Bristol-Myers withdraws FDA NDA for asunaprevir

Bristol-Myers pulls U.S. marketing application for hepatitis C treatment
Oct 7 (Reuters) - Bristol-Myers Squibb said it withdrew its U.S. marketing application for a drug combination to treat hepatitis C.

The drugmaker will continue to pursue marketing approval of daclatasvir, one part of the combination, the company said in a statement.

Bristol-Myers said the combination treatment of daclatasvir and asunaprevir was approved in July for use in Japan.

Bristol-Myers Squibb Statement about Asunaprevir in the U.S.

PRINCETON, N.J.--(BUSINESS WIRE)--

Given the rapidly evolving hepatitis C (HCV) treatment landscape in the U.S., Bristol-Myers Squibb (BMY) has decided that it will not pursue U.S. Food and Drug Administration (FDA) approval of the dual regimen of daclatasvir and asunaprevir for the treatment of HCV genotype 1b patients in the United States and has therefore withdrawn its new drug application (NDA) for asunaprevir, an NS3/4A protease inhibitor. The company will continue to pursue FDA approval of daclatasvir, a potent, pan-genotypic NS5A complex inhibitor (in vitro), which is currently being investigated globally in multiple treatment regimens for HCV patients with high unmet need.

Bristol-Myers Squibb’s HCV strategy has always been to focus on the unique unmet medical need of each local market. For example, in Japan we were pleased to receive regulatory approval for the dual regimen of daclatasvir and asunaprevir in July, bringing Japanese patients with HCV the first all-oral, interferon- and ribavirin-free treatment regimen.

The dual regimen was developed to meet the distinct need of the Japanese patient population, and we believe this treatment has the potential to play a major role in curing HCV patients in Japan, as well as in other markets where the HCV patient population is similar to Japan. In the EU, daclatasvir was recently approved for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of HCV infection in adults. Similarly, we believe that daclatasvir-based regimens have the potential to fill continued unmet medical need in the U.S. and elsewhere in the world.

We plan to submit additional data for daclatasvir to the FDA from our ongoing clinical trial program focused on difficult-to-treat patients, including patients with HCV genotype 3, patients who are pre- and post-liver transplant, and patients co-infected with HIV. Next month at the annual meeting of The American Association for the Study of Liver Diseases (AASLD), we will present new data from several daclatasvir-based regimens. We look forward to bringing daclatasvir to patients in the U.S. and will continue to work closely with the FDA to advance our regulatory application, with the aim of bringing the investigational product to market as quickly as possible. 

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Three-Drug Combo Knocks Out HCV: Daclatasvir/Asunaprevir/BMS-791325

Three-Drug Combo Knocks Out HCV
Published: Oct 8, 2013

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

 

SAN FRANCISCO -- A triple-drug regimen for hepatitis C (HCV) led to a cure in about 90% of patients without using elements of the standard therapy for the disease, a researcher said.

In a randomized phase II trial, the combination of so-called "direct-acting agents" completely knocked out the virus in between 89% and 94% of patients 12 weeks after the end of therapy, according to Maribel Rodriguez-Torres, MD, of the Fundación de Investigación in San Juan, Puerto Rico.

The combination of investigational drugs was "generally well tolerated" in patients with the difficult-to-treat genotype 1 of the virus, Rodriguez-Torres reported at the IDWeek meeting here.

For years, standard HCV therapy has included pegylated interferon alfa and ribavirin, drugs that are both difficult to take and in some cases dangerous.

And that therapy leads to sustained virologic responses in no more than half of patients with genotype 1, although adding either of the approved direct-acting agents – telaprevir (Incivek) and boceprevir (Victrelis) – improves those outcomes markedly.

So researchers are seeking regimens that both target the virus directly -- interferon and ribavirin do not -- and have better outcomes.

In this case, they are testing once-daily daclatasvir, an NS5A replication complex inhibitor; twice daily asunaprevir, an NS3 protease inhibitor; and the as-yet-unnamed non-nucleoside NS5B polymerase inhibitor, BMS-791325, given twice a day.

The study is encouraging for those hoping that interferon- and ribavirin-free regimens will soon be approved, according to Arthur Kim, MD, of Massachusetts General Hospital in Boston, who was not involved in the study but who moderated the session at which it was presented.

