Hepatitis C - Danoprevir shows potential in phase 2 trials

Related - Novel HCV therapy leads to rapid response

New hepatitis C drug shows potential in phase 2 trials

Bethesda, MD -- The addition of danoprevir to the current treatment regimen for patients with hepatitis C leads to high rates of remission, according to a new article in Gastroenterology, the official journal of the American Gastroenterological Association. The current standard of care for hepatitis C patients includes a combination of peginterferon and ribavirin.

"Despite recent advances, the current hepatitis C treatment regimen is burdensome on the patient and prone to adverse events," said Patrick Marcellin, lead study author from the Service d'Hépatologie and Inserm CRB3, Hôpital Beaujon, APHP University of Paris. "The promising results from this study offer hope that danoprevir can improve the quality of life for patients suffering from this disease."

Investigators conducted a phase 2, randomized, placebo-controlled study and found that, within just one week of treatment, the addition of danoprevir to the current treatment regimen (peginterferon alfa-2a/ribavirin) led to reductions in levels of hepatitis C virus in the blood. Overall, danoprevir was well tolerated and demonstrated an 85 percent sustained virologic response rate (or no detectable virus in the patient's blood after six months).

Importantly, 79 percent of patients who added danoprevir to their treatment regimen achieved an early virologic response and were eligible for a shortened treatment schedule.

Studies of lower doses of danoprevir on top of the current standard of care, to reduce overall danoprevir exposure while maintaining the drug's effectiveness, are underway. Interim effectiveness and safety data are promising.

Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver. Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer. Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain. For more information on hepatitis, please read the AGA brochure "Understanding Hepatitis."

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This research was funded by F. Hoffmann-La Roche Ltd.

About the AGA Institute
The American Gastroenterological Association is the trusted voice of the GI community. Founded in 1897, the AGA has grown to include 17,000 members from around the globe who are involved in all aspects of the science, practice and advancement of gastroenterology. The AGA Institute administers the practice, research and educational programs of the organization. http://www.gastro.org.

About Gastroenterology
Gastroenterology, the official journal of the AGA Institute, is the most prominent scientific journal in the specialty and is in the top 1 percent of indexed medical journals internationally. The journal publishes clinical and basic science studies of all aspects of the digestive system, including the liver and pancreas, as well as nutrition. The journal is abstracted and indexed in Biological Abstracts, Current Awareness in Biological Sciences, Chemical Abstracts, Current Contents, Excerpta Medica, Index Medicus, Nutrition Abstracts and Science Citation Index. For more information, visit http://www.gastrojournal.org.
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Hepatitis C - Danoprevir yielded high rates of sustained virologic response

Infectious Diseases

Novel HCV therapy leads to rapid response 

 

By: DENISE NAPOLI, Family Practice News Digital Network 

 

Combination therapy with the second-generation protease inhibitor danoprevir yielded high rates of sustained virologic response in hepatitis C.

Moreover, a large portion of patients also demonstrated an extended rapid virologic response up to 20 weeks, reported Dr. Patrick Marcellin and his colleagues in the October issue of Gastroenterology.

Dr. Marcellin, of the Hôpital Beaujon in Clichy, France, and his coinvestigators looked at 225 treatment-naive adults with hepatitis C virus (HCV) genotype 1 infection, including those who had a serum RNA level of 50,000 IU/mL or more. 

Exclusion criteria included advanced fibrosis or cirrhosis, anemia, poorly controlled diabetes, or body mass index less than 18 kg/m² or greater than 36 kg/m². 

The goal of this phase II, randomized, placebo-controlled study (ATLAS) was to evaluate the efficacy of treatment with danoprevir plus peginterferon alfa-2a/ribavirin for 12 weeks, compared with peginterferon alfa-2a/ribavirin alone. 

Patients were randomized to one of three doses of oral danoprevir or placebo: 300 mg every 8 hours, 600 mg every 12 hours, or 900 mg every 12 hours. 

All doses and placebo were given with standard combination HCV therapy, including subcutaneous peginterferon alfa-2a 180 mg/week plus oral ribavirin (1,000 mg/day for patients with a body weight less than 75 kg or 1,200 mg/day for patients weighing 75 kg or more). 

At week 12, treatment with danoprevir or placebo was stopped, and peginterferon alfa-2a/ribavirin was continued for a total duration of 24 or 48 weeks, according to patient response. 

Dr. Marcellin found that by week 1, mean decreases in HCV RNA ranged from 3.95 to 4.28 log₁₀ IU/mL in the danoprevir groups, compared with 0.77 log₁₀ IU/mL in the placebo group.

By week 2, according to the investigators, more than half of the danoprevir patients and none of the placebo recipients had achieved undetectable HCV RNA levels. 

Indeed, broken down by dose, the researchers calculated that 74% of the danoprevir 300-mg group achieved a rapid virologic response (undetectable serum HCV RNA at week 4), with 65% maintaining an extended rapid virologic response (eRVR), defined as an undetectable HCV RNA that lasted from weeks 4 through 20. 

Among the patients taking 600-mg doses, 88% achieved an RVR, with 79% maintaining an eRVR at week 20. 

Finally, 86% of patients in the 900-mg treatment group achieved an RVR, although only 18% reached an eRVR. 

Patients with an eRVR stopped all treatment at 24 weeks.

"Relapse occurred in 18%, 8%, and 11% of patients treated with danoprevir 300 mg, 600 mg, and 900 mg, respectively, versus 38% in the placebo group," the authors wrote. 

Looking at the side-effect profile, Dr. Marcellin reported that fatigue, headache, nausea, insomnia, myalgia, and chills were the most common adverse events for both the treatment and placebo groups.

They also observed reversible, grade 4 elevations in alanine aminotransferase (ALT) levels between weeks 6 and 12 in 2% of danoprevir-treated patients, including three in the 900-mg cohort and one in the 600-mg cohort. 

Treatment was discontinued, and serum ALT levels returned to within 1.5 times the upper limit of normal within a month for all four patients, the authors added. 

"Notwithstanding the low incidence of reversible ALT elevations observed with high-dose danoprevir in this trial, danoprevir also appears to have a better tolerability profile than either boceprevir or telaprevir, as evidenced by the lower incidence of rash and anemia among danoprevir-treated patients compared with placebo recipients," concluded the investigators. 

Indeed, they pointed to other studies showing that coadministration of low-dose ritonavir, another protease inhibitor, "significantly inhibits danoprevir reactive metabolite formation, proposed to be associated with ALT elevations." 

"Studies to further evaluate the efficacy and safety of danoprevir in different patient groups are ongoing," the researchers said. 

