The hepatitis C virus (HCV) is a highly mutable, heterogeneous, enveloped RNA virus transmitted through the blood of infected carriers. Classified into eleven major genotypes, genotypes 1-3 have a worldwide distribution, with subtypes 1a and 1b accounting for approximately 60 per cent of infections. Due to its long latency period and constantly mutating genome, the highly infectious blood-borne pathogen has proven particularly difficult to control; worldwide, more than 170 million chronic carriers are estimated to be at risk of developing liver cirrhosis or hepatocellular carcinoma.
For more than a decade, standard of care has been based on the combination of pegylated versions of the immunomodulator interferon-alpha (IFN) and the ribonucleoside antiviral agent ribavirin (RBV), administered for 24 or 48 weeks. While these regimens can achieve viral eradication in 40-50 per cent of patients with HCV genotype 1 infection, and in approximately 80 per cent of patients with genotypes 2 and 3, they are limited by significant side effects and contraindications in a high proportion of patients.
In 2011, a new class of HCV therapeutics specifically targeting key viral growth and replication mechanisms, called direct-acting antivirals (DAAs), entered the market. HCV protease inhibitors boceprevir (Victrelis; Merck) and telaprevir (Incivo; Vertex, Janssen) were first and, while both remained dependent on the IFN + RBV backbone, the agents significantly improved virologic response rates in the genotype 1 patient population. In 2013, the approvals of the HCV NS3/4A protease inhibitor simeprevir (Olysio; Medivir, Janssen) and the HCV NS5B inhibitor sofosbuvir (Sovaldi; Gilead) signalled the beginning of a new wave of DAAs. Sofosbuvir became the first ever IFN-free HCV treatment to be approved.
Convenient all-oral treatments
Research has been driven by the need for a convenient, all-oral treatment that improves the tolerability profile of IFN-based regimens and provides efficacy across all HCV genotypes and in difficult-to-treat subpopulations, such as patients with advanced cirrhosis and those co-infected with HIV. To this end, the HCV pipeline has advanced with speed and success. Over the coming year, several IFN-free, DAA-based regimens and fixed-dose combinations (FDCs) are expected to reach the market.
Bristol-Myers Squibb's (BMS) NS5A inhibitor daclatasvir is fast approaching the finish line, with regulatory approval pending in the European Union (EU), the United States (US) and Japan for its use in combination with other antiviral agents, including sofosbuvir or the NS3 inhibitor asunaprevir (BMS). Already, the daclatasvir + sofosbuvir combination regimen is available on a compassionate-use basis in the EU. The ongoing phase 3 ALLY trials are evaluating this combination across genotypes 1-6 in both treatment-naïve and -experienced patients, as well as in cirrhotic patients and in those having undergone liver transplantation.
The asunaprevir + daclatasvir combination is currently being assessed in the phase 3 Hallmark studies. Results to date have shown that sustained virologic response at 12 weeks post-treatment (SVR12), considered to be an end-point reflective of a functional cure, was achieved in 90 per cent of treatment-naïve patients and in 82 per cent of patients unresponsive to or ineligible for IFN + RBV therapy. The dual regimen is also performing well with the addition of the NS5B inhibitor BMS 791325 (BMS). This triple DAA combination is being evaluated as an FDC in the phase 3 UNITY trials. Interim phase II results reported an SVR12 rate of 94 per cent in treatment-naïve patients with genotype 1 infection treated for 12 weeks.
The cost of novel HCV drugs remains a significant concern ... and the milestone launch of Sovaldi was dampened by controversy over its price tag
The FDC comprising the NS5A inhibitor ledipasvir (Gilead) and sofosbuvir is also awaiting regulatory approval. Submissions were made in the EU, the US and Canada in February 2014 for its use as an IFN-free treatment for HCV genotype 1 infection, and included positive results from the phase 3 ION programme. Across the three ION studies, 1,952 patients with genotype 1 HCV infection were randomised to receive ledipasvir/sofosbuvir once daily, with or without RBV, for 8, 12 or 24 weeks. The rates of SVR12 were exceptionally high, despite more than half the study population having infection compounded by compensated cirrhosis. An intent-to-treat analysis showed that SVR12 was achieved in up to 97.7 per cent of treatment-naïve patients who received the FDC without RBV. In treatment-experienced patients, 96.4 per cent and 99 per cent achieved SVR12 when RBV was added to the 12- and 24-week regimens, respectively .
