + RBV vs. Boceprevir + PEG + RBV	SVR24	Terminated
NCT01500772	N/A	III	Protease Inhibitor Failures (GT 1)	Alisporivir + PEG + RBV	SVR12	Terminated
NCT02094443	N/A	II	Interferon Ineligible/Failures (GT 2, 3)	Alisporivir (300 or 400 mg BID) + RBV	Pharmacodynamics / Safety	Completed
NCT02753699	N/A	III	Previously ALV-treated patients	Observational Follow-up	Durability of SVR	Completed

Comprehensive Safety and Tolerability Assessment

The safety profile of Alisporivir was extensively characterized across a large clinical program. While generally considered to have an acceptable profile, particularly in the absence of interferon, the emergence of a rare but serious adverse event ultimately led to the cessation of its development for HCV.

Overview of the Adverse Event (AE) Profile

Across studies involving more than 2,000 patients, Alisporivir was often described as having a favorable and acceptable safety profile.[13] A critical distinction in its safety profile emerged when comparing interferon-free regimens to those containing interferon. When Alisporivir was combined with pegylated interferon and ribavirin (PEG/RBV), the most frequently reported adverse events were largely consistent with the known side-effect profile of PEG/RBV therapy itself. These included constitutional symptoms like headache and fatigue, gastrointestinal issues like nausea, and hematological abnormalities such as anemia and neutropenia.[12]

Characterization of Common Adverse Events of Interest

Several specific adverse events were observed more frequently with Alisporivir treatment and were monitored closely throughout the clinical program.

• Hyperbilirubinemia: A dose-dependent, unconjugated hyperbilirubinemia was the most common laboratory abnormality associated with Alisporivir.[12] This was identified early in development and was determined to be a mechanistic, on-target effect rather than a sign of hepatocellular injury. Alisporivir inhibits the organic anion-transporting polypeptide (OATP) and multidrug resistance-associated protein 2 (MRP2) transporters in the liver, which are responsible for bilirubin uptake and excretion.[12] This inhibition leads to a benign, reversible elevation in serum bilirubin that is not associated with liver toxicity. In clinical trials, this effect was generally transient and resolved upon treatment discontinuation.[15]
• Hypertension: An increased incidence of elevated blood pressure was noted in patients receiving Alisporivir compared to control groups.[21] In the ESSENTIAL I trial, hypertension was reported as an adverse event in 19% of patients in the Alisporivir 400 mg BID arm, compared with only 2% in the PEG/RBV control arm.[49]
• Hematologic Effects: While interferon-based therapy is known to cause myelosuppression, the addition of Alisporivir appeared to exacerbate certain hematologic side effects. Specifically, higher rates of anemia and thrombocytopenia were observed in patients receiving Alisporivir plus PEG/RBV compared to those receiving PEG/RBV alone.[21]

The Critical Safety Signal: Pancreatitis

The pivotal event in Alisporivir's development history was the emergence of pancreatitis as a serious adverse event (SAE) of special interest.

• FDA Clinical Hold: In April 2012, the U.S. Food and Drug Administration (FDA) placed the Alisporivir development program on a partial clinical hold.[36] This action was taken in response to reports of a small number of patients developing acute pancreatitis during clinical trials.[51]
• Case Details: The reports indicated a cluster of approximately 3 to 7 cases of pancreatitis across the global program, which had enrolled around 1,800 patients at the time.[35] Critically, one of these cases was fatal.[21]
• Association with Interferon: A key observation was that all of the reported pancreatitis cases occurred in patients who were receiving Alisporivir as part of a triple-therapy regimen that included pegylated interferon and ribavirin.[35] Pancreatitis is a known, though infrequent, risk associated with interferon therapy itself.[35] This raised the crucial question of whether Alisporivir was an independent cause of pancreatitis or if it potentiated the known risk associated with interferon.[36]

Comparative Safety: Interferon-Free vs. Interferon-Containing Regimens

Further analysis of the comprehensive safety database revealed a stark difference in the risk profile of Alisporivir depending on the presence of interferon.

• Superior Profile of Interferon-Free Regimens: A large, pooled analysis of the clinical database, involving data from over 2,000 patients, confirmed that Alisporivir administered in interferon-free regimens was well-tolerated and had a markedly superior safety profile compared to interferon-containing combinations.[49] Rates of common interferon-related side effects like anemia, neutropenia, thrombocytopenia, headache, fatigue, and pyrexia were significantly lower in the interferon-free arms.[49]
• Absence of Pancreatitis Signal in IFN-Free Trials: Most importantly, in a cohort of 260 patients treated with interferon-free Alisporivir regimens for at least six weeks, there were zero reported cases of pancreatitis.[49]
• Comparative Incidence: In the large Phase 3 trials, the incidence of pancreatitis in the Alisporivir plus PEG/RBV arms (0.35% to 0.6%) was not statistically different from the incidence in the PEG/RBV control arms (0.41% to 0.8%).[43] While this suggests Alisporivir may not have increased the baseline risk, the clustering of cases and the fatality were sufficient to trigger regulatory action.
• Preclinical Findings: Subsequent preclinical safety studies in a cerulein-induced pancreatitis rat model showed that Alisporivir, either alone or in combination with interferon and ribavirin, did not cause or exacerbate pancreatic damage. In fact, some data suggested a protective effect, consistent with its known mechanism of inhibiting cyclophilin-D and the mitochondrial permeability transition pore.[55]

