n reportS n

Emerging Therapeutic Options in Virus

Fred Poordad, MD; and Vandana Khungar, MD, MSc

Growing Epidemic and Limitations of Current Therapies

Chronic (HCV) infection affects approximately Abstract 170 million people. The average period between infection and The current standard of care for patients with the development of complications from is 20 to 30 years. chronic hepatitis C virus (HCV) infection is Chronic HCV infection is becoming an increasingly significant pegylated alfa in combination with health burden in the United States. The disease often leads to cir- . Treatment duration and efficacy depend heavily on HCV genotype. A sustained virologic 1,2 rhosis and sometimes hepatocellular carcinoma. response (SVR) is achieved only in approximately Since the early 1990s, interferon has been the backbone of HCV 40% of patients. Side effects of the current stan- infection therapy, initially as monotherapy 3 times a week. Later, dard of care often make adherence to therapy difficult, further reducing the chance for an SVR. it was combined with ribavirin© Managed (RBV), Care and finally,& a pegylated Numerous patient-related and virus-related form was developedHealthcare and given Communications, once weekly. The current LL Cstandard factors can determine response to treatment. of care for patients with HCV infection is pegylated interferon alfa Nonresponders are a large proportion of the cur- rent HCV-infected population, and the number of (PEG) in combination with RBV. Two forms of pegylated inter- patients with HCV infection is growing, neces- feron, pegylated interferon alfa-2a and pegylated interferon alfa-2b, sitating newer therapies with higher efficacy and are currently approved by the US Food and Drug Administration potentially fewer side effects. A new era of direct (FDA) for the treatment of HCV infection. Treatment duration acting antiviral (DAA) compounds has emerged. The first 2 inhibitors for HCV infection, and efficacy depend heavily on HCV genotype. Genotype 1, the and , are coming to market most common in the United States, is the most difficult to treat in 2011. Other protease compounds in develop- and usually requires 48 weeks of therapy. A sustained virologic ment include TMC-435, , BI-201335, BMS-650032, and . The numerous response (SVR) is achieved only in approximately 40% of patients. other therapies that have potential in the treat- The 3000-patient IDEAL (Individualized Dosing Efficacy versus ment of HCV infection include nucleoside inhibi- flat dosing to Assess optimaL pegylated interferon therapy) study, a tors, non-nucleoside inhibitors, NS5A inhibitors, DAA combinations, therapeutic vaccines, human multicenter, US trial in patients with genotype 1 HCV infection, monoclonal antibodies, immune modifiers, and showed comparable efficacy (approximately 40% with an SVR) interferon lambda. between pegylated interferon alfa-2a and alfa-2b when combined (Am J Manag Care. 2011;17:S123-S130) with ribavirin.3 While this is a reasonable SVR, it does not serve the majority of patients. Genotypes 2 and 3 comprise 30% of US , usually require 24 weeks of therapy, and have SVR rates of 80% to 85%.4 Side effects of the current standard of care often make adher- ence to therapy difficult, further reducing the chance for an SVR.5 can also exacerbate autoimmune conditions. Assessing predictors of response prior to treatment, including the use of IL-28B gene testing, can help to minimize risks, select patients most appro- priate to receive therapy, and guide management. Patient-related factors that can determine response to treatment include ethnicity, sex, body mass index, and the presence of metabolic syndrome.6 Virus-related factors include HCV genotype, baseline viral load, degree of fibrosis, the presence of steatosis, and coinfection For author information and disclosures, see end of text. with HIV.7 A single nucleotide polymorphism near the IL28B gene

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Mod to High potency High potency +/- Multi-genotypic coverage Multi-genotypic coverage Intermediate barrier to resistance Low barrier to resistance

C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B

NS5B Non Nucleoside Inhibitors (NNI) NS5B Nucleoside Inhibitors (NI) Low potency Intermediate to high potency Limited-genotypic coverage Pan genotypic coverage Low barrier to resistance High barrier to resistance