AbbVie is developing a DAA-based, IFN-free regimen centred on the protease inhibitor ABT 450. Regulatory filings were submitted in the US in April 2014, with EU submissions planned for the following month. This regimen comprises the once-daily FDC of ABT 450 (pharmacologically enhanced with ritonavir) and the NS5A inhibitor ABT 267, administered with the twice-daily non-nucleoside polymerase inhibitor ABT 333. The entire regimen is being trialled in more than seven phase 3 clinical studies, which include treatment-naïve and -experienced patients with genotype 1a or 1b HCV infection, with and without cirrhosis or co-infection with HIV. Virologic response rates to date have been impressive; in genotype 1b treatment-naïve and treatment-experienced patients, SVR12 was achieved in 99 per cent and 100 per cent of participants, respectively, when the regimen was administered without RBV. The TURQUOISE II study in cirrhotic patients has recently demonstrated SVR12 rates as high as 91.8 per cent following 12 weeks' treatment and 95.9 per cent after 24 weeks' treatment.
An IFN-free FDC comprising the NS3/4A protease inhibitor MK 5172 and the NS5A inhibitor MK 8742 is being developed by Merck. With pan-genotypic activity and improved resistance profiles compared with their first-generation counterparts, both compounds can be considered second-generation variants in their respective DAA classes. Results from the phase 2 C-WORTHY study showed promising virologic response rates in a number of patient subpopulations. According to an intent-to-treat analysis, a virologic response was observed in 98 per cent of treatment-naïve, genotype 1 patients given once-daily MK 5172/MK 8742 without RBV for 12 weeks. Of 29 patients co-infected with HCV/HIV, 100 per cent achieved a virologic response after 12 weeks' treatment. The phase 3 C-EDGE programme, scheduled to commence in June 2014, will evaluate the FDC across multiple HCV genotypes, as well as in patients with chronic kidney disease, cirrhosis, co-infection with HIV, and those on opiate substitution therapy.
In addition to these late-stage regimens vying for approval, the number of DAAs in phase 2 development indicates that research remains committed to continual improvement. AbbVie is co-formulating its next-generation compounds ABT 530 and ABT 493, its ritonavir-free protease inhibitor, and Gilead has GS 5816 poised for phase 3 development with sofosbuvir. Achillion Pharmaceuticals has DAAs sovaprevir, neceprevir and ACH 3102 in the works, Idenix and Janssen are collaborating on samatasvir and TMC 647055, and phase 2 development of JNJ 56914845 (Janssen) is also underway. While the majority of DAAs in the pipeline act on the HCV NS3/4A serine protease, NS5A polymerase or NS5B polymerase, additional targets are also emerging. The HCV p7 protein is being targeted by BIT 225 (Biotron) and the HCV NS4B protein has also been identified for its potential druggability.
If HCV research has indeed been directed toward the creation of a well-tolerated, pan-genotypic, all-oral, IFN-free regimen with minimal contraindications and a high barrier to drug resistance, the late-stage results from these DAA regimens are certainly a testament to the success of these efforts. However, despite the vast improvements in efficacy and tolerability over their standard-of-care counterparts, these regimens will arrive with their own limitations.
The cost of novel HCV drugs in the marketplace remains a significant concern. The milestone launch of sofosbuvir, for example, was dampened by controversy over its $1,000 per pill price tag. With a number of regimens approaching commercialisation, an atmosphere of competition may help to mitigate this issue. In any event, access to these drugs is likely to remain a hot topic due to the proportion of the HCV population residing in developing countries. As well as its geographic dispersal, this population is characteristically diverse within itself. For this reason, it cannot be assumed that a 'boxed set' FDC product will be as efficacious for one patient as it is for another. Individual patient needs and economic factors may drive a 'mix and match' approach to tailor inter-company drug cocktails for maximal efficacy and cost-effectiveness. It is certainly hoped that in time collaborative drug-interaction studies may clinically validate such uses.
Aside from any lingering question marks or potential limitations, it cannot be denied that these are exciting times in the field of HCV therapeutics. It remains to be seen whether one or more of the aforementioned DAA-based, IFN-free regimens succeeds in providing a long-term, clinically meaningful, true 'miracle cure' for the millions of patients infected with HCV worldwide. This promising pipeline is, without doubt, one to watch.