"Once you are able to attack multiple viral targets," he told MedPage Today, "it seems that even if there is baseline resistance or some poor prognostic indicators, the multiple targeting works to eradicate the virus and overcome the barriers."

As the new regimens work their way through the clinical trials process, he said, he and other doctors are trying to delay treatment "unless it is absolutely necessary."

But he cautioned that so far the "novel paradigms" are still being tested. "We're still waiting for the phase III trials and larger numbers," Kim said.

The study so far includes 66 patients in four treatment arms differing by the length of therapy and the dose of BMS-791325, Rodriguez-Torres reported.

The primary endpoint is the so-called SVR12 – viral levels too low to be quantified 12 weeks after the end of treatment.

Outcomes appeared similar regardless of the doses and length of treatment, Rodriguez-Torres reported -- in three arms, 94% of patients (or 15 out of 16) reached the primary endpoint.

In the fourth arm -- with 12 weeks of treatment and a higher dose of BMS-791325 -- 16 of 18 patients (89%) reached SVR12. One patient had viral breakthrough while on therapy and another relapsed during follow-up, she said.

Investigators saw only one serious adverse event -- a case of renal calculus that was judged not to be related to the study drugs, she reported.

There were no adverse events that led to patients stopping treatment and only one clinical adverse event that reached grade 3 or 4 -- a headache that resolved as treatment continued.

Investigators did not see any grade 3 or 4 laboratory abnormalities, Rodriguez-Torres said.

Follow-up is continuing and the study is being expanded to include other patient populations, Rodriguez-Torres said, adding: "We call it the study that never ends."

The study was supported by Bristol-Myers Squibb. Rodriguez-Torres reported financial links with the company and several authors are employees of BMS.

http://www.medpagetoday.com/MeetingCoverage/IDWeek/42136

 

Related @ Healio

 

Interferon-free regimen safe, effective for patients with HCV genotype 1

October 8, 2013

A regimen of daclatasvir, asunaprevir, and a non-nucleoside NS5B inhibitor yielded high sustained virologic response rates among patients with hepatitis C genotype 1 in a study presented at ID Week 2013 in San Francisco.

 

Researchers randomly assigned 32 noncirrhotic, treatment-naive patients with hepatitis C genotype 1 to 60 mg NS5A inhibitor daclatasvir (DCV) once daily and 200 mg protease inhibitor asunaprevir (ASV) and 75 mg non-nucleoside NS5B inhibitor BMS-791325 twice daily for 24 (group 1; n=16) or 12 weeks (group 2; n=16). An additional 34 patients then were randomly assigned 60 mg DCV once daily and 200 mg ASV and 150 mg BMS-791325 twice daily for 24 (group 3; n=16) or 12 weeks (group 4; n=18).

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Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C: Open Issues and Future Perspectives

Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C: Open Issues and Future Perspectives

The Scientific World Journal
Volume 2013 (2013), Article ID 704912, 9 pages
Full Text - http://dx.doi.org/10.1155/2013/704912

Hee Bok Chae, Seon Mee Park, and Sei Jin Youn

Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, 1 Sunwhan-ro, Heungdok-gu, Cheongju 361-711, Republic of Korea
Received 30 March 2013; Accepted 6 May 2013
Academic Editors: Q. Z. Dong, Y. Hiasa, P. Loyer, and S.-N. Lu

Copyright © 2013 Hee Bok Chae et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Currently, two direct-acting antivirals (DAAs) show well-established efficacy against hepatitis C virus (HCV), namely, first-wave protease inhibitors telaprevir and boceprevir. Most clinical trials have examined DAAs in combination with standard of care (SOC) regimens. Future therapeutic drugs were divided into three categories. They are second-wave protease inhibitors, second-generation protease inhibitors, and polymerase inhibitors. Second-wave protease inhibitors are more improved form and can be administered once a day. Oral drug combinations can be favored because interferon (IFN) not only has to be given as intradermal injection, but also can cause several serious side effects. Combination of drugs with different mechanisms shows a good sustained virological response (SVR). But several mutations are associated with viral resistance to DAAs. Therefore, genotypic resistance data may provide insights into strategies aimed at maximizing SVR rates and minimizing resistance. Combined drug regimens are necessary to prevent the emergence of drug-resistant HCV. Many promising DAA candidates have been identified. Of these, a triple regimen containing sofosbuvir shows promise, and treatment with daclatasvir plus asunaprevir yields a high SVR rate (95%). Oral drug combinations will be standard of care in the near future.