Protease Inhibitors on chromosome 19, coding for interferon-lambda-3, is asso- The NS3-NS4A is used by the hcV for ciated with a 2-fold difference in SVr rates among patients. post-translational processing and viral replication. inhibitors Patients with genotype cc, cT, or TT are more likely to of this protein lead to rapid viral decline, but cannot be achieve an SVr than others.8 used as monotherapy due to rapidly developing resistance.11 up to 60% of patients with hcV genotype 1 infection do hence, combinations with Peg/rBV have been studied. not clear the virus despite currently available therapy.9 up to table 2 outlines the various protease inhibitors currently 80% of black patients with hcV genotype 1 do not respond in clinical development, and details those which have been to the current standard of care.10 Nonresponders are a large assessed in phase 3 trials. table 3 compares the protease proportion of the current hcV-infected population, and the inhibitors with Peg/rBV. The first dAAs will be the linear number of patients with hcV infection is growing, creating serine protease inhibitors, telaprevir and boceprevir. the need for newer therapies with higher efficacy and poten- tially fewer side effects vital. Boceprevir A new era of direct acting antiviral (dAA) compounds Boceprevir was studied in the SPriNT (Serine Protease is now beginning, with the first 2 protease inhibitors coming inhibitor Therapy)-2 trial with 1100 treatment-naïve to market in 2011. The dAA therapies will be the biggest patients. The overall SVr rate was 66% (68% in non-black development since the addition of rBV to interferon and patients and 53% in blacks compared with controls [40 and the pegylation of interferon. Adding an oral antiviral to the current standard of care (Peg/rBV) may double the SVr n Table 1. Combination Therapies with 2 or More rate in patients with genotype 1 hcV infection. The NS3- Direct Acting Antivirals 4A protease inhibitors and NS5B ribonucleic acid (rNA)- Drug combination Class Study phase dependent rNA polymerase inhibitors have received the BMS-650032+BMS-790052 PI+NS5a 2a most attention (Figure). Beyond the initial 2 agents, sever- Danoprevir (RG7227)+RG7128 PI+NPI 2b al more are likely to be approved, although combinations of GS-9190+GS-92568 PI+NNPI 2a dAAs will likely be the next phase of therapy, perhaps with- BI-201335+BI-207127 PI+NNPI 2a out interferon in some cases. table 1 outlines the currently PI indicates protease inhibitor; NPI, nucleoside polymerase inhibitor; NNPI, non-nucleoside polymerase inhibitor. proposed combination therapies with 2 or more dAAs.

