Switching From Nonspecific to Targeted Therapies

The clinical management of patients with hepatitis C virus (HCV) infection represents an ideal opportunity for the benefits of precision medicine and the individualization of patient care. This is particularly true given the importance of genetic and nongenetic factors that have recently been identified as critical to HCV infection management.¹

Table 1. Recently Approved Direct-Acting Antivirals and Indications

Product

Date Approved

Class

Indication

Co-Pay Programs

Sovaldi

(sofosbuvir)¹

December 2013

NS5B polymerase inhibitor

Sovaldi is a hepatitis C virus (HCV) nucleotide analogue NS5B polymerase inhibitor indicated for the

treatment of chronic HCV infection as a component of a combination antiviral treatment regimen

• Sovaldi efficacy has been established in subjects with HCV genotype 1, 2, 3, or 4 infection, including

those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and

those with HCV/HIV-1 coinfection.

Olysio (simeprevir)²

November 2013

NS3/4A protease inhibitor

Olysio is a hepatitis C virus NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis

C infection as a component of a combination antiviral treatment regimen.

• Olysio efficacy has been established in combination with peginterferon alfa and ribavirin in HCV

genotype—infected subjects with compensated liver disease (including cirrhosis).

• Olysio must not be used as monotherapy.

• Screening patients with HCV genotype 1 infection for the presence of virus with the NS3 Q80K

polymorphism at baseline is strongly recommended. Alternative therapy should be considered for

patients infected with HCV genotype 1a containing the Q80K polymorphism.

Victrelis (boceprevir)³

May 2011

NS3/4A protease inhibitor

Victrelis is an HCV NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C

genotype—1 infection, in combination with peginterferon alfa and ribavirin, in adult patients with

compensated liver disease, including cirrhosis, who are previously untreated or who have failed

previous interferon and ribavirin therapy, including prior null responders, partial responders, and

relapsers.

• Victrelis must not be used as a monotherapy and should only be used in combination with peginterferon

alfa and ribavirin.

• The efficacy of Victrelis has not been studied in patients who have previously failed therapy with a

treatment regimen that includes Victrelis or other HCV NS3/4A protease inhibitors.

Incivek (telaprevir)⁴

May 2011

NS3/4A protease inhibitor

alfa and ribavirin, for the treatment of genotype 1 chronic hepatitis C (CHC) in adult patients with

compensated liver disease, including cirrhosis, who are treatment naïve or who have been previously

treated with interferon-based treatment, including prior null responders, partial responders,

and relapsers.

Incivek must not be used as monotherapy and must only be used in combination with peginterferon

alfa and ribavirin.

A high proportion of previous null responders (particularly those with cirrhosis) did not achieve

sustained virologic response (SVR) and had telaprevir resistance—associated substitutions emerge

on treatment with Incivek. Incivek efficacy has not been established for patients who have previously

failed therapy with a treatment regimen that includes Incivek or other HCV NS3/4A protease

inhibitors.

Until recently, interferon-based therapy combined with ribavirin has been the standard of care for patients with hepatitis C infection. A number of viral and host factors have been described as significant determinants of the treatment outcome of interferon-based therapy for HCV. However, HCV genotype has traditionally been the strongest predictor of response to interferon/ribavirin therapy. Genotype information is helpful in determining treatment and predicting therapeutic response and duration.^2-4

Hepatitis C virus is classified into 6 genotypes and more than 50 subtypes. Genotype 1 is the most common in the United States; genotypes 4 through 6 account for a small minority of cases.3 Patients with HCV genotype 2 or 4 are approximately 3 times more likely to respond to therapy with interferon or interferon plus ribavirin compared with patients who have HCV genotype 1. In addition, patients with genotype 1 generally require 48 weeks of combination treatment, while 24 weeks may be adequate for patients with genotypes 2 or 3.3