1. Introduction
Until now, combined treatment with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) (known as PR therapy) has been the standard of care (SOC) for patients chronically infected with hepatitis C virus (HCV). However, direct-acting antiviral agents (DAAs) are assuming a more prominent role. At present, only two first-generation DAAs (telaprevir (TVR) and boceprevir (BOC)) are available, although many other candidate DAAs are being developed. TVR and BOC are used only in developed countries to treat patients chronically infected with HCV. They are not used commonly in developing countries because of their high cost.

We can classify DAAs according to their action sites, such as protease inhibitor, polymerase inhibitor, NS5B inhibitor, and NS5A inhibitor. The main mechanism of action of DAAs is the inhibition of enzyme, for example, protease or polymerase, but the NS5A inhibitor has a different mechanism of action from other DAAs. It inhibits the assembly of this replication complex (Table 1) (Figure 1) [1, 2]. Another approach to HCV therapy is to target the host factors that the virus uses for its own life cycle, for example, cyclophilin inhibitors or nitazoxanide. In this paper, we will focus on only DAAs and will not cover other treatment options, like cyclophilin, HCV vaccine. We will discuss the efficacy and limitations of both currently approved and new candidate drugs.

Table 1: Characteristics of HCV direct-acting antiviral classes.

Characteristic Protease inhibitors Protease inhibitors Polymerase inhibitors Polymerase inhibitors NS5A inhibitors   First generation Second generation Nucleoside analogs Non-nucleoside analogs   Potency High Variable among HCV genotypes High Variable Moderate Consistent across genotypes Variable Variable among HCV genotypes High Multiple HCV genotypes Barrier to resistance Low Low High Very low Low PK Variable qd-tid qd qd Variable qd-tid qd Adverse event Rash (SJS, TEN), anemia, hyperbilirubinemia appetite loss, renal toxicity, elevation of uric acid Anemia hyperbilirubinemia Mitochondrial nuclear interaction (RBV) Variable Variable Drug Telaprevir Boceprevir Simeprevir Asunaprevir Faldaprevir Sofosbuvir Mericitabine BMS-791325 Daclatasvir Clinical trial TVR: ADVANCE [7], ILLUMINATE [8], REALIZE [9] BCV: SPRINT-2 [10], RESPOND-2 [12] SMV: PILLAR [14], ASPIRE [15] ASV: AI447-011 [16] FDV: SILEN-C2 [17], SOUND-C2 [18, 19] SOF: ATOMIC [20], ELECTRON [21] MRB: JUMP-C [22], INFORM-1 [23], INFORM-SVR [24]   DCT: AI447-011 [25] Comments   Better barrier, pan-genotypic Single target active site Allosteric, many targets Multiple antiviral mechanisms of action

PK: pharmacokinetics; qd: once a day; tid: three times a day; RBV: ribavirin. Modified from [1]. SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis; TVR: telaprevir; BCV: boceprevir; SMV: simeprevir; ASV: asunaprevir; FDV: faldaprevir; SOF: sofosbuvir; MRB: mericitabine; DCV: daclatasvir. Figure 1: Targets for direct-acting antivirals. Modified from [2]. Click Figure To Enlarge

2. Currently Available DAAs
In May 2011, the U.S. Food and Drug Administration (FDA) approved TVR and BOC for use in combination therapies with PegIFN-α and RBV for adult patients chronically infected with HCV genotype 1. The drugs are used to treat patients with compensated liver cirrhosis, who are treatment-naïve or who have been previously treated with IFN-based regimens [3, 4]. Both TVR and BOC inhibit the viral NS3/4A serine protease, which is essential for replication [5, 6].

2.1. Telaprevir (TVR)
Three phase III clinical trials have been conducted to evaluate the efficacy of TVR when administered to treatment-naïve chronic HCV (genotype 1) patients in combination with PegIFN-α-2a and RBV [7, 8]. In the ADVANCE trial, patients received TVR together with PegIFN-α and RBV (PR) for either 8 (T8PR) or 12 (T12PR) weeks, followed by PegIFN-α or RBV (PR) alone in a response-guided therapy [7]. Extended rapid virological response (eRVR) was defined as undetectable HCV RNA levels at weeks 4 and 12. The patients who did not achieve an eRVR received PegIFN-α plus RBV for a total of 48 weeks. The overall SVR rates for patients in the T8PR and T12PR groups were 69% and 75%, respectively. The SVR rate for the control group with only PR was 44% [7].

