Science Reveals an Important Difference Between Critical Components of Harvoni and Viekira Pak

Some of the basic research behind NS5B inhibitors reveals an often overlooked, but clinically important difference between Viekira Pak and Harvoni.

In 3 short years, direct-acting antivirals (DAAs) went from being adjuncts to treatment with peginterferon and ribavirin to all-oral regimens with broad efficacy across hepatitis C virus (HCV) genotypes.

First among the DAAs were the NS3/4A serine protease inhibitors telaprevir and boceprevir. These protease inhibitors were ineffective without background therapy, and required use of complex response-guided algorithms for use.

Unlike these early DAAs, modern treatment for HCV act against two other parts of HCV: NS5A and NS5B. The NS5A component is a scaffold that is important in production of new HCV virus, and the NS5B component is important in producing new RNA to make each new HCV virus capable of infecting more cells.

By targeting NS5B, medications occupy the sites in the NS5B RNA polymerase, terminating the formation of RNA chains, resulting in incomplete copies of RNA and unviable viruses. Because the NS5B protein is found across all types of HCV, inhibition of NS5B should be similarly effective across all HCV genotypes—a property known as pangenotypic activity.

However, the pangenotypic activity of NS5B inhibitors depends on where a drug binds to NS5B. Scientists have found that nucleotide and nucleoside inhibitors tend to bind to NS5B closer to the site of catalytic activity, whereas nonnucleoside inhibitors tend to bind to NS5B farther from the catalytic site, resulting in a higher risk of resistance and inconsistent activity across HCV genotypes.

As a result, researchers at Pharmasset Inc—the company that originated sofosbuvir—searched for nucleoside-type inhibitors acting directly at the NS5B catalytic site, rather than nonnucleoside inhibitors that bind farther from the desired area.

These investigations resulted in the discovery, development, and ultimate FDA approval of sofosbuvir in December 2013. Although sofosbuvir was effective alone, its use initially required background therapy with injectable peginterferon and oral ribavirin.

On October 10, 2014, the combination of sofosbuvir and the NS5A inhibitor ledipasvir became the first single-tablet regimen approved by the FDA for treatment of HCV, marketed under the trade name Harvoni. Safety and efficacy for the product were evaluated in three large phase 3 studies (ION-1, -2, and -3) comprising nearly 2000 patients with HCV.

In ION-1, treatment-naive patients with hepatitis C with genotype 1 HCV, both with and without cirrhosis, experienced sustained viral response 12 weeks after the end of therapy (SVR12) in 98% to 99% of cases. Similar activity was noted in the remaining two studies, and some populations may be eligible for a shorter course of treatment (8 weeks), rather than the usual 12-week treatment course for most patients, or the extended 24-week treatment course for treatment-experienced patients with compensated cirrhosis.

Harvoni is not the only NS5B/NS5A inhibitor on the US market. Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir) is another combination regimen that includes the NS5A inhibitor ombitasvir and the nonnucleoside NS5B inhibitor dasabuvir.

Because dasabuvir is structurally a nonnucleoside NS5B inhibitor, it tends to bind to NS5B farther from the catalytic site NS5B inhibitors with a nucleoside- or nucleotide-like structure (such as sofosbuvir).

As a result of this structural difference, Viekira Pak borrows additional antiviral efficacy through the NS3/4A protease inhibitor paritaprevir, a booster for paritaprevir exposure (ritonavir), and in some cases ribavirin—a component of traditional HCV regimens that may cause severe side effects, such as blood dyscrasias.

Through an understanding of the basic science behind development of novel anti-HCV therapies, it is clear that not all NS5B inhibitors are equivalent. Based on early research, NS5B inhibitors with a nucleotide- or nucleoside-like structure may have basic drug design properties superior to those of the nonnucleoside NS5B inhibitors.

This difference in basic structural design seems to have borne out in clinical efficacy data. Although both Viekira Pak and Harvoni are effective in the treatment of HCV, Viekira Pak borrows additional efficacy from a ritonavir-boosted NS3/4A inhibitor and (in some cases) ribavirin, whereas Harvoni accomplishes similar results with just 2 medications.

References

• McQuaid T, Savini C, Seyedkazemi S. Sofosbuvir, a Significant Paradigm Change in HCV Treatment. Journal of Clinical and Translational Hepatology. 2015;3:27-35.
• Sovaldi (sofosbuvir) tablets [package insert]. Foster City, CA: Gilead Sciences, Inc; 2013.
• Harvoni (ledipasvir and sofosbuvir) tablets [package insert]. Foster City, CA: Gilead Sciences, Inc; 2014.
• Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) [package insert]. North Chicago, IL: AbbVie Inc; 2014.
• Copegus (ribavirin) tablets [package insert]. South San Francisco, CA: Genentech, Inc; 2002.