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n Table 2. Protease Inhibitors in Development RBV responsiveness compared with 32% developing RAVs if Drug Study phase they did not. The predominant adverse event in both of the Telaprevir 3 phase 3 trials was anemia, defined as hemoglobin (Hb) below Boceprevir 3 10 g/dL, which occurred in 50% of patients given boceprevir. TMC-435 2 Discontinuations due to anemia, however, occurred in less than 2% of patients. The majority of patients with anemia BI-201335 2 were treated with an erythropoietic stimulating agent (ESA) Vaniprevir 2 at the discretion of the investigator to maintain Hb between Halted 10 and 12 g/dL.14 Danoprevir 2 BMS-850032 1 Telaprevir ACH-1625 1b ADVANCE (A New Direction in HCV Care: A Study GS-9256 2 of Treatment-naïve Hepatitis C Patients with Telaprevir), a ABT-450 2 phase 3 trial in treatment-naïve patients, studied telaprevir in combination with PEG/RBV. Patients received 12 weeks IDX-320 1 of telaprevir, with 24 or 48 weeks of PEG/RBV, based on GS-9451 2 response-guided parameters of viral negativity between ACH-2684 Preclinical weeks 4 and 12 (extended rapid virology response [eRVR]), MK-5172 1 with almost 60% of patients qualifying for the shorter dura- tion. SVR rates of 75% were achieved (compared with 44% with control). The predominant adverse event of rash occurred in 56% of patients; however, only 7% discontin- 23%, respectively]; P = .004 and P = .044) with a regimen ued telaprevir due to rash. Anemia occurred at a rate of that used a 4-week lead-in of PEG/RBV followed by the 40%. ESAs were not allowed in this study.15 A companion addition of boceprevir for 24 weeks.12 A response-guided study in treatment-naïve patients called the ILLUMINATE therapy paradigm was then used to determine ultimate (Illustrating the Effects of Combination Therapy with length of PEG/RBV of 28 weeks or 48 weeks based on viral Telaprevir) revealed an SVR of 72%, high SVR rates in negativity at and beyond week 8. Overall, approximately those achieving an eRVR, and no benefit of extending 50% of patients qualified for the shortened duration (28 PEG/RBV beyond 24 weeks in those achieving eRVR.16 weeks of therapy), and approximately 25% required 24 The REALIZE (Re-treatment of Patients with weeks of boceprevir and 48 weeks of PEG/RBV. The remain- Telaprevir-based Regimen to Optimize Outcomes) trial ing 25% of patients discontinued due to futility at week 24 assessed telaprevir in patients who previously received treat- or side effects.13 ment. Results were recently presented and revealed SVR In the 404 patient nonresponder trial called RESPOND rates of 64% compared with 17% with control. Although (Retreatment with HCV Serine Protease Inhibitor Boceprevir a 4-week lead-in arm did not reveal differences in SVR and Peginteron/Rebetol)-2 trial, SVR rates were 66% in the rates, complete data regarding the predictability of SVR 48-week arm and 59% in the response-guided arm, both and resistance based on PEG/RBV response has not been significantly better than the control (21%) (P <.0001). presented. Patients with a previous relapse had an SVR rate The study included previous relapsers and those who had of 86% (24% with control), partial responders had an SVR some interferon responsiveness, having achieved at least a rate of 57% (15% with control), and null responders 31% 2-log decline of virus with PEG/RBV. Interestingly, 25% of (5% with control).17 patients demonstrated very little interferon response dur- ing the 4-week lead-in, having less than a 1-log decline in Dosing With Boceprevir and Telaprevir virus prior to beginning boceprevir. These patients had SVR Both boceprevir and telaprevir are dosed 3 times daily, rates of only 34% compared with 73% to 79% in patients with anemia rates of 40% to 50%; rash is common with tela- with some interferon response at the end of lead-in. Most previr, and dysgeusia with boceprevir. Both were associated importantly, the lead-in appears to be an excellent predictor with significantly higher SVR rates compared with controls, of risk of resistance-associated variants (RAVs), with fewer and both can be used with either PEG/RBV regimen on than 10% of patients developing variants if they had PEG/ the market. Patient compliance with the dosing schedule

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n Table 3. Profile of First Wave Protease Inhibitors When Combined With Peginterferon/Ribavirin Mechanism of Action Prevents viral replication by inhibiting HCV NS3 protease, an enzyme used in the post- translational processing of viral polypeptides Efficacy G1 Naive: SVR = 63% to 75%

