New Generation DDAs

Six drugs promise to further revolutionize HCV treatments
by Larry Buhl

The hepatitis C (HCV) treatment revolution is a little more than a year old, but by 2014 a second wave will add important reinforcements in fighting the virus. The first protease inhibitors, Merck’s boceprevir (Victrelis) and Vertex’s telaprevir (Incivek/Incivo), marked the beginning of the direct-acting antiviral (DAA) era last year, and were greeted with great fanfare and hope.

However, both drugs were developed for use with pegylated interferon, which has serious side effects, and ribavirin. Boceprevir and telaprevir are also primarily for the treatment of genotype 1 HCV infection, which leaves out genotypes 2 through 6. The prevalence of different HCV genotypes around the world, as well as increasing numbers of patients with harder-to-treat disease, co-morbidities, or advanced liver disease means that a greater variety of treatment options is needed.

The work has continued in the development of shorter-regimen, all-oral DAAs that are easy to tolerate for all genotypes. Proof-of-concept for safe and effective all-oral, interferon-free regimens has been established, and dozens of drugs from different classes are in development, and include once-daily protease inhibitors, NS5a inhibitors, and nucleotide polymerase inhibitors.

Below are six second-generation DAA drugs now in Phase III clinical trials.

Simeprevir, or TMC435 (Janssen/Tibotec and Medivir): once-daily HCV protease inhibitor
Simeprevir is being developed for use with pegylated interferon and ribavirin. Simeprevir is a once-daily HCV NS3/4A protease inhibitor that has shown so far to be effective against HCV genotype 1. Past trials have shown a favorable safety profile, and shown sustained response rates when added to standard therapy. In these studies, simeprevir is taken as a tablet, once a day with pegylated interferon and ribavirin.

BI 201335 (Boehringer Ingelheim): once-daily HCV protease inhibitor
Like Simeprevir, BI 201335 is being developed with pegylated interferon and ribavirin (PEG-IFN/RBV), and with other DAAs in interferon-free trials. In a Phase II trial, researchers concluded that the drug may be effective as an interferon-free regimen for treating chronic HCV genotype 1 infection, including patients with cirrhosis.

GS-7977 (Gilead): once-daily nucleotide polymerase inhibitor.
Gilead plans to combine GS-7977 with another drug, GS-5855, in a trial of 800 patients starting soon. A previous study of GS-7977, combined with ribavirin, found nine out of nine patients who were previously untreated had a sustained response to the drug, with no signs of virus in their bodies after finishing the therapy.

Daclatasvir, or BMS-790052 (Bristol-Myers Squibb): once-daily, pan-genotypic NS5a inhibitor
Daclatasvir is an NS5a replication complex inhibitor (The function of NS5A is not fully understood, but it appears to play an important role in viral replication). In Phase II trials it deemed effective in interferon-free regimens combined with GS-7977 or asunaprevir (BMS-650032) in treating chronic genotype 1 infection. Daclatasvir is also being studied with BMS-986094 in triple therapy (with pegylated interferon plus ribavirin), and in quadruple therapy (with asunaprevir, pegylated interferon, and ribavirin).

Asunaprevir, or BMS-650032 (Bristol-Myers Squibb): twice-daily protease inhibitor
Asunaprevir, an inhibitor of the viral enzyme serine protease NS3, is being studied with the company’s other DAAs (the NS5a inhibitor daclatasvir and BMS-791325, a non-nucleoside polymerase inhibitor), with and without pegylated interferon alfa or pegylated interferon. Asunaprevir’s twice-daily dosing may limit its use.

Danoprevir, RG7227, (Hoffmann-La Roche and Genentech): twice-daily ritonavir-boosted HCV protease inhibitor
In clinical trials, danoprevir has shown high rates of viral clearance when used as a monotherapy, in combination with RG7128, and when combined with Pegasys and ribavirin. In the Phase II DAUPHINE study, up to nintey-three percent of genotype 1 and 100 percent of genotype 4 patients achieved SVR12 with ritonavir-boosted danoprevir, IFN and ribavirin. That is considered a clinical cure.

Larry Buhl is a freelance journalist and screenwriter living in Los Angeles.

October 2012

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