Dr. Marcellin and his fellow investigators reported financial relationships with numerous pharmaceutical companies, including Roche, the maker of danoprevir, which also funded this study.

View on the News

Danoprevir's role still unclear
Second-generation protease inhibitors (PIs) currently in development are generally thought to have less drug-drug interactions, improved dosing schedules, as well as less frequent and less severe side effects. Many of the second-generation PIs are macrocyclic molecules, which have been shown to generally be more potent and, depending on the location of the macrocycle, able to retain activity against resistant variants. Common wild-type and drug-resistant variants of the NS3 protein include Q80K, R155K, V36M/R155K, A156T, and D168A (ACS Chem. Biol. 2013;8:1469-78). They have also shown increased efficacy against genotype 1, though they still have limited efficacy against other genotypes (Curr. Gastroenterol. Rep. 2013;15:303 [doi: 10.1007/s11894-012-0303-3]).

This report on danoprevir clearly shows it is a potent, pan-genotypic, macrocyclic second-generation PI that meets all of these criteria. However, the grade 4 elevations in alanine aminotransferase (ALT) levels seen in 2% of danoprevir-treated patients (including three in the 900-mg cohort and one in the 600-mg cohort) that were seen in this study became a major roadblock to the phase III development of the compound. Instead, the coadministration of low-dose ritonavir, another protease inhibitor, which significantly inhibits danoprevir reactive metabolite formation, has allowed the compound to move forward into advanced studies without the hepatotoxicity concern [J. Hepatol. 2012;56(Suppl 2):S467; Hepatology 2012;56(Suppl 1):552A; Hepatology 2012;56(Suppl 1):231A; J. Hepatol. 2012;56(Suppl 2):S555].

The role for a ritonavir-boosted PI in all-oral interferon-free regimens remains to be defined over the coming years. This is not the only PI that requires boosting (ABT450); however, the field is quickly becoming crowded with PIs that do not require ritonavir (asunaprevir, faldaprevir, simeprevir, and vaniprevir). The role for danoprevir in the United States is therefore still unclear.

Dr. Paul J. Pockros is director of the Liver Disease Center of the division of gastroenterology/hepatology at the Scripps Clinic, director of the Scripps Clinic Liver Research Consortium, and director of clinical research at the Scripps Translational Science Institute, La Jolla, Calif. He is a researcher, speaker, and advisory board member for Roche/Genentech.

Danoprevir enhances sustained HCV response rates

Drug & Device Development

Danoprevir enhances sustained HCV response rates

Last Updated: 2013-07-12 17:02:23 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Danoprevir with interferon and ribavirin produced high sustained viral response rates (SVR) in patients with hepatitis C virus (HCV)-1, in a multinational phase II trial.

Researchers say 237 treatment-naïve patients with HCV-1 were randomly assigned to receive peginterferon alfa-2a/ribavirin with danoprevir or placebo for 12 weeks, and ultimately, 225 received at least one dose of study drug.

After the first week of treatment, HCV RNA fell by an average of 3.95 to 4.28 log10 IU/mL with various doses of danoprevir, compared with a 0.77 log10 IU/mL decrease in the placebo group, according to Dr. Patrick Marcellin from Hopital Beaujon, Clichy, France, and colleagues.

Patients in the danoprevir group achieved maximum reductions in HCV RNA after four to six weeks of treatment, and they sustained these reductions throughout the first 24 weeks of treatment. In contrast, placebo patients did not achieve maximum reductions in HCV RNA until week 20.

The proportion of danoprevir-treated patients with a rapid virological response was 74% in the 300-mg group, 88% in the 600-mg group, and 86% in the 900-mg group, compared with 7% in the placebo group.

SVR rates with danoprevir were 68% with 300 mg, 85% with 600 mg, and 76% with 900 mg, compared with 42% with placebo.

Relapse rates were higher with placebo (38%) than with danoprevir (18% with 300 mg, 8% with 600 mg, 11% with 900 mg).

Only three patients (1.4%) had detectable danoprevir resistance mutations at baseline, and all three achieved undetectable HCV RNA at week 12. Two of these patients achieved SVR, and one relapsed, the research team reported online June 28 in Gastroenterology.

Another eight patients (4%) developed viral resistance-related breakthrough or partial response during danoprevir therapy, whereas five patients (4%) had viral breakthrough during therapy in the placebo group.

Adverse events generally followed a similar pattern in the danoprevir and placebo groups, but four danoprevir patients had transient, dose-related, grade 4 elevations in alanine aminotransferase (three in the 900-mg group and one in the 600-mg group). ALT returned to pre-elevation levels 15-25 days after danoprevir was stopped.

Serious adverse events affected 7-8% of the danoprevir groups, compared with 19% of patients in the placebo group.

"Recognizing the high potency of danoprevir, but desiring an improved pharmacokinetic profile, a ritonavir-boosted formulation of danoprevir has been developed for subsequent clinical studies," the researchers say in their paper. "Interim efficacy and safety data recently reported for the combination of ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin in treatment-na�ve patients with HCV genotype 1 or 4 infection in the DAUPHINE study are promising."

According to its website, Roche expects to file the New Drug Application for danoprevir in 2016.

Funding for the study came from Roche/Genentech, which employed 11 of the 22 authors and had various relationships with the other 11 authors.

The authors did not respond to a request for comment.

SOURCE: http://bit.ly/12tecnJ

Gastroenterol 2013.

2013 Pipeline Report - 28 HCV interferon-free regimens in development

Treatment Action Group 2013 Pipeline Report

At the 7th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention held in Kuala Lumpur, Malaysia the HIV i-Base/Treatment Action Group (Tag) released their comprehensive 2013 Pipeline Report. In the report both organizations advocate a global effort for national leaders and regulatory authorities to work together and expedite research needed to bring safe HIV, HCV and tuberculosis drugs to market.

For the HCV community, there is a particular article written by Tracy Swan from (Tag) which offers an update on the new HCV drugs currently in phases II/III trials.

The author writes:

"An impressive 26  new HCV drugs are being studied in phases II/III in at least 28 interferon-free regimens, which are bringing the potential of  faster, all-oral HCV cures rapidly toward approval for the world’s 185 million people living with HCV"

2013 Pipeline Report - Hepatitis C Drug Development Catapults Onward 

Excerpt from the press release;

In the 2013 “HCV Treatment Pipeline,” Tracy Swan (TAG) notes that the “confluence of a robust HCV drug pipeline, shortened regimens, and [shorter] posttreatment follow-up are extraordinary. The new FDA breakthrough therapy designation may speed things up as well. By the end of 2014, [new HCV drugs] from four different classes and fixed-dose combinations (FDCs) are likely to be approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), offering the potential for off-label mixing and matching.” An impressive 26 new HCV drugs are being studied in phases II/III in at least 28 interferon-free regimens, which are bringing the potential of faster, all-oral HCV cures rapidly toward approval for the world’s 185 million people living with HCV.