G1 Treatment Experienced: average SVR in previous null responders: approximately 30% SVR in previous partial responders: approximately 55% SVR in previous relapsers: approximately 75% to 85% Resistance Low when IFN responsive, high in null responders Safety Discontinuations due to adverse events = PegIFN + RBV alone Side effects caused by or exacerbated by protease inhibitor (when compared with PegIFN + RBV) include anemia, rash, dysgeusia Administration Oral, every 8 hours Duration of Treatment 24 wks (triple 12 wks + PegIFN/RBV 12 wks) for approximately 50% to 60% G1 naive patients; 36 to 48 wks for all G1 treatment-experienced patients G1 indicates genotype 1; HCV, hepatitis C virus; IFN, interferon; RBV, ribavirin. and the high rates of anemia (and rash with telaprevir) are ations due to adverse events were reported. The most com- concerns. mon adverse events reported were nausea, headache, and flu-like symptoms. TMC-435 Other protease compounds in development are further BI-201335 behind boceprevir and telaprevir. Phase 3 trials with TMC- BI-201335 is a specific HCV NS3/4A protease inhibitor 435, however, are starting in treatment-naïve and relapsed studied in chronic HCV genotype 1 infection. It was admin- patients at a dose of 150 mg daily. Results of the phase 2b istered as 14-day monotherapy in treatment-naïve patients PILLAR (Protease Inhibitor TMC435 trial assessing the opti- followed by combination PEG/RBV for an additional 14 days. maL dose and duration as once daiLy Anti-viral Regimen) It has also been studied in treatment-experienced patients for study reveal SVR rates in those relegated to a response- 28 days as combination therapy with PEG/RBV.20 A median guided duration of 24 weeks of therapy (approximately 80% viral load reduction of at least 3 log10 was achieved in all dose of patients) to be approximately 90%. SVR results in the groups. On-treatment viral rebound was noted in most patients 48-week control arm are not yet available, but are expected on monotherapy, but only in 3 of 19 treatment-experienced to be higher than that of other studies based on week 24 patients receiving triple combination therapy with lower dos- on-treatment response rates of over 80%. The appeal of this ages of BI-201335. A recent study revealed that HCV NS3 compound beyond the expected high efficacy is its once daily variants that confer resistance to the were selected dosing, and no apparent risk of rash or anemia.18 during treatment. The variants do not alter sensitivity to PEG/ RBV, as the treatment-naïve patients with resistant virus did MK-7009 (Vaniprevir) display antiviral responses during combination therapy. A phase 2, randomized, placebo-controlled, double-blind study of MK-7009 (a non-covalent competitive inhibitor of BMS-650032 HCV NS3/4A protease) in combination with PEG/RBV was BMS-650032 is an HCV NS3 protease inhibitor with performed in treatment-naïve patients with HCV infection. demonstrated antiviral activity in single and multiple MK-7009 was given for 28 days with PEG/RBV in 1 of 5 ascending dose studies in patients with chronic HCV geno- regimens: placebo, 300 mg twice daily, 600 mg twice daily, type 1 infection. In healthy patients, BMS-650032 was well 600 mg once daily, or 800 mg once daily; all patients con- tolerated at doses up to 1200 mg once daily and up to 600 tinued PEG/RBV for an additional 44 weeks. The primary mg twice daily for 14 days. A mean decline in HCV RNA end point was undetectable HCV RNA at day 28 (a rapid of 2.5 log10 at 24 hours after a single 600 mg dose was noted. viral response [RVR]). RVR rates were 1/18 (5.6%), 12/16 No deaths or discontinuations due to adverse events were (75%), 15/19 (78.9%), 11/16 (68.8%), and 14/17 (82.4%), reported. respectively.19 No serious adverse events and no discontinu- Other Protease Inhibitors

