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4.1.0 HCV Direct-Acting Antivirals

4.1.0 HCV Direct-Acting Antivirals (DAAs)

In order to reproduce, HCV requires the proper functioning of various enzymes. These enzymes are the
targets of some of the next generation of anti-HCV drugs. DAAs include NS3/4A protease inhibitors and
polymerase inhibitors, which can be non-nucleoside NS5B, nucleoside NS5B or NS5A inhibitors.

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4.1.1 Protease inhibitors

Once HCV enters a liver cell, its genes guide the production of proteins that will become the inner core and surface coat of new viral units. First of all, the HCV makes an immature protein--a kind of unfinished sheet of material, which the Hep C protease cuts into the finished proteins, which then become the virus's outer cloak. Scientists have developed protease inhibitors, which stick to protease and stop its scissor-like function. These drugs have been used in the treatment of HIV for years. (www.veritasmedicine.com).

Two of them—Merck’s Boceprevir (Victrelis) and Vertex’s Telaprevir (Incivek)—have recently been approved in the US and Canada. They now form part of standard treatment there.

Jay H. Hoofnagle, M.D., discussed (New England Journal of Medicine, April 30, 2009) the preliminary results with protease inhibitors combined with PegIFN and RBV, which were about the same as standard treatment alone. He pointed out that the relapse rates were lower, so the SVR (sustained viral response) was improved with the addition of the protease inhibitor. Dr. Hoofnagle reminded us of the Hep C treatment landmarks we have seen:

  1. Use of interferon (IFN)
  2. Addition of ribavirin (RBV or R)
  3. Pegylation of interferon (2001)

...and stated, “Telaprevir, an agent developed specifically to target HCV, represents a new era of therapy for
hepatitis C.”

Many very promising protease inhibitors and DAAs (Direct-Acting Antivirals) are still in pre-clinical
development such as AVL-181, AVL-192, EA-058, EA-063, and IDX316. Stay tuned!

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4.1.1a PF-03491390 (IDN-6556)

Idun Pharmaceuticals designed small molecule caspase protease inhibitors to inhibit cell death in tissues and organs. Idun has since been acquired by Pfizer. The compound IDN-6556 was found safe and well tolerated in a Phase I clinical trial involving 50 adults, some with Hep C. (PRNewswire Jan. 31, 2002, Idun Pharmaceuticals' Clinical Trial Demonstrates Safety Of Liver Disease Drug, and May 20, 2002, IDN-6556, a caspase inhibitor completes Phase I clinical trial for HCV).

Phase II trials found that the product, taken orally once or twice daily for 14 days, lowered aminotransferases and was well tolerated. It has been given orphan drug status in the US for use in transplant patients.

A subsequent trial in 204 HCV patients divided them into 4 arms: 1) placebo 2) 5 mg 3) 25 mg or 4) 50 mg, taken orally twice daily for a maximum of 12 weeks. AST/ALT tests were performed each week, and good drops in AST/ALT levels occurred from the start in those taking the drug. AST/ALT levels returned to pretreatment levels when the drug was stopped. Increased doses did not help. The most common side effects were fatigue and headaches.
(http://chronicfatiguesyndrome.researchtoday.net/archive/6/4/1621.htm 29 April 2010 in Aliment Pharmacol Ther, 31(9): 969-78.)

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4.1.1b ITMN-191

“Preclinical studies have also shown that ITMN-191 is over 100 times more potent than other protease inhibitors in clinical development,” said InterMune’s CEO. He explained that their product targets the HCV protease more exclusively, without inhibiting the other proteases in the body, compared to other less selective compounds.
(www.fool.com/investing/high-growth/2007/07/20/intermunes-sharp-focus.aspx July 2007)

In a previous Phase I study, ITMN-191 reduced viral load an average of 3.8 logs as monotherapy for 14 days in treatment-naive genotype 1 patients.

ITMN-191 or placebo was tested in combination with pegIFN alpha-2a and RBV for 14 days. HCV RNA was undetectable in most of ITMN-191 treated patients in all dosing arms at day 15. No viral rebound was seen during treatment. (EASL Conference 2009)

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4.1.1c TMC435

TMC435, a second-generation protease inhibitor given once a day was safe and effective in the phase IIb “PILLAR” randomized trial. The goal was to collect data about the viral load at week 24 and at week 72 (24 weeks after ending treatment). 386 GT1 patients received TMC435, 75 or 150 mg daily or placebo and pegIFN/RBV for 24 or more weeks, depending on the response. The higher dose for the longest time produced the best rate of 86% undetectable at 24 weeks.

There was an unexpected high 65% response rate among the placebo patients taking pegIFN/RBV alone. 79% to 86% of the patients receiving the TMC435 qualified for the short 24-week therapy. Of those, 85% to 96% had undetectable virus at week 24.

Strangely 3.6% of adverse events caused dropouts in the TMC435 arms, compared with 5.2% in the control arm. 6.5% of adverse events in the TMC435 group were called serious compared with 13% among those taking a placebo.

