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The story of a ‘political drug’ against hepatitis C

Huang Siang Ping, a farmer from Penang Island, Malaysia who participated in the STORM-C1 trial, which cured him of hepatitis C. He is one of the protagonists featured in a mini-documentary filmed in Malaysia by DNDi. (Credits: DNDi/Abang Amirrul Hadi)

Malaysia, along with several Geneva-based NGOs, has developed a new antiviral drug for hepatitis C, ravidasvir. For the Drugs for Neglected Diseases initiative (DNDi), which initiated the project, the objective was clearly political: to bring down the price of the drug in a market dominated by molecules that were at the time unaffordable. Dr. François Bompart, director of the hepatitis C initiative at DNDi from 2018 to 2020, where he is now in charge of access to medicines, shares the story in a Q&A.

Heidi.news - How did this drug, ravidasvir, come about?

François Bompart - It goes back to around 2013. At that time, sofosbuvir, a new drug against hepatitis C produced by Gilead, was introduced. From a medical point of view, it was a revolution: the virus was totally suppressed, and patients were cured, with a very well-tolerated treatment and over a very short period of time, from three to six months. But this drug was sold at around 80,000 dollars per patient, a price that was unheard of at the time. It was like a lightning strike, which really caused a scandal.

And that's why DNDi started developing a competing drug.

We asked ourselves what we could do about it, from an activist perspective. DNDi's R&D director at the time (Dr. Shing Chang, ed.) went looking for interesting molecules and identified ravidasvir, produced by a Californian biotech company called Presidio. We entered into an agreement with them and an Egyptian pharmaceutical company (Pharco) to develop the drug, on the condition that it would be made available at a low price to middle-income countries. That is, those who are not rich enough to pay the price of industrialised countries, and not "poor" enough to benefit from voluntary licensing agreements.

F Bompart Dec 2018_recadré.jpg
Dr François Bompart spent most of his career at Sanofi, where he was in charge of access to medicines. He joined DNDi in 2016, where he works on the same issues but on the NGO side. (Rights reserved/Courtesy)

What was the point of Presidio selling its drug at a modest price?

At the time, they were only at the stage of small studies on healthy volunteers, so they were happy that we were interested in them and that we were helping them develop the drug. The market for direct-acting antivirals against hepatitis C turned out not to be as lucrative as some people had initially thought, which makes it difficult to raise money. They also retained the rights for industrialised countries, in Western Europe and North America, so it's still interesting for them.

That's where Malaysia comes in?

Yes, that's right. Malaysia was attractive to us because it was a country that had a real political will to tackle hepatitis C. It must also be said that they have approximately 400,000 sick people there (1.25 per cent of the population, ed.). The big problem with this disease is that there are very few political decision-makers, let alone financial decision-makers, who are sensitive to it. In Malaysia, the important decision-makers are getting involved. They also have a well-developed health system and good scientists. We approached them when they were in the process of designing a national hepatitis C strategy.


Several Geneva-based NGOs were also involved in the project...

Yes, DNDi set up this clinical trial in partnership with the Malaysian government, with funding from MSF. Diagnosing hepatitis is a cumbersome, three-step process that requires money and staff, with the risk of losing many patients. With the help of the NGO Find, our alter ego for diagnosis, Malaysia was able to move diagnosis from large teaching hospitals to local frontline hospitals. And this work was funded by Unitaid, also based in Geneva. It all synergized together.

Timeline

  • 2013-2014: the U.S. drug company launches sofosbuvir (Sovaldi), the first direct-acting antiviral against hepatitis Co.

  • 2016: DNDi launches trials to develop ravidasvir, a competing antiviral to sofosbuvir.