Swan notes, however, that not all optimal combinations are being studied, with some sponsors preferring combinations of their own proprietary compounds, while many sponsors take too long to study their new drugs in people coinfected with HIV and HCV, and those with cirrhosis.

In her companion chapter, “Low- and Middle-Income Countries Defuse Hepatitis C, the ‘Viral Time Bomb,’” Karyn Kaplan (TAG) describes how a worldwide movement is forming to ensure that when new all-oral HCV cures are approved, that governments, health systems, and providers will be ready for them. Kaplan points to recent progress instigated by HCV activists in countries such as Egypt, Georgia, Thailand, and Ukraine.

The press release is available here

2013 "HCV Treatment Pipeline" - By Tracy Swan

Hepatitis C Drug Development Catapults Onward 
By Tracy Swan

Highlights:
HCV Treatments in Phase II and Phase III
The Best Combinations
Interferon-Free Regimens in Development for HCV Genotype 1
Interferon-Free Regimens in Development - HCV Genotypes 2, 3, & 4
Cross-company Trials
Next in Line: Simeprevir, Faldaprevir, and Sofosbuvir
Without a PEG to Stand on: The Sofosbuvir Saga Goes on
Biting the (Magic) Bullet
Twinkle, Twinkle, Little (Lone) Star
AbbVie: All Hands on Deck
Bristol-Myers Squibb: All In!
(Genotype) 3 is the new 1
SVR in HCV Genotypes 2 and 3
Cirrhosis: From Frontier to Proving Ground
HIV/HCV Coinfection
Faldaprevir plus PEG-IFN/RBV
Simeprevir plus PEG-IFN and RBV
From Excess to Access
Where Should All the Research Go?

Access the report here.........

Next Chapter:
Low-  and Middle-Income Countries Defuse Hepatitis C, the “Viral Time Bomb” 

Update
2013 SVR Rates

Durability of SVR in HCV patients treated with peg/riba and a direct-acting anti-viral

Durability of SVR in chronic hepatitis C patients treated with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral

K. Rutter1, H. Hofer1, S. Beinhardt1, M. Dulic2, M. Gschwantler2, A. Maieron3, H. Laferl4, A. F. Stättermayer1, T.-M. Scherzer1, R. Strassl5, H. Holzmann5, P. Steindl-Munda1, P. Ferenci1,* Article first published online: 26 MAY 2013 DOI: 10.1111/apt.12350 

Alimentary Pharmacology & Therapeutics
Volume 38, Issue 2, pages 118–123, July 2013

Summary
Background
The introduction of direct-acting anti-virals has increased sustained virological response (SVR) rates in chronic hepatitis C genotype 1 infection. At present, data on long-term durability of viral eradication after successful triple therapy are lacking.

Aim
To evaluate the long-term durability of viral eradication in patients treated with triple therapy, including direct-acting anti-virals.

Methods
Patients who participated in randomised, controlled trials or an extended access programme of treatment with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral (telaprevir, danoprevir, faldaprevir, simeprevir, mericitabine, balapiravir) were followed after achieving SVR. The median follow-up after the patients was 21 (range: 7–64) months.

Results
One hundred and three patients with chronic hepatitis C genotype 1 infection [f/m: 34/69; GT-1b: 67 GT-1a: 34, GT-4: 2; mean age: 47.6 years (45.5–49.7; 95% CI)] achieving a SVR triple therapy were followed. Two cases of late relapses (2/103, 1.9%; 95% CI: 0.24–6.8) were observed. One patient was cirrhotic, both carried the genotype 1b and completed the prescribed treatment. The relapses occurred 8 and 12 months after cessation of anti-viral treatment. Cloning sequencing revealed identical sequence in both patients. Resistance analysis revealed no presence of viral resistance.

Conclusion
Like the SVR after peginterferon-α2/ribavirin combination treatment, HCV eradication after triple therapy remains durable after long-term follow-up.

Introduction
Eradication of HCV is the ultimate goal of anti-viral therapy. The commonly used parameter for viral eradication is a sustained virological response defined by undetectable HCV-RNA 6 months after end of successful therapy. Sustained virological response is commonly considered as parameter for cure of chronic hepatitis C. Long-term follow-up studies in patients treated by peginterferon/ribavirin have shown that HCV eradication is durable with follow-up periods of more than 20 years.[1-5] Achieving a SVR prevents progression to end stage liver disease and occurrence of hepatocellular carcinoma.[6-8] Moreover, successful treatment of HCV is associated with reduced hepatic morbidity, liver related deaths and improvement of health-related quality of life.[7-11] Recent reports even documented a reversal of cirrhosis many years after achieving sustained virological response (SVR).[12-14]

Currently we are witnessing the development of potent anti-viral drugs for treatment of chronic hepatitis C. The first two licensed protease inhibitors almost doubled the rate of SVR both in treatment-naïve[15, 16] and treatment-experienced patients.[17, 18] It is unknown whether the encouraging long-term data of dual combination therapy can be extrapolated to triple therapy with direct-acting anti-virals. So far, no data on the long-term outcome of patients with SVR following triple therapy have been reported. Aim of our study was to analyse virological follow-up of a large cohort of SVR patients participating in phase 2 or 3 trials or an extended access programme treated with peginterferon/ribavirin in combination with different direct-acting anti-virals.

Patients and methods
Patients
Patients participated in prospective randomised trials of treatment with pegylated interferon-alfa, ribavirin (PEGIFN/RBV) with a direct-acting anti-viral[15, 18-20] or in a named patient early access programme for telaprevir and were routinely invited for follow-up examinations.[3] Patients were selected according to the inclusion and exclusion criteria of the respective trial. All patients were Caucasians. Patients receiving placebo or no ribavirin were excluded from this analysis. A total of 103 out of 113 patients (91.2%) with SVR after DAA containing therapy attended follow-up visits at the out-patient clinics of the 4 participating tertiary referral centres. SVR was achieved in 43 patients receiving telaprevir, 30 on faldaprevir,[21, 22] 20 on simeprevir[23], 3 on danoprevir, 5 on ritonavir boosted danoprevir, 5 on mericitabine[24],3 on ritonavir boosted danoprevir and mericitabine and 2 on balapiravir.[25] For details see Table 1.

