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4.1.2 Polymerase Inhibitors

4.1.2 Polymerase Inhibitors

The HCV NS5B protein is a viral–dependant RNA polymerase. It looks like a flat donut and contains 3 areas which interact, called fingers, palm and thumbs. These areas form a circle around the active site, creating a hole. This hole, or cleft, is a target for drug development. The NS5B Coding region is very similar in all the genotypes, and is unique to HCV. (McHutchison, J. MD, Hepatology, November 2002)

Several companies are developing polymerase inhibitors. They stop the virus from replicating in one of two ways. Nucleoside analogues stop the elongation of the RNA strands, and non-nucleoside inhibitors block the polymerase itself. Ribavirin is a nucleoside analogue, but its mechanism is not well understood yet.

Besides the products below, many other polymerase inhibitors in pre-clinical trials. These are exciting times!

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4.1.2a R7128, R1626, GS-6130, GS-7851, GS-7977, PSI-938,

In October of 2004, Roche and Pharmasset partnered to develop nucleoside polymerase inhibitors for HCV. GS-6130, a nucleoside analogue in preclinical development, is their favorite candidate. It proves to be effective against the virus in the laboratory, and can probably be used orally. They hope that it will be effective when combined with Pegasys and Copegus for non-responders, and are planning a Phase I trial in healthy volunteers in 2006.) Roche is also developing these polymerase inhibitors: R 1270, R1479, R1626, R7128 (in collaberation with Roche) is being studied with pharmasset. R7128 is a prodrug of GS-6130 (www.pharmasset.com/psi-6130.asp 2007)


Pharmasset’s R7128, a polymerase inhibitor, is a prodrug of GS-6130 (formerly PSI-6130). In a previous 4-week Phase 1 study conducted in 81 treatment-naive patients, R7128 showed good short-term antiviral activity with safety and tolerability comparable to standard treatment (pegIFN/RBV). Up to 88% of patients achieved undetectable viral levels with R7128, 1000 mg 2x/day plus standard treatment (SOC) , compared to 18.75% treated with standard treatment alone. In genotype 2 or 3 non-responders, results with R7128 1500 mg 2x/day plus standard treatment resulted in 90% of patients achieving undetectable viral levels after 4 weeks, compared to 60% with standard treatment.

The Phase 2b trial will enroll about 400 treatment-naïve genotype 1 or 4 patients, and combine R7128 with standard treatment in an attempt to improve SVR and shorten treatment time. The trial will be held in North America, Europe and Australia. Patients will be enrolled in one of 5 arms:

  • R7128 500 mg 2x/day with SOC for 12 wks, then 12 wks SOC (12+12)
  • R7128 1000 mg 2x/day with SOC for 12 wks, then 12 wks SOC (12+12)
  • R7128 1000 mg 2x/day in combination with SOC for 8 wks, followed by 16 wks of SOC (8+16)
  • R7128 1000 mg 2x/day with PEGASYS SOC for 12 wks, followed by 36 wks SOC (12+36)
  • A control arm with SOC for 48 wks.

Patients in the 24-week arms will discontinue all treatment at week 24 if they have achieved RVR, defined as undetectable levels of HCV at week 4 (a strategy known as "RVR-guided" treatment), and maintain undetectable levels of HCV until week 22. Patients who do not achieve an RVR at week 4 will continue on SOC until week 48.

A Phase IIa clinical trial of Roche's polymerase inhibitor R1626 which treated 104 naïve genotype 1 patients for 4 weeks followed by 44 weeks of standard treatment (peg-IFN + ribavirin), led to 84% of genotype 1 patients achieving undetectable viral loads in those receiving the 1,500 mg dose twice daily, compared to 65% with standard treatment alone. The drug has shown no development of resistance. SVR rates are not yet available. IIb trials began in November and are fully enrolled with about 500 patients. (www.natap.org/2008/EASL/EASL68.htm)

GS-7851 (Formerly PSI-7851)
Pharmasset reported data from its Phase Ia trial of GS-7851, a polymerase inhibitor, which showed the drug to be safe in humans, and b a Phase Ib trial in patients with genotype 1. GS-7851 is a uridine nucleotide analog approximately 15 to 20 times more powerful than Pharmasset's polymerase inhibitor R7128. GS-7851 has been shown to be effective against all of the most common HCV genotypes in laboratory trials. This study will assess the safety, tolerability and antiviral activity in HCV-infected individuals treated with GS-7851 over 3 days, in ascending doses. Results from both studies are expected in the second half of 2009. (PRNewswire-FirstCall via COMTEX News Network June 9, 2009 via Natap)

Trial arms with PSI-938 are on hold due to elevated enzymes at higher doses.