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n Table 4. Polymerase (NS5B) Inhibitors negativity. A genotype 2/3 study with 12 weeks of PSI-7977 Nucleoside Polymerase Inhibitors therapy is underway because this compound is pangenotypic Drug Study phase in its coverage. Results look encouraging up to week 12, with RG7128 2b most patients having undetectable viral levels at the end of IDX-184 2a dosing.21 PSI-7977 2b PSI-938 2b RG7128 INX-189 1a Another similar compound, RG7128, an oral cytidine NI, Non-Nucleoside Polymerase Inhibitors is dosed twice daily and demonstrated efficacy in HCV infec- Drug Study phase tion. In a phase 2b trial of 408 patients with HCV genotypes GS-9190 2b 1 and 4, dosing of 500 mg and 1000 mg twice daily for 8 to 2a 12 weeks and PEG/RBV for 24 to 48 weeks produced week-12 ANA598 2b viral negativity rates of 68% to 88%, revealing efficacy in both ABT-333 2b genotype 1 subtypes and genotype 4.22 ABT-072 2a When given in conjunction with a protease inhibitor IDX-375 1 (R7227/ITMN-191) over a 2-week period, a proof of concept BI-207127 2a was achieved, revealing that potent viral suppression can be VX-222/VCH-222 1 achieved with no viral breakthrough when combing 2 DAAs VX-916/VCH-916 1 that act on different targets. VX-759/VCH-759 1 PSI-938 PSI-938 is a guanine nucleoside analog that is dosed daily. Danoprevir (600 mg twice daily) has been shown to have It is currently being studied in a phase 1 trial. Interim results good efficacy and safety in HCV infection. It is currently showed potent antiviral activity with daily doses of 100, 200, being assessed in an ongoing phase 2 study. ACH-1625 is a and 300 mg. potent, nearly pangenotypic compound that is dosed once These compounds appear to have tremendous potential daily and has a good safety profile. However, mild hyperbiliru- with a high barrier to resistance, and reasonable safety profiles. binemia is a concern. Similarly, ABT-450 is a once-daily com- pound dosed with , and showed good week-4 efficacy. IDX-184 and INX-189 Several other protease inhibitors are in development, either in IDX-184 is a nucleotide prodrug. The clinical development combination with other DAAs or with PEG/RBV. program for this agent was put on hold due to observations of elevated liver enzymes when used in combination with a Polymerase Inhibitors protease inhibitor. The clinical development program is set to Polymerase inhibitor agents bind to the NS5B RNA- resume in 2011. INX-189 is a methylguanosine analog, and it dependent RNA polymerase. This class can be divided into is currently being evaluated in a phase 1b trial.23 2 classes, based on which part of the protein they bind to. Compounds that bind to the are nucleoside analog Toxicities With NI Compounds inhibitors (NI), and those that bind to various other sites are Toxicities have been observed with NI compounds. R1626 called non-nucleoside inhibitors (NNI). Table 4 outlines the has been associated with significant toxicity issues, including polymerase inhibitors. neutropenia and ocular toxicity. Prior to that, NM283 was discontinued due to gastrointestinal toxicity. Nucleoside Inhibitors PSI-7977 Non-Nucleoside Inhibitors PSI-7977, a uridine nucleotide analog, is one of the most This heterogeneous class of compounds can bind to at potent compounds in this class. In a phase 2b study in 125 least 4 different sites, and has a lower potency compared with treatment-naïve patients, PSI-7977 100 mg, 200 mg, and other therapies. However, as a part of combination regimens 400 mg was given once daily with PEG/RBN for 4 weeks fol- with other DAAs, they may be of value. Table 4 lists several lowed by PEG/RBV for 36 more weeks. Efficacy rates at day compounds currently being explored. These agents may be best 28 and week 12 were very high, achieving 75% to 94% viral used in combination, rather than as part of a regimen with

