Where There's A Cure There's Controversy: Raymond Schinazi's Storyarticle 2

"All these controversies do not compare to what I had to go through to get to where I am today," says Professor Raymond F Schinazi, the serial academic entrepreneur who led the original group that created the cure for hepatitis C (HCV), Sovaldi (sofosbuvir), as well as many hepatitis B and HIV drugs now on the market.

In 2013, the FDA approved Sovaldi and news of the high price tag placed on it by Gilead Sciences shocked many politicians, media commentators, and patient advocates. (Also see "Gilead wins OK for Sovaldi, but $1,000-a-day price criticized" - Scrip, 7 Dec, 2013.) By association, Schinazi's scientific breakthrough was tainted with claims of pharmaceutical company greed. Dr Schinazi led the original chemistry group at Pharmasset Inc. – a company he co-founded with Dennis Liotta (a fellow chemistry professor at Emory University and co-inventor of the HIV drug emtricitabine alongside Woo-Baeg Choi and Schinazi) in 1998 – that created the precursors to Sovaldi, PSI-6130 and PSI-6206. Gilead Sciences Inc. bought Pharmasset in 2012 for $11.2bn. [See Deal]

An interview with Schinazi encompasses many topics that cannot be ignored, but equally cannot be comfortable for the Egyptian-born Italian chemist and virologist, to discuss.

Exile From Egypt

Life for the Schinazi family prior to 1962 was relatively stable in Egypt. A well-established Jewish family, originally from Livorno, Italy, they lived in the port city of Alexandria and owned three trading businesses. Then everything changed. After a day at the beach the family came home to find their house sealed, cars taken, business closed and bank accounts sequestered. The family of four were given an allowance of their own money of Egyptian £20 a week to live on, but the situation made it impossible for the family to stay in Egypt.

This may not have come as a huge shock. Earlier, in 1956, at the height of the Suez Crisis when France, the UK and Israel coordinated their attack on Egypt in an attempt to gain control of the Suez Canal and oust President Nasser from power, the Schinazi family had witnessed their French relatives thrown out of Egypt and returned to France. Bombs dropped by the British fell on nearby buildings and churches. The six-year-old Raymond learnt a lesson he still puts into practice today, never place a bed next to a window. The shattered glass from the bomb is still fresh in his mind, memories of his "little traumatic adventures" when he was still a child.

Forward to 1962, finding themselves as refugees, the family of four boarded a ship to a refugee camp in Naples. Once in Italy Schinazi's father, a "smart businessman", found work with the meat industrialist Campofrio in Spain and his son was sent to a Jewish private school called Carmel College in England, enabled by a fund that lent money to British-educated students from Egypt wishing to study in the UK. Schinazi says that he has no anger toward the Egyptian people and that he cried when he heard the news of President Nasser's death in 1970. "He was like a father figure to us, even though he had done enormous harm to my family, I was very upset; it is part of my life," he explains.

The charity that was shown to his family left a huge impression and Schinazi credits his moral obligation to create new drugs to these early experiences. However, he also discusses his Anglo-Egyptian education that may explain his unapologetically entrepreneurial nature. He recalls: "In Egypt you learn early how to negotiate and you learn how to become a businessman, in a way, and you learn to find solutions very early in life if nothing is available."

Schinazi has since gone back to Egypt, albeit 40 years after his exile, to facilitate negotiations between the Egyptian government and foreign companies, including Gilead for Sovaldi, an experience he describes as emotional. "I never worked or consulted for Gilead. I worked for humanity, I worked for my university; and in that capacity I tried to advise the Egyptians and that helped a lot," he says.

"Today they have cured HCV from over 600,000 people using generic and proprietary drugs in Egypt; they are relatively cheap but in those days it was life and death. Everybody wanted that drug, the people lined up for miles trying to get it. Every family in Egypt was affected," he explains. "That’s the irony of things, it’s remarkable. We were kicked out by the military and now I’m shaking hands with the military. Now I’m helping to cure Egyptians infected with HCV."

