Other Antiviral Agents in Development

HCV drug development has recently focused on drugs that specifically target the hepatitis C virus -- referred to as "STAT-C" (Specifically Targeted Antiviral Therapy for HCV). In addition to the protease and polymerase inhibitors, there are candidates in development that inhibit additional targets: NS5a, alpha-glucosidase, and cyclophilin B.

Other Antiviral Agents (oral)

Product	Manufacturer	Status
A-831	Arrow Therapeutics/Astra Zeneca	Phase I/II
Celgosivir (MX-3253)	Migenix	Phase II
DEBIO-025	Debiopharm S A	Phase II, also studied in HIV/HCV coinfected people

A-831: Hepatitis C NS5a Inhibitor

Arrow's A-831, an internal ribosomal entry site (IRES) inhibitor, interferes with the initiation of HCV's translation process. A phase I study of A-831 has been initiated in healthy volunteers, and a phase I/II study assessing safety, tolerability, pharmacokinetics, and activity in men with hepatitis C is underway; results are expected in 2008. In 2007, AstraZeneca acquired Arrow Therapuetics, Ltd. Since then, there has been no further news about the development of A-831.

Celgosivir (MX-3253): Hepatitis C Alpha-Glucosidase Inhibitor

Alpha-glucosidase inhibitors prevent removal of the glucose residue necessary for the assembly of HCV virions. Migenix's celgosivir (MBI-3253) is an oral drug made from the Australian black bean chestnut tree. A 12-week viral kinetics study has evaluated the activity of celgosivir and pegylated interferon, with or without ribavirin, versus standard of care, in a group of 57 treatment-experienced persons (null responders (N=11), non-responders (N=36), partial responders (N=21), and relapsers (N=2)) with HCV genotype 1 (see Terms for Response to Treatment). Early virological response rates were highest in the triple-combination arm (42% versus 10% for standard of care). No additional toxicities or side effects were reported in the celgosivir arms, with the exception of increased flatulence and mild diarrhea (Kaita 2007). An ongoing phase II trial is assessing safety, efficacy, and pharmacokinetics of two doses of celgosivir (400 mg/day and 600 mg/day), plus pegylated interferon and ribavirin, versus standard of care for 12 weeks in treatment-naïve persons with HCV genotype 1.

DEBIO-25: Cyclophilin B Inhibitor

Cyclophilins bind to cellular proteins that regulate the immune system. Cyclophilin inhibitors, such as cyclosporine, are used to prevent post-transplantation organ rejection, but not all cyclophilin inhibitors have immunospuppressive activity. So far, one candidate, DEBIO-025, is in clinical trials for HCV.

DEBIO-025 is active against hepatitis C and HIV. Safety, pharmacokinetics, and activity of 1,200 mg/day of DEBIO-25 were assessed in a 15-day study of people with HIV, and HIV/ HCV coinfection. HCV RNA decreased by at least 2 log in all but one of 19 participants; those with genotype 3 and 4 had larger drops (-4.2±1.1 and -3.4±1.9, respectively) than people with HCV genotype 1 (-3.0±0.9).

Adverse events included abnormally elevated bilirubin (reported in ten participants, four of whom discontinued treatment), and lowered platelet count; all abnormalities resolved upon discontinuation of treatment (Flisiak 2006). An ongoing, five-arm phase II study is assessing safety, pharmacokinetics, and activity of lower doses (400–800 mg/day) of Debio 25 plus standard of care in people with HCV genotype 1 who did not respond to pegylated interferon and ribavirin. Results are expected in mid-to-late 2010.

Nitazoxanide: the Upstart

Avid followers of HCV-specific antiviral agents were surprised by results from a phase II study of nitazoxanide (Alinia®), which was FDA-approved in 2002, to treat diarrhea from two intestinal parasites (Cryptosporidium parvum and Giardia lambia).

Nitazoxanide (oral)

Product	Manufacturer	Status
Nitazoxanide	Romark	Phase II

In part of the sponsor's aptly titled STEALTH-C (Studies to Evaluate Alinia for Treatment of Hepatitis C) program, nitazoxanide was evaluated in a study of 96 treatment-naive and 24 treatment-experienced people with hepatitis C genotype 4 (see Table 6. STEALTH-C: HCV Genotype 4 Study Design and Interim Results). An ongoing trial in the US, STEALTH-2, is evaluating a 4-week nitazoxanide lead-in, followed by 48 weeks of pegyated interferon, ribavirin and nitazoxanide versus placebo and standard of care, in 60 treatment-experienced people with HCV genotype 1.