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n Table 5. NS5A Inhibitors IC41 induces HCV-specific interferon-gamma secreting Drug Study phase CD4+ and CD8+ T cells.28 A total of 35 patients received BMS-790052 2 6 vaccinations with IC41. It did not prevent HCV relapse PPI-461 1 in patients with ongoing interferon treatment, but HCV- GS-5885 1 specific T-cell responses were inducible and associated with BMS 824393 1 lower relapse rates.29 The induction of neutralizing antibodies is a key feature of most vaccines. Infusion of neutralizing antibodies is also PEG/RBV alone. used for postexposure prophylaxis. Recombinant E1E2 gly- Notable compounds in this category include ANA598, coproteins with MF59 containing a CpG oligonucleotide currently being assessed in a phase 2 study. ANA598 200 and elicited strong CD4+ T helper responses but no CD8+ T 400 mg is given twice daily following a loading dose of 800 cell responses. Recombinant nonstructural proteins 3, 4, mg. Undetectable virus at week 12 was achieved in 75% of and 5 also stimulated strong CD4+ T helper responses when patients, with good tolerability.24 adjuvanted with Iscomatrix containing CpG. A single Two compounds, ABT-333 and ABT-072, are being immunization regimen was shown to elicit broad T cell studied in phase 2 trials. In patients with genotype 1 HCV responses and neutralizing antibodies.30 infection, they are being dosed once or twice daily in con- GI-5005 is a whole, heat-killed Saccharomyces cerevisiae junction with PEG/RBV for 12 weeks followed by PEG/RBV therapeutic vaccine expressing HCV NS3 and core anti- for another 36 weeks.25,26 gens that elicits antigen-specific responses to improve the rate of immune-mediated elimination of HCV-infected NS5A Inhibitors hepatic cells.23 Triple therapy with GI-5005, PEG, and Compounds that inhibit the NS5A protein are now being RBV improved EVR, compared with PEG and RBV alone. assessed as pangenotypic agents that can be used with PEG/ No new toxicities were noted with triple therapy. RBV, or in combinations with other DAAs. The first-in-class In a proof of concept trial, 133 patients with HCV BMS-790052 is given at doses of 3, 10, and 60 mg with PEG/ genotype 1 infection were randomized to triple therapy with RBV for 12 weeks followed by PEG/RBV therapy. Preliminary the GI-5005 vaccine, designed to elicit a T-cell response data from the phase 2a study indicate good antiviral effects specific to HCV plus PEG and RBV or standard PEG/RBV and good tolerability. A phase 2b study is planned. In nonre- therapy alone. Overall, the difference in SVR rates between sponders, combination with a protease inhibitor will be exam- the vaccine and control group was statistically significant, ined. Several other NS5A agents are also in development and with SVR rates of 47% and 35%, respectively (P = .037). appear to be a promising partner compound in combination Currently, a phase 2 trial is evaluating GI-5005 triple regimens. Table 5 outlines the NS5A inhibitors. therapy. Triple therapy and novel combination strategies with GI-5005 and other HCV inhibitory agents will be use- DAA Combinations ful in the future.31 Table 1 lists combination therapies with 2 or more DAAs. This is the expected evolutionary pathway of small Human Monoclonal Antibodies molecules. The hope of an interferon-free era may not be Chronic HCV infection is characterized by a high turn- realized in the next few years, but selected patients may be over of infected cells and de novo infection of target cells. cured with oral agents alone. Until then, many combination A potential target for antiviral therapy is de novo infection. studies will assess 2 or more DAAs with and without an The envelope protein E2 is a target to block de novo infec- interferon backbone. tion, and this can be achieved by entry inhibitors. MBL- HCV1, a fully humanized monoclonal antibody to a linear Vaccines epitope of HCV E2 glycoprotein, was developed and neutral- Currently, no vaccine exists for the prevention or man- izes pseudoviruses from multiple HCV genotypes. The anti- agement of HCV infection. Therapeutic vaccines boost body completely neutralizes infectious HCV particles in cell the immune system and may be effective in the treatment culture. Based on in vitro studies, the monoclonal antibody of HCV. IC41 is a synthetic peptide vaccine with 7 rel- anti-E2 was investigated to prevent HCV infection in unin- evant HCV T-cell epitopes and the T-helper cell (Th)1/ fected chimpanzees.32 Three chimpanzees each received a Tc1 adjuvant poly-L-arginine.27 In healthy volunteers, single dose of the anti-E2 antibody intravenously, then were

