Tests on new TB drugs have not yet been completed and some results have been worrying.
Tuberculosis is a disease of the poor: today, 95% of global cases occur in low- and middle-income countries. Without a profit incentive, the impetus for companies to make new drugs is small, leaving patients and doctors with few good treatment options.
But with the rise of multidrug-resistant (MDR) TB, which has a mortality rate of nearly 80% and is about 100 times more expensive to treat than “ordinary” TB, new treatments are needed more than ever.
Now, after a decades-long dry spell, two new medicines are finally coming on to the scene. Phase II studies, which demonstrate safety and effectiveness in a small group of people, show that bedaquiline, produced by the Belgium pharmaceutical company Janssen, and delamanid, produced by the Japanese drug firm Otsuka, may be significantly better at clearing the TB bacterium from MDR TB patients' sputum when compared with the current treatment — and in just a quarter of the time.
“This is potentially revolutionary," says Gilles van Cutsem, medical co-ordinator for Médicines sans Frontières (MSF) in South