This situation is one that Schinazi would never have imagined as a 13-year-old boy. Once settled in Britain and flourishing at school, his dream of becoming a nuclear physicist was soon smothered and instead his attentions turned to chemistry. He attended Bath University studying chemistry at undergraduate level, followed by a PhD in organic chemistry. Frustrated by the siloed nature of the sciences department, Schinazi sought to bring chemistry, biology and pharmacology together. "I believe science is universal, it's a language, chemistry is a language. It doesn’t matter whether you speak Russian, Spanish, or Arabic, if you can draw chemical structures that's a language. I understand that language and I understand how to make medicinal compounds too." He describes his colleagues and himself at this time as "little gods". "We were synthesizing new small molecules for the first time in human history, [we were] little gods because you're creating something from scratch, and this is the beauty of chemistry. With chemistry you're creating new molecules, new bioactive entities."

However, the language of chemistry was soon left wanting and Schinazi decided to broaden his scientific horizons to enable him to apply his skills to drug development. "The glory is in the biology not in the chemistry, so that's where everything changed. I was motivated to develop something useful, there's no point in making these compounds, publishing and showing how clever you are, but no use to anybody."

He recalls a very stark lesson in the application of medicine two years before leaving Egypt. His mother (now 93 years old) suffered a miscarriage and her womb became infected with fungi. "At that point everybody thought she was going to die," he says, the family knew there was an anti-fungal drug that was available in the US, but not in Egypt, so Schinazi's grandfather managed to get a TWA pilot to buy the drug, mycostatin, in the US which was used to cure Schinazi's mother. "I said, 'Wow, this is pretty good. You have a little pill, you take it and it cures you. How wonderful, let’s do that, let's save people’s lives, that's a great thing'."

Today, Schinazi is associated with 15 New Drug Applications (NDAs), and has published more than 500 peer-reviewed papers, authored at least 100 US patents and seven books. Although his name has most recently associated with Sovaldi, as a world leader in nucleoside chemistry, Schinazi has been a pioneering influence in virology. He has founded five biotechnology companies including Pharmasset, Triangle Pharmaceuticals Inc. and Idenix Pharmaceuticals Inc. He is an inventor or has been associated with several medicines, including the HIV drugs stavudine, lamivudine and emtricitabine, and the hepatitis B treatment telbivudine. More than 94% of HIV-infected individuals in the US on combination therapy take at least one of the drugs he invented.

Success And Criticism

It is probably because of his huge success and continued commitment to work that he is able to be so candid about the criticism he has received over the funding and pricing of Sovaldi. "The bottom line is, I’m the guy who founded Pharmasset with my own credit card; I hired all the chemists, I hired all the biologists and the management including the last CEO, I had a vision and I executed the vision successfully. So, you are being criticised for doing what is really public good and saving lives."

There have been accusations that he benefitted from government funding to develop sofosbuvir while working as professor of pediatrics at Emory University (a position he has held for the past 39 years) and at the Atlanta Department of Veterans Affairs, an Emory-affiliated hospital. When Gilead Sciences bought the company he co- founded, Pharmasset, in 2012 for $11.4bn, he pocketed more than $400m. (Also see "Pharmasset soars on $11B offer, but Gilead investors disturbed" - Scrip, 21 Nov, 2011.) He claims he has never received VA or NIH funding in support of his work on HCV and disclosed his activities at Pharmasset as chairman and director to both Emory and the VA. It is mainly the rubbing together of Schinazi's public and private interests that have called into question how much civic time and money went into developing blockbuster drugs that some members of the public simply cannot afford without health insurance coverage.

Batting away the controversy, Schinazi simply puts the claims down to jealousy and on people who came to the party late and claimed the success as their own. The fact is that without Pharmasset, there would be no Sovaldi and its precursors, he says. "Without Sovaldi there would not be a high cure rate for HCV as early as 2013. Yes, there are good drugs now for HCV other than Sovaldi, but somebody had to be the pioneer."