S128 n www.ajmc.com n MARCH 2011 Emerging Therapeutic Options given a challenge with HCV 1a strain H77. No HCV RNA patients with genotype 1 infection.36 was detected in the serum of the chimpanzees who received 250 mg/kg of MBL-HCV1 through week 20, while the 0 mg/ Albumin Interferon kg and 50 mg/kg group became infected by day 14. A phase 1 Phase 3 clinical trials with albumin interferon alfa-2b, study in humans is planned. the fusion protein of human serum albumin and interferon alpha, are complete. Human serum albumin is made in the Immune Modifiers and Others liver and has a half-life of 20 days. Albumin interferon alfa-2b New therapeutic approaches for patients who have a has a longer half-life and a duration of antiviral activity that low SVR with traditional therapies are underway, including allows for dosing intervals of 2 to 4 weeks. In a phase 3 trial, immune modifiers and other drugs. albumin interferon alfa-2b 900 μg administered every 2 weeks showed comparable efficacy to PEG in patients with HCV Nitazoxanide genotype 1 infection. SVR rates were 51%, 48%, and 47% Nitazoxanide is a thiazolide approved for diarrhea from in the PEG, albumin interferon alfa-2b 900 μg, and 1200 μg cryptosporidiosis. In a double-blind, placebo-controlled study groups, respectively.37 Safety concerns over pulmonary toxic- in 13 US centers, 125 treatment-naïve patients with HCV ity, however, will prevent approval of this compound based genotype 1 infection were randomized to receive nitazoxanide on current data. (n = 75) or placebo (n = 37) twice daily over a 4-week lead-in followed by 48 weeks of nitazoxanide or placebo, plus pegin- Interferon Lambda terferon 180 μg weekly and weight-based RBV. In those with Interferon lambda is a novel type III interferon, which HCV RNA levels greater than 600,000 IU/mL, complete binds to a unique cell surface receptor, induces an intracel- EVR and EVR rates were higher in the nitazoxanide group lular antiviral response, and efficiently inhibits HCV replica- compared with placebo (57% vs 39%, and 79% vs 61%, tion in vitro. Researchers hope that interferon lambda will respectively).33 Based on current data, it is unlikely that this have comparable antiviral activity to PEG, but with a better compound will have a role in treating HCV infection when tolerability profile. Studies are ongoing. combined with PEG/RBV. Author Affiliation: Department of Medicine, Cedars‑Sinai Medical Center, Los Angeles, CA. Cyclophilin Inhibitors Funding Source: Financial support for this work was provided by Merck Debio 025 & Co, Inc. Debio 025 is a non-immunosuppressive cyclosporine A Author Disclosure: Dr Poordad reports being a consultant or a member of the advisory board for Abbott, Achillion, Anadys, Gilead, Merck, Novartis, (CsA) derivative that selectively inhibits cyclophilins. Host Pfizer, and Vertex. He also reports being a member of the speakers’ bureau for cell cyclophilins are essential for efficient HCV replication Gilead, Roche, and Vertex. He has received grants from Abbott, Achillion, Anadys, Bristol-Myers Squibb, Gilead, Merck, Novartis, Pfizer, Pharmasset, in hepatocytes. Combination therapy with interferon alfa- and Vertex. Dr Khungar has nothing relevant to disclose. 2b and Debio 025 for 24 weeks produced an SVR in 42% Authorship Information: Concept and design (FP, VK); drafting of the of patients with HCV genotype 1b infection and high viral manuscript (FP, VK); and critical revision of the manuscript for important intellectual content (FP, VK). loads.34 Address correspondence to: Fred Poordad, MD, Department of Medicine, Cedars-Sinai Medical Center, 8635 W Third St, Ste 1060, Los Angeles, CA NIM811 90048. E-mail: [email protected]. Another cyclophilin inhibitor called NIM811 was admin- istered in 40 healthy volunteers. No further development of this compound is expected. References

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5. Fried MW. Side effects of therapy of hepatitis C and their man- plus pegIFN alfa-2a (40KD)/RBV: planned week 12 interim analy- agement. Hepatology. 2002;36:S237-S244. sis from the PROPEL study. Hepatology. 2010;52(4 suppl):A81. 6. Bressler BL, Guindi M, Tomlinson G, et al. High body mass index 23. Kolykhalov A, Liu Y, Bleiman B, et al. Characterization of the in is an independent risk factor for nonresponse to antiviral treat- vitro selected Hepatitis C virus replicon Mutants Resistant to the ment in chronic hepatitis C. Hepatology. 2003;38:639-644. Phosphoramidate analog of 2’-C-Methyl-Guanosine, INX-189. 7. Zeuzem S. Heterogeneous virologic response rates to inter- Hepatology. 2010;52(4 suppl):A1888. feron-based therapy in patients with chronic hepatitis C: Who 24. Lawitz EJ, Rodriguez-Torres M, Rustg VK, et al. Safety and anti- responds less well? Ann Intern Med. 2004;140:370-381. viral activity of ANA598 in combination with pegylated interferon 8. 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