This complex safety picture reveals that Alisporivir became a victim of its therapeutic context and timing. The pancreatitis signal emerged exclusively within the interferon-based standard-of-care paradigm. At the very same time, the entire field of HCV treatment was being revolutionized by the arrival of all-oral, interferon-free DAA regimens that were not only more effective but also vastly safer and better tolerated.[53] This seismic shift in the therapeutic landscape meant that even if the pancreatitis risk was determined to be an interaction with interferon, the clinical and commercial rationale for continuing to develop an interferon-based or even an interferon-sparing regimen with Alisporivir had evaporated. Its development for HCV was halted not just by a safety signal, but by a safety signal that appeared at the precise moment its target market and the standard of care became obsolete.

Regulatory and Corporate Development Trajectory

The history of Alisporivir is marked by a promising partnership between a mid-sized and a large pharmaceutical company, a pivotal regulatory setback, and a subsequent strategic reorientation toward rare diseases.

Early Development and the Debiopharm-Novartis Partnership

Alisporivir, originally known as DEB 025, was discovered and initially developed by Debiopharm Group™, a Swiss-based biopharmaceutical company.[38] Following highly successful Phase I and Phase IIa studies that demonstrated potent, pangenotypic antiviral activity, the asset attracted major industry interest.[18]

In February 2010, Debiopharm announced a major strategic collaboration, granting an exclusive worldwide license (with the exception of Japan) to Novartis for the development, manufacturing, and commercialization of Alisporivir for the treatment of Hepatitis C.[18] The terms of the agreement included a significant upfront payment to Debiopharm, as well as substantial future payments contingent on development and sales milestones, plus royalties on net sales.[18] This partnership provided the financial and operational resources of a large pharmaceutical company to drive Alisporivir through late-stage clinical development and global registration.[50]

The 2012 FDA Partial Clinical Hold: A Turning Point

Under Novartis's stewardship, Alisporivir was advanced into a comprehensive Phase 3 program. However, in April 2012, the program encountered a critical and ultimately insurmountable obstacle. The U.S. Food and Drug Administration (FDA) mandated a partial clinical hold on the entire Alisporivir development program.[36]

This regulatory action was a direct result of the emergence of several cases of acute pancreatitis, including one fatality, in patients participating in the clinical trials.[51] The hold required an immediate cessation of Alisporivir dosing in all ongoing studies and halted the recruitment of new patients.[45] This event effectively froze the late-stage development of the drug, introducing significant delays and casting a long shadow of uncertainty over its safety profile and future viability.

Return of Rights and Subsequent Strategic Shifts

The clinical hold, combined with the rapidly evolving HCV treatment landscape, led to a re-evaluation of the asset's strategic value. In January 2015, nearly three years after the hold was initiated, Debiopharm announced that it had regained full global rights to the Alisporivir program from Novartis.[48]

The official reason provided by Novartis was a strategic portfolio transformation, in which HCV-related indications were no longer a primary focus.[48] While portfolio prioritization is a common practice in large pharmaceutical companies, this decision was undoubtedly influenced by the unresolved regulatory uncertainty stemming from the clinical hold and, perhaps more importantly, the dramatic commercial success of new, all-oral, interferon-free direct-acting antiviral (DAA) regimens. These new therapies offered cure rates exceeding 95% with far superior safety profiles, effectively rendering the market for an add-on to interferon therapy obsolete. For a company like Novartis, the complex calculation of remaining development costs, regulatory risk, and a rapidly diminishing market potential made the continuation of the Alisporivir program for HCV commercially non-viable.

Upon reacquiring the asset, Debiopharm signaled its intent to continue development, leveraging the extensive existing data package to explore other potential indications beyond HCV and to seek new partnerships.[48]

European Medicines Agency (EMA) Status

Alisporivir has had two notable interactions with the European Medicines Agency (EMA).