GS-7977 (Formerly PSI-7977)
Pharmasset hopes that GS-7977, a nucleotide polymerase inhibitor, will allow people to be treated without IFN. It is quite effective in GT1, 2 and 3. The drug has been tested with pegIFN/RBV, with SVRs over 90%. Researchers conducted a Phase II trial with 40 GT2/3 patients for 12 weeks.

One of the 4 arms had no IFN, but all received RBV. GT2 and 3 are easier to treat, so the plan was they could be “rescued” with IFN if necessary. All of the patients tested undetectable at week 12, and for those tested at 24 weeks, 100% are still undetectable. Phase III trials will combine GS-7977 with RBV, but not IFN, which is expected to make the treatment safer and more tolerable. The drug works on all genotypes and there have been no cases of breakthrough so far, but the studies have been very small. There has been a trial with GT1, but combined with pegIFN/RBV, in which 91% tested undetectable at week 12.
(Hepatology 2011; 54(4): Abstract 34 www.medpagetoday.com/MeetingCoverage/AASLD/)

Gilead has acquired Pharmasset as of January 2012. Early data from the Phase II “Electron” trial raise hopes that a simple combination of two pills may cure genotype 1 patients. 35 patients (25 treatment-naïve and 10 non-responders) were treated with GS-7977 plus ribavirin. 100% of them tested undetectable at 4 weeks of treatment. The results from 4 weeks post-treatment and further trial data will be presented in Seattle’s Conference on Retroviruses and Opportunistic Infections (CROI), March 5-8.

GS-7977 was being used in a 14-day combination study with the promising guanine nucleotide analog PSI-938.(www.natap.org/2010/HCV/011111_01.htm Click HERE or see 4.1.5e)

Trial arms with PSI-938 are on hold due to elevated enzymes at higher doses. (www.natap.org/2011/HCV/12171101.htm)

PSI-938, Pharmasset’s oral guanosine nucleotide analog polymerase inhibitor, was fast-tracked by the US FDA. It showed favorable results from its NUCLEAR study which treated treatment-naïve GT1 patients for 14 days with either PSI-938 alone or together with GS-7977. 92% of patients in the combo arms tested undetectable. The next step was the QUANTUM trial, with the same combination of drugs, without interferon, in an attempt to find a more tolerable treatment. (www.natap.org/2011/HCV/08201102.htm)

Trial arms with PSI-938 are on hold due to elevated enzymes at higher doses, discovered during regular monitoring of patients receiving 300 mg daily of PSI-938. There were no irregular results in patients receiving GS-7977 in another arm of the same trial. Elevated liver enzymes are fairly common with many drugs, but in hepatitis patients, they can be a serious cause for alarm. (www.natap.org/2011/HCV/12171101.htm)

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4.1.2b MK-0608, MK3281

Two polymerase inhibitors, triphosphates of 2'-C-methyl-adenosine and 2'-C-methyl-guanosine, have been shown to be effective against HCV. In this study, these substances were changed by including another substance called a 7-deaza modification, making them 20 times more powerful. These have been tested in animals and in mice. (Olsen, DB; et al Antimicrob Agents Chemother. 2004 Oct; 48[10]: 3944-53) (www.natap.org/2006/AASLD/AASLD 47.htm)

MK-0608, a nucleoside analogue polymerase inhibitor, is being developed by Merck. Tests were done in six HCV-infected chimps with IV or oral dosing. IV dosing showed a greater than 5 log drop in viral load, with no rebound with daily treatment for 37 days, and a delay in rebound after the end of treatment. The resulting mutant virus seems to be weaker than the original. SVR was not obtained, but the product looks like an excellent candidate to be used with other products. (www.natap.org/2006/ICAAC/ICAAC13.htm Sept 2006)

MK-3281, is another polymerase inhibitor. Results from its Phase I trial found it to be safe and well-tolerated in healthy volunteers, and doses given twice a day were a possibility. (www.natap.org/2009/EASL/EASL28.htm)

There has been no more news, and the trial has been terminated. (http://clinicaltrials.gov/ct2/results?term=MK-3281)

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4.1.2c Vertex Polymerase Inhibitors

Vertex acquired these 3 HCV polymerase inhibitors from ViroChem Pharma in March of 2009, and worldwide
rights to ALS-2200 AND ALS-2158 in June 2011.