Table 1. Patients with SVR in triple therapy studies and long-term follow-up
 

Drug	Study	No. recruiteda	All with SVR 24; n (%)	No. with SVR and FUb
EAP, extended access programme. a Only patients receiving PEGIFN/RBV plus a direct-acting anti-viral. b Patients completed treatment and long-term follow-up. Virological test used in the central laboratories of the studies. c Roche COBAS Taqman HCV/HPS assay: limit of quantification <25 IU/mL; limit of detection 10 IU/mL. d Roche COBAS Ampliprep/COBAS, limit of detection 15 IU/mL. e Roche COBAS Taqman version 1.0, limit of quantification 30 IU/mL; lower limit of detection 10 IU/mL.
Telaprevir	Prove 2,[19]e C208,[20]c ADVANCE,[15]c REALIZE,[18]c EAP	53	43 (81.1)	40
Simeprevir	ASPIRE (NCT00980330),c PILLAR (NCT00882908),c	26	20 (77.0)	19
Faldaprevir	SILEN 1,[25]c SILEN 3 (NCT00984620)c	39	30 (76.9)	26
Danoprevir	ATLAS (NCT00869661)d	3	3	3
Ritonavir boosted Danoprevir	DAUPHINE (NCT01220947)c	10	5	5
Mericitabine	PROPEL,[21]d	8	5	5
Ritonavir boosted Danoprevir + Mericitabine	MATTERHORN (NCT01331850)c	9	5	3
Balapiravir [22]d		11	2	2

Routine laboratory parameters like alanine aminotransferase (ALT) and alpha-fetoprotein (AFP) were determined at every follow-up visit. EDTA blood was used for genetic testing. The SNPs for IL28B rs 12979860 were analysed by the StepOnePlus Real time PCR System (Applied Biosystems, Foster City, CA, USA) as described previously.[26] Baseline data are summarised in Table 1.

Virological tests
HCV was quantified during the studies in central laboratories using different PCR assays described in subscript Table 1. During follow-up, viral load of HCV was quantified by real-time PCR (COBAS TaqMan HCV Test Version 2; Roche Diagnostics, Pleasanton, CA, USA) in all patients. Genotyping of HCV was determined by Versant genotype assay (LiPA 2.0; Bayer HealthCare LLC, Subsidiary of Bayer Corporation, Tarrytown, NY, USA). Sequencing of HCV-RNA was performed for one patient by Böhringer-Ingelheim Canada (by Marquis Martin) using the ABI 3730 Genetic Analyzer (Applied Biosystems) detection system. The second sequencing of HCV-RNA was performed by the department of virology (HH) using the ABI 3130XL Genetic Analyzer (Applied Biosystems).

Clinical follow-up
All patients were asked to return to follow-up visits after 6 months and then at least once a year. Out of 113 patients, 103 patients returned to follow-up visits. At the clinical visits, routine blood tests, including alfa-1-fetoprotein and quantitative HCV-RNA determination (by TaqMan HCV Test), were obtained. Patients with pre-treatment cirrhosis were asked to perform a liver ultrasound examination prior to the visit. If necessary [in case of hepatic decompensation or suspicion for hepatocellular carcinoma (HCC)], further examinations were performed as needed. The institutional review board approved this retrospective non-interventional analysis.

Statistical analysis
Database management and statistical analysis were performed using commercially available software systems (Microsoft Office Excel 2010; Microsoft Corporation, USA and SPSS 2006 for Windows version 16). Quantitative variables were expressed as mean with the 95% confidence interval or as median (range). Data were analysed by using Student′s t-test for Gaussian variables, Mann–Whitney U-test for non-Gaussian variables as well as Chi-squared test. To determine, whether variables were normally distributed or not, the Kolmogorow–Smirnow test was applied. All P-values were two-tailed and assumed to be statistically significant if P ≤ 0.05.

Results
Characteristics of patients

A total of one hundred and three patients (f/m = 34/69, age: 47.6 ± 8.7; years ± s.d.) with a sustained virological response (SVR) were evaluated. Patient′s characteristics are shown in Table 2. A total of 23 patients (17 Nonresponder/6 Relapser) were treatment experienced, while 80 were treatment naive.

Table 2. Patient characteristics

	n (%)
a In five patients fibrosis grade was assessed by Fibroscan, none of them had F4. b IL28 rs12979860 was not available in all patients. c Follow-up [months, median (range)] after achieving SVR (=24 weeks after end of treatment).
n (f/m)	103 (34/69)
Age (mean ± s.d.)	47.6 ± 8.7
BMI (kg/m2)	24.7 + 3.6
HCV-Genotype
HCV-1a	34 (33.0)
HCV-1b	67 (65.1)
HCV-4	2 (1.9)
Cirrhosis (liver biopsy available in 98a)	18 (18.4)
Follow-up [mo, median(range)]c	21 (7–64)
IL28 rs12979860 available in 79b
CC	23 (29.1%)
C/T	44 (55.7%)
T/T	10 (12.7%)
Treatment
Protease inhibitor	93 (90.3)
NS5B Polymerase inhibitor	7 (6.8)
Both	3 (2.9)

One hundred and one patients were chronically infected with HCV-genotype 1 (HCV-1a: 34; HCV-1b: 67), two patients with HCV-genotype 4 (both received mericitabine). Ninety-three patients with HCV-genotype 1 received a protease inhibitor, seven patients a NS5B inhibitor (balapiravir or mericitabine) and three patients a combination of protease and NS5B inhibitor together with pegylated interferon-alfa and ribavirin at the four Austrian study sites (for details see Table 1).

Two relapses (2/103, 1.9%) occurred during follow-up after achieving a sustained virological response: One late relapse was seen in a 51-year-old female noncirrhotic patient (Fibroscan: 5.8 ± 0.5 kPa) infected with genotype 1b. She was a carrier of the IL-28B rs12979860 T/C genotype. She was treatment naïve and received triple therapy (3 days lead in with peginterferon/ribavirin followed by peginterferon/ribavirin/faldaprevir 120 mg daily) for 12 weeks and peginterferon/ribavirin for a total of 24 weeks.

HCV-RNA became undetectable at week 4 and remained undetectable throughout the whole therapy. She was HCV-RNA negative after 24 weeks of follow-up (SVR24) and had aminotransferases in normal range. Two months later, she came to the out-patient unit because of abdominal pain. Laboratory test showed detectable HCV-RNA (=8 months after end of treatment; viral load: 1.33 E5 IU/mL). The positive HCH RNA was confirmed several times.