• Paediatric Investigation Plan (PIP): In July 2012, the EMA granted a waiver for a PIP for Alisporivir in the therapeutic area of infectious diseases. This decision acknowledged that the drug was not likely to be used in the pediatric population for this indication.[2]
• Orphan Drug Designation: In a clear manifestation of the strategic pivot away from HCV, Alisporivir was granted orphan drug designation by the EMA on March 16, 2022. The designation (EU/3/22/2590), sponsored by Fondazione Telethon Ets, is for the "treatment of collagen VI-related myopathies".[2] This is a significant regulatory milestone that provides the sponsor with incentives, including scientific advice from the EMA and a period of market exclusivity upon potential approval, to develop the drug for this rare, debilitating condition.

Exploration of Therapeutic Potential Beyond HCV

Following the discontinuation of its development for Hepatitis C, the unique biological activities of Alisporivir have prompted its investigation in other therapeutic areas, most notably other viral infections and rare muscular dystrophies.

Rationale and Clinical Investigation in Coronaviral Infections (COVID-19)

The reliance of various coronaviruses on host cyclophilins for their replication provided a strong scientific rationale for evaluating Alisporivir as a potential treatment for COVID-19.

• Preclinical Rationale: In vitro studies demonstrated that Alisporivir effectively inhibits the replication of multiple coronaviruses, including MERS-CoV and, importantly, SARS-CoV-2.[2] The proposed mechanism of action in this context is twofold: a direct antiviral effect by decreasing viral load within infected cells, and a potential host-modulatory effect by reducing the risk of excessive immune-mediated lung damage.[32] The drug's tendency to distribute widely and accumulate in the lungs was considered an additional advantage.[33]
• Phase II Clinical Trial: Based on this preclinical evidence, an investigator-initiated, randomized, open-label, proof-of-concept Phase II trial was launched in France in early 2021.[32] The study aimed to enroll 90 hospitalized patients with early-stage COVID-19 who were not yet requiring mechanical ventilation. The primary objective was to assess the effect of Alisporivir on viral load reduction. Patients in the investigational arm were to receive a dose of 600 mg twice daily for 14 days, administered either orally or via a nasogastric tube, in addition to the standard of care.[32]

Preclinical Evidence and Regulatory Status in Muscular Dystrophies

A more promising and strategically focused area for repurposing Alisporivir has been in the treatment of certain rare genetic muscular dystrophies. This effort leverages Alisporivir's ancillary mechanism of action related to mitochondrial function.

• Scientific Rationale: The pathogenesis of several muscular dystrophies, including Duchenne muscular dystrophy (DMD), involves mitochondrial dysfunction. A key element of this dysfunction is the inappropriate opening of the mitochondrial permeability transition pore (mPTP), which is regulated by the mitochondrial protein cyclophilin-D.[2] By inhibiting cyclophilin-D, Alisporivir can prevent mPTP opening, thereby protecting mitochondria from stress-induced damage, preserving respiratory function, and preventing myocyte cell death.[2]
• Preclinical Evidence: Compelling preclinical data supports this hypothesis. Studies using primary muscle cell cultures derived from DMD patients have shown that Alisporivir treatment can rescue defective mitochondrial respiration and restore the normal respiratory reserve capacity.[27] Furthermore, in a severe zebrafish model of DMD, treatment with Alisporivir led to a substantial recovery of respiratory function, which correlated with improved muscle ultrastructure and increased survival of the animals.[27]
• Regulatory Validation: This strategic pivot received significant validation from regulatory authorities. On March 16, 2022, the European Medicines Agency (EMA) granted Alisporivir a positive opinion for orphan drug designation for the treatment of collagen VI-related myopathies, another group of severe genetic muscle disorders.[2] This designation provides a clear regulatory path forward and valuable incentives for the development of Alisporivir in this area of high unmet medical need.

Synthesis and Manufacturing Overview

Alisporivir is a complex semi-synthetic macrocyclic peptide, whose manufacturing process begins with a naturally occurring fermentation product and involves specific, targeted chemical modifications.

Origin as a Cyclosporine A Derivative

The starting material for the synthesis of Alisporivir is Cyclosporine A (CsA), a cyclic undecapeptide originally isolated from the fungus Tolypocladium inflatum.[6] Alisporivir is therefore classified as a semi-synthetic derivative. The synthesis is not a de novo total synthesis but rather a modification of the pre-existing CsA scaffold.[22]

The core of the synthetic strategy involves chemically altering two specific amino acid residues in the CsA backbone. These modifications are precisely designed to change the molecule's pharmacological profile: retaining the high-affinity binding to cyclophilins (the basis of its antiviral activity) while eliminating the ability of the drug-cyclophilin complex to bind to calcineurin (the interaction responsible for immunosuppression).[14]

Patented Synthesis Method

While the exact industrial manufacturing process is proprietary, a patented method provides insight into a viable and efficient route for producing Alisporivir.[58] This method is designed to be high-yielding and produce high-purity material suitable for pharmaceutical use.

