$300 hepatitis C combination 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 US$300 for a course of treatment if it proves safe and effective, DNDI executive director Bernard Pécoul announced ahead of the 2016 International Liver Congress in Barcelona on Wednesday.

The studies aim to test an affordable pangenotypic combination and to provide data for regulatory submission.

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

Glossary

middle income countries

The World Bank classifies countries according to their income: low, lower-middle, upper-middle and high. There are around 50 lower-middle income countries (mostly in Africa and Asia) and around 60 upper-middle income countries (in Africa, Eastern Europe, Asia, Latin America and the Caribbean).

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

exclusion criteria

Defines who cannot take part in a research study. Eligibility criteria may include disease type and stage, other medical conditions, previous treatment history, age, and gender. For example, many trials exclude women who are pregnant, to avoid any possible danger to a baby, or people who are taking a drug that might interact with the treatment being studied.

generic

In relation to medicines, a drug manufactured and sold without a brand name, in situations where the original manufacturer’s patent has expired or is not enforced. Generic drugs contain the same active ingredients as branded drugs, and have comparable strength, safety, efficacy and quality.

pharmacokinetics (PK)

How drugs are processed and used in the body, including how they are absorbed, metabolised, distributed and eliminated.

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 cured between 86% and 100% of people treated, 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, the only currently recommended pangenotypic combination. The studies will test the combination using a public health approach, where the only criterion determining treatment will be cirrhosis status. Study participants who do not have cirrhosis will receive a 12-week course of treatment; people with cirrhosis will receive a 24-week course of treatment. 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,” Bernard Pécoul of DNDI told aidsmap.com.

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) prequalification – 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 co-infection with HIV and hepatitis is high in Thailand and these data will also be especially relevant in Brazil, Eastern Europe and southern Europe, where co-infection is common.

Recruitment will begin in July 2016, and the 300-person Malaysian study aims to complete recruitment within three 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 genotype 5 predominates.

The study forms part of a five-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 as a public health problem. The original sofosbuvir product Sovaldi, manufactured by Gilead Sciences, costs $27,921 in Spain and $53,010 in the United Kingdom (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 the hepatitis C drugs sofosbuvir and daclatasvir, respectively, have concluded with generic companies. Of the up to 150 million people infected with chronic hepatitis C globally, approximately 75% live in middle-income countries.

Achieving widespread access to a combination 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 flexibilities contained in 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 ravidisvir means that it will be widely available at an affordable price.

Ravidasvir was licensed to Pharco by Presidio, a US-based biotechnology company, for manufacturing in Egypt. Presidio has licensed ravidasvir separately to DNDI in a broad range of middle-income countries with a higher burden of hepatitis C including India, Brazil, South Africa, Thailand, Indonesia and South Korea, and DNDI also has an option to take up a license to sell the drug in higher-income countries (Europe, North America, Australasia and Japan) from 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 Dr 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.