ANTI VIRALS THAT CONTROL HIV AND CURE HEPATITIS C

Raymond Schinazi The doctor who oversaw the development of two anti-viral drugs that help control HIV and a medication that cures hepatitis C, is a Jew and was born in Alexandria Egypt. When Israel and Egypt fought a war in 1956, Egyptian Jews became personae non grata, and his family moved to Italy. He later studied at Bath in the UK. “As a student he lived on 100 English pounds a month, worked as a parking attendant to help pay his way, and didn’t have real money in his pocket until he won 3000 pounds in the Spanish lottery.” After receiving his British degree he did his post doc work in Yale and spent three years making “chemicals similar to Nucleosides.”

Nucleotides "can be thought of as nucleosides without a phosphate group."

DNA and RNA are strings of 4 nucleotides.

In the right circumstances nucleosides enter a cell--an enzyme adds a phosphorous to the molecule-- and it becomes a nucleotide.

Described as a “bear-sized man who speaks bluntly, negotiates fiercely, and favors splashy, multicolored shirts,” Dr Schinazi enjoyed the science but not the weather at Yale." “We had two really cold winters in a row in New Haven, with tons and tons of snow.”

When the world learned HIV was caused by a virus, Schinazi was a professor of Pediatrics at the VA hospital in Atlanta. As he explained (in interviews) he “couldn’t just sit around and do nothing. He wanted to attack the virus with nucleoside analogues and the VA resisted. Eventually Schinazi helped develop two of the more significant anti HIV drugs and made sure Emory University profited from the sale of the medications.

As Shinazi explained in an interview, after leaving England he came to the United States and “worked with Bill Prusoff at Yale."

Considered by some as the father of antiviral chemotherapy, William H. Prusoff (Bill) spent most of his career studying analogs of thymidine, a nucleoside building block of DNA, with an eye toward developing therapeutic agents. In the late 1950s, he synthesized one of the first thymidine analogs, 5-iododeoxyuridine and Professor Herbert E. Kaufman found that the compound disrupted the ability of the virus to reproduce and was an effective topical treatment for herpes virus keratitis.

At one point Shinazi asked Maurice Hilleman, one of the giants in vaccinology, if he had a position at Merck in the field of anti-virals but there wasn't a position for him.

"Pharma, Shinazi explained, wanted people who were chemists to stay in chemistry, biology to stay in biology, virology to stay in virology. They didn't intermix disciplines." Shinazi considered himself a chemist, who wanted to be a biologist, who wanted to become a virologist, who wanted to become a pharmacologist, who wanted to become a biochemist.

"I was a bit out of the box at the time, and I felt that for me academia would be best. When HIV came along, I was actually in a clinic. My lab was next door to HIV patients and you could see them outside the door dying slowly. That leaves a tremendous impact and motivates you to find a solution to the problem. Putting the clinical people and the PhD's side-by-side is so important.

"Pharma, he said, rarely takes risks, because they have to explain everything to management. It's what you find on the way to, sometimes. You find unexpected things. Pharma would never have discovered lamivudine (3TC) and emtricitabine (FTC)."

When he decided to tackle HIV Shinazi wondered how he could create a modified nucleoside that might interfere with the growth of HIV. Then he went to a meeting in Montreal, Québec, Canada—an International AIDS Society meeting. Dr. Bernard Belleau presented data on dioxolanes nucleosides—2 oxygen and a carbon. ” I observed that and thought, if you can make 2 Os on one 5-membered ring, why not an O and S?

"There's also a bit of serendipity in science, as you know. So, he was trying to make FTC. In other words, hook up to the base a sugar with a 5-membered ring. You do that with something called a Lewis acid."

The postdoc Shinazi worked with was a chemist from Korea. His name was Woo-Baeg Choi, and he didn't know anything about nucleoside chemistry, "which actually helped. There was one bottle on the shelf in my lab containing stannic chloride, which is a Lewis acid.

Nobody used stannic chloride then, but when he did, he got two chemicals that were 99% right enantiomers." (Enantiomers are a pair of molecules that (like a pair of hands) exist in two forms that are mirror images of one another.)

(In chemistry isomers are molecules with identical molecular formulas, the same number of atoms of each element – but distinct arrangements of atoms in space. They do not necessarily share similar chemical or physical properties.)

