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EASL 2016: $300 Hepatitis C Combination with Ravidasvir to Enter Clinical Trials


The Drugs for Neglected Diseases Initiative (DNDi) is launching clinical trials in Thailand and Malaysia to test a combination of sofosbuvir and ravidasvir, an NS5A inhibitor, in at least 800 people with all genotypes of hepatitis C virus (HCV). The combination, manufactured by Egyptian company Pharco, could be made available for $300 for a course of treatment if it proves safe and effective, DNDi executive director Bernard Pécoul announced ahead of the 2016 EASL International Liver Congress this week in Barcelona. The studies will aim to test an affordable pangenotypic combination and to provide data for regulatory submission.

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Affordable pangenotypic treatment would allow many lower- and middle-income countries to treat a wide range of people with hepatitis C, without the need for genotype testing, reducing the cost of treating each patient.

Ravidasvir has already been studied in patients with genotype 4 HCV infection in Egypt, where a recently presented study showed that a combination of ravidasvir and sofosbuvir (Sovaldi) cured between 86% and 100% of treated people, according to duration of treatment and whether ribavirin was included in the regimen.

The studies in Malaysia and Thailand will test the combination in comparison with sofosbuvir and daclatasvir (Daklinza), the only currently recommended pangenotypic combination. The studies will test the combination using a public health approach, where the only criterion determining treatment eligibility will be cirrhosis status. Study participants who do not have cirrhosis will receive a 12-week course of treatment, while people with cirrhosis will receive a 24-week course.

The study will recruit people with all genotypes of HCV; genotypes 3 and 6 are particularly prevalent in both countries, "and we wanted to test in countries with a large genotype range -- and particularly 3 and 6 which are the most complex to treat," Pécoul said.

The studies will examine efficacy, safety, and pharmacokinetics of the study drugs with a view to providing clinical as well as manufacturing data for regulatory submission -- including World Health Organization (WHO) pre-qualification -- of the ravidasvir/sofosbuvir combination manufactured by Pharco.

The studies will also provide data on drug-drug interactions, in particular with antiretroviral drugs for HIV treatment. The prevalence of coinfection with HIV and HCV is high in Thailand, and these data will also be especially relevant in Brazil, Eastern Europe, and southern Europe, where coinfection is common.

Recruitment will begin in July 2016, and the 300-person Malaysian study aims to complete recruitment within 3 months, indicating that study results may become available during 2017. DNDi also hopes to study the combination in populations in South Africa and Mozambique, where HCV genotype 5 predominates.

The study forms part of a 5-year strategy for development of affordable treatments for hepatitis C launched by DNDi. The cost of hepatitis C treatment is a major barrier to curing people and eliminating hepatitis C as a public health problem. The original sofosbuvir product, Sovaldi, manufactured by Gilead Sciences, costs around $84,000 in the U.S., $53,000 in the U.K., and $27,900 in Spain (although prices paid might be considerably lower due to negotiations regarding volume).

Voluntary licensing agreements between Gilead and Indian manufacturers have resulted in very large cost reductions. A recent analysis suggests that the cost of manufacturing a combination of sofosbuvir and daclatsavir in India might fall to under $200 if order volumes continue to grow. But purchase of the Indian generic versions of the drugs is restricted to named lower-income countries, and many middle-income countries are excluded from purchasing generic versions of each drug by the terms of voluntary licensing agreements.

Malaysia and Thailand are among the many middle-income countries that are excluded from the voluntary licensing agreements that Gilead and Bristol-Myers Squibb, the intellectual property holders of sofosbuvir and daclatasvir, respectively, have concluded with generic companies. Of the up to 150 million people with chronic hepatitis C globally, approximately 75% live in middle-income countries.

Achieving widespread access to a combination regimen at less than $300 per course of treatment will require some governments to take decisions regarding which tools they can use to reduce the price of sofosbuvir. For some countries, this will be taking advantage of voluntary licenses; for others it will be use of the TRIPS-Plus provisions of international trade agreements, which allow governments to oppose patent applications or to override patents and use compulsory licenses on public health grounds.

The licensing status of ravidasvir means that it will be widely available at an affordable price. Ravidasvir was licensed to Pharco by Presidio, a San Francisco-based biotechnology company, for manufacturing in Egypt. Presidio has licensed ravidasvir separately to DNDi in a range of middle-income countries with a higher burden of hepatitis C including India, Brazil, South Africa, Thailand, Indonesia, and South Korea. DNDi also has an option to take up a license to sell the drug in higher-income countries (Europe, North America, Australasia, and Japan) starting in March 2018. No patents cover lower-income countries in Africa and Asia. Ravidasvir is licensed to other companies in North Africa, the Middle East, Russia and China.

Pharco chief executive officer Sherine Helmy told a press conference that he hopes that the price of the combination will fall by $50 a course until it reaches $150 a course in 2020. He also hinted that Pharco may have other affordable drugs in development that could be paired with ravidasvir to replace sofosbuvir.



Drugs for Neglected Diseases Initiative. Drugs for Neglected Diseases Initiativeand Pharco Pharmaceuticals to test affordable hepatitis C regimen with support of Malaysian and Thai governments. Press release. April 13, 2016.