  • 2017: A standoff between Malaysia and Gilead allows Kuala Lumpur to lower the price of sofosbuvir from the negotiated floor price of $12,000 to $300, by issuing a compulsory license

  • June 2017: completion of the ravidasvir-sofosbuvir clinical trial (phase 2-3) in Malaysia

  • 2021: publication of ravidasvir results in the Lancet


In 2016, you found yourself developing ravidasvir in Malaysia... in combination with Gilead's sofosbuvir, your initial target. Why did you make this choice?

For scientific reasons. You always need two molecules with different viral targets to treat hepatitis C, a bit like anti-HIV “cocktails”. We looked at all the compatible antivirals and the unanimous conclusion was that the sofosbuvir was the best, and it was already fully developed so we were reassured about the safety profile and the dose to be given. This gave us the best chance of developing our drug successfully.

How did this somewhat unnatural marriage work out? Did you go knocking on Gilead's door?

I believe there have been informal contacts with Gilead, which have not led to anything.  But since we were in the framework of a clinical trial, we could acquire the molecule via generic manufacturers, without going through the license holder. This is what we did, by going through the Egyptian laboratory, Pharco, to obtain the drug.

This was also the context of a 2017 standoff between Malaysia and Gilead over the price of sofosbuvir - which Kuala Lumpur won.

There are regulations in international agreements that in the event of a health emergency, a government can impose the temporary lifting of patents. Malaysia has announced its intention to buy sofosbuvir from a generic company without Gilead's approval. This is an indirect effect of DNDi's presence, of R&D work and advocacy around hepatitis C. All of this made Malaysia consider it important enough to dare playing the compulsory license trick.

In response to this announcement, the company abruptly decided to grant a voluntary license to Malaysia - as well as to Thailand, Belarus and Ukraine, where trials were also planned. In Malaysia, this resulted in a reduction in the cost of sofosbuvir treatment from $12,000 to $300 per patient.

The results of the ravidasvir-sofosbuvir trial have just been published in the Lancet. What about it?

Yes, it was a trial on 300 patients that gave very high cure rates, in the order of 97 per cent. There are also interesting results in patients co-infected with HIV. We still have to be careful, it's early in the life of the drug. But we think it is a little better than the reference treatment currently used in Malaysia in patients with genotype 3, the most difficult to treat. This represents half of the patients in the country, which has just granted conditional approval for the treatment.

What is your assessment of this effort?

At DNDi, we usually work on drugs that do not yet exist because there is no market for them. This was not the case there: at most, one could say that the world did not need a new hepatitis C drug. We invested to challenge the status quo, with the hope that ravidasvir would demonstrate some clinical superiority. It's too early to tell, but it gave us the legitimacy to put the issue of antiviral pricing on the table. Fundamentally, it's a political drug.


Box: Expensive antivirals for hepatitis C

When not cured spontaneously, hepatitis C can degenerate over decades, causing cirrhosis and liver cancer. It affects an average of 1 per cent of the population worldwide. The arrival of direct-acting antivirals from the end of 2013 turned the management of this viral disease on its head, making it finally curable. Currently, the market is dominated by two American laboratories: Gilead and Abbvie. In Switzerland, a treatment against hepatitis C (a combination of two antiviral drugs for three months) costs about 30,000 francs per person —reimbursed by the health insurance without restriction, but only since 2017.


Box: Voluntary or compulsory license, what’s that about?

The use of a drug falls under the intellectual property regime. In order to obtain a generic drug, which is less expensive, countries must get the explicit agreement of the patent holder via a so-called voluntary licensing scheme. This leaves the patent holder free to set whatever conditions it wishes, or even to refuse to enter into the agreement. This is sometimes the case for middle-income countries.

To get around this problem, a system of compulsory licenses was set up in the wake of the 2001 Doha Declaration. It allows a generic drug to be used without the agreement of the original patent holder in the event of a public health emergency. But using this tool has a political cost. Industrialised countries, particularly the United States, tend to fiercely defend the interests of their pharmaceutical industry if they feel that these are threatened.


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This article was originally published in French on Heidi.news and was translated by Tess Barbey