The ILLUMINATE, another TVR trial, focused on defining the utility of response-guided therapy (RGT) in patients that did achieve an eRVR. All patients received an initial 12-week course of TVR-based triple therapy, followed by treatment with PegIFN-α plus RBV [8]. Patients who achieved an eRVR at week 20 were randomized to receive either an additional 3- or 28-week course of PegIFN-α plus RBV. The overall SVR rate for all patients was 72%. The SVR rates for those patients (65%) who achieved an eRVR and received either an additional 3- or 28-week course of PegIFN-α plus RBV were 92% and 88%, respectively.

The REALIZE, the third trial of TVR, was conducted for patients who experienced treatment failure after SOC therapy [9]. The clinical trial had three arms. Patients in the first arm received T12PR triple therapy for 12 weeks, followed by a placebo plus PR for 4 weeks and then PR alone for 32 weeks. The patients in the second arm received placebo plus PR (lead-in phase) for the first 4 weeks, followed by TVR-based triple therapy for 12 weeks and then PR alone for 32 weeks (48 weeks in total). The patients in the third arm received PR alone for 48 weeks (control group). The overall SVR rates for the three groups were 64%, 66%, and 17%, respectively. The best response rate was observed for those patients in each group that had previously relapsed after PR therapy (83%, 88%, and 24%, resp.) [9].

In summary, the triple regimen including TVR showed good response in genotype 1 patients. The SVR rate can be maximized using a response-guided paradigm. The triple regimen was also effective in treatment-failure patients, especially who relapsed after PR therapy.

2.2. Boceprevir
Let us look at two important phase III clinical trials on BOC. The first one, SPRINT-2, evaluated the efficacy of BOC in two cohorts of treatment-naïve patients [10]. All patients were first treated with a lead-in therapy comprising PegIFN-α-2b plus weight-based RBV for a period of 4 weeks, followed by one of three regimens. After the lead-in, patients were assigned to one of three groups. (1) Group 1, PegIFN-α-2b, RBV, and placebo for an additional 44 weeks. (2) Group 2, BOC, PegIFN-α-2b, and RBV for an additional 24 weeks, followed by 20 more weeks of PegIFN-α-2b if HCV RNA was detectable at weeks 8 and 24. (3) Group 3, BOC, PegIFN-α-2b, and RBV for an additional 44 weeks, that is, SOC therapy (Figure 2) [11]. The overall SVR rates were higher in the BOC-treated arms (63% and 66%) than in the SOC arm (38%), but differed according to race. In black patients, the SVR rates were 42% in the RGT arm, 53% in the fixed duration arm, and 23% in the SOC arm.

Figure 2: Phase III trials of boceprevir in patients with hepatitis C genotype-1 infection. (a) SPRINT-2 trial in previously untreated patients. (b) RESPOND-2 trial for previously treated patients; patients were partial responders and relapsers and null-responders. PR: pegylated interferon-α-2b 1.5 μg/kg per week plus weight-based ribavirin 600–1400 mg per day. BOC: boceprevir 800 mg every 8 h. ^aHepatitis C RNA treatment weeks 8–24 undetectable. ^bHepatitis C RNA treatment week 8 detectable, treatment week 24 undetectable. ^cHepatitis C RNA treatment weeks 8–12 undetectable. ^dHepatitis C RNA treatment week 8 detectable, treatment week 12 undetectable. Excerpted from Pearlman [11].

 

Click To Enlarge

 

The RESPOND-2 trial was a phase III clinical trial [12]. The subjects were prior partial responders or relapsers with PegIFN-α-2b and RBV. Null responders were not studied in this trial. (1) Group 1, PegIFN-α-2b, RBV, and placebo for an additional 44 weeks. (2) Group 2, BOC, PegIFN-α-2b, and RBV for an additional 32 weeks, followed by 12 more weeks of PegIFN-α-2b and RBV if HCV RNA was detectable at week 8, but undetectable at week 12. (3) Group 3, BOC, PegIFN-α-2b, and RBV for an additional 44 weeks. Therapy was discontinued in patients who were HCV RNA positive at week 12 (Figure 2) [11]. The overall SVR rates at week 24 were 21%, 59%, and 66%, respectively in Group 1, Group 2 (RGT), and Group 3 (48 weeks). These triple therapy appear to yield even higher rates of SVR, 29, 69, and 75% in prior relapsers than in partial responders (7%, 40%, and 50%).

