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FROM THE ANAlyST'S COUCH Hepatitis C therapies Irena Melnikova Hepatitis C virus (HCV) is the major cause of the immune system of the host. Therefore, Novartis), R803 (Rigel Pharmaceuticals), liver disease worldwide and a potential source protease inhibition could produce a double XTL-2125 (XTL Biopharmaceuticals) and of high morbidity and mortality in the future. hit against the virus.
The World Health Organization estimates Telaprevir (VX-950; Vertex/Johnson & Nevertheless, several new polymerase that approximately 170 million people, Johnson/Mitsubishi) is the most advanced inhibitors are progressing through the pipeline 3% of the world's population, are chronically novel anti-HCV therapy in development. (Table 1). Roche currently holds a lead position infected with HCV, and 3–4 million new In the clinical trials conducted so far, with two compounds, R1626 and R7128; R7128 infections occur each year. According to the telaprevir has demonstrated unprecedented is licensed from Pharmasset. Experts suggest Centers for Disease Control and Prevention, antiviral activity, offering hope for improved that out of the two, R7128 might have a more over 3 million people have chronic HCV efficacy and reduced duration of treatment attractive profile as it has been well tolerated in the US, and the current annual rate of (24 weeks). Furthermore, telaprevir is the first so far, whereas R1626 has been associated infection is around 30,000.
drug to demonstrate activity in patients who with fairly significant haematological toxicity The current standard of care for HCV have failed prior therapy. Interim analysis (neutropaenia). In treatment-naive patients, is a combination of PEGylated–interferon of the Phase IIb PROVE3 trial showed that R7128 has produced a rapid virological (PEG–IFN) and ribavirin. PEG-IFNs 52% of patients treated with a 24-week response in comparison with telaprevir when available on the market include PEG–Intron telaprevir-based regimen maintained HCV used in combination with standard of care: (Schering–Plough) and Pegasys (Roche). RNA levels that were undetectable 12 weeks 85% and 79% of patients, respectively, achieved Marketed ribavirin includes Rebetol post-treatment (SVR 12)3. Patients who undetectable levels of HCV RNA after 4 weeks (Schering–Plough), Copegus (Roche) and have previously failed standard-of-care of treatment4. Whether the potent antiviral various generic versions. The overall clinical treatment represent a significant market activities of the new generation of polymerase success rate, referred to as sustained virological opportunity, and Vertex plans to initiate inhibitors will translate into a clinical benefit response (SVR), of this combination therapy Phase III development in this setting. remains to be seen for a large majority of the is only around 50%1. The treatment is lengthy However, telaprevir is expected to be compounds in the pipeline.
(48 weeks for genotype 1 HCV) and associated approved for the treatment-naive population with frequent and sometimes serious side first. A 24-week, Phase III trial of telaprevir effects including neuropsychiatric events, compared with current standard treatment Similar to HIV, the future of HCV therapy is flu-like symptoms and haematological in treatment-naive patients with genotype 1 likely to involve combination therapy with toxicities. It is also contraindicated for many HCV is ongoing. If successful, approval in this novel drugs that have different modes of patients1. Overal , it is estimated that only 10% setting is anticipated in late 2010/early 2011.
action5. In the short-term, such drugs would of patients with chronic HCV are successful y Although telaprevir has the potential to be be added to the current IFN-based regimen treated with the current standard of care.
first to market, there is an increasingly large (FIG. 1). With time, potent antiviral number of competitive protease inhibitors combinations could displace IFNs altogether. HCV pipeline
in development — for example, boceprevir However, lessons learned from the HIV Over two dozen molecules are being studied (Schering–Plough), ITMN-191 (InterMune/ epidemic suggest that owing to the high for their potential to supplement or replace Roche) and TMC435350 (Tibotec/Medivir) heterogeneity and high mutation rate of either or both elements of the standard (Table 1) — that may offer better tolerability HCV, drug resistance is likely to emerge PEG–IFN/ribavirin combination2 (Table 1). and more convenient dosing (once a day during treatment with specific inhibitors Most of the efforts have focused on antiviral versus three times a day) compared with of viral protease and polymerase even in a therapies, specifically two viral enzymes: telaprevir. However, superior efficacy and combination setting5. Therefore, exploring the NS3–4A serine protease and the NS5B reduced duration of treatment are expected additional targets that are vital for various RNA-dependent RNA polymerase.
to remain major drivers for the adoption of stages of the viral life cycle remains important.