Table 6. STEALTH-C: HCV Genotype 4 Study Design and Interim Results

Study Arm and N	RVR HCV RNA Undetectable at Week 4	ETR HCV RNA Undetectable at end of Tx	SVR 12 HCV RNA Undetectable 12 weeks after completion of Tx
Triple: N=40 (Tx naive=29; Tx experienced=11) 12-week lead-in of nitazoxanide 500mg/twice daily, followed by 36 weeks of nitazoxanide + 180µg PEG-IFN + RBV	Tx naive = 72% Tx experienced = 27%	Tx naive = 93% Tx experienced = 36%	Tx naive = 79% Tx experienced = 25%
Dual: N=40 (Tx naive=29; Tx experienced=11) 12-week lead-in of nitazoxanide, 500mg/twice daily, followed by 36 weeks of nitazoxanide + 180µg PEG-IFN	Tx naive = 62% Tx experienced = 27%	Tx naive = 69% Tx experienced = 45%	Tx naive = 68% Tx experienced = 8%
Standard of Care: N=40 (Tx naive only) 180µg PEG-IFN + RBV for 48 weeks	Tx naive = 35%	Tx naive = 50%	Tx naive = 45%

Sources:

Korba BE, Monerto AB, Glenn JS, et al. (abstract 21) Nnitazoxanide: a potent antiviral agent against HBV and HCV. Frontiers in Drug Development in Viral Hepatitis (HEP-DART). Lahaina, Hawaii. December 9-13, 2007.

Romark Laboratories, press release. Available on-line at: www.romark.com/news/11022007.aspx (accessed 2 March 2008).

Rossignol J-F, Elfert A, El-Gohary Y, Keefe EB. (abstract 178) Interim data from a randomized controlled trial of nitazoxanidepeginterferon-ribavirin, nitazoxanide-peginterferon, and peginterferon-ribavirin in the treatment of patients with chronic hepatitis C genotype 4. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA. November 2-6, 2007.

Without more information on study population (liver histology, baseline viral load, body mass index), adverse events, side effects, and SVR, it is difficult to fully and accurately evaluate these results; hopefully, data from STEALTH-2 will address gaps in data.

Ribavirin Substitute

Taribavirin

Taribavirin, the ribavirin prodrug formerly known as viramidine, went back to the drawing board after disappointing efficacy results from phase III studies, VISER 1 and VISER 2.

Ribavirin Substitute (oral)

Product	Manufacturer	Status
Taribavirin	Valeant	Phase II

An ongoing phase II study is evaluating safety and efficacy of weight-based viramidine (20, 25, and 30 mg/kg/day) vs. weight-based ribavirin, administered in combination with peginterferon alfa-2b to therapy-naive patients with chronic HCV-genotype 1 infection.

Anti-Fibrotics

While attention has mainly been focused on viral eradication, some therapies are being developed to slow or prevent additional liver scarring.

Anti-Fibrotics (oral)

Product	Manufacturer	Status
Farglitazar	GlaxoSmithKline	Phase II
GS 9450 (LB84451)	Gilead	Phase IIa
MitoQ	Antipodean	Phase II
PF-3491390 (IDN-6556)	Pfizer	Phase II

Caspase Inhibitors (GS 9450 and PF-03491390)

GS 9450 and PF-03491390 are caspase inhibitors. Caspase inhibitors block a crucial step in programmed cell death (also called apoptosis), a process that occurs in the liver at higher-than-normal levels in people with chronic hepatitis C and other liver diseases. Inhibiting caspase may lead to decreased fibrosis.

A study of safety, tolerability, efficacy, and pharmacokinetics of GS 9450, Gilead's once-daily caspase inhibitor, in people with hepatitis C is ongoing in Europe.

In a 14-day study of PF-03491390, liver enzyme levels (ALT: alanine aminotransferase; and AST: aspartate amino transferase) decreased significantly at all doses above 5 mg/twice daily, and normalized in some people who received the drug twice or three times daily. There were no serious adverse events (Pokros 2007a). A larger study is ongoing.

MitoQ

MitoQ was created to protect mitochondria (cellular structures that produce energy). A 28-day phase II study in people with hepatitis C was launched in February 2007 in New Zealand.

Farglitazar

Farglitazar is a peroxisome proliferator-activated receptor (PPAR) gamma agonist. Among their many other functions, PPARs control inflammatory responses in the liver and other parts of the body. An ongoing phase II study is evaluating antifibrotic activity of Farglitazar in persons who could not tolerate, or did not respond to, HCV treatment.

Immunomodulatory Therapies

Toll-Like Receptor Agonists

Toll-like receptors (TLRs) recognize specific pathogens by patterns on their surface. TLRs signal the immune system by binding to these invaders. Their signal triggers a cascade of responses, activating innate and adaptive immunity. Toll-like receptor agonists stimulate immune responses by binding to TLRs. So far, ten toll-like receptors have been identified. Although two earlier candidates, Actilon and ANA 975, have been discontinued, this approach remains promising.