2.3. Vaniprevir (MK-7009)
Vaniprevir is a macrocyclic hepatitis C virus nonstructural protein 3/4A protease inhibitor. Treatment-naïve patients with HCV genotype 1 infection were randomized to receive open-label PegIFN and RBV in combination with blinded placebo or vaniprevir (300 mg bid, 600 mg bid, 600 mg qd, and 800 mg qd) for 28 days, and then open-label PegIFN and RBV for an additional 44 weeks. Across all doses, vaniprevir was associated with HCV RNA levels approximately 3 log₁₀ IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%–83.3% versus 5.6%;  for all comparisons). Vomiting appeared to be more common at higher vaniprevir doses (40% in 600 mg bid group) [13].

2.4. Preliminary Data from Patients with Other Genotypes Treated with DAAs
2.4.1. HCV Genotype 2
The SVR rate for patients infected with HCV genotype 2 and treated with SOC is almost 80%. There is no space for DAAs to show any increase of treatment effect because it is enough high. DAAs may be less effective in this patient group than in patients infected with HCV genotype 1. TVR, the first agent to directly target viral replication, is effective against HCV-2 but not against HCV-3 (see below). Foster et al. evaluated combined treatment with TVR plus PegIFN-α-2a and RBV in five patients infected with HCV-2 and compared the results with those obtained after treating nine patients with TVR alone or treating nine patients with PR (control group). Triple combination therapy yielded an SVR rate of 100%, which is remarkable considering the 89% rate observed in patients receiving standard PR [26]. Other NS3/4A protease inhibitors, nucleoside and non-nucleoside reverse replicase inhibitors, and NS5A inhibitors have antiviral activity against HCV-2. One of the most promising drugs is a nucleotide analogue polymerase inhibitor called PSI-7977 [27]. An open-label study (the PROTON study) evaluated the efficacy of PSI-7977 in 15 patients infected with HCV-2, in 10 patients infected with HCV-3, and in a larger group of patients with HCV-1 infection [28]. That study reported an RVR of 96% after the triple combination of 400 mg of PSI-7977 plus PR. Twenty-four HCV-2 and HCV-3 patients who completed the 12 weeks of treatment achieved SVR (96%).

2.4.2. HCV Genotype 3
The SVR rate for patients infected with HCV genotype 3 and treated with SOC is almost 80% [29]. TVR and BOC have revolutionized the treatment of genotype 1 HCV. Indeed, both have recently been recommended for use in combination with standard PR regimen for the treatment of patients chronically infected with HCV genotype 1. However, both BOC and TVR are ineffective against HCV-3.

2.5. Future Therapeutic Options
Two available DAAs, TVR and BOC, have several limitations. The role of these drugs is a supplement to PegIFN. These two drugs can cause severe side effects, for example, anemia, rash, and hyperbilirubinemia. Lastly, their dosing schedule is three times a day. The therapeutic drugs that are being developed for future use try to resolve these limitations of currently available DAAs. These new drugs fall into three categories: second-wave protease inhibitors, second-generation protease inhibitors, and polymerase inhibitors.

2.5.1. Second-Wave Protease Inhibitors
Second-wave protease inhibitors offer several advantages over currently available drugs. In the near future, improved pharmacokinetics will allow a once-a-day dosing schedule, which means that the side-effect profiles should be more tolerable. Second-wave protease inhibitors have similar genotype coverage and similar resistance profiles to those of TVR and BOC and will replace the first-generation protease inhibitors currently used for PR combination therapy, thereby becoming the initial partners in the first generation of “all-oral regimens.”

