The chances of any one chemist discovering a drug that works—a molecule that is safe and improves people’s lives in a meaningful way—are small. The chances of discovering an actual cure? Minuscule.
Medicinal chemist Michael Sofia has managed to beat the odds. He invented what is now one of the most successful drugs in the pharmacopoeia: sofosbuvir, better known as Gilead Sciences’ blockbuster hepatitis C virus treatment Sovaldi. For many people with HCV, the pill sliced the treatment time for the virus from a year to just 12 weeks while eliminating the harsh side effects of older, less effective therapies.
That quick cure made Sovaldi the biggest drug launch in history. Approved late in 2013, Sovaldi brought in more than $10 billion for Gilead last year.
Now, Sofia has set his sights on the hepatitis B virus, another serious liver infection. He’s spent the past three years thinking about what a cure for HBV might look like and, through a biotech firm he cofounded called OnCore Biopharma, acquiring promising molecules.
In January, OnCore was acquired by Canada’s Tekmira Pharmaceuticals, which has its own HBV activities. Now at the helm of Tekmira’s R&D operation and in charge of a broad new drug pipeline, Sofia faces the challenge of repeating the success of Sovaldi. No pressure.
Despite an available vaccine, the hepatitis B virus chronically infects some 240 million people around the world, almost twice the number who have HCV, according to the World Health Organization. Although a handful of antivirals are approved to treat HBV, they don’t work for most people; those who do respond aren’t actually cured and have to take the pills for the rest of their lives.
Sofia first started contemplating how to cure hepatitis B while at Pharmasset, the Princeton, N.J.-based biotech where he discovered sofosbuvir.
Then, in 2011, Gilead put down $11 billion to acquire Pharmasset. Although Sofia was offered a job at Gilead, he had learned during earlier stints at big pharma firms that he prefers a more entrepreneurial environment. He stayed on as an adviser to Gilead during a transitional period but was already starting to think about a hepatitis B-focused start-up.
In mid-2012, Sofia, along with three other Pharmasset veterans, launched OnCore in Doylestown, Pa. The idea was to build on their collective experience in HCV to tackle HBV.
They knew that a cure for HBV would likely require a combination of drugs, just as the HCV cure did. And as for HCV, an effective HBV treatment would need to cripple the virus’s ability to replicate.
But HBV has two more survival tricks that make it more complicated to fight than HCV: The virus can evade detection by modulating the host immune system, and in its most clever ploy, it leaves a reservoir of viral DNA in the liver of its host. As Sofia explains, even if replication is shut down, the reservoir allows the virus to bounce back with new viral proteins, genomic material, and, ultimately, new viral particles.
Sofia and his OnCore partners were convinced that eliminating the virus would require a drug cocktail that addresses each of those survival mechanisms—viral replication, immune system control, and the liver viral reservoir. With that goal in mind, they set out to assemble a portfolio.
The tiny company was self-funded until mid-2014, when one of the original investors in Pharmasset provided its first round of external funding, allowing Sofia and his team to quickly acquire a collection of assets.
One of their first purchases was OCB-030, a sangamide-based cyclophilin inhibitor from Stockholm’s NeuroVive Pharmaceutical. Cyclophilin inhibitors were also explored in HCV, but Sofia points out that OCB-030 is structurally very different than the molecules tested in HCV. Moreover, it has proven more potent in preclinical studies, he says.
Other acquisitions include Enantigen Therapeutics, another Doylestown-based start-up. It brought surface antigen secretion inhibitors, meant to tackle viral immune control, and capsid assembly inhibitors, which target the viral reservoir.
OnCore also licensed several projects from the Blumberg Institute, a nonprofit research institute associated with the Hepatitis B Foundation that is also located in Doylestown. Two of those projects focus on other ways to attack the viral reservoir, which is composed of covalently closed circular DNA.
“We believe strongly that cccDNA is going to be the solution to the cure, ultimately, and we’ve put a lot of effort into this area,” Sofia says.
Armed with a portfolio of molecules spanning multiple mechanisms of action, OnCore’s managers intended to take the company public. They had gone so far as to compile the lengthy document required by the Securities & Exchange Commission, known as the S-1, before selling stock to the public and were in the midst of a road show to potential investors. Then Tekmira came calling.
Tekmira was one of several companies that OnCore had been chatting with as it explored the potential for treating HBV with small interfering RNA. “It became clear when we talked to the people at Tekmira that they had a very similar vision,” Sofia says. And because there was minimal overlap between Tekmira’s siRNA capabilities and compounds and OnCore’s small-molecule ones, “it became a natural fit.”
In January, Tekmira and OnCore agreed to merge in a deal that gave OnCore shareholders 50% of Tekmira’s stock. At the time, the combined company was valued at $750 million.
For Tekmira, the deal was transformative. Although several other companies—including Gilead, Alnylam, and Arrowhead Research—are working on HBV treatments, industry watchers were happy to see a broad collection of assets under one roof. News of the merger sent Tekmira’s stock price up roughly 50%.
When the transaction closed in March, Sofia became the chief scientific officer of Tekmira. He is now part of a team of roughly 120 people—about twice the size of Pharmasset during most of its existence, although still a far cry from a big pharma firm.
Meanwhile, Tekmira’s siRNA-based HBV treatment, TKM-HBV, is already in a Phase I trial, and a Phase I trial of OCB-030 is planned for the second half of this year. If all goes well, analysts expect the company to start its first study combining TKM-HBV and OCB-030 next year.
As trials begin to roll out, Sofia expects to see a transformation in how HBV is treated. “HBV is where HCV was about 12 years ago,” he says. “You can imagine a stepwise scenario like you saw in HCV where new therapies improve cure rates, then reduce duration of therapy, and ultimately get to the point where we all want to be—an all-oral, combination therapy with a high cure rate.”
Sofia would like to be a part of finding that cure. Still, he knows he’s the rare medicinal chemist to have even one cure under his belt. “Sofosbuvir is a hard act to follow,” he says.