VX-759 (was VCH-759) is an oral, non-nucleoside inhibitor of HCV polymerase, thought to be especially effective against genotypes 1a and 1b. This study assessed the effect on viral kinetics, viral resistance, pharmacokinetics, safety and tolerability of VCH-759 given as monotherapy for 10 days, with a follow-up 14 days later. 32 naive genotype 1 patients received either placebo, 400 mg 3 times a day, (average drop 1.9 log10), or 800 mg 3 times a day (average drop 2.3 log10), or 800 mg twice a day, (average drop 2.5 log10). VCH-759 was well tolerated.

The most frequent adverse events were gastrointestinal disorders reported even in the placebo group. VCH 759 achieved a 2 log10 or larger decline in HCV RNA at doses of 800 mg 3 times daily and twice daily. VCH-759 was well tolerated with no serious adverse events and no discontinuation. Further studies combining VCH-759 with current therapies are suggested.
(www.natap.org/2007/AASLD/AASLD41.htm Nov 2007)

A group of researchers in Quebec studied VX-759 in a Phase Ib clinical trial, in genotype 1a and 1b patients, and found it produced a rapid reduction of viral load of 1.5 log10 or more during the first 2 days of treatment, in all the patients. The treatment lasted 10 days. There were basically two types of response: SVR or breakthrough. The study shows that it will probably be necessary to combine the drug with another to prevent resistance.

VX-916 is a non-nucleoside polymerase inhibitor. It produced a rapid drop in viral load with an average decrease of 0.6, 1.5, 1.5 and 1.5 log10 over 3 days of treatment, with doses of 100 or 200 mg 3x/day, and 300 or 400 mg 2x/day, respectively. Breakthroughs in some subjects were associated with the presence of polymerase mutations and some of these persisted through day 140 of the trial. This study indicates that monotherapy with VCH-916 will result in HCV polymerase mutations and that combination therapy is probably necessary. (EASL 2009) No recent clinical trial results have been released.

VX-222 is a non-nucleoside polymerase inhibitor which showed good antiviral activity during 3 days of treatment using a range of doses. The 32 subjects were treatment-naive genotype 1 patients. The results of this international, multicenter, Phase Ib/IIa study were presented at the 45th EASL Meeting (EASL 2010) in Vienna. 75% were GT1a. The others were GT1b. 80% were men, and the average age was 50 years. There were 5 arms: 250 mg twice-daily, 500 mg twice-daily, 750 mg twice-daily, or 1500 mg once-daily, or else placebo, for 3 days. After finishing, they were offered pegIFN/RBV for up to 48 weeks.

The drug produced at least a 3 log decline at day 4 in each arm except with the placebo. There were no drop outs due to side effects. A Phase II trial has begun, combining the VX222 with telaprevir, or with telaprevir + pegIFN/RBV.

ALS-2200 AND ALS-2158
Vertex and Alios BioPharma have begun two Phase I clinical trials with the nucleotide analogue NS5B polymerase inhibitors ALS-2200 and ALS-2158—oral drugs produced by Alios. Preclinical studies show that both drugs work by inhibiting the polymerase in all genotypes, including those usually found outside the US. Each drug is slightly different from the other but work even better when combined. One trial is studying safety and side effects of the drugs in healthy volunteers. The other is testing ascending doses in genotype 1 patients. Results are expected in the spring of 2012, and hopefully they will lead to Phase II trials of all oral, IFN-less regimens which may include Incivek or VX-222 and perhaps ribavirin, starting during the second part of 2012.

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4.1.2d Tegobuvir (GS-9190)

Tegobuvir (GS-9190) is a non-nucleoside HCV NS5B polymerase inhibitor produced by Gilead Sciences. GS-9256, also produced by Gilead, is a macrocyclic HCV NS3 protease inhibitor. These products work well together in GT1 patients, when combined with pegIFN/RBV, according to reports from EASL 2011, where the company shared posters from its Phase IIb trial about combining tegobuvir with pegIFN/RBV, and other earlier reports on tegobuvir combined with GS-9256, with other products.

Tegobuvir + Standard Therapy
The first study presented was a Phase IIb trial, tegobuvir plus pegIFN/RBV, for either 24 or 48 weeks. 252 treatment naïve GT1 patients with or without cirrhosis were enrolled. The first group took pegIFN/RBV, standard doses + placebo for 48 weeks. The 2nd group took pegIFN/RBV + 40 mg tegobuvir for 48 weeks. The 3rd group was the same dosing as group 2, but stopped if they had an extended rapid virological response (eRVR), or continued for 48 weeks. SVR rates were 56% in all 3 arms. The SVR rate in the patients who achieved RVR and could stop treatment at 24 weeks was 96%, but more of them dropped out because of the side effects (fever, muscle pain, itching), lowering the average.