Eradication of HCV with interferon/ribavirin therapy may be permanently accomplished in up to 80% of patients with HCV genotypes 2 or 3, but only in about 40% of patients infected with HCV genotype 1 or 4. In addition to the relatively low sustained virologic response (SVR) rate in patients with genotype 1, these therapies are contraindicated in many patients with comorbidities. Patients frequently experience adverse events, and those not responding to therapy or relapsing have few other treatment options.⁵

Other factors related to viral clearance with interferon/ribavirin therapy include advanced age, insulin resistance, advanced fibrosis, and hepatic steatosis. In addition, ethnicity plays a role; fewer African-American patients respond to interferon/ ribavirin-based therapy than do Caucasians.2 Response rates to treatment are higher in females, Asians, Caucasians, and those with lower HCV RNA levels.^1,2

Clearly, particular subgroups of patients are not ideal candidates for treatment with interferon/ ribavirin therapy because they are less likely to respond to therapy and/or more likely to experience adverse events. The development of targeted therapies for treatment of hepatitis C infection may offer these patients an improved opportunity for successful resolution of HCV.

Development of targeted antiviral agents to treat HCV has progressed rapidly in recent years (Table 1). In 1999, the subgenomic replicon system was established, which resulted in the screening of small molecules that may inhibit viral replication, or direct-acting antivirals (DAAs). These include inhibitors of the viral protease NS3/4A, the polymerase NS5B, and the protein NS5A.² Inhibitors of other viral proteins are also in clinical trials.

In 2011, the standard of care for treatment of HCV genotype 1 changed dramatically with the addition of the DAAs telaprevir and boceprevir used in combination with pegylated interferon— based and ribavirin-based triple therapy. These protease inhibitors (PIs) are designed to mimic the natural NS3/NS4A protease substrate in genotype-1 HCV, which leads to inhibition of the replication process.⁴ Although improved response rates and shorter treatment durations have been observed, limitations exist, particularly for patients with comorbidities and prior treatment failures. New therapies and combinations of therapies are under investigation with the future goal of all-oral treatment regimens that are free of interferon.⁴

Unfortunately, these NS3/4A PIs exhibit rapid emergence of resistance, despite initial high potency and clinical activity; for this reason, they must be administered in combination with interferon and ribavirin.5 However, this triple therapy has led to significant improvements in response rates for patients with genotype 1 HCV, with SVR rates as high as 75% and reduction in therapy duration by as much as half.⁵

Second-generation NS3/4A PIs are also in development. Simeprevir, a second-generation NS3/4A PI, was approved in late 2013 for treatment of chronic HCV,6,7 and faldaprevir is in phase III studies.⁵

NS5B PIs comprise 2 types—nucleos(t) ide analogue inhibitors and non-nucleotide inhibitors. The former mimic the natural substrates of the polymerase and are incorporated into the RNA chain, resulting in direct chain termination. These have potential action against all HCV genotypes because the active site of NS5B is highly conserved. In addition, resistance to these agents is usually low. Sofosbuvir and mericitabine are 2 agents in this class.⁵ In contrast, non-nucleoside inhibitors bind to discrete sites outside of the active polymerase center, resulting in a conformational protein change that inhibits the polymerase from a distance. Resistance is more frequent with these agents. Non-nucleoside inhibitors include tegobuvir, filibuvir, BI-207127, VX-222, ANA598, and ABT-333.5

Sofosbuvir, a NS5B PI that was approved in December 2013, marked a dramatic change in the treatment of hepatitis C infection. Specifically, use of this agent in patients with HCV genotypes 2 or 3 does not require concurrent interferon therapy to achieve excellent SVR rates. In addition, SVR danoprevir, vaniprevir, MK-5172, and BI-201335. These agents may become important components of combination therapy for treatment of HCV.⁵

Most patients are expected to respond to combinations of the available DAAs. However, hard-to-treat populations may require additional or alternative therapies; these include DAAs directed against other viral proteins, drugs that interfere with host factors, and entry inhibitors.² New DAAs are directed against NS2, NS3, and NS4B. Alisporivir, a cyclophilin A antagonist, is an agent that interferes with host factors necessary for HCV replication. Studies have shown activity of this agent in patients who have failed to respond to other agents and/or in patients who have HCV genotype 2 or 3.^8,9

Another host-targeted agent, miravirsen, specifically targets the micro-RNA miR-122 involved in the gene expression and HCV viral rates are significantly higher in patients with genotype 1 compared with use of other therapies. “The cure rate—the SVR rate—went from about 75% previously to about 90%,” reported Steven Flamm, MD, medical director of the liver transplant program, Northwestern University, Evanston, Illinois.