Stimulating immune responses is a promising approach for HCV therapy, but TLR agonists may be less effective for HIV-positive persons, due to HIV-associated chronic immune activation (Ayash-Rashkovsky 2005).

Toll-Like Receptor Agonists (subcutaneous infusion)

Product	Manufacturer	Status
IMO-2125	Idera Pharmaceuticals	Phase I

IMO-2125

In September 2007, Idera launched a phase I study of IMO-2125 in treatment-experienced people with any HCV genotype.

Mono- and Polyclonal Antibodies (Subcutaneous or Intravenous Infusion)

HCV is universally recurrent after liver transplantation. Hepatitis B immunoglobulin has been successful at preventing recurrent hepatitis B infections in liver transplant recipients, so a similar approach is being used to prevent HCV from recurring after liver transplantation.

Mono- and Polyclonal Antibodies (Subcutaneous or Intravenous Infusion)

Product	Manufacturer	Status
Bavituximab	Peregrine Pharmaceuticals	Phase I, also being studied in HIV/HCV coinfected people
Civacir	Nabi Biopharmaceuticals/Kedrion	Phase II

Bavituximab

Peregrine Pharmaceuticals is conducting phase I studies of a monoclonal antibody, bavituximab (formery known as tarvicin), in treatment-naive and treatment-experienced people with HCV. An additional phase I study is assessing safety, tolerability, pharmacokinetics, and activity of bavituximab in 24 HIV/HCV-coinfected people. The company is planning to study bavituximab in combination with other anti-HCV therapies.

Civacir

An ongoing, phase II study is evaluating safety, pharmacokinetics, and efficacy of Civacir (hepatitis C immune globulin) in preventing or lessening the severity of recurrent HCV, in 30 liver transplant recipients. Results are expected in mid-2010.

Novel Interferon Formulations

Companies have been working on ways to optimize interferon, since it will remain the backbone of HCV treatment for some years. These new formulations of interferon are long-lasting; they may be more effective, and perhaps less toxic than pegylated interferon.

Novel Interferon Formulations (Subcutaneous Injection or Mini-Pump Device)

Product	Manufacturer	Status
Albuferon	Human Genome Sciences/Novartis	Phase III
Locteron	Biolex Therapeutics/OctoPlus N V	Phase IIa
Omega Interferon	Intarcia	Phase II
Peg-Interferon Lambda	Zymogenetics	Phase I

Albuferon

Albuferon is a formulation of interferon alfa-2b that has been fused to human albumin, to confer long-term exposure from a single infusion. Currently, albuferon is given every two weeks (versus once weekly administration of pegylated interferon, and daily injections of consensus interferon).

Phase II studies have compared different doses and schedules in both treatment-naive and treatment-experienced people (see Table 7. Albuferon vs. Standard of Care in Treatment-Naive People with HCV Genotype 1; and Table 8. Albuferon in Non-Responders to Pegylated Interferon Plus Ribavirin, below).

A pair of phase III studies, ACHIEVE 1 (treatment-naive patients with HCV genotype 1, and ACHIEVE 2/3 (treatment-naive patients with HCV genotype 2 or 3) are currently underway. However, the 1,200 µg dose has been reduced to 900 µg, due to the greater incidence of serious pulmonary adverse events in the 1,200 µg arm. Efficacy of the 900 µg dose is expected to be equivalent to standard of care, based on data from the treatment-naive phase II study.

Table 7. Albuferon vs Standard of Care In Treatment-Naive People With HCV Genotype 1 (N=458)

Regimen	SVR	Discontinued for Adverse Events
Low-dose, every 2 weeks, Albuferon 900µg + RBV	58.5%	9.3%
High-dose, every 2 weeks, Albuferon 1200µg + RBV	55.5%	18.2%
High-dose, every 4 weeks, Albuferon 1200µg + RBV	50.9%	12.1%
Control, PEG-INF + RBV	57.9%	6.1%

Source:

Zeuzem S, Yoshida EM, Benhamou Y, et al. (abstract 180) Sustained virologic response rates with albinterferon alfa-2b plus ribavirin treatment in IFN-naive, chronic hepatitis C genotype 1 patients. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA. November 2-6, 2007.

Table 8. Albuferon in Non-Responders to Pegylated Interferon Plus Ribavirin

Regimen	SVR
Low-dose, every 2 weeks, Albuferon 900µg + RBV	30%
High-dose, every 2 weeks, Albuferon 1200µg + RBV	13%
High-dose, every 4 weeks, Albuferon 1200µg + RBV	25%
Higher-dose, every 2 weeks, Albuferon 1500µg + RBV	9%
Highest-dose, every 2 weeks, Albuferon 1800µg + RBV	17%

Source:

Nelson D, Rustgi V, Balan V, et al. (abstract 51) Sustained virologic response with albinterferon alfa-2b plus ribavirin treatment in prior interferon therapy nonresponders. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA. November 4, 2007.