Tegobuvir with GS-9256
The second study presented preliminary results from a trial of 46 subjects who took either (1) tegobuvir/GS-9256 alone, (2) tegobuvir/GS-9256/ribavirin or (3) tegobuvir/GS-9256/pegIFN/ribavirin for 4 weeks before continuing on pegIFN/RBV alone. At 24 weeks, the response rates were 100%, 100%, and 67%, respectively.
(www.hivandhepatitis.com/2011conference/easl2011/docs/04232010a.html 4/23/11)

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4.1.2e Filibuvir (FBV-formerly PF 00868554)

Filbuvir is one of the direct-acting anti-HCV agents. More specifically, it is an NS5B non-nucleoside polymerase inhibitor. In two recent Phase Ib studies, several different doses were tested in both treatment-naïve and –experienced subjects with GT1. The doses went from 200 to 1400 mg daily for 3 to 10 days. The best results were seen with the higher doses, resulting in an average drop of 2.30 log10 in the naïve patients taking 700 mg twice daily.

In the experienced patients, the highest dose was 450 mg daily, and it produced a viral load drop of 2.20 log10. Side effects were mild to moderate, and there were no drop-outs. Trials are underway combining the drug with pegIFN/RBV in treatment-naïve patients.

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4.1.2f ABT-333 and ABT-072

Abbott’s ABT-333, the company’s first HCV drug, a non-nucleoside polymerase inhibitor, was safe and well tolerated at single, ascending doses up to 2000 mg. The anti-viral potency of single ascending doses up to 1200 mg was dose proportional, and not affected by food. The most common side effects were nausea, abdominal discomfort and headache. Adverse events or laboratory abnormalities were mostly mild. There were no ECG changes. The company has other HCV candidates in preclinical development, as well, such as its oral protease inhibitor ABT-450, developed with Enanta. (HCV Advocate Email Alert Jun 17, 2008 and www.enanta.com)

In an early clinical trial, treatment with ABT-333 alone for 2 days followed by 26 days combining it with pegylated interferon + ribavirin (P/R) resulted in a 3.73 log10 decrease in viral load compared 1.37 log10 average drop in patients receiving P/R alone.

ABT-072, like ABT-333, is a non-nucleoside polymerase inhibitor, and it has been developed to treat those with genotype 1 infection in combination with other products. It been used safely in clinical trials. In an early clinical trial, subjects receiving two days of ABT-072 monotherapy had an average maximum 1.3 log10 decrease compared to a 0.3 log10 IU/mL drop with a placebo.

In a recent, ongoing Phase IIa clinical trial (Study M11-602) in 50 patients, both ABT-333 and ABT-072 were tested in various dosages. The trial began with 3 days of monotherapy with each of the drugs, and then pegIFN/RBV was added to each for a total of 12 weeks. PegIFN/RBV is to be continued without the polymerase inhibitor for a total of 48 weeks. Results at 12 weeks were presented in February 2011. Both drugs were more effective than the placebo. The trial is a small one, but the genotype 1b patients responded better than the genotype 1a, generally, with either of the polymerase inhibitors. At 12 weeks the cEVR was as follows: 69.6% in the ABT-072 group and 75% in the ABT-333 dose groups. There was 1 patient who had viral rebound in the ABT-072 group, and none in the ABT-333 group.

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4.1.2g Setrobuvir (ANA598)

Anadys Pharmaceuticals’ Setrobuvir (ANA598) is an oral non-nucleoside polymerase inhibitor for the treatment of HCV, designed to inhibit the virus in genotypes 1a and 1b. It has proven to be highly powerful in cell cultures and has been proven safe in over 150 human subjects.

The product has US FDA fast-track status as of December 2008. At the EASL Conference 2009, the company reported that ANA598 produced viral load reductions at the end of treatment (day 4) of over 2 log10 (more than 99%) at all dose levels. With twice daily dosing, 200 mg produced an average viral load drop of 2.4 log10; 400 mg produced a 2.3 log10; and 800 mg produced a 2.9 log10. Genotype 1a subjects showed average drops of 1.4 log10, 1.8 log10, and 2.5 log10 at those doses, and genotype 1b patients showed average drops of 2.6 log10, 2.5 log10, and 3.2 log10.
Anadys has now begun a Phase IIb study combining it with pegIFN/RBV (Pegasys/Copegus) in non-responders and treatment-naïve patients. Results at 12 weeks of treatment are expected shortly, and 24-week results are expected in the last quarter of this year.

On June 2, 2011, the product was granted a US patent.