When discussing the furore surrounding the pricing issue, he parks the issue firmly at the Gilead marketing department door. When Gilead launched Sovaldi it didn’t use the word 'cure' in campaigns, he says, and the difference between a treatment and a cure is very significant. Pricing for the latter of those options is a lot less controversial. Also, the demand for the drug was huge with many warehoused patients waiting for a "safe and highly effective drug", he says.

"When I've failed, and I’ve failed many times, I never gave up," he says. "Admittedly, Gilead may have made a mistake by charging initially about a $1,000 per pill, but the reality is that nobody has ever paid that price. It’s a misconception." Although Schinazi had no involvement in setting the pricing of Sovaldi, Gilead's pricing methodology is based on the GDP for the country and the price of similar, less effective and older HCV medicines, he says. The current HCV treatments have fallen in price, but initially they were based on the cost of interferon treatments which were painful, long (a year), rarely effective and still costly.

"And you have to amortize it," he continues. "Because even if you calculate the price of a treatment – for an innovative treatment not a generic, but something that took years and years of hard work and many failures to get to that point – I never ever imagined that we would have a drug that cures at a 95% rate. Show me one viral disease where you have a cure. It’s remarkable, for the first time in the history of humankind, you have a drug that actually cures a viral disease."

Criticism has fallen on the issue of money and disregarded accomplishment, he says, adding that he did not instigate the scientific research into sofosbuvir and its precursors with the intention of making money for himself and the pharma industry. His sole mission and his drive was focused on finding a cure of HCV since this virus has no latent phase and can be eradicated, he continues. Although he does well to shrug off the connection to corporate greed, he is also keen to highlight his numerous accomplishments in HIV, HBV and HCV.

Finding A Cure

It is not just HCV that Schinazi is connected with, of course, but also his pioneering scientific breakthroughs in HIV. He is positive that finding a cure for HIV will happen, despite the ethical issues surrounding a process whereby a drug-stabilized patient has to stop treatment for the disease to rebound. "If you ask the patients, at least 50% of patients will say, 'I’ll take the risk, if I can get cured.' In the absence of a cure, people will take these pills forever, especially young people who have HIV," he says. "So there is a lot of dilemma at the regulatory authorities, who are very concerned about that. I think with time it will happen. People will find what is called a functional cure, this will happen, probably in my lifetime. Whether you’re going to have a sterilising cure is another story, that will take a lot of time."

In practical terms, finding a cure for hepatitis B has most recently taken up a lot of Schinazi's time. HBV affects more people than HIV and HCV combined, around 450 million people globally. “We need to keep our laboratory running with all the young bright minds and future leaders and I cannot do it alone. A cure for hepatitis B; that’s huge." He admits that finding the cure for HBV will bring yet more controversies if payers are unwilling to pay for it, but this has not stopped him from his work.

Schinazi spends almost $4m a year to run his Emory laboratories, mostly from royalties from his inventions. He could have retired to play golf or go fishing, but he says he is much happier reinvesting in cures for life-threatening infections. Schinazi, at 66, has a strong drive to still cure disease, he explains, and this keeps him going. "The momentum after coming out of Egypt, this momentum drove me to become who and what I am and I think this is important to have drive, to be enthusiastic and be passionate about what you want to do. There is nothing better than saving lives, and when you get a letter from a patient, out of the blue, thanking you for what you’ve done, it’s so gratifying. I respond to every single one of them.”

Maybe the FDA approval of Sovaldi, emtricitabine and lamivudine will not be Schinazi's lasting legacy, but cures for HIV or HBV infections will be significantly more challenging. As it stands, he has no plans to retire, he's having too much fun, he chuckles. "I have about 50 people doing research in my group. I have beautiful young minds working and they're motivated and I’m in relatively good health and there is no reason for me not to continue doing what I love so long as I have worthwhile ideas."