As evidenced by a number of high-profile Several cyclophilin inhibitors, such partnerships with big pharma (Table 2), as Debio-025 (Debiopharm), NIM811 the HCV field has generated multiple (Novartis) and SCY-635 (Scynexis), are in value-creation opportunities for smaller The concept of polymerase inhibition for Phase I/II clinical trials. Cyclophilin has been biotech companies. Even preclinical antiviral therapy has been successfully demonstrated to be an important host factor programmes have received economics that are established for HIV, hepatitis B and herpes that supports HCV replication. Another more typical of Phase II programmes (Table 2). viruses. Unfortunately, so far, tackling HCV potentially promising approach to treating polymerase has proved to be challenging. HCV infections would be the inhibition of viral Several polymerase inhibitor programmes entry into the cel . XTL Biopharmaceuticals, NS3–4A protease activity is required for have been discontinued owing to lack of Replicor, Progenics Pharmaceuticals, Samaritan viral replication and is partial y responsible efficacy and/or safety issues. These include Pharmaceuticals and Trimeris have early stage for the ability of HCV to evade clearance by valopicitabine (Idenix Pharmaceuticals/ HCV fusion/entry inhibitor programmes. ▶ NATURE REVIEWS drug discovery
VOLUME 7 OCTOBER 2008 799
HEpATiTiS C THERApiES market indiCatOrs
▶ In the next 5–10 years, novel therapeutics are expected to produce major breakthroughs in the treatment of HCV, such as increased cure Treatment duration (weeks) rates, reduced duration of therapy, improved tolerability/side effect profiles and more convenient dosing schedules and routes of administration (oral therapy). Furthermore, response (SVR; %) an increased number of patients is expected to seek treatment owing to advances in therapy.
The current cost of 48-weeks of therapy is PEG-IFN-RBV PEG-IFN-RBV-PI or PolI PEG-IFN-RBV-PI-PolI approximately US$35,000. Introduction Figure 1 evolution of Hcv therapy. IFN, interferon; PEG, pegylated; PI, protease inhibitor; PolI,
of novel anti-HCV drugs that wil be used polymerase inhibitor; RBV, ribavirin.
Nature Reviews Drug Discovery
in combination with PEG–IFN/ribavirin could double or even triple the ful cost of treatment. Therefore, the HCV market is projected to grow from over $2 bil ion in Table 1 selected HCV drugs in development
2007 to $10–15 billion in 2017.
Irena Melnikova, Ph.D., is a Senior Associate at TVM Capital, 101 Arch Street, Long-acting albumin– Boston, Massachusetts 02110, USA. interferon-a2b fusion e‑mail: Long-acting, controlled release interferon-a 1. Strader, D. B. et al. Diagnosis, management, and Valeant Pharmaceuticals Taribavirin (viramidine) Pro-drug of ribavirin treatment of hepatitis C. Hepatology 39, 1147–1171
Vertex/Johnson & Telaprevir (VX-950) Protease inhibitor 2. Jensen, D. M. & Ascione, A. Future directions in therapy for chronic hepatitis C. Antivir. Ther.13 (Suppl. 1),
31–36 (2008).
Boceprevir (SCH503034) Protease inhibitor 3. Vertex. Vertex Reports 52% SVR 12 Rate for a 24-week Telaprevir-based Regimen in Genotype 1 Hepatitis C Protease inhibitor Patients Who Failed Prior Treatment. Vertex web site Protease inhibitor > (2008).
4. HIV and Hepatitis.com. R7128 Demonstrates Potent Boehringer Ingelheim Second-generation Protease inhibitor Anti-HCV Activity in Combination with Pegylated Interferon/Ribavirin; Ongoing Trial to be Expanded. protease inhibitor HIV and Hepatitis.com web site [online], Protease inhibitor > (2008).
Polymerase inhibitor 5. Modi, A. A. & Hoofnagle, J. H. New therapies for hepatitis C. Hepatology 46, 615–617 (2007).
Polymerase inhibitor Polymerase inhibitor Polymerase inhibitor Medline Plus Health Topics Hepatitis c:

Polymerase inhibitor All links Are AcTive in THe online Pdf
Sources: Company information.
Table 2 selected HCV partnerships
Partnership (date) Product
Mechanism of action stage
Long-acting albumin– Phase II • Upfront $45million, milestones $507.5million • 50:50 split on US profits Novartis (June 2006) • Royalties on ex-US sales Vertex/Johnson & NS3–4A protease • Upfront $165million, milestones $380million • Fund 50% of development costs • Mid-20% royalties on ex-US sales, excluding Japan and Asia NS3–4A protease • Upfront $60 million, milestones $470 million • Fund 67% of development costs • 50:50 split on US profits, royalties on ex-US sales NS3–4A protease • Upfront $57 million, milestones $250 million for one compound, more compounds inhibitor milestones for additional compounds • Double-digit royalties • Option to fund 40% of development costs in exchange for 40% of profits Sources: Company information 800 OCTOBER 2008 VOLUME 7

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