The biotech industry gets its fair share of criticism. Take for example HBO’s John Oliver shining his light on biopharma last week and proclaiming drug companies are like high school boyfriends: more interested in getting into patients’ bodies than actually being effective once they’re inside.
That soundbite prompted us at the WEEKLY to wonder: Is a 90% cure rate for a disease afflicting 3.5 million in the U.S. and possibly 200 million worldwide effective?
We’re talking about hepatitis C and the new generation of drugs put on the market just last year to cure it: Gilead’s (Foster City, CA) Harvoni and Sovaldi, and AbbVie’s (North Chicago, IL) Viekira Pak.
Before these drugs, hepatitis C patients could expect a standard treatment involving a combination of interferon and ribavirin. Interferon is delivered via repeat injections to patients and works by “revving up” the entire immune system, which leads to unpleasant side effects such as fatigue, anxiety, flu-like symptoms and gastrointestinal distress. In exchange for those unpleasant side effects, that drug combo has a ~50% success rate.
Contrast with Harvoni’s ~90% hepatitis C cure rate, and we can all agree this therapeutic is a bright spot for our industry and a story that deserves to be told. Let’s break down the science behind the new drugs fighting hepatitis.
Simple Virus, Complex Problem
For all the damage some viruses can cause, they’re actually very simple structures. Consisting of genetic material (either RNA or DNA) and a batch of proteins to aid with host cell infection, viruses stealthy infiltrate our bodies.
Though viruses cannot make their own proteins, they are generally able to make copies of their own genetic material by using the polymerase proteins found inside the infectious particle. Most RNA-based viruses, such as the HIV, HCV and influenza, have polymerase enzymes with a very high error rate—in other words, they make a lot of mistakes when copying the viral genome, resulting in mutations.
The high mutation rate and the challenge of targeting a virus without negatively impacting the host cells are major hurdles for antiviral drug development. So it is a BIG deal when a truly safe and effective antiviral drug makes it to the marketplace.
What is Hepatitis C?
Hepatitis is a liver disease caused by infection with the hepatitis C virus (HCV), a blood borne pathogen. Chronic infections may initially be asymptomatic, and if left untreated, serious problems such as cirrhosis (scarring) or cancer of the liver can occur. Liver disease due to HCV infection is the leading indication for liver transplants in the United States. Currently there is no vaccine available for HCV.
An Easier Pill to Swallow: Sovaldi and Harvoni
Small molecule drug Sovaldi, approved at the end of 2013, has been widely heralded as the beginning of a new era in HCV treatment. Marketed by Gilead, Sovaldi was granted breakthrough therapy status by the FDA because it is more effective and has fewer side effects than interferon with ribavirin.
Sovaldi can be used in combination with interferon and ribavirin, or ribavirin alone, depending on when the HCV is diagnosed and the severity of the disease. Sovaldi conquers HCV from a bottom-up approach, disrupting the viral replication stage. Interferon fights HCV from the top-down, prompting the entire immune system to beef up an assault.
As a nucleotide analog polymerase inhibitor, Sovaldi inhibits the viral polymerase –the enzyme used by HCV to replicate its genetic material (RNA). To make copies of the viral RNA, the polymerase simply connects new building blocks (nucleotides) together in the same order as the existing viral RNA. The analog drug is structurally very similar to nucleotides found in nature, so the polymerase will subsequently incorporate it into a growing RNA strand. However, it has been chemically modified so once incorporated, the polymerase is unable to add any additional nucleotides, thereby halting viral replication.
In October 2014, the FDA approved Harvoni, a combination product consisting of Sovaldi and a second compound, ledipasvir, which inhibits the HCV protein NS5A. The precise function of NS5A in the viral life cycle is not known, however it is thought to play a role in viral replication, assembly and secretion. The exact mechanism of action of ledipasvir is not known, but it is thought to bind to the NS5A protein and inhibit its role in the HCV life cycle.
Mixing it up with Viekira Pak
The end of 2014 gifted yet another breakthrough therapy approval for HCV—AbbVie’s Viekira Pak. A cocktail of three new drugs, Viekira Pak is also a significant improvement over interferon and ribavirin treatments.
- The first component of Viekira Pak, dasabuvir, is a non-nucleoside analog inhibitor of the viral polymerase. It simply binds to the virus in such a way that it creates a conformational or shape change to the enzyme itself, rendering it ineffective.
- The second component, paritaprevir, inhibits the viral protein NS34A, which is critically important in the HCV lifecycle and is a protease, or an enzyme that “cleaves” other proteins. When HCV infects liver cells, it hijacks the cell’s protein making machinery for its own use. One of the proteins produced is a long “polyprotein,” or protein composed of many smaller proteins. In order for those smaller proteins to do their job, they must be released from the polyprotein and the NS34A protease does so by cutting the polyprotein into smaller bits. Paritaprevir works by binding the part of NS34A that does the actual cutting, preventing it from doing its job.
- The third component, ombitsavir, inhibits the HCV protein NS5A, as described above for the ledipasvir component of Harvoni.
Viruses with high mutation rates are unlikely to develop mutations that confer resistance to all three drugs at once, and treating them with a drug cocktail such as Viekara Pak can be a successful strategy.