Cloning sequencing in this patient showed the same sequence in the sample taken after relapse as in the sample obtained at screening. Resistance analysis revealed no presence of viral resistance. She received a retreatment with pegIFN/RBV and telaprevir for a total of 24 weeks and was HCV-RNA undetectable at end of treatment. She is currently on treatment-free follow-up.

The second late relapse occurred in a 59-year-old treatment-naïve, cirrhotic, male patient, who was chronically infected by HCV-genotype 1b and carrier of IL-28B genotype rs12979860 T/C. He received triple therapy (peginterferon/ribavirin/faldaprevir 120 mg daily for 24 weeks and peginterferon/ribavirin for a total of 48 weeks). HCV-RNA became undetectable at week 4 and remained undetectable throughout the whole therapy. After 24 weeks of follow-up, HCV-RNA was not detected (SVR24) and aminotransferases were normal. At a routine control examination 12 months after end of treatment, increased ALT was detected. HCV quantification revealed a viral load of 288 IU/mL. The genotype of the pre-treatment and the postrelapse sample was HCV-1b and cloning sequencing revealed identical sequence in both samples. Resistance analysis revealed no presence of viral resistance. No signs of hepatic decompensation or HCC occurrence were observed.

In both patients, HCV-RNA increased to pre-treatment levels within the next months. Of the remaining 101 patients, 90 (89.1%) had aminotransferases within the normal range at the last follow-up. AFP levels were available in 60 patients and were within the normal range in 54/60 (90%) patients. In the patients with slight increase AFP levels abdominal ultrasound revealed no signs of hepatic mass. No patient took immunosuppressive medication in the posttreatment follow-up period.

Discussion
This study confirms that SVR equals permanent HCV eradication by whatever interferon-based anti-viral treatment it was achieved. Our data indicate that the favourable long-term outcome reported after peginterferon/ribavirin combination therapy seems to hold true for patients treated with a triple therapy with peginterferon/ribavirin in combination with a direct anti-viral agent. To the best of our knowledge, this is the first study reporting long-term virological outcomes in patients with hepatitis C after successful anti-viral triple therapy.

There are theoretical concerns regarding the durability of HCV eradication after successful direct-acting anti-viral-based triple therapy. During direct-acting anti-viral treatment resistance-associated variants with reduced replication fitness compared with the wild type virus may emerge. If these resistance-associated variants cannot be eliminated by the required peginterferon/ribavirin backbone, strains with reduced replication fitness may persist in low concentration and may account for late relapses.

In the ADVANCE study, 1 of 357 patients evaluated had a confirmed late relapse after early discontinuation of treatment (randomised to the arm 8 weeks of telaprevir followed by dual therapy) at week 12.[15] In the PROVE 2 study, 2 late relapses were observed 36 and 48 weeks after the end of treatment.[19] In a phase 2 trial of an interferon-free regime (ritonavir boosted protease inhibitor ABT-450 combined with the nonnucleoside inhibitor of HCV NS5B polymerase ABT-072), one patient had a late relapse 36 weeks after end of treatment.[27] Thus data on longer follow-up are of major importance in the era of direct-acting anti-virals in HCV treatment.

In our study, two patients with a sustained virological response (SVR24) experienced a relapse 2 and 6 months later. Both patients completed a full course of anti-viral treatment without dose modifications or discontinuations of medications with peginterferon/ribavirin and faldaprevir. The serum samples of both patients (taken at baseline and after relapse) revealed no viral resistance and showed viral homology to samples collected at screening. Neither of the two patients showed a risk behaviour regarding HCV infection before reappearance of HCV. Thus, in both patients a late relapse rather than a newly acquired infection seems to be the reason for reappearance of hepatitis C virus. Obviously, an ongoing occult HCV infection cannot be excluded with certainty.[28]

Overall, our data show that it seems appropriate to extrapolate the encouraging long- term data of dual combination therapy to triple therapy with direct-acting anti-virals. The late relapse rate was 1.9% (95% CI: 0.24–6.8) as compared to 0.18% (0.004–1.01) in a much larger cohort of patients with SVR after dual therapy.[29] As all patients treated with direct-acting anti-virals in combination with PEGIFN/RBV achieving similar rates of SVR were followed prospectively, a potential selection bias is unlikely. However, in parallel to reported late relapses after successful dual therapy), late relapses after triple therapy – although a rare event – seem to occur within the first months after SVR like in the cases in our cohort. The fact that both relapses were observed in patients receiving faldaprevir occurred possibly just by chance, as the mode of action and the efficacy of the protease inhibitors are similar. Nevertheless, it seems advisable to confirm a successful HCV eradication within the first year of follow-up after achieving a sustained virological response. From our data, no impact on the durability of SVR after interferon-free treatments can be inferred.

In conclusion, our study shows that HCV eradication by triple therapy remains durable and confirms an excellent long-term prognosis of HCV patients with SVR. To assess the long-term clinical benefit of triple therapy, studies with a longer follow-up and larger patient numbers are needed.

Authorship
Guarantor of the article: Peter Ferenci.

Author contributions: Karoline Rutter: data collection, data analysis, writing of the manuscript. Albert Friedrich Stättermayer, Sandra Beinhardt, Thomas-Matthias Scherzer, Melisa Dulic, Michael Gschwantler, Andreas Maieron, Hermann Laferl, Petra Steindl-Munda: acquisition of data, critical revision of the manuscript for important intellectual content. Robert Strassl and Heidemarie Holzmann performed the virological assays. Peter Ferenci and Harald Hofer: study concept and design, analysis and interpretation of data, outlining and revising the manuscript. All authors approved the final version of the article.

Acknowledgements
Declaration of personal interests: The authors would like to thank Kerstin Zinober for her help in data collection and management and Martin Marquis, Böhringer-Ingelheim Canada for clonal sequencing.

Declaration of funding interests: Peter Ferenci is a member of the global advisory board and of the speaker's bureau of ROCHE, Basel CH and Rottapharm-Madaus, Monza, Italy. He is also advisor to Böhringer-Ingelheim, Vertex/Tibotec, Idenix, Achilleon, Glaxo Smith-Kline, Gilead and MSD and receives an unrestricted research grant from ROCHE Austria and MSD Austria. Harald Hofer, Michael Gschwantler, Petra Steindl-Munda and Andreas Maieron serve as speakers for Roche Austria, MSD Austria, Bristol-Myers Squibb and Janssen Austria. Karoline Rutter serves as speaker for Madaus-Rottapharm and MSD, Austria. All other authors have no financial disclosures to report.