Locteron-interferon

Locteron-interferon is a continuously released formulation of interferon alfa-2b, currently in phase IIa. SELECT-1 is assessing safety, tolerability, activity, and pharmacokinetics of Locteron, given every two weeks, plus daily ribavirin, in 32 treatment-naive people with HCV genotype 1. Early results have been presented (see Table 9. Week 12 Results from SELECT-1). A single, unspecified serious adverse event occurred; otherwise, adverse events were mild, although weakness, joint and muscle pain, and headache were common. More data will be presented at the end of 2008.

Table 9. Week 12 Results from SELECT-1

Regimen	EVR (defined as >2 log drop)
160 mcg Locteron interferon-alfa 2b + RBV	n/a
320 mcg Locteron interferon-alfa 2b + RBV	88%
480 mcg Locteron interferon-alfa 2b + RBV	100%
640 mcg Locteron interferon-alfa 2b + RBV	n/a

Source:

Dzyublyk I, Yegorova T, Moroz L, et al. (abstract LB10) Phase 2a study to evaluate the safety and tolerability and antiviral activity of 4 doses of a novel, controlled-release interferon-alfa 2b (Locteron) given every 2 weeks for 12 weeks in treatment-naive patients with chronic hepatitis C (genotype 1). 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA. November 4, 2007.

Omega Interferon

The lackluster 37% SVR rate from a phase II study of Omega interferon and ribavirin in treatment-naive people with HCV genotype 1 has not dissuaded the sponsor, Intarcia, from initiating another trial. They have launched a phase II study, in treatment-experienced people with HCV genotype 1, assessing safety and efficacy of Omega interferon and ribavirin with a novel twist: Omega interferon is administered via the DUROSR, an implantable mini-pump.

Interferon Lambda

Interleukin 29, also referred to as interferon lambda, is a synthetic version of an antiviral protein produced by the body. It is being studied with or without ribavirin, in people with hepatitis C who relapsed after treatment with pegylated interferon. Data on safety and activity of different doses, given either once weekly or biweekly, are expected in 2009.

Preventive and Therapeutic Vaccines

Preventive

The phase I study of Chiron's HCV E1/E2 preventive vaccine candidate has been completed; no additional information is available.

Preventive Vaccine

Product	Manufacturer	Status
HCV E1/E2 Vaccine	Chiron	Phase I

Therapeutic

Two therapeutic vaccines were discontinued: Innogenetics halted development of INN-0101, for lack of efficacy; and Novartis stopped HCV E1E2 due to local and systemic adverse events (joint and muscle pain, weakness, and fatigue). Several other candidates, however, remain in the pipeline.

Therapeutic Vaccines

Product	Manufacturer	Status
ChronVac-C	Karolinska Institute/Tripep/Inovio	Phase I/II
GI-5005	Globe Immune	Phase II
IC41	Intercell/Novartis	Phase II
PEV2A PEV2B	Previon Biotech	Phase I
TG4040	Transgene	Phase I/II

ChronVac-C

Safety and tolerability of ChronVac-C, a DNA-based therapeutic vaccine, are being studied in treatment-naive people with HCV genotype 1 and a low hepatitis C viral load. ChronVac-C is administered with a brief electrical pulse (a process called electroporation) that creates temporary pores in cell membranes that allow the vaccine to enter cells. Data are expected in 2009.

GI-5005

GI-5005 is a yeast-based vector expressing hepatitis C NS3 and core proteins, and is intended to stimulate the immune system to clear HCV-infected cells. A phase I study reported immune responses in 23% of participants, as measured by ELI-Spot. ALT normalization occurred in 50% of the highest-dose cohort, and 11% of participants had decreases in HCV RNA, ranging from 0.7 to 1.4 log (Schiff 2007). A phase II study of GI-5005 is being conducted in 120 people with HCV genotype 1, who are either treatment-naive or non-responders to previous therapy, comparing 48 weeks of GI-5005 plus pegylated interferon and ribavirin to 48 weeks pegylated interferon and ribavirin.

IC41

IC41 uses synthetic T-cell peptides with a polyarginine adjuvant to prime the immune response. Phase II results were encouraging; IC41 significantly reduced hepatitis C viral load in treatment-naive people with HCV genotype 1. Intercell and Novartis are planning further studies of IC41.

PEV2A PEV2B

PEV2A PEV2B uses man-made antigens to stimulate helper (CD4 cell) and killer (CD8 cell) immune responses. An ongoing phase I study is assessing safety and immune responses in healthy volunteers.

TG4040

TG4040 uses a modified viral vector (MVA: modified vaccinia Ankara) to target immune responses to HCV's NS3, NS4, and NS5B proteins. It is being studied in treatment-naive and treatment-experienced relapsers. Results of these phase I studies are expected by the end of 2008.