“Not only that, but for patients with the less common kinds of hepatitis C, genotypes 2 or 3, which we also see in the US, the first interferonfree regimens were approved—sofosbuvir and ribavirin,” Flamm said.

NS5A inhibitors in development include daclatasvir, ABT-267, GS-5885, and PPI-461.5 Other PIs in development include asunaprevir replication, which leads to very effective viral suppression with few adverse events.5

Yet another potential strategy is to prevent viral entry into hepatocytes by neutralizing antibodies or blocking an entry factor. These agents, currently in phase II trials, may prove useful in certain difficult-to-treat population subgroups.⁵

Late-Stage Trials of HCV Interventions (Currently Enrolling)

Interventions

Study Title

Drug: telaprevir +

peginterferon alfa

+ ribavirin

Drug: peginterferon

alfa + ribavirin

Early Access Program of Telaprevir With

Peginterferon and Ribavirin in Chronic Hepatitis

C Subjects (NCT01508286)

Biological: Civacir

10%

Civacir Polyclonal Immune Globulin (IgG) to Prevent

Hepatitis C Virus (HCV) Recurrence in Liver

Transplant Patients (NCT01804829)

Drug: ABT-450/

ritonavir

Drug: ABT-333

Drug: ABT-267

A Follow up Study Designed to Obtain Long

Term Data on Subjects Who Either Achieved a

Sustained Virologic Response or Did Not Achieve

a Sustained Virologic Response in an Abbott

Sponsored Hepatitis C Study (NCT01773070)

Drug: eltrombopag Study of Quadruple Therapy

With Eltrombopag

for Chronic Hepatitis C (NCT01821625)

Drug: ABT-450/r/

ABT-267

Drug: ABT-333

Drug: ribavirin

(RBV)

A Study to Evaluate the Safety and Effect of

ABT-450, Ritonavir and ABT-267 (ABT-450/r/

ABT-267) and ABT-333 Coadministered With

Ribavirin (RBV) in Hepatitis C Virus (HCV) Genotype

1-infected Adults With Compensated Cirrhosis

(NCT01704755)

Drug: Legalon SIL

(silibinin)

Drug: pegylated

interferon alfa 2b

Drug: ribavirin

Randomized Study for the Assessment of

Silibinin (Legalon SIL) in the Treatment of Naïve

Genotype 4 Patients With Chronic Hepatitis C

(NCT01871662)

Drug: LDV/SOF

Drug: RBV

Efficacy and Safety of Ledipasvir/Sofosbuvir

Fixed-Dose Combination for 12 Weeks in

Subjects With Chronic Genotype 1 or 4 HCV and

HIV-1 Co-infection (NCT02073656)

Drug: LDV/SOF

Drug: RBV

Efficacy and Safety of Ledipasvir/Sofosbuvir

Fixed-Dose Combination for 12 Weeks in

Subjects With Chronic Genotype 1 or 4 HCV and

HIV-1 Co-infection (NCT02073656)

All-oral therapies for treatment of hepatitis C infection are in late-stage trials. The combination of sofosbuvir and the NS5A inhibitor ledipasvir will soon be considered by the US Food and Drug Administration for approval. In addition, phase III trials of the combination therapy of ABT-450, NS5A inhibitor ABT-267, and nonnucleoside inhibitor ABT-333 have produced high SVR rates across the board, with the lowest rate being 90% in treatment-naïve genotype 1a patients who received the 3 drugs without ribavirin for 12 weeks (PEARL-IV trial). This same combination produced a 100% SVR rate in treatment-experienced patients with genotype 1b virus. Treatment-naïve patients with genotype 1b experienced 99% cure rates with this combination either with or without ribavirin, and even in the harder-to-treat genotype 1a patients, a 97% SVR rate was achieved when the combination was given for 12 weeks with ribavirin.¹⁰