TMC435 is, according to Norah Terrault of the University of California San Francisco, the “front-runner” of the 2nd generation of protease inhibitors. She was one of the monitors of the AASLD session where it was presented. The drug is designed for once-daily use, compared to the present drugs which need 3 doses daily, and there are fewer side effects.
(www.medpagetoday.com/MeetingCoverage/AASLD/ and Fried M, et al. Hepatology 2011; Abstract LB-5)

Tibotec has begun enrolment of about 1,125 genotype patients for Phase III trials, in 24 countries, testing its protease inhibitor TMC435. Two trials are enrolling treatment-naïve patients (called QUEST-1 and QUEST-2), and another (called PROMISE) is enrolling relapsers. The investigational drug or a placebo will be given once daily for 12 weeks, combined with standard treatment (24 or 48 weeks, according to patient response in all of the trials.) In QUEST-1, Pegasys/Copegus will be used. In QUEST-2, either Pegasys/Copegus or PegIntron/Rebetol will be given. Patients enrolled in PROMISE will be given TMC435 or placebo plus Pegasys/Copegus.
( http://www.clinicaltrials.gov or email info@tibbe.jnj.com)

A trial is beginning in 2012 combining TMC435 and BMS-790052.

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4.1.1d Vaniprevir (MK-7009)

Merck’s Vaniprevir is a NS3/4A HCV protease inhibitor.

The Phase IIa study of MK-7009 for 28 days combined it with SOC in treatment-naive patients with genotype 1. 95 treatment-naïve patients took a placebo or SOC plus 300 mg 2X/day, 600 mg 2x/day, 600 mg/day, or 800 mg/day of MK-7009 for 28 days. All patients continued SOC for 44 weeks more.

RVR rates in the MK-7009 arms ranged from 69% to 82% vs. 6% of the control group. All of the MK-7009 results were superior to the control arm. More than 80% treated with MK-7009 had undetectable virus on day 28. 77% to 94% were still undetectable on day 42. All subjects in the 600 mg/2x daily group tested undetectable days 21 through 42. MK-7009 showed no adverse events causing discontinuation. (EASL Conference 2009)

Merck has released the results of its Phase IIb study of Vaniprevir combined with standard treatment. The study treated 91 GT1, treatment-naïve, non-cirrhotic subjects for 4 weeks, then with standard treatment alone for another 44 weeks, and noted an improved response rate over standard treatment alone. Most of the patients had a RVR (week 4).

The doses of 600-1200 mg daily of Vaniprevir resulted in SVR rates of 7884%, compared to 63% with standard treatment alone. The side effects of the optimum doses of vaniprevir included mild to moderate vomiting but no patient dropped out because of that.

A Phase III trial has been announced for treatment-naïve subjects in Japan, combining the drug with pegIFN/RBV, but is not yet recruiting (June 2011)

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4.1.1e Narlaprevir (SCH 900518)

Merck’s Narlaprevir (NVR), previously called SCH 900518, is an NS3 protease inhibitor. It was given to 40
genotype 1 treatment-naïve and experienced subjects, alone or combined with pegIntron. The patients took SCH 900518 alone first for 7 days, then waited 4 weeks before adding 14 days of pegIntron to the SCH 900518.

Afterwards, all were given SOC. Many of both treatment-experienced and naïve patients’ viral load dropped below 25 IU/mL during combination therapy with PegIntron (with or without ritonavir) on day 15. SCH 900518 alone or combined with pegIFN was found to be safe. Good drops in viral load were achieved. (EASL Conference 2009)

Narlaprevir boosted by Ritonavir (RTV) can be dosed once a day. Results of the NEXT-1, Phase II trial were presented at AASLD 2011, showing SVR rates as high as 85% in GT1 patients when NVR/r (NVR + RTV) taken only once a day was combined with pegIFN/RBV for 12 weeks, followed by pegIFN/RBV alone for 12 weeks. Results showed that a lead-in treatment with pegIFN/RBV alone did not improve SVR rates. Average SVR rates in African Americans was 66.7% and in GT1a was 75%.

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4.1.1f PHX1766

In October 2008, Phenomix began a Phase Ia clinical trial of PHX1766, an oral NS3/4A protease inhibitor of HCV. The study is taking place in the Netherlands and plans an enrolment of about 24 healthy subjects and six HCV+ patients who are to be treated with single ascending doses of PHX1766 in order to assess safety, tolerability, as well as viral load reductions in those infected. (http://www.hcvadvocate.org Oct 28, 2008)

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4.1.1g BI 201335

BI 201335 is an NS3/4A protease inhibitor produced by Boehringer Ingelheim Pharmaceuticals. A Phase I trial examined both treatment-naïve and experienced genotype 1 patients. The naïve patients were treated with monotherapy for 14 days, then with the drug combined with standard therapy for another 14 days. The experienced patients took the triple combination for all 28 days. All of the groups had an average viral load reduction of 3 log10 or more. Relapse occurred in most patients receiving monotherapy. Only 3 of the experienced patients receiving the lower doses of BI 201335 relapsed. The drug was deemed safe, effective, and well-tolerated. (EASL 2009 via NATAP)