One enantiomer turned out to be less toxic than the other. Both were active and are still used to treat HIV."

One became emtricitabine and is sold as Emtriva^®.

The other was a chemically similar compound, 3TC (lamivudine. It is sold as Epvir^®).

Shinazi convinced Emory to patent the drugs and both drugs were sold to industry. Emory was eventually paid more than $500 million.

The drug that cures hepatitis C.

“The HCV RNA (genome) was discovered in 1989. It turned out to be a strand of 9600 RNA nucleotides in a special protein envelope. During the decade after its discovery scientists had no way of efficiently replicating the virus in lab-grown cells. Then in the late 1990s, Bartenschlager’s and Rice’s labs devised a method to make “replicons.” Replicons are fragments of the virus’s RNA that are capable of autonomously replicating in hepatoma cells. Using replicons researchers were able to screen thousands of potential drug candidates in their search for a drug that inhibited hepatitis C.

In 1998 Raymond Schinazi and Dennis Liotta formed Pharmasset a company that described itself as being a clinical stage pharmaceutical company and stated that its primary focus is "the development of oral therapeutics for the treatment of hepatitis C.

Michael Sofia, a Ph.D. in organic chemistry, was one of the company's main researchers. Before he came to Pharmasset, Sofia had been a research scientist at a number of biotech companies. Sofia was the company's senior vice President of Chemistry between 2005 and 2012.

Sofia's researcher team found a compound in their library that worked against hepatitis C. It was a 2'-fluoro-cytidine, and had a 2'-fluoro group in the down position of the pentose ring. The compound was not potent, but it gave the researchers a base. The scientists made a difluoro derivative of the nucleoside and the chemical had anti-HCV activity, but was a very weak inhibitor of the hepatitis C virus in humans. Then the group made the 2'-fluoro-2' methyl, a molecule that had never been made before. It wasn't easy to make. The compound was a cytosine, analog, a nucleoside that entered the cell. Then an enzyme added a phosphate, and the molecule became a nucleotide; a second phosphate and third phosphate were added and it became a triphosphate.---and the triphosphate inhibited the HCV polymerase."

But the compound had a flaw. It could get deaminated at the monophosphate level and become the U analog. And the researchers knew that from monkey work that the U analog is not active at all. It is totally inactive.

The drug was rescued by a brilliant biochemist by the name of Murakami, a Japanese scientist who worked at Pharmasset. He learned how the drug is metabolized in cells and found that the U analog, once it's formed, is also phosphorylated. And the end product of this phosphorylation is the active ingredient in what we know today, as sofosbuvir. It has a long half life. That's why sofosbuvir can be given once a day. And it has a good affinity for the Hepatitis C polymerase; it's very selective for that. Then the scientists made a pro-drug of the U analog and believed it would be active since they were never able to develop resistance to the cytosine analog. They made the pro-drug, and that became sofosbuvir.

Gilead bought Parmasset for $11.9 billion and in the U.S. the cost of a course of medicine that cured hepatitis C rose from $35,000 (the price Pharmasset allegedly planned to charge for a curative dose of drug) to over $80,000. There was a delay in developing the combination, but eventually the company had a combination, which today we know as Harvoni, or Epclusa.

In an interview journalist Jon Cohen asked Shinazi about “ sofosbuvir's price tag of $1000 per pill.” Shinazi answered “Gilead set the price, which he calls “obscene.” But at the same time, he blasts critics who suggest sofosbuvir's price is not “reasonable” or “rational”—and that he profited too much. “Is it fair to pay $3 for a bottle of water?” he asks. “Do you complain when you're thirsty? This is something that cures you from a disease.”

“These are fabulous drugs that work against every single genotype. And what is amazing is the need of this drug in a country like Egypt. Because 1 in 5 people in Egypt is infected with hepatitis C.