The process described in the patent starts with a linear peptide precursor, H-D-MeAla-EtVal-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal-MeBmt-alphaAbu-OH, which itself is derived from CsA through a series of chemical steps including protection, oxidation, and degradation to open the macrocycle, followed by coupling reactions.[58] The final and most critical step is the macrocyclization of this linear precursor to form the Alisporivir ring structure.

The patented method highlights the use of triphosgene as a particularly effective cyclizing agent. The key steps of this cyclization are:

1. The linear peptide is dissolved in an organic solvent such as methylene dichloride, along with coupling reagents like 1-Hydroxy-7-azabenzotriazole (HOAt) and N,N'-Diisopropylcarbodiimide (DIC).[58]
2. A solution of triphosgene is added dropwise to the reaction mixture under an inert atmosphere (e.g., nitrogen).[58]
3. The reaction is allowed to proceed for an extended period (e.g., 24 hours) to ensure complete cyclization.
4. The process can be enhanced by the addition of a catalyst, such as activated carbon or pyridine, which can further improve the reaction yield.[58]
5. Following the reaction, the mixture is worked up through a series of extraction and washing steps, and the final product is purified, typically by column chromatography.

This method is reported to achieve product yields of over 80% and purity levels exceeding 95%, making it a robust and scalable process for industrial manufacturing.[58]

Expert Analysis and Future Outlook

The developmental history of Alisporivir offers a compelling and cautionary narrative of profound scientific innovation, immense clinical promise, critical safety-related setbacks, and ultimately, strategic resilience. Its trajectory encapsulates many of the core challenges and complexities inherent in modern pharmaceutical R&D, providing valuable lessons for the development of host-targeting agents and the navigation of rapidly evolving therapeutic landscapes.

The Promise: Alisporivir's core strength lies in its novel host-targeting mechanism of action. By inhibiting the host protein cyclophilin A, it presented a solution to the two greatest challenges in antiviral therapy at the time: viral resistance and limited genotypic coverage. Its demonstrated pangenotypic activity and exceptionally high barrier to resistance were truly differentiating features that positioned it as a potential cornerstone of future HCV therapy. The rational design that successfully cleaved this potent antiviral activity from the immunosuppressive effects of its parent compound, Cyclosporine A, was a triumph of medicinal chemistry.

The Peril: The downfall of the Alisporivir program for HCV was not due to a single factor but rather a confluence of three interconnected challenges. First, the emergence of a severe, albeit rare, safety signal in the form of pancreatitis created a significant regulatory hurdle that would have been difficult and time-consuming to resolve. Second, this safety signal appeared exclusively in the context of its therapeutic partner, interferon, a drug with its own well-known toxicity profile, including a risk of pancreatitis. This created ambiguity about causality but inextricably linked Alisporivir's risk profile to an already problematic standard of care. Third, and most decisively, this all occurred at the precise historical moment when the entire HCV treatment paradigm was being revolutionized by the advent of all-oral, interferon-free direct-acting antiviral regimens. These new therapies offered higher cure rates with vastly superior safety, rendering the clinical need for an agent like Alisporivir in an interferon-containing regimen obsolete.

The Pivot: The subsequent repurposing of Alisporivir represents a prudent and scientifically-driven strategy to salvage value from a well-characterized asset. The pivot towards rare diseases, particularly collagen VI-related myopathies, is strategically sound. It leverages a distinct, well-understood ancillary mechanism of action—the inhibition of the mitochondrial permeability transition pore—that is directly relevant to the pathophysiology of the target disease. The validation of this strategy through the EMA's granting of orphan drug designation is a critical milestone, providing a defined regulatory pathway and significant commercial incentives that can make development viable even for a smaller market.

Future Challenges and Outlook: Despite the promising new direction, the path forward for Alisporivir is not without challenges. The primary task will be to demonstrate clear clinical efficacy in these new, often heterogeneous, and difficult-to-study rare disease populations. Crucially, it must do so while establishing an impeccable safety profile. The shadow of the pancreatitis signal, regardless of its context-dependency, will necessitate exceptionally rigorous safety monitoring in all future clinical trials, as regulators will be highly sensitive to any signs of toxicity.

In conclusion, Alisporivir is highly unlikely to ever achieve the blockbuster status once envisioned for it in the vast HCV market. Its story serves as a powerful reminder that scientific novelty and clinical efficacy alone do not guarantee success; a drug's fate is equally determined by its safety, its therapeutic context, and the competitive environment into which it emerges. However, through a strategic and scientifically-grounded pivot, Alisporivir's unique pharmacology may yet allow it to find a valuable therapeutic niche. Its potential to address the high unmet need in rare mitochondrial and muscular diseases offers a viable path to registration and a meaningful clinical impact, representing a partial but important reclamation of a scientifically compelling pharmaceutical asset.

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