Simeprevir (TMC435) is an NS3/4A protease inhibitor that is taken orally once per day; the drug is currently undergoing phase III clinical trials for the treatment of HCV infection [30]. The PILLAR study (a phase IIb trial) was designed to test the efficacy of simeprevir when used in combination with PR for either 24 or 48 weeks. An SVR was achieved in 68–76% of patients treated with this triple therapy regimen, and approximately 80% of subjects were eligible to receive shortened 24 weeks of therapy. The result of subgroup analysis was very high SVR (93–96%) [14]. Adverse effects were similar to those observed after SOC therapy. The lowest rate of relapse (8%) was found in the study arm receiving TMC 435 (150 mg/day) plus PR for 24 weeks.

The ASPIRE trial was a phase IIb trial for genotype 1 patients who had failed previous treatment with PR therapy. All patients received PR for 48 weeks. The best results were observed in the group treated with triple therapy with simeprevir 150 mg (SVR) plus PR in comparison with placebo plus PR, which achieved an SVR of 85% versus 37% in prior relapsers, 75% versus 9% in partial responders, and 51% versus 19% in prior nonresponders [15].

Faldaprevir (BI201335) is another NS3/4A protease inhibitor that has completed phase II testing (the SILEN-C1 study) and can be administered using a once-per-day dosing schedule. The treatment regimen included BI201335 in addition to PR for 24 weeks at doses of 120 and 240 mg, followed by another 24 weeks of standard therapy [17]. The overall SVR rate was 83% for the 240 mg dose. Ninety-two percent of the patients that showed an eRVR also achieved an SVR, regardless of the duration of subsequent PR therapy. Adverse events (mostly gastrointestinal) meant that treatment was discontinued in 7.3% of subjects.

Asunaprevir (BMS-650032) is a twice-daily protease inhibitor that is being developed for use with daclatasvir (an NS5A inhibitor) and BMS 791325 (a non-nucleoside inhibitor) in both IFN-containing and IFN-free regimens. Asunaprevir plus daclatasvir was the first regimen to cure HCV-infected patients without the need for IFN [16]. However, asunaprevir is not an ideal protease inhibitor because a twice-per-day schedule may be associated with hepatotoxicity.

2.5.2. Second-Generation Protease Inhibitors
Two second-generation protease inhibitors, MK-5172 and ACH-2684, are currently under clinical trial. MK-5172 is a novel macrocyclic NS3/4a protease inhibitor that is currently undergoing phase II clinical trials. R155 is the main overlapping position for drug resistance, and different mutations at this site within the NS3 protease confer resistance to nearly all protease inhibitors. However, MK-5172 shows potent antiviral activity against HCV viruses harboring mutations at position R155. Based on its preclinical profile, MK-5172 is expected to have broad-spectrum activity against multiple HCV genotypes (including genotype 3) and other clinically important drug-resistant variants. Indeed, trials in genotype-1-positive patients show that 75% had HCV RNA levels below the limit of detection. In addition, the drug was generally well tolerated [31].

ACH-2684 is a macrocyclic, noncovalent, reversible inhibitor of the NS3 protease. Phase Ib clinical trials showed that administration of ACH-2684 to patients infected with HCV genotype 1 achieved a mean 3.73 log₁₀ reduction in HCV RNA levels after 3 days of monotherapy at a single dose of 400 mg/day. In addition, ACH-2684 was safe and well tolerated [32]. Thus, this drug shows great promise, although further clinical trials are needed.

2.5.3. Polymerase Inhibitor-Nucleoside Inhibitors
Two HCV nucleos(t)ide analogues have entered phase II/III clinical trials: mericitabine and sofosbuvir.

2.5.4. Nucleoside Inhibitors in Clinical Trials with Interferon
Mericitabine (RG 7128): the JUMP-C trial (phase II) investigated the safety and efficacy of mericitabine (RG 7128) (1000 mg bid) plus PR after 24 weeks of response-guided therapy. The overall SVR rates were higher in patients treated with mericitabine plus PR than in patients treated with PR alone (58% versus 36%) [22].

Sofosbuvir (GS-7977): the ATOMIC study (another phase II trial) evaluated combined treatment with sofosbuvir plus PR in 316 noncirrhotic patients infected with HCV genotypes 1, 4, or 6. This study evaluated the proper duration of treatment for genotype 1 patient. Patients infected with HCV genotype 1 were randomized into two groups: one group received sofosbuvir plus PegIFN/RBV for 12 or 24 weeks, and the other received sofosbuvir plus PR for 12 or 24 weeks, followed by rerandomization (1 : 1) into two further groups that received either an additional 12 weeks of sofosbuvir alone or an additional 12 weeks of sofosbuvir plus RBV. The results of an interim analysis showed that patients who received 12 weeks of therapy with the triple combination of sofosbuvir plus PR achieved SVR rates of 90% [20].

