New antiviral medications from Gilead Sciences Inc. and Bristol-Myers Squibb Co. have transformed the way hepatitis C is treated, making it a curable disease. Treatment regimens combining Bristol-Myers’ Daklinza with Gilead’s Sovaldi were approved by European authorities as effective against most strains of the hepatitis C virus, but a combination pill can’t be manufactured because the two companies haven’t collaborated on making one.
In 2001, before India started recognizing product patents, Cipla Ltd revolutionized the treatment of HIV by making the first pill that combined three different therapies, patented by three different western drug makers. Now, generic drug makers in India are working on a one-pill cocktail of the ingredients in Daklinza and Sovaldi that could compete with blockbuster Gilead drugs.
“For sure, in India, it can happen," said Dharmesh Shah, managing director of Mumbai-based BDR Pharmaceuticals International Pvt. Ltd, one of the Indian companies in early stages of researching such a pill. “If one can circumvent on the individual product patents, and with a proper regulatory approval, for sure the combination can come in."
Patent applications in India for Sovaldi, also known as sofosbuvir, and Daklinza, also known as daclatasvir, are being challenged by groups of patients, lawyers and scientists. Decisions on whether Indian patents will be awarded to the two US companies are pending. If they don’t win patents, it would pave the way for Indian generics and combination pills.
India’s patent office has rejected patents for drugs including Novartis AG’s cancer treatment Gleevec and Roche Holding AG’s HIV treatment Valcyte. In 2012, an Indian patent appeals board revoked patent protection for Roche’s hepatitis C injection Pegasys. The patent office didn’t answer calls seeking comment.
If the patent challenges on the Gilead and Bristol-Myers drugs fail, Indian companies would need to win licences to copy the patented drugs and combine them. Bristol-Myers is in advanced discussions with Indian drug makers for licences to make and sell generic daclatasvir in 90 countries, spokesman Rob Perry said via e-mail. The intended agreements would allow the development of combination medicines if the licensee has rights to other drugs, Perry wrote.
Gilead last year licensed 11 generic drug makers including Hetero Labs Ltd, Cipla and Aurobindo Pharma Ltd to make and sell generic sofosbuvir in 101 developing countries. Those agreements also allow the development of combination medicines with other companies’ drugs, Cara Miller, a Gilead spokeswoman, wrote by e-mail. Spokespeople for Cipla, Hetero and Aurobindo didn’t respond to e-mails seeking comment.
There are six common strains of hepatitis C. Genotype 1 is the most common hepatitis C strain, accounting for 46% of cases. That’s followed by genotype 3, which is more common in India and Southeast Asia and infects almost one-third of patients globally.
The European Commission in August last year approved Daklinza for use in combination therapy across genotypes 1, 2, 3 and 4, which together account for 94% of the world’s hepatitis C cases—meaning that a combined regimen could be effective in a wide swath of patients.
The World Health Organization (WHO) in May put the Gilead and Bristol-Myers treatments on its essential medicines list, which guides governments on what drugs to make widely available.
“Evidence continues to accumulate that of the existing regimens, sofosbuvir + daclatasvir provides the broadest genotypic coverage," wrote Stefan Wiktor, leader of WHO’s Global Hepatitis Program in Geneva, in an e-mail, referring to Sovaldi and Daklinza by their generic names. Because the combination works across different strains of the hepatitis C virus it is well-suited to low-income countries where genotype testing isn’t available, he said.
Combination therapy is key for HIV, malaria and tuberculosis, as well as chronic conditions like diabetes because it improves patient adherence, according to the WHO. Such pills also simplify distribution, making them useful to poor countries. Also, the cost of a fixed-dose combination pill can be less than that of the separate products.
Founded in 2003, BDR supplies low-priced generic versions of expensive drugs and bulk ingredients in India and other developing countries. To decide whether to pursue the hepatitis C combination product, Shah is closely watching for decisions from the Indian patent office. BDR isn’t licensed to make either drug at this time. The first regulatory filings by Indian companies for the combo pill “should happen in the very near future," Shah said.
Making a new fixed dose combination requires tests to prove it is chemically stable, studies to show ingredients work the same way as the original drug, and possibly also human trials if Indian regulators ask for them.
Gilead’s own blockbuster combo pill, Harvoni, combines sofosbuvir and another drug it developed. Harvoni, approved last year by the US Food and Drug Administration for genotype 1, was Gilead’s best-selling medicine in the quarter ended June with sales of $3.6 billion.
FDA approved daclatasvir for use in combination with Sovaldi to treat genotype 3 infections in July. The combination is also being reviewed on a priority basis by the FDA to treat patients co-infected with HIV, advanced cirrhosis of the liver and post-transplant patients.
Gilead and Bristol-Myers didn’t hold late-stage trials of the combination, however, because Gilead decided to pursue Harvoni, which combined its own drugs, believing it could bring it to market faster than a medicine requiring inter-company collaboration. After Gilead’s Sovaldi was approved by regulators, Bristol-Myers did late-stage human trials of its drug in combination regimens with Sovaldi to secure approvals in the US and Europe.
Gilead is also working on a new experimental drug combination that showed high cure rates across multiple hepatitis C strains in four final stage trials. Gilead spokeswoman Cara Miller in an e-mailed response to questions said it will file that combination with US regulators by the end of the year, then apply for inclusion on the WHO essential medicine list and work as quickly as possible to register it in developing countries.
Gilead’s license agreements allowing Indian generic drug makers to make and sell generic Sovaldi also give them the rights to make the experimental combination pill it is studying now.
In Bangladesh, which isn’t required under a World Trade Organization agreement to recognize pharmaceutical patents, Incepta Pharmaceuticals Ltd is interested in developing a generic of Gilead’s experimental combination, as well as a generic pill combining sofosbuvir and daclatasvir, said Ehsan Aziz, general manager of marketing, in an e-mail. Bloomberg