Anadys Pharmaceuticals has just been acquired by Roche.
(www.roche.com/media/mediareleases/med cor-2011-10-17.htm Oct 17, 2011)

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4.1.2h BI 207127

The Phase Ib trial enrolled 48 genotype-1 patients with mild fibrosis, who were treated orally with 100, 200, 400 or 800 mg of the polymerase inhibitor BI 207127 every 8 hours over 5 days. All were followed for 10–14 days. 13 of the patients were treatment naïve. BI 207127 was safe and mostly well tolerated. A moderate drug-related skin inflammation was managed easily, and no dose reduction or discontinuation was needed.

In the 800 mg group, 5 of 9 patients showed more than 4 log viral load drop, which lasted at least 24 hours after the last dose was taken. There were no cases of breakthrough. No response was seen with the placebo. Viral load drops of more than or equal to 2 logs were achieved in most of patients receiving doses of 400 mg or 800 mg every 8 hours. Lab results varied little from baseline. Investigators judged tolerability of BI 207127 as good in 88% of treated patients. A trial with 1,200 mg is ongoing, and a 4-week combination study was expected to begin in late 2009. (www.natap.org/2009/EASL/EASL08.htm)

Results were presented in late 2011 for the SOUND-C1 non-interferon trial of BI 201335 + BI 207127 (a Protease-Polymerase combo).

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4.1.2i INX-189

The US Food and Drug Administration (FDA) has given INX-189 Fast Track status. The pharmaceutical company Inhibitex has developed this oral NS5B nucleotide polymerase inhibitor, which has demonstrated effectiveness in all of the genotypes, can be administered once a day, seems compatible with other antivirals, and has a high barrier to resistance, based on interim data from its Phase Ib clinical trial, which has since been completed. (www.natap.org/2010/newsUpdates/01131107.htm - Cached Jan 9, 2011)

INX-189, given once-daily at 9 mg, 25 mg, 50 mg and 100 mg for 7 days showed viral drops of 0.64, 1.00, 1.47, and 2.53 logs respectively.

The company presented an update at the AASLD 2011 conference, with data from the first arm of its trial designed to evaluate higher doses of INX-189, alone or combined with RBV for 7 days in treatment-naive patients GT 1 subjects.

Those who took 200 mg INX-189 once-daily showed a viral load drop of up to 4.25 log with that new, higher dose. There were no serious adverse events seen.

The trial includes other arms of 100 mg INX-189 taken once a day with RBV, 100 mg INX-189 twice daily alone, 100 mg INX-189 with food, and perhaps higher doses of INX-189 alone.

A Phase I trial in healthy volunteers of INX-189 together with a direct acting antiviral compound has begun, in order to pave the road for a Phase II trial of IFN-free combinations to be completed by the end of 2012.

A Phase II trial began in September with 90 GT2/3 treatment-naïve subjects, combining the drug with pegIFN/RBV.
(http://m2m.tmcnet.com/news/2011/11/04/5906617.htm Nov 4, 2011 and
www.natap.org/2010/newsUpdates/01131107.htm Jan 9, 2011)

As of January 7, 2012, Bristol-Myers acquired Inhibitex. Bristol-Myers Squibb has complimentary drugs in development with which INX-189 can be paired with hopes of producing oral “cocktails” to ward off resistance, shorten treatment time, improve cure rates, and eliminate side effects.

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4.1.2j TMC649128

Medivir, together with Tibotec, has develped TMC649128, a nucleoside NS5B polymerase inhibitor, which has had good results in preclinical trials, showing that it was effective for several genotypes and not prone to creating resistance. They hope to see it combined with other direct-acting antivirals. The company has begun a placebo-controlled Phase Ia trial in healthy volunteers in Belgium.
(www.prnewswire.co.uk/cgi/news/release?id=311330 February 10, 2011)

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4.1.2k Other polymerase inhibitors of interest

Mericitabine (RG7128): Pharmasset and Roche presented the results of their “PROPEL” clinical trial which studied 408 mostly GT1 patients, and included some with cirrhosis. These patients were treated for 8 or 12 weeks with RG7128, an NS5B polymerase inhibitor, together with pegIFN/RBV, then with pegIFN/RBV alone, with a total treatment duration of 24 or 48 weeks.

The drug was proven safe and no resistance was found. The treatment-naïve, GT1/4 patients experienced complete EVR.

IDX19368 and IDX19370
Idenix has two polymerase inhibitors, IDX19368 and IDX19370, which they plan to test soon.

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4.1.1l MK-5172

Hepatitis C FAQ

4.1.3 NS5A Inhibitors


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