Sofosbuvir

Sofosbuvir (brand name Sovaldi) is a drug developed by Gilead Sciences used to treat hepatitis C infection. In combination with other therapies, Sofosbuvir can effectively cure hepatitis in 90 percent of patients. It inhibits the RNA polymerase that the hepatitis C virus (HCV) uses to replicate its RNA. It was discovered at Pharmasset and developed by Gilead Sciences.

Sofosbuvir is a component of the first all-oral, interferon-free regimen approved for treating chronic hepatitis C. Interferon-free therapy for treatment of hepatitis C reduces the side effects associated with use of interferon.

In 2013, the Food and Drug Administration (FDA) approved sofosbuvir in combination with ribavirin (RBV) for oral dual therapy of HCV genotypes 2 and 3, and for triple therapy with injected pegylated interferon (pegIFN) and RBV for treatment-naive patients with HCV genotypes 1 and 4. Sofosbuvir treatment regimens last 12 weeks for genotypes 1, 2 and 4, and 24 weeks for treatment of genotype 3. This is typically half the time as with prior treatments. The label further states that sofosbuvir in combination with ribavirin may be considered for patients infected with genotype 1 who are interferon-ineligible.

The price of sofosbuvir, quoted in various media sources as $84,000 to $168,000 for a course of treatment in the U.S., £35,000 for 12 weeks in the UK, and €60,000 in Germany has engendered considerable controversy, particularly with respect to accessibility in developing countries.

Medical uses
Sofosbuvir is used for the treatment of chronic hepatitis C, genotypes 1, 2, 3 and 4, in combination with pegylated interferon and ribavirin, or with ribavirin alone. It is also used in HCV patients with an HIV coinfection. The treatment is based on a number of clinical trials, for example the ELECTRON trial which showed that a dual interferon-free regimen of sofosbuvir plus ribavirin produced a 24-week post-treatment sustained virological response (SVR24) rate of 100% for previously untreated patients with HCV genotypes 2 or 3.

In early 2014, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) jointly published a recommendation for the management of hepatitis C. In this recommendation, sofosbuvir and ribavirin, with or without pegylated interferon, are part of all first-line treatments for HCV genotypes 1 to 6, and are also part of some second-line treatments.

Adverse effects
As sofosbuvir is always combined with other drugs such as ribavirin and interferon, only the adverse effects of these combinations have been evaluated. Common side effects are fatigue, headache, nausea, rash, and irritability. Most side effects are significantly more common in interferon containing regimens as compared to interferon-free ones. For example, fatigue and headache are nearly cut in half, influenza-like symptoms are reduced to 3–6% as compared to 16–18%, and neutropenia is almost absent in interferon-free treatment.

Interactions
Sofosbuvir is a substrate of P-glycoprotein, a transporter protein that pumps drugs and other substances from intestinal epithelium cells back into the gut. Therefore it is theorised that inducers of intestinal P-glycoprotein, such as rifampicin and St. John's Wort, could reduce the absorption of sofosbuvir.

Mechanism of action
Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate. The triphosphate serves as a defective substrate for the NS5B protein, which is the viral RNA polymerase, and thus acts as an inhibitor of viral RNA synthesis. Prior to the discovery of sofosbuvir, a variety of nucleoside analogs had been examined as anti-hepatitis C treatments, but these exhibited relatively low potency. This low potency arises in part because the enzymatic addition of the first of the three phosphate groups of the triphosphate is slow. The design of sofosbuvir avoids this slow step by building the first phosphate group into the structure of the drug during synthesis. Additional groups are attached to the phosphorus to temporarily mask the two negative charges of the phosphate group, thereby facilitating entry of the drug into the infected cell. The NS5B protein is a RNA-dependent RNA polymerase critical for the viral reproduction cycle.



Sofosbuvir and other nucleotide inhibitors of the HCV RNA polymerase exhibit a very high barrier to resistance development. This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid resistance development has proved to be an important cause of therapeutic failure.

History
The New Drug Application for sofosbuvir was submitted on April 8, 2013 and received the FDA's Breakthrough Therapy Designation, which grants priority review status to drug candidates that may offer major treatment advantages over existing options.

In December 2013, the FDA approved sofosbuvir for the treatment of chronic hepatitis C.

Research
Combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or ledipasvir, have shown sustained virological response rates of up to 100% in people infected with HCV.

Data presented at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013 showed that a triple regimen of sofosbuvir, ledipasvir, and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100% for both treatment-naive patients and prior non-responders with HCV genotype 1. Gilead has developed a sofosbuvir + ledipasvir coformulation that is being tested with and without ribavirin.

Pricing controversy
Sofosbuvir will cost $84,000 for 12 weeks of treatment used for genotype 1 and 2, and $168,000 for the 24 weeks used for genotype 3. The price in the United Kingdom is expected to be £35,000 (~$59,000) for 12 weeks. The California Technology Assessment Forum, a panel of academic pharmacoeconomic experts, representatives of managed care organizations, and patient advocates, voted on March 10, 2014, that the drug should be considered a low value treatment compared to older treatments. The Forum concluded that health care costs in California could increase by $18–29 billion/year because of this medication. The German insurance organization AOK announced in August, 2014 that it has already spent €123 million for Sovaldi since the drug was introduced in January of the same year.

The price has stirred controversy, with critics contending the drug is unaffordable and supporters suggesting that the drug brings price savings relative to older treatments associated with severe side effects, lengthy treatment, and low cure rates.

Some patient advocates, such as Jennifer Cohn of Doctors without Borders and the organization Doctors of the World have sharply criticized the price of sofosbuvir as reflecting "corporate greed" and ignoring the needs of patients in developing countries. As of January 2014 Gilead was reported to be in discussions with several Indian generics manufacturers to make sofosbuvir available in India at a price below that of existing generic products. The company has stated that it expects the price of treatment with sofosbuvir-based regimens to be in the "high hundreds to low thousands" in developing markets.