Monday, December 16, 2013

Sovaldi (sofosbuvir) - Gilead's New Blockbuster

Two years and roughly one month ago, Gilead Sciences, Inc. announced the acquisition of Pharmasset, Inc. The transaction of roughly $11 billion was made by Gilead to boost it's Hepatitis C virus (HCV) drug pipeline. Pharmasset at the time did not have a single major drug on the market, however, the small biotechnology company based in New Jersey was developing a drug called sofosbuvir, which promised to be a blockbuster anti-HCV therapeutic.

On December 6th the Food and Drug Administration officially approved sofosbuvir, (brand named Sovaldi) roughly six years after it was first synthesized. Gilead and others are projecting blockbuster status and billions of dollars in revenue.

HCV, the target of sofosbuvir, is often described as the shadow epidemic, or silent epidemic. HCV is responsible for rapidly increasing rates of liver cancer, as well as other types of liver disease in the United States. HCV can cause inflammation and scarring of the liver. What is most problematic about the virus, is that many of the approximately three million infected Americans are unaware they have the virus. About one-third of the six thousand Americans who get liver transplants each year do so because of damage from HCV infection. The Centers for Disease Control (CDC) now recommends that all Americans born between 1945 and 1965 - the baby boomers, who make up three-quarters of those infected—also be screened.

Numerous celebrities have been also been diagnosed: Pamela Anderson, Lou Reed, Linda Lovelace, Etta James, Rocky Aoki, Anthony Kiedis, Keith Richards, Steven Tyler, Jack Kevorkian, Mickey Mantle, Allen Ginsberg, Evel Knievel, etc.

HCV is one of a number of viruses that infect the liver. Along with Hepatitis B and D, HCV is transmitted primarily via blood exposure (although other routes are possible). Unlike HBV, no vaccine exists for HCV.

Current treatment protocols for HCV infection involve weekly injections of interferon (usually pegylated alpha interferon). Interferon is naturally produced by your body to combat viral infections. When you get infected with influenza, interferon is what makes you feel tired, feverish, malaise, and all the generally bad stuff that goes along with a viral infection. Interferon is important however, because it boosts the immune system (which is why it is useful against HCV infection). However, imagine all of those "bad" feelings as side effects of the drug: reduced appetite, hair loss, anemia, fatigue, depression, etc.

Unfortunately current treatment protocols, with those terrible side-effects, are not that effective against certain strains (there are six genotypes and numerous sub-genotypes of HCV, all having slightly different responses to current therapeutics) of HCV. Another compounding factor is that people infected with HCV also commonly are infected with HBV or HIV as well (co-infection).

Sofosbuvir is the first HCV treatment that does not require interferon injections, can be taken simply as a pill in combination with other drugs, and typically works much faster than existing protocols. Sofosbuvir is as close to ideal as you can get; one pill a day, very high cure rates, shorter treatment duration, and fewer side effects.

One of the primary issues with early HCV drug development was that a lot of researchers had moved from the HIV drug development "gold rush" after developing numerous anti-HIV drugs. They had great success with nucleoside analogs (which disrupt the viral DNA) and protease inhibitors (which disrupt viral replication) but the needed a way to get the drugs directly to the liver (where HCV replicates) and get it to stay there. Transporting a drug to the liver is easy, everything goes to the liver. The problem is, they might not enter liver cells (hepatocytes), or they more than likely wouldn't stay inside the cells, and just be metabolized and spread throughout the body, or excreted.

Once sofosbuvir was developed it began human trials in 2010. Following numerous trials Pharmasset's medical advisory group realized that sofosbuvir could potentially treat HCV patients without interferon. Further research has suggested that sofosbuvir could also help cure hard-to-treat patients, like those who also have HIV, or more advanced liver disease

Sofosbuvir does have limits, however.
  1. HCV genotype one has always been the most difficult to treat, and even with sofosbuvir, most patients still need a combination of interferon injections and ribavirin.
  2. It may be too expensive. Gilead announced the wholesale cost of sofosbuvir will be a thousand dollars per pill, with the total cost of treatment easily exceeding a hundred thousand dollars per patient.
All in all this is an exciting new drug. Really makes me want to go out and invest in Gilead (even though I know these biotechs are notoriously fickle due to the irrational FDA effect). Keep an eye on this therapy though, and maybe in a few years we will get some data that shows how effective this drug really is. Hopefully the price can be dealt with.

Lance D. Presser has a PhD in Microbiology and Immunology, and is a Public Health Laboratorian.

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