2.5.5. Nucleoside Inhibitors in Clinical Trials without Interferon
Mericitabine (RG 7128): the INFORM-1 study provided the first proof of principle that combined treatment with mericitabine plus danoprevir (an NS3/4 protease inhibitor) in the absence of IFN is effective at reducing HCV RNA levels. At day 14, the highest combined dose (1000 mg mericitabine and 900 mg danoprevir bid) resulted in a median −5.1 log₁₀ IU/mL reduction in HCV RNA levels in treatment-naïve patients and a median −4.9 log₁₀ IU/mL reduction in HCV RNA levels in patients that did not respond to previous PR therapy [23].

The INFORM-SVR trial (a phase IIb trial) evaluated the efficacy of a 12- or 24-week interferon-free regimen comprising ritonavir-boosted danoprevir (DNV/r, 100 mg/100 mg) plus mericitabine (1000 mg, bid), either with or without RBV, in treatment-naïve patients infected with HCV genotype 1. The data showed that 71% of the patients infected with HCV genotype 1b who received 24 weeks of DNV/r, mericitabine, and RBV achieved an SVR; however, only 26% of patients infected with genotype 1a achieved an SVR. Higher SVR rates were reported in patients who were rapid virological responders [24].

Sofosbuvir (GS-7977/PSI-7977): the ELECTRON trial evaluated the efficacy of sofosbuvir plus RBV in the absence of IFN. The results showed that treatment-naïve patients infected with HCV genotypes 2 or 3 achieved an SVR rate of 100%. In addition, patients infected with HCV genotype 1, who did not respond to previous treatment with PR, received sofosbuvir plus RBV for 12 weeks; however, 89% of patients relapsed after the end of treatment [21].

2.5.6. Interferon-Free Combination Trials
The SOUND-C2 study (faldaprevir plus BI 207127, with or without RBV): the Sound-C2 study is an open-label, randomized, phase IIb study of 362 treatment-naïve patients infected with HCV genotype 1 who were allocated to one of five treatment arms [18]. The final results showed that up to 85% of HCV patients infected with genotype 1b achieved an SVR. The optimal regimen was 28 weeks of faldaprevir (120 mg once daily), and BI 207127 (600 mg bid). The overall SVR rate was 70%, compared with 85% in the prevalent genotype-1b patient subgroup [19].

The Aviator study (ABT-450/r, ABT-267, or ABT-333 plus RBV): the Aviator phase IIb study assessed the safety and efficacy of ABT-450/r, ABT-267, or ABT-333 plus RBV (administered for 8, 12, or 24 weeks) in noncirrhotic treatment-naïve patients and in patients who did not respond to previous treatment with PR [33]. The SVR in treatment-naïve patients infected with genotype 1 HCV was 97.5% after 12 weeks, whereas the SVR in PR nonresponders infected with genotype 1 was 93.3%. Treatment-naïve patients infected with genotype 1a achieved an SVR of 96% after 12 weeks, whereas PR nonresponders achieved an SVR of 89%. For those patients infected with genotype 1b, the SVR was 100% for both treatment-naïve and PR nonresponders.

Daclatasvir plus sofosbuvir with or without RBV: this trial was designed to test the efficacy of combined treatment with daclatasvir plus sofosbuvir against HCV genotypes 1, 2, and 3. Daclatasvir plus sofosbuvir were administered, either with or without RBV, for 12 or 24 weeks and either with or without a 7-day run-in with sofosbuvir [34]. A total of 44 patients infected with genotypes 2 or 3 HCV were enrolled in three arms: one arm comprised a 7-day run-in with sofosbuvir followed by 23 weeks of daclatasvir plus sofosbuvir; another arm comprised daclatasvir plus sofosbuvir for 24 weeks; and the other comprised daclatasvir plus sofosbuvir plus RBV for 24 weeks. Eighty-eight percent of patients in the first group achieved an SVR at week 12, compared with 100% in the second group and 86% in the third group.