The company has begun to recruit 1,875 patients HCV+ patients, starting with North America, for a Phase III trial which will investigate BI 201335 plus pegIFN/RBV in both treatment-naive and -experienced HCV+ GT1 patients. The US FDA has granted Fast Track designation for BI 201335. There are currently three Phase III trials enrolling patients in the US, Canada, Taiwan and Korea. Results from the Phase III studies are expected in the first half of 2013.
(www.natap.org/2011/HCV/04301103.htm 27 April 2011)

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4.1.1h ACH-1625

On March 30, 2011, Achillon Pharmaceuticals proudly announced results of its Phase IIa clinical trial showing RVR (Rapid Virologic Response) rates of 75-81% with a once-daily dose of its protease inhibitor ACH-1625, combined with pegIFN/RBV. The trial is treating 64 patients with either 200 mg, 400 mg or 800 mg of the drug plus pegIFN/RBV for 4 weeks, and then pegIFN/RBV for 44 weeks more. Most of the patients are GT1a (genotype 1a), but 1 out of 4 are GT1b. 75% were IL28b genotype CT/TT, those who have less chance of responding to IFN. There was no breakthrough in any of the patients who completed 4 weeks of ACH-1625 treatment. The second part of the trial, adding on pegIFN/RBV, has begun.

"These data reflect a positive outcome with high RVR, irrespective of IL28B status, which places ACH-1625 among the most potent protease inhibitors in development," stated the Vice President and Chief Medical Officer of Achillion. Future plans include combining the drug with other direct acting antivirals, and a 2012 trial combining it with ACH-2928, their NS5A inhibitor.

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4.1.1i AVL-192

Avila Therapeutics, Inc. is developing targeted covalent drugs, which bond to and attack a unique structure of the HCV protease that is not found in human proteases. This is the first time that the protease has been inhibited irreversibly using a targeted covalent drug. The company believes this technology can also be applied to other areas such as cancer. The company presented results of its preclinical studies that show AVL-192 to be very potent against the mutations of the HCV that seem to appear in other drug trials. AVL-192 is an oral drug. They say the drug is possibly their best-in-class candidate because it retains its potency even long after it is removed, and works in all the genotypes. They expect that dosing will be once daily. The drug may possibly be used as monotherapy. [Source: natap.org. See: http://www.avilatx.com]

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4.1.1j Ritonavir (ABT-450)

ABT-450, now called Ritonavir (RTV), is an oral acylsulfonamide protease inhibitor developed by Abbott and Enanta. The drug works better if boosted with RTV, according to information reported at the AASLD 2010. The study (M11-602) had 3 arms. 24 GT1 patients received either ABT-450/r (boosted with ritonavir) or either of the polymerase inhibitors ABT-072 or ABT 333. 11 patients received a placebo. The companies reported that ABT-450/r 3-Day monotherapy lowered the viral load significantly.

The product boosted with RTV became 28-48 times more powerful, so it will be produced together with low-dose RTV so it can be taken once a day. The maximum viral load decrease was 4.02 log10. There were no serious adverse events.

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4.1.1k BMS-791325

BMS-791325 is an NS5B protease inhibitor produced by Bristol-Myers-Squibb. It has passed through Phase I
safety trials. There are several clinical trials ongoing, and some are recruiting. Here are two interesting ones:
An all-oral, non-interferon study of BMS-791325 is scheduled to start in November 2011 and end December 2013. It will combine BMS-650032, BMS-790052, and BMS-791325 in genotype 1 treatment-naïve subjects.

A Phase I trial in healthy Japanese subjects without hepatitis C will start in February 2013 and is planned to be completed by June 2013. They are not yet recruiting.
Sources: http://clinicaltrials.gov/ct2/show/NCT01455090?term=BMS-791325&rank=2



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4.1.1l MK-5172

Merck announced at the AASLD 2011 that their next-generation NS3/4 protease inhibitor MK-5172 lowered the viral load to undetectable with 7 days of monotherapy, in 75% of GT1 patients and in 38% of GT3 patients. 87% of GT1 patients treated with the highest dose (800 mg) of MK-5172 had their viral load lowered to undetectable.

The antiviral activity continued for some days beyond treatment, with no viral rebound seen during treatment, no discontinuations due to side effects, and no serious lab test results affecting patient safety. The study is ongoing. At 1 month follow-up viral loads were still below their starting point in some patients.

A Phase II study is now enrolling patients. (Also, NATAP’s Jules Levine reported that Merck announced a very powerful NS5A inhibitor that showed a 3.8 drop in viral load after 6 days in a chimpanzee.)
(www.merck.com and NATAP)

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Table of Contents


4.0.1 Hepatitis C treatments in current clinical development

Hepatitis C FAQ

4.1.2 Polymerase Inhibitors


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