World Hepatitis Day: How the 'Academia-Industrial-Government Complex' Cured a Nasty Disease

July 28^th is World Hepatitis Day. 

Could there be a better reason to take a look at one of modern medicine's greatest success stories? Because that’s exactly what the decades-long battle to find a drug that cured hepatitis C (HCV) was [1]. I know this because I was part of the mad scramble among dozens of companies trying to get to the finish line first. (Unfortunately, Wyeth didn’t get there at all, much to the distress of the dozens of us who worked in this area.)

First to finish ≠ success

In this case, the aphorism "be careful what you wish for" sure applies. The two "winners" were Vertex and Schering/Merck. It's impossible to say with certainty, but Vertex may have recouped its discovery and development costs, while Schering/Merck didn't even come close.  

Both companies spent billions of dollars developing [2] the first-generation HCV protease inhibitors, only to have them rendered obsolete very quickly by a second-generation of direct-acting HCV therapies that were safer, simpler, and far more effective. 

Vertex's Incivek (telaprevir) became one of the fastest-selling drugs in pharmaceutical history, generating more than $1.5 billion in sales in 2012 alone, highlighting the urgent need for an effective HCV drug. But that number dropped by more than 90% by 2014. After the approval of Sovaldi (sofosbuvir) in late 2013 and the fixed-dose combination therapies that followed, Incivek and Victrelis hopped into the toaster, never to return. If this doesn't highlight the nature of pharmaceutical R&D, then nothing does. 

Why the urgent need?

Only a few decades ago, chronic hepatitis C was a leading cause of cirrhosis, liver cancer, and liver transplantation. Millions of people worldwide lived infected with an insidious viral infection that progressed, often silently, for years before causing irreversible liver damage. Today, a short course of pills cures more than 95 percent of patients. In 1989, when HCV was first discovered, such treatments were not even imagined. 

Where did these drugs come from?

This article will give you a taste of how new medicines are really invented. 

Contrary to two conflicting popular narratives, neither the government, academia, nor the pharmaceutical industry deserves most of the credit. They all do.

Looking back, it's clear that the cure resulted from a partnership between academic scientists, typically funded by the NIH, who solved fundamental biological problems and industrial scientists who transformed those discoveries into medicines. Neither government, academia, nor industry could have pulled this off; all three made essential contributions.

Two choices, both tough

There are two basic ways to determine whether a chemical compound might become an antiviral drug.

One approach is the enzyme assay. Viruses, like all other lifeforms [2], depend on enzymes to replicate, and these enzymes can be isolated and tested against enormous libraries of chemical compounds. Modern high-throughput screening systems allow researchers to evaluate hundreds of thousands, sometimes millions, of compounds to determine whether any inhibit an essential viral enzyme. Sometimes these assays find no inhibitors, and sometimes they find thousands. 

Identifying one or more of these inhibitors sounds like a success, but it's anything but. 

A compound may work beautifully in a test tube yet fail completely as a drug because it cannot enter cells, where viruses actually replicate. Medicinal chemists have spent countless years trying to solve this problem. Many extraordinarily potent enzyme inhibitors ultimately prove worthless because they cannot cross cell membranes.

That is why cell-based assays are often preferable.

Instead of asking whether a compound inhibits an isolated enzyme, a cell-based assay asks a more practical question: Does it stop the virus from replicating inside a living cell? If the answer is yes, you've already solved one of the biggest obstacles because the compound has demonstrated that it can enter the cell. The disadvantage is that you initially do not know how it works, e.g., what step in the viral life cycle is being inhibited. 

But, hepatitis C didn't cooperate

Early hepatitis C research was crippled because no one could make the virus replicate in cultured liver cells. This is bizare because, hepatitis C replicates like a madman in the human liver but stubbornly refuses to do so in isolated cells in the lab. Other viruses, including norovirus, behave similarly, and this can greatly hamper antiviral drug discovery.

Without a cell-based assay, research was largely reduced to educated guesswork. The alternative was to test compounds in animals, an approach with a very low probability of success. Worse still, the best animal model for hepatitis C was the chimpanzee, whose use in biomedical research has since been largely discontinued for ethical reasons. We often joked that we were trying to discover drugs with both hands tied behind our backs.

Then academia solved the problem

Using sophisticated molecular biology, Ralf Bartenschlager and Charles Rice independently developed what became known as the hepatitis C subgenomic replicon. Although the underlying science is far too complex for this article, the concept is surprisingly elegant. They removed the viral genes responsible for making the structural components of hepatitis C, leaving behind only those required for viral RNA replication.

When this modified viral RNA was introduced into Huh-7 liver cells, it replicated efficiently. For the first time, medicinal chemists had a practical cell-based assay that could identify compounds capable of stopping hepatitis C replication.

Initially, some researchers questioned whether this artificial system would accurately predict what would happen in patients. It did.

The HCV replicon quickly became the standard screening tool used throughout the pharmaceutical industry. Later, complete infectious cell culture systems were developed, but the replicon had already transformed hepatitis C drug discovery.

One of the drugs identified using this system was sofosbuvir, the nucleotide polymerase inhibitor that became the foundation of modern hepatitis C therapy. Combined with other direct-acting antivirals, it made cure rates exceeding 95 percent routine.

The significance of this work was recognized in 2020 when Harvey Alter, Michael Houghton, and Charles Rice were awarded the Nobel Prize in Physiology or Medicine for discoveries leading to the identification of hepatitis C virus and ultimately to curative therapies.

Without the subgenomic replicon developed in academic laboratories, there would have been no practical way to discover these drugs. Without the thousands of compounds synthesized, optimized, tested, manufactured, and evaluated in clinical trials by pharmaceutical companies, the replicon would have remained an elegant scientific achievement rather than the foundation of curative medicines.

That is how drug discovery actually works.

Academia excels at fundamental biological discoveries. Industry excels at transforming those discoveries into safe and effective medicines. The hepatitis C cure is not a victory for one over the other. It is a reminder that some of medicine's greatest advances occur only when each does what it does best.

NOTES:

[1] Although there are many varieties of hepatitis, the three most important are A, B, and C (clever, no?). Hep A is a short-lived, but usually not serious, infection from spoiled food. Hep B is a bit like Hep C, in that it attacks the liver over time and causes liver cancer, but the two viruses are very different. Unlike Hep C, there is a vaccine to prevent it. You have to be out of your gourd not to get it for you and your kids. Wanna argue? Go ahead.