Daclatasvir, asunaprevir, and BMS-791325: daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in phase III of development. Asunaprevir is an NS3 protease inhibitor that is also undergoing phase III development along with daclatasvir. BMS-791325 is a non-nucleoside inhibitor of the NS5B polymerase and is currently undergoing phase II development as a component of daclatasvir-based treatment regimens. This phase II study examined the efficacy of these DAAs in HCV G1 treatment-naïve patients [25]. The trial split patients into two groups. Group 1 received a 24-week course of daclatasvir, asunaprevir, and BMS-79132. Group 2 received a 12-week course of daclatasvir, asunaprevir, and BMS-79132. The result was that 94% of patients showed an undetectable viral load at week 4 and at the end of the trial in Group 1. One hundred percent of patients had an undetectable viral load at the end of the trial in group 2.

2.6. Optimized Treatment Algorithms for the Management of HCV Patients
This paper did not focus on general approaches for treating patients that are chronically infected with HCV. Instead, it focused on treatments based on DAAs and particularly on clinical trials of DAAs that target HCV genotype 1. HCV genotypes 2 and 3 can be effectively treated with current SOC therapy. Genotype 4 is the most difficult genotype to treat. The standard treatment for HCV genotype 4 is a 48-week course of PR. Furthermore, patients infected with HCV genotype 4 who have previously relapsed, or are non-responders, are unlikely be cured by the PR regimen. The optimized treatment algorithms are shown in Figures 3 and 4 [35].

Figure 3: Proposed algorithm for the use of protease inhibitors in treatment-naïve HCV genotype 1 infected patients. Pretreatment assessment should include careful consideration of lifestyle factors, comorbid conditions, potential drug interactions, and assessment for the presence of cirrhosis. In noncirrhotic patients, the presence of factors predictive of a poor response to therapy should be patients with no risk factors for a poor response to therapy; the decision to use a 4-week lead-in with peginterferon and ribavirin and to continue on SOC in those who achieve an RVR should only be taken following careful and balanced discussion with the patient. Excerpted from Ramachandrean et al. [35].

 

Figure 4: Proposed algorithm for the use of protease inhibitors in HCV genotype 1 infected patients who have had previous virological failure on treatment. Pretreatment assessment should include careful consideration of lifestyle factors, comorbid conditions, potential drug interactions, assessment for the presence of cirrhosis, and the presence of factors predictive of a poor response to therapy. Identification of the degree of previous response should be attempted. If this information is not available, patients should be considered as prior null responders to maximize cure rates. In cirrhotic prior null responders, the decision to watch and wait for novel therapies or to use a 4-week lead-in with peginterferon and ribavirin to identify patients more likely to achieve an SVR should only be taken following careful and balanced discussion with the patient. Excerpted from Ramachandrean et al. [35].

 

3. Conclusion

In conclusion, only two DAAs have been approved for the treatment of patients infected with HCV (TVR and BOC). Both are used in combination with PR therapy. Although several clinical trials examined the efficacy of IFN-free regimens (to avoid the side effects associated with IFN), most clinical trials have examined the efficacy of DAAs when used in combination with IFN. Response-guided therapy using the PegIFN-α regimen can be used with DAA therapy to select nonresponders. TVR and BOC play an important role in the treatment of patients chronically infected with HCV genotype 1. Genotypes 2 and 3 (but not genotype 4) can be effectively treated with SOC therapy. Of the emerging second-generation treatments, a triple regimen containing sofosbuvir shows great promise in terms of treatment efficacy. In addition, the combination of two oral drugs (daclatasvir and asunaprevir) achieved a high SVR rate (95%). Another oral drug combination (mericitabine and danoprevir) was examined in the INFORM study and achieved an SVR rate of 71%. Thus, future regimens may not require the use of IFN injections. Drug resistance will become a problem in the field of chronic HCV research; however, current data suggest that it is not yet a significant factor.

 

Authors’ Contribution

Hee Bok Chae acquired the data and wrote the paper. Seon Mee Park consulted a direction of the paper. Sei Jin Youn performed proofreading and critical revision.

 

Acknowledgments

This work was supported by a Chungbuk National University grant, 2012. Dr. Chae is a member of the advisory committee for both BMS Korea and Gilead Korea.

 

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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

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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