"So, here's this young man who was kicked out by Nasser, from Egypt in 1962. And, in Hawaii, I got a call from the ambassador to Egypt asking me to come to Egypt, immediately. This was before the drug was approved. It was December 2011. In February 2012, I show up in Egypt for the first time in 47 years. The people greet me—all the military people, the same people who kicked my family and I out of Egypt. And they know I'm Jewish. Of course, they want our drug. They didn't know how to approach Gilead, and so on, but we found a way for Gilead to deliver the drug to Egypt for $1,000. They were ready to pay $3,000, by the way, but we negotiated it down to $1,000. So, I helped them. And then of course, they made their own generic formulation. They have great chemists there, they actually manufacture the drug in Egypt—in Alexandria, the city I was born in. They make sofosbuvir there. They formed a whole company, a whole structure, and now they deliver the drug for $60 a cure—a cure, not a treatment. President El-Sisi, last year, invited me to Egypt for an ExCon meeting. He invited all the African leaders, all the African scientists to come to Egypt to discuss medical issues, but especially hepatitis C. And there, he offered the drug free of charge to every single African country, because he could make it very inexpensively. So, I raise my hat to him. Our own president, as you know, has just decided, earlier this year, to do the same thing, but it hasn't happened yet. There are more than 2 million people infected with hepatitis C in the United States. Egypt has come from being a red zone to where they have cured more than 5 million Egyptians of hepatitis C and rising every day. It was a lot of suffering, and every single family was affected in one way or another. And the first time I went there, as I told you, it was the military who invited me, because they had a lot of their soldiers dying of hepatitis C, and they wanted to do something about it. I don't think many people are able to say that one year, you go to Egypt to get an award, and then, the next year, you go to Israel and get another award. So, I thought it was funny that I got involved in both countries. And I'm very pro-Egypt, and I'm very pro-peace. I want both of them to live peacefully forever, if that's possible. And I think peace through health is a very important concept that we need as scientists to push forward.”

As Nobel Prize winner Joseph Stiglitz explained, patents are created for each nation’s needs. They give the inventor a monopoly for a number of years. When they are appropriately designed, they promote innovation and societal well-being. When they are not appropriately designed, people die and innovation is suppressed.

“Cairo, 8 April 2014. Preliminary examination of the patent application on sofosbuvir at the Egyptian Patent Office showed that it is unlikely to be patented. “The invention” does not satisfy the novelty and inventiveness criteria to be granted a patent. The final decision has not been issued yet; however, it is clear that sofosbuvir will not be patented in Egypt.“ Sofosbuvir “is not new” and does not merit patent protection.” (1)

“On May 9, 2016, the Indian Patent Office granted the US pharmaceutical company Gilead a patent for sofosbuvir, a direct-acting antiviral for the treatment of hepatitis C virus (HCV). . In 2014, 11 Indian generic companies signed a voluntary license agreement with Gilead for the production of the HCV medicines sofosbuvir and ledipasvir/sofosbuvir combination tablet,

"The Indian companies can supply in India and export to 100 low-income and middle income countries, potentially providing access to the products for about 100 million people living with HCV. The agreement prohibits the generic companies from supplying these drugs to a number of middle income countries which are home to more than 50 million people with HCV.”

(In an article in the New York Times Stiglitz argues that “America has attempted to foist its intellectual property regime on others through the World Trade Organization. The drug industry claims that without patent protection, there would be no incentives for research and all would suffer. I believe some patents actually impede rather than foster innovation and our policies help increase inequality abroad.” Joseph E. Stiglitz July 14, 2013 New York Times.)

April 9, 2024 According to the world health organization

Hepatitis C virus infection occurs in all WHO regions.

The highest burden of disease is in the Eastern Mediterranean Region with 12 million people chronically infected.

In the South-East Asia Region (9 million), European Region (9 million) and the Western Pacific Region (7 million) people are chronically infected.

Eight million people are chronically infected in the African Region and 5 million the Region of the Americas.

https://www.who.int/news-room/fact-sheets/detail/hepatitis-c

https://archive.nytimes.com/opinionator.blogs.nytimes.com/2013/07/14/how-intellectual-property-reinforces-inequality/?smid=pl-share

https://www.science.org/doi/full/10.1126/science.348.6235.622

https://twn.my/title2/health.info/2014/hi140402.htm

2. https://www.thelancet.com/pb/assets/raw/Lancet/pdfs/S0140673616306560.pdf

3. Fire in the Blood a movie on you tube

https://pmc.ncbi.nlm.nih.gov/articles/PMC3210744/