With interferon-free therapies now in clinical trials the promise of treating hepatitis C without interferon is soon becoming a reality, with the elimination of interferon toxicity will be reduced and according to data from the 2012 liver meeting efficacy improved. The most common adverse events seen in the new agents under development are provided.
In 2012 serious side effects halted the development of the following drugs: Idenix Pharmaceuticals experimental hepatitis C drug IDX184 a HCV nucleotide polymerase inhibitor and Bristol-Myers BMS-986094, which was formerly known as INX-189, another nucleotide polymerase inhibitor:
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Idenix says FDA seeks more time to review hepatitis C drug
Idenix looks to Plan B as FDA hep C review plods on
IDX184-Idenix hepatitis C drug put on partial hold
Bristol-Myers to Hold Talks On Settling Claims of Hepatitis C Patients
BMS halts the development of BMS-986094 due to patient death
Current Prospects for Interferon-free Treatment of Hepatitis C in 2012
Ideally, interferon-free DAA combination therapy will reduce toxicity associated with HCV treatment as well improving efficacy. It is clear that protease inhibitor-based triple therapy with PEG-IFN and RBV increases overall toxicity, particularly
skin rashes and cytopenias.[4,5] Transient bilirubin elevations are frequently observed in patients taking NS3 serine protease inhibitors associated with a class effects on bilirubin transporters, and bilirubin elevations have also been reported with alisporivir. Gastrointestinal side effects, jaundice and anemia have been reported with some DAA combinations.[18,25] The ongoing requirement for RBV in many of these regimens will continue to cause some anemia and rashes, although it appears that the severity of anemia is less severe when RBV is not used in conjunction with PEG-IFN.
Although the nucleotide polymerase inhibitors and other classes of new DAAs have great potential, it should be noted that a significant number of drugs have been developed but had their development halted because of toxicity.
Some recent examples include discontinuation of development of BMS-986094 (cardiac and renal toxicity), GS −938 (liver test abnormalities); the non-nucleoside polymerase inhibitor tegobuvir (serious adverse events) and trials of the cyclophilin
inhibitor alisporivir have been halted because of pancreatitis.....continue reading...
Interferon free therapy with direct acting antivirals for HCV
Several trials with DAA combinations have reported increased SVR, low resistance and a good safety profile.
Sound-C2 study: faldaprevir, BI 207127 with or without ribavirin (Boehringer-Ingelheim)
The most common adverse events (AEs) were mild skin changes (itchy skin, rash or photosensitivity) or gastrointestinal disorders and transient indirect hyperbilirubinaemia, which sometimes presented as jaundice. Thirty-six per cent
of patients experienced some form of side effect, 12% of these were considered severe and 8% led to discontinuation of treatment. IFN-free phase III studies with Faldaprevir, BI 207127 and RBV are ongoing.
Aviator study: ABT-450/r, ABT-267, ABT-333 and ribavirin (Abbott)
The treatment was well tolerated. Four of 448 patients (1%) in the 8- and 12-week arms discontinued treatment because of adverse events. Of five serious AEs (1%), one (arthralgia or joint pain) was possibly study drug-related.
In the trial, the most common adverse events were fatigue (28 and 27%) and headache (28 and 31%) for treatment-naïve and null responders respectively.
Electron study: sofosbuvir (GS-7977), GS-5885 and ribavirin (Gilead)
Both Sofosbuvir in combination with ribavirin and sofosbuvir in combination with GS-5885 and ribavirin were well tolerated. The most common AEs were headache,fatigue, upper respiratory tract infection and nausea. The most common
clinically significant grade 3/4 laboratory abnormality was a haemoglobin reduction.
Daclatasvir, asunaprevir and BMS-791325 (BMS)
There were no discontinuations because of adverse events. Headache was the most common adverse event in this study (31%, 10/32). There were no deaths, discontinuations owing to AEs, or serious AEs owing to study drugs. Most AEs
were mild to moderate in severity. The most common AEs (≥10% total) were headache, diarrhoea and asthaenia. No grade 3–4 elevations in liver enzymes (ALT/AST) or bilirubin were observed. One grade 3 AE (headache) resolved after 7
days with continued study treatment and one grade 3–4 laboratory abnormality (lymphopaenia) was recorded in Group 2 at a single study visit concomitant with influenza. All other AEs were grade 1 or 2.
Daclatasvir and asunaprevir (BMS) in genotype 1b prior null responders
There were no serious adverse events owing to study drug in the patients treated with daclatasvir and asunaprevir combination therapy, no deaths and no treatment discontinuations owing to AEs. Most AEs were mild to moderate. The
most common AEs were headache, diarrhoea, asthaenia, and insomnia.
Grade 3–4 ALT/AST elevations were infrequent and none were accompanied by elevated total or direct bilirubin. All AST/ALT elevations improved without intervention.
Zenith study: VX-222, telaprevir and ribavirin (Vertex)
The most common adverse events during oral therapy are shown here, and included diarrhoea, rash, pruritus, nausea, fatigue. Also, anaemia was reported in 13%.
There were no serious adverse events, but grade ¾ Aes occurred in 7%.
Haemoglobin less than 10 occurred in 7 or 15%, but there were no cases of haemoglobin < 8.5.
New therapeutic strategies in HCV: polymerase inhibitors
The following sections provide an overview of novel therapeutic strategies involving nucleoside/nucleotide analogue and non-nucleoside inhibitors of the HCV RNA-dependent RNA polymerase. A table is provided on the Polymerase inhibitors in clinical development noting few side effects. Side effects include Gastrointestinal, Neutropenia, lymphopenia, neurotoxicity and hepatotoxicity.
New therapeutic strategies in HCV: second-generation protease inhibitors
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.
Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C
The standard treatment for hepatitis C virus (HCV) infection is interferon, which is administered subcutaneously
and can have troublesome side effects. We evaluated sofosbuvir, an oral nucleotide inhibitor of HCV
polymerase, in interferon-sparing and interferon-free regimens for the treatment of HCV infection.
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HCV Studies Give Hope for Interferon-Free Therapy
The two studies included the investigational drugs ABT-450, an inhibitor of the viral NS3 protease, boosted with low-dose
ritonavir, and ABT-333, a non-nucleoside NS5B polymerase inhibitor and nucleotide polymerase inhibitor sofosbuvir combined with ribavirin.
Note that in two open-label studies of interferon-sparing therapy for HCV, novel oral antiviral medications led to
sustained reductions in viral load, particularly among treatment-naive patients.
These new agents, when vetted in a randomized-controlled fashion, may provide a useful option for patients seeking to avoid the side-effects of interferon therapy.
Exploratory Study of Oral Combination Antiviral Therapy for Hepatitis C
There is a need for interferon-free treatment regimens for hepatitis C virus (HCV) infection. The goal of this study was to
evaluate ABT-450, a potent HCV NS3 protease inhibitor, combined with low-dose ritonavir (ABT-450/r), in
addition to ABT-333, a nonnucleoside NS5B polymerase inhibitor, and ribavirin, for the treatment of HCV infection
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