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Danoprevir:Roche, Ascletis to develop & commercialise danoprevir in China for treatment of hepatitis C

Roche, Ascletis to develop & commercialise danoprevir in China for treatment of hepatitis C                                
Basel
Tuesday, April 16, 2013, 09:00 Hrs  [IST]
                       

Roche, one of the world’s largest biotech companies, and Ascletis, an emerging biotechnology company, have entered into a collaboration to develop and commercialise Roche’s investigational drug danoprevir in China for the treatment of hepatitis-C virus (HCV). Danoprevir is an investigational protease inhibitor which is active against HCV genotypes 1 and 4.

Under the terms of the agreement, Ascletis will fund and be responsible for the development, regulatory affairs and manufacturing of danoprevir in greater China, including Taiwan, Hong Kong and Macau and receive payments upon reaching certain development and commercial milestones from Roche. Ascletis and Roche will collaborate for the clinical development and the commercialisation. The contract also involves royalties.

It is estimated that over 10 million patients in China are chronically infected with HCV. The majority of these are genotype 1b, which has proven highly responsive to danoprevir. Roche and Ascletis are joining forces to develop a therapy with the potential to address a serious public health problem and to provide an effective new treatment option for Chinese patients with HCV. Protease inhibitors have become a core component of highly effective future HCV treatments.

Commenting on the agreement, Luke Miels, head of Roche Pharmaceuticals Asia Pacific, said, “Our strategy is based on bringing innovative, differentiated medicines to patients. The decision to develop danoprevir based on its promising profile in HCV Genotype 1b, and to do this via collaboration with our partner Ascletis represents another example of this strategy in action.”

Jinzi J Wu, president and CEO at Ascletis added, “No marketed direct antiviral agents (DAAs) are currently available for hepatitis C in China. Roche is a global leader in the development of innovative Hepatitis C therapies, and we are pleased to be collaborating with Roche to develop and eventually commercialize this much needed medicine for Chinese patients. Furthermore, we are very encouraged by the clinical data that have emerged to date and looking forward to bringing this novel DAA to patients in need.”

Ascletis is dedicated to discovering, developing and commercializing important new treatments for cancer and infectious diseases. Ascletis is focused on clinical development of innovative medicines and commercialization for the growing Chinese pharmaceutical marketplace.

 

http://www.pharmabiz.com/NewsDetails.aspx?aid=74810&sid=2

HCV: second-generation protease inhibitors

Liver International

Special Issue: Proceedings of the 6th Paris Hepatitis Conference, International Conference on the Management of Patients with Viral Hepatitis

Volume 33, Issue Supplement s1, pages 80–84, February 2013

 Get PDF (116K

 

New therapeutic strategies in HCV: second-generation protease inhibitors

Virginia C. Clark,
Joy A. Peter,
David R. Nelson*

Article first published online: 3 JAN 2013

DOI: 10.1111/liv.12061

Keywords:
Hepatitis C;
protease inhibitors;
ACH 2684;
MK 5172

Abstract
Telaprevir and boceprevir are the first direct-acting antiviral agents approved for use in HCV treatment and represent a significant advance in HCV therapy. However, these first-generation drugs also have significant limitations related to thrice-daily dosing, clinically challenging side-effect profiles, low barriers to resistance and a lack of pan-genotype activity. A second wave of protease inhibitors are in phase II and III trials and promise to provide a drug regimen with a better dosing schedule and improved tolerance. These second-wave protease inhibitors will probably be approved in combination with PEG-IFN and Ribavirin (RBV), as well as future all-oral regimens. The true second-generation protease inhibitors are in earlier stages of development and efficacy data are anxiously awaited as they may provide pan-genotypic antiviral activity and a high genetic barrier to resistance.

Abbreviations
AEs adverse effects
cEVR complete early virological response
PIs NS3-4A protease inhibitors
RVR rapid virological response
SVR sustained viral response

A large number of NS3-4A protease inhibitors (PIs) have reached clinical development, including two drugs, telaprevir and boceprevir, that have already been approved for use in combination with pegylated IFN-α (PEG-IFN) and ribavirin (RBV) in patients infected with genotype 1 hepatitis C virus. Telaprevir and boceprevir significantly improve virological outcomes in both treatment-naїve [1, 2] and -experienced genotype 1 patients [3, 4]. However, the clinical utility of these first-generation PIs is limited by a thrice-daily dosing schedule (with food), increased rates of adverse effects (AEs) (anaemia and rash), a low genetic barrier to resistance and extensive drug–drug interactions. These limitations highlight the opportunities for improvement in protease inhibitors. This review will discuss the newer protease inhibitors under late-stage development, which should be more potent, with higher barriers to viral resistance, and improved dosing regimens.

Second-wave protease inhibitors

 

Second-wave protease inhibitors offer several advantages over currently available drugs. Improved pharmacokinetics will allow a once-a-day dosing schedule and the side-effect profiles are more tolerable. However, these agents have similar genotype coverage and similar resistance profiles to telaprevir and boceprevir, and do not represent true second-generation PIs. The improved PIs have been referred to as second-wave PIs. They will probably replace first-generation PIs in combination with PEG-IFN/RBV to become the initial partners in the first generation of all-oral regimens. The following drugs are currently in phase II and III development (Table 1).

Table 1. HCV protease inhibitors
 

Telaprevir	Approved	First generation
Boceprevir	Approved	First generation
Simeprevir	Phase 3	Second wave
BI1335	Phase 3	Second wave
Asunaprevir	Phase 3 (all oral)	Second wave
Danoprevir/r	Phase 2	Second wave
Sovaprevir	Phase 2	Second wave
ABT450/r	Phase 2	Second wave
MK 5172	Phase 2	Second generation
ACH 2684	Phase 2	Second generation

Simeprevir (TMC435; Tibotec, Beerse, Belgium; Medivir Pharmaceuticals, Stockholm, Sweden; Janssen, Beerse, Belgium) is a once-a day-oral NS3/4A protease inhibitor currently in phase III clinical development for the treatment of HCV infection. Phase I and II trials have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once-a-day dosing, and demonstrates potent antiviral activity and efficacy [5]. The final results of two phase IIb trials of TMC435 with PEG-IFN/RBV in naïve and treatment-experienced populations have been completed [6]. PILLAR study enrolled 368 treatment-naïve subjects with genotype 1 and compared two different doses (75mg vs 150 mg) and durations (12 weeks vs 24 weeks) of simeprevir therapy in combination with PEG-IFN/RBV for either 24 or 48 weeks. A sustained viral response (SVR) was achieved in 68–76% of patients with this triple therapy regimen and approximately 80% of subjects were eligible to receive shortened 24 weeks of therapy with very high SVR (93–96%). Adverse effects were similar to standard therapy, and the lowest rate of relapse was found in the study arm receiving 150 mg daily TMC435 in addition to PEG-IFN/RBV for 24 weeks (8%). In addition, SVR rates in the 150-mg dosing arms did not differ according to HCV subtype (1a vs 1b), but as expected, SVR was highest in the IL28B CC genotype.
 