In the past year, a significant breakthrough in HCV genomics has taken place that has led to improved ability to predict response of therapy. Clinical trials have examined the association between the interleukin-28B (IL28B) gene and the efficacy of triple therapy or interferon-free treatment of HCV. Specifically, certain IL28B polymorphisms are strongly associated with response to interferon/ribavirin treatment, as well as with spontaneous clearance of HCV. Other reports have implicated IL28B genotypes in inflammatory status, progression of fibrosis, and adverse clinical outcomes overall. The addition of IL28B genotypic information can predict HCV eradication during treatment, which is important in determining whether or not continuing therapy outweighs the risk of adverse events.

Kapil Brijmohan Chopra, MD, director of hepatology at the Center for Liver Disease, University of Pittsburgh Medical Center, said of the significance of the IL28B genotype: “This basically is a single nucleotide polymorphism, a snip that is detected on chromosome 19 and basically the interleukin 28B codes for interferon lambda. Interferon lambda has antiviral activity against hepatitis C genotype 1, both in vitro and in vivo, basically working through downstream signaling of interferon gamma, which appears to involve interferon alpha. It has been clearly found that patients with a TT genotype will be poor responders to interferon/ribavirin with a 25% chance of achieving an SVR, whereas a patient who is heterozygous (ie, a CT genotype) has a 30% to 35% chance of SVR. The patients with CC genotype will have a response rate as high as 80%.”

IL28B genotyping should prove useful for personalized treatment of chronic HCV in this era of DAAs, although the role has yet to be fully elucidated.^1,2

When choosing therapy, consideration should be given to the following questions: (1) Which patients require therapy? (2) Will therapy be effective? (3) How well will therapy be tolerated? New and emerging targeted therapies provide the opportunity for precision treatments of hepatitis C infection and may soon yield an all-oral treatment regimen with the best possible response rates, the shortest duration of therapy, and the fewest adverse events.

References:

1. Armstrong GL, Wasley A. Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144(10):7005-7014.

2. Jesudian AB, De Jong YP, Jacobson IM. Emerging therapeutic targets for hepatitis C virus infection. Clin Gastroenterol Hepatol. 2013; 11(6):612-619.

3. CDC. Hepatitis. http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm. Accessed March 4, 2014.

4. Ghany M, Nelson D, Strader D, et al. AASLD Practice Guideline: an update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Disease. Hepatology. 2011;54:1433-1444.

5. Naggie S. Management of hepatitis C virus infection: the basics. Top Antivir Med. 2012;20(5):154-161. 6. Choo QL, Richman KH, Han JH, et al. Genetic organization and diversity of the hepatitis C virus. Proc Natl Acad Sci USA. 1991;88:2451-2455.

7. Johnson & Johnson. http://www.jnj.com/news/all/OLYSIOsimeprevir- Receives-FDA-Approval-for-Combination-Treatment- of-Chronic-Hepatitis-C. Accessed March 4, 2014.

8. Nelson DR, Ghalib RH, Sulkowski M, et al. Efficacy and safety of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon alpha-2A and ribavirin in previously null-responder enotype 1 HCV patients. J Hepatol. 2009;50:S40.

9. Pawlotsky JM, Sarin SK, Foster GR, et al. Alisporivir plus ribavirin achieves high rates of sustained HCV clearance (SVR24) as interferon (IFN)-free or IFN-add-on regimen in treatmentnaïve patients with HCV GT2 or GT3: final results from VI TAL-1 study. Hepatology. 2012;56(suppl 4):233.

10. Second-to-market strategy in HCV: an interview with AbbieVie’s Barry Bernstein. The Pink Sheet, March 3, 2014. http://www.pharmamedtechbi.com/publications/the-pink-sheet. Accessed March 11, 2014.