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FDA Approves Sofosbuvir (Sovaldi) for Hepatitis C Genotypes 1, 2, 3, and 4


The U.S. Food and Drug Administration on Friday approved the first hepatitis C virus (HCV) polymerase inhibitor, sofosbuvir, to be marketed by Gilead Sciences under the brand name Sovaldi. Sofosbuvir was approved for use with ribavirin for people with HCV genotypes 2 or 3 -- making it the first-ever interferon-free hepatitis C treatment -- and in combination with pegylated interferon/ribavirin for people with harder-to-treat HCV genotypes 1 or 4.

"Today’s approval represents a significant shift in the treatment paradigm for some patients with chronic hepatitis C," said Edward Cox, director of the FDA's Office of Antimicrobial Products.

The advent of direct-acting antiviral agents (DAAs) has brought about a revolution in the treatment of chronic hepatitis C. For many years the standard of care was pegylated interferon plus ribavirin, which requires 24 to 48 weeks of therapy, causes difficult side effects including flu-like symptoms and depression, and cures fewer than half of people with HCV genotype 1. Adding one of the first-generation HCV protease inhibitors -- boceprevir (Victrelis) or telaprevir (Incivek) -- can shorten treatment and raise sustained response rates, but these drugs come with their own side effects. Because of difficulty of treatment, many people with hepatitis C and their doctors have been waiting for better therapies, especially interferon-free regimens.

Sofosbuvir and Janssen's HCV protease inhibitor simeprevir (Olysio) -- which won FDA approval in late November -- are the first of a new generation of direct-acting antivirals that can further shorten treatment, improve tolerability, and push cure rates into the 80%-100% range, even for difficult-to-treat patients.

Sofosbuvir (formerly GS-7977, and prior to that PSI-7977 before Gilead bought Pharmasset in 2011) is a uridine nucleotide analog that acts as a defective RNA building block, preventing HCV's NS5B polymerase enzyme from copying genetic material to make new virus.

Sofosbuvir has demonstrated high rates of sustained virological response -- continued undetectable viral load 12 or more weeks after finishing treatment, which is considered a cure -- in Phase 3 clinical trials both in combination with pegylated interferon/ribavirin and in all-oral regimenswith ribavirin alone. It has also demonstrated promising results with other DAAs (including daclatasvir, ledipasvir, and simeprevir) in earlier studies, several of which were presented this year at the EASL International Liver Congress and AASLD Liver Meeting. Combining drugs that target different steps of the HCV lifecycle improves potency and reduces the emergence of drug resistance.

The FDA approved dual therapy using 400 mg once-daily sofosbuvir plus 1000-1200 mg/day weight-based ribavirin for people with HCV genotypes 2 or 3. Sofosbuvir has no food requirements. Reflecting the recent realization that genotype 3 is harder to treat, duration of therapy is 12 weeks for genotype 2 and 24 weeks for genotype 3.

As expected, the FDA approved sofosbuvir in combination with pegylated interferon alfa-2a (Pegasys or PegIntron) and ribavirin for 12 weeks for people with HCV genotypes 1 or 4. But it also said that sofosbuvir plus ribavirin for 24 weeks may be considered for genotype 1 patients who are ineligible for or unable to tolerate interferon.

The FDA unexpectedly expanded sofosbuvir's indication to include HIV/HCV coinfected people and patients with hepatocellular carcinoma awaiting liver transplantation, based on promising study results in both populations.

The most common side effects of sofosbuvir combination therapy in clinical trials were fatigue, headache, nausea, insomnia, and anemia. The major concern with ribavirin is hemolytic anemia. Pegylated interferon can cause numerous side effects, as noted. Because ribavirin may cause birth defects, these regimens should not be used by pregnant women or their male partners.

Sofosbuvir is not metabolized by the CYP450 enzyme system and does not have significant interactions with many medications, including most antiretrovirals for HIV (with the exception of tipranavir [Aptivus]). However, it may interact with agents that are potent P-glycoprotein (P-gp) inducers in the intestine, for example rifampin or St. John’s wort.

Over years or decades chronic hepatitis C infection can lead to serious liver disease including advanced fibrosis, cirrhosis, and hepatocellular carcinoma, and it is the leading cause of liver cancer and main indication for liver transplantation in the U.S. Effective treatment can reduce or halt disease progression, though people who already have advanced liver damage may still develop liver cancer and should continue to be screened.

"Today marks a landmark advance in the treatment of hepatitis C, opening up new opportunities to stop the spread of this virus and the ravages of this disease," said John Ward, Director of CDC’s Division of Viral Hepatitis. "However, new therapies only work if people receive treatment...CDC continues to urge every baby boomer in America and others at risk to get tested for hepatitis C. Widespread screening, together with new cures, promises to slash the burden of hepatitis C in this country and save thousands of lives."

"The approval of simeprevir and sofosbuvir are historic events, both for folks with hepatitis C alone as well as those with HIV/HCV coinfection, where complications from liver failure have emerged as a major cause of suffering and death," said Jay Lalezari of Quest Clinical Research in San Francisco, which is currently enrolling hepatitis C drug trials. "These new drugs, along with others in the pipeline, will render hep C easy to treat in most cases and, in their way, are as life-changing as the drugs we use to treat HIV."

Price a Potential Barrier

The Wholesale Acquisition Cost for sofosbuvir is $1000 per pill, adding up to $84,000 for 12 weeks of treatment for genotypes 1, 2, or 4, or twice that amount for patients with genotype 3 who need 24 weeks.

Gilead has established a patient assistance program called Support Path ( for people who are uninsured, underinsured, or otherwise in need of financial assistance to pay for sofosbuvir. Support Path has high income limits relative to many similar programs, offering assistance for people with incomes up to $100,000 for a family of up to 3 people. Case managers will help patients and providers identify coverage options such as federal programs (Medicaid or Medicare) and the new Affordable Care Act health exchanges.

In addition, the Sovaldi Co-pay Coupon Program will provide co-pay assistance for eligible people with private insurance who need help paying for out-of-pocket medication costs and covering insurance deductibles. According to Gilead, most patients will pay no more than $5 co-pays. Gilead also said that it is developing a treatment access program focusing on countries with the greatest burden of hepatitis C.

"As a person who was cured of HCV using Sovaldi, I am very excited by the approval of Sovaldi and delighted that the FDA indication includes genotype 1, 2, 3, and 4 patients as well as pre-liver transplant patients and people coinfected with HIV," said Lynda Dee of the Fair Pricing Coalition. "But I am very concerned that the exorbitant $84,000 price tag for a 12-week course of Sovaldi, plus an additional $9,000 for the interferon/ribavirin needed for the indicated treatment regimen for genotype 1 patients, will present a barrier to access for many patients who have been waiting for Sovaldi approval."

Full prescribing information for Sovaldi is available online.



Gilead Sciences. U.S. Food and Drug Administration Approves Gilead’s Sovaldi (Sofosbuvir) for the Treatment of Chronic Hepatitis C. Press release. December 6, 2013.

Food and Drug Administration. FDA approves Sovaldi for chronic hepatitis C. Press release. December 6, 2013.

R Klein and K Struble. FDA Hepatitis Update -- Approval of Sovaldi (sofosbuvir) tablets for the treatment of chronic hepatitis C. December 6, 2013.