ASPIRE was a randomized, double-blind, placebo-controlled phase IIb trial, which assessed the efficacy and safety of simeprevir in combination with PEG-IFN/RBV in 462 patients with genotype 1 HCV who had failed a previous PEG-IFN/RBV regimen. The ASPIRE study randomized patients to seven treatment arms, each of which was given simeprevir in combination with 48 weeks of PEG-IFN-2a/RBV. SVR rates were significantly higher in all simeprevir-containing treatment arms compared with PEG-IFN/RBV alone. The best results were obtained in the 150-mg dosing groups with a SVR of 85% vs 37% in prior relapsers, 75% vs 9% in partial responders and 51% vs 19% in prior non-responders. It is also important to note that higher 24-week SVR rates were observed with simeprevir-containing therapy in difficult-to-treat patient subgroups, including patients with cirrhosis and a previous non-response (31% SVR in non-response cirrhotics). As has been seen with most PI-based studies, breakthrough or relapse was associated with a resistant virus (42/43 people who experienced breakthrough and 34/36 who relapsed). Subjects with HCV genotype 1a were more likely to have the R155K mutation alone or with additional mutations, whereas people with HCV genotype 1b had the D168V mutation [7].
 

In both the naïve and treatment-experienced trials, TMC435 was generally well tolerated with no evidence of significant safety signals related to rash, anaemia or neutropaenia. However, transient elevations of direct and indirect bilirubin were seen in subjects who took a 150-mg dose of simeprevir. Elevations in bilirubin were not associated with an elevation of AST or ALT, returned to baseline with the cessation of therapy and are believed to be related to interference with bilirubin transporters.
 

Finally, simeprevir may also provide opportunities for use in non-genotype 1 patients. A phase IIa proof-of-concept trial provided evidence that TMC435 has a broad spectrum of activity against multiple HCV genotypes except for genotype 3 [8]. Monotherapy with oral TMC435 200 mg q.d. for 7 days was associated with potent antiviral activity in patients infected with genotypes 2, 4, 5 and 6. The greatest antiviral activity was observed among patients infected with genotypes 4 and 6, followed by genotypes 2 and 5. Of note, no antiviral activity was seen against genotype 3. Thus, simeprevir seems to offer significant improvement over boceprevir and telaprevir: once-a-day dosing, improved safety profile (lack of rash and anaemia) and expanded antiviral activity across more genotypes.

BI201335 (Boehringer Ingelheim Pharmaceuticals, Ingelheim, Germany) is another NS3/4A protease inhibitor with once-a-day dosing that has completed phase 2 testing. SILEN-C1 study reported the efficacy data from a randomized phase II trial with 429 genotype 1 treatment-naïve patients [9]. The treatment regimen included BI201335 in addition to PEG-IFN/RBV for 24 weeks at doses of 120 and 240 mg, followed by another 24 weeks of standard therapy. Response-guided therapy was evaluated and achievement of an eRVR (HCV-RNA negative at week 4 and week 12) resulted in randomization to stop therapy at week 24 or continue with PEG-IFN/RBV for a total of 48 weeks. The overall SVR rate was 83% for the 240-mg dose (lower for the 120-mg dose), and 92% of the patients with an eRVR achieved a SVR regardless of the subsequent duration of PEG-IFN/RBV. Adverse events (mostly gastrointestinal) resulted in drug discontinuation in 7.3% of subjects. SILEN-C2 study evaluated 288 partial or non-responders and evaluated the 240-mg dose, either once or twice daily in combination with PEG-IFN/RBV for 24 weeks [10]. The highest SVR was achieved in the once-a-day dosing groups: it was 50% in partial responders and 35% in non-responders. It should be noted that patients with cirrhosis were not included in this study. Both SILEN-C1 and C2 tested the efficacy of a 3-day lead-in with PEG-IFN/RBV. The expectation was that the lead-in would limit the development of resistance by providing better antiviral drug coverage when the PI was introduced. For unknown reasons, the lead-in arms in both trials showed a significant decrease in efficacy, and this strategy to limit resistance has been abandoned. SILEN-C3 evaluated treatment-naïve, genotype 1 patients and randomized them to either 12 or 24 weeks of once-a-day 120 mg BI 201335. Both groups received PEG-IFN/RBV for 24 weeks and patients who did not achieve an eRVR continued PEG-IFN/RBV until week 48. SVR rates were similar for both durations, 65% vs 73% overall and 82% vs 81% in those with eRVR respectively. Through all of the SILEN-C phase 2 trials, the adverse-event profile of BI 201335 appeared to be mild rash and photosensitivity along with some GI toxicity (nausea, diarrhoea and vomiting). As with a few other PIs under development, BI 201335 is associated with a transient rise in indirect or unconjugated bilirubin that is related to inhibition of the bilirubin transporter (inhibition of hepatic uptake of uridine diphosphate glucuronosyl transferase 1 family polypeptide A1, UGT1A1)[11]. The once-per-day dosing regimen that is moving forwards into phase 3 trials has fewer adverse events than the twice-per-day dosing regimen.

Danoprevir/r (RG7277; Roche, Basle, Switzerland; Intermune Pharmaceuticals, Brisband, CA) is a twice-a-day, ritonavir-boosted HCV protease inhibitor with good antiviral activity against genotypes 1, 4 and 6. Of note, the early hepatotoxicity signals of the drug were virtually eliminated by the addition of ritonovir boosting, which leads to strong inhibition of CYP3A and increased through concentrations of the PI. DAUPHINE is a large phase 2 trial in naïve patients that evaluated three different doses (50, 100 and 200 mg danoprevir, boosted with 100 mg ritonavir, twice daily) and response-guided therapy in combination with PEG-IFN/RBV [12]. Twelve weeks after stopping therapy, antiviral negativity (SVR12) was 93% in the 200-mg dosing arm, 83% in the 100-mg arm and 67% in the 50-mg arm. At the 200-mg dose, the response was not influenced by either HCV subtype (1a vs 1b) or IL28B genotype (CC vs non-CC), suggesting that this regimen leads to potent viral suppression. Of note, genotype 4 patients had a 100% SVR 12 across all dosing arms. Danoprevir is also being evaluated in IFN-free regimens combined with the nucleoside inhibitor, Mercitabine (RG7128) [13].

 

Asunaprevir (BMS-650032; Bristol-Myers Squibb, New York, NY) is a twice-daily protease inhibitor being developed in both IFN-containing and free regimens with daclatasvir, an NS5A inhibitor and BMS 791325, a non-nucleoside inhibitor. Asunaprevir was initially studied at a dose of 600 mg twice per day, but was decreased to 200 mg twice per day because of increased liver enzymes. The combination of asunaprevir and daclatisvir was the first regimen to successfully cure HCV-infected patients without the use of IFN [14]. Despite potential approval in an IFN-free combination in genotype 1b patients and a potential quad regimen, asunaprevir is not likely to become the PI of choice for this second wave of PIs because of the twice-per-day administration and potential association with hepatotoxicity.
 

Sovaprevir (ACH-1625; Achillion Pharmaceuticals, New Haven, CT) is another NS3 protease inhibitor with very high potency, reporting a half-maximal inhibitory concentration of ~1 nm. A phase IIa study reported that ACH-1625, with PEG-IFN/RBV, resulted in a RVR in 75–81% of subjects compared with a RVR of 20% in patients receiving PEG-IFN/RBV alone [15]. A phase IIb study is under way at this time, but given the true second-generation PI also from Achillion (see below), it is less likely that this PI will be carried through to phase III trials.
 

ABT-450/r (Abbott, Abbott Park, IL; Enanta Pharmaceuticals, Watertown, MA) ABT-450 is being evaluated with ritonavir boosting to increase plasma concentrations and enable once-a-day dosing. A recent analysis included 35 treatment-naїve chronic hepatitis C patients randomly assigned to receive ABT-450/ritonavir or placebo [16]. Participants received ABT-450/ritonavir at doses of 50/100 mg, 100/100 mg or 200/100 mg once daily, or placebo, as monotherapy for 3 days, followed by 12 weeks of ABT-450/ritonavir or placebo at the same dose in combination with PEG-IFN/RBV. During the 3 days of monotherapy, the response was similar in all three ABT-450/ritonavir dose arms, with a mean maximum HCVRNA decrease of around 4 log IU/ml, compared with 0.36 log IU/ml in the placebo group. In an intent-to-treat analysis at 4 weeks, 88% of patients receiving ABT-450/ritonavir plus PEG-IFN/RBV had achieved a RVR (RVR; HCV RNA <25 IU/ml) compared with only 9% in the placebo arm. At 12 weeks, 92% receiving ABT-450/ritonavir vs 18% receiving placebo had achieved a complete early virological response (cEVR, again HCV RNA <25 IU/ml). HCV sub-genotype (1a or 1b), baseline HCV RNA and IL28B gene pattern were not associated with differences in virological response. ABT-450/r is also being studied in all-oral regimens and is more likely to receive approval in this IFN-free pathway.

Second-generation protease inhibitors

 

Two second-generation protease inhibitors, MK-5172 and ACH-2684, are in various stages of clinical development. These true second-generation PIs are expected to have broader genotype coverage and higher barriers to resistance, which represents a significant shift from the second-wave PIs.
 

MK-5172 (Merck & Co., Inc, Whitehouse Station, NJ) is a novel macrocyclic NS3/4a protease inhibitor under phase II clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major HCV genotypes, notably variants resistant to earlier protease inhibitors. R155 is the main overlapping position for resistance and different mutations at this amino acid site within NS3 protease confer resistance to nearly all protease inhibitors in development. However, MK-5172 exhibits potent antiviral activity against variants carrying mutations at position R155. Thus, based on its preclinical profile, MK-5172 is expected to be broadly active against multiple HCV genotypes, including genotype 3 as well as clinically important resistance variants making it highly suited for incorporation into newer all-oral regimens. MK-5172 was given in doses of 50–800 mg QD (monotherapy) to 48 men with HCV genotype 1 and 30 HCV genotype 3 patients for 7 days [17]. There were six arms (including a placebo arm). The maximum change in HCV levels was a decrease of −5.37 IU/ml in HCV genotype 1 and −4.41 IU/ml in genotype 3 patients. In the genotype 1 patients, 75% (30 of 40 pts) were below the level of HCVRNA quantification (25 IU/ml). The drug was generally well tolerated. In early-stage studies, MK-5172 in various doses has been shown to work across different genotypes [18] and can be dosed once a day, which makes it an attractive candidate for future clinical development.
 

ACH-2684 (Achillion Pharmaceuticals) is a macro-cyclic, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-2684 demonstrated pico-molar potency, excellent pharmacokinetic properties and a safety profile at high drug exposures that strongly supports once-a-day dosing. ACH-2684 also exhibits rapid and extensive partitioning to the liver, as well as high liver/plasma ratios in preclinical studies. It has preclinical activity against the six known genotypes of HCV and exhibits equipotent activity against HCV genotypes 1a and 1b at an IC50 of approximately 100 pm [19]. Achillion Pharmaceuticals, Inc reported proof-of-concept data from a Phase 1b clinical trial demonstrating that patients with HCV genotype 1 treated with ACH-2684 achieved a mean maximum 3.73 log¹⁰ reduction in HCV RNA after 3-day 400-mg monotherapy with once-a-day dosing. The compound also demonstrated good safety and tolerance both in healthy volunteers and in patients with HCV. This PI seems to represent an ideal partner for all-oral regimens that can help deliver pangenotypic activity with a high barrier to resistance.

Conclusion

 

The development of protease inhibitors represents a significant milestone in improving the efficacy of HCV treatment. However, the limitations of first-generation PIs have opened the door for continued drug development in this class. Several other direct-acting antivirals are under development [20]. Simeprevir, asunaprevir and BI are second-wave PIs in phase III trials, and will probably obtain approval with PEG-IFN/RBV in 2014. To be used in an all-oral regimen, second-wave PIs will need to be used in combination with other direct-acting antivirals to overcome the low genetic barrier to resistance. These combinations could include PIs and a nucleoside inhibitor with a high genetic barrier to resistance or PIs with a non-nucleoside inhibitor (or NS5A inhibitor) with a non-overlapping resistance profile. The future of protease inhibitors lies in the further development of second-generation drugs with a broad genotypic coverage and a high genetic barrier for resistance, which may be the ideal backbone for an all-oral HCV treatment regimen.

Disclosure

 

The authors have no disclosure.

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