Michael Sofia, the co-discoverer of Sovaldi (sofosbuvir, Gilead Sciences Inc.), was one of three researchers to win a Lasker-DeBakey Clinical Medical Research Award last week. The Lasker Foundation honored Sofia, along with the University of Heidelberg's Ralf Bartenschlager and Rockefeller University's Charles Rice, "for development of a system to study the replication of the virus that causes hepatitis C and for use of this system to revolutionize the treatment of this chronic, often lethal disease."
The strides made in the ability to treat hepatitis C virus (HCV) infection are a triumph of modern medicine.
What is now routine clinical practice "was really only aspirational in the early 2000s," Sofia told reporters at a press conference announcing the winners.
As recently as 10 years ago, HCV treatment consisted of the worst of both worlds – low cure rates and severe side effects.
The interferon-based regimen was so grueling that dropout rates of 20 percent were typical. Of those able to stand the treatment, fewer than half were cured. And "the idea of getting rid of interferons was somewhat unimaginable in a curative therapy," Sofia said.
Sofia is now focused on hepatitis B work as the founder and chief scientific officer of Arbutus Biopharma Inc., but received the award for work done while at Pharmasset Inc., which was bought by Gilead in 2011.
Finding Sovaldi was dependent on the existence of cell cultures that were themselves unexpectedly challenging to develop, Rice told reporters. HCV is "a uniquely human virus" that replicates only in humans and chimpanzees. The first full mouse model of HCV infection was developed only three years ago. (See BioWorld Today, Aug. 1, 2013.)
After HCV was isolated in 1989, researchers expected they would soon be able to grow it in cell lines. But between difficulties in finding a sequence of HCV that was capable of replicating at all and finding cell lines that could support its replication – the first HCV clones were capable of infecting and replicating in primate livers, but killed off such a large fraction of liver cells in culture that it took insertion of a drug resistance gene to identify survivors – took a decade.
Bartenschlager told BioWorld Insight that "the relevance, and the importance of developing such tools, was never in question," despite the fact that tools development is often perceived as an unglamorous and ungrateful line of work within science.
But though it was initially fairly easy to interest both funding agencies and researchers in the problem "as the failures increased over time, it was more difficult to convince people to fund it and to convince people to keep working on it."
That was also the case in Rice's lab, where "the NIH and the review study sections appreciated the importance . . . [but] we were all frustrated by the speed of progress" before success finally came.
Sofia was modest, saying his own role in "our contributions really come from using the tools that [Bartenschlager and Rice] developed," he said. By using those tools to screen cells, the team at Pharmasset was able to identify the precursor of what would become sofosbuvir.
Sofosbuvir is sold under the trade name Sovaldi, and Harvoni is a combination of sofosbuvir and ledipasvir. Most recently, Epclusa, a combination of sofosbuvir and the NS5A inhibitor velpatasvir that is active against all genotypes of HCV, was approved by the FDA in June. (See BioWorld Today, June 29, 2016.)
Together, the three drugs earned Gilead $4 billion in sales in the second quarter of 2016. The wholesale acquisition price for a 12-week course of Epclusa is $74,760.
The advent of Sovaldi and its cousins has enabled cure rates in excess of 90 percent with eight to 12 weeks of treatment, prompting the WHO to set a goal of elimination of hepatitis C at its 2015 Glasgow summit.
The goal remains ambitious, not least because the WHO also estimates that 90 percent of the estimated 180 million HCV-infected individuals are unaware of their infection.
Price is another barrier. If the average layperson knows anything about the new hepatitis C drugs, it is likely to be their exorbitant price tag – Sovaldi's U.S. sticker price is $1,000 per pill.
In contrast to other poster children for unsustainable prices, though, there is broad consensus that in the case of Sovaldi, Harvoni and Epclusa, at least the price is in line with the fact that the drugs have transformed hepatitis C treatment.
Drugs or drug-device combinations like Daraprim (pyrimethamine, Turing Pharmaceuticals LLC), Nitropress (nitroprusside, Valeant Pharmaceuticals Inc.), Isuprel (isoproterenol, Valeant Pharmaceuticals Inc.) and the Epipen (Mylan NV) have outraged the public, and individuals who need them for survival, not just due to their high prices but because those prices are determined by factors that appear to have as much in common with extortion as with free market efficiency. (See BioWorld Today, Sept. 30, 2015, Dec. 11, 2015, and Aug. 26, 2016.)
Even price increases in some drugs that were clearly innovative when they came to market have blurred the line between return on investment and greed. Gleevec (imatinib, Novartis AG) was clearly a breakthrough when it was approved in 2001, and won its discoverers Brian Druker, Nicholas Lydon and Charles Sawyers the 2009 Lasker-DeBakey award. But the fact that its price has quadrupled since approval is not credibly explained with the need to recoup the outlays made during clinical development. (See BioWorld Today, March 18, 2016.)
There is fairly wide skepticism, including by members of Congress, that the sofosbuvir drugs strike the correct balance between innovation and price. (See BioWorld Today, June 12, 2014.)
But what no one doubts is that there is an innovation side to the equation.
Lasker Foundation President Claire Pomeroy told reporters that "over 800,000 people have been cured – cured! – of their hepatitis C infection."
And Sovaldi can cure the tough cases as well as the easy ones, including patients who might have once gone on to die of their disease. "It cures patients who have severe cirrhosis or fibrosis, it cures HIV co-infected patients, it can prevent the need for liver transplants," Sofia said.
Pomeroy refrained from commenting on Sovaldi's pricing woes. She told BioWorld Insight the award "was really given for the beauty and the power of this science, and the impact of basic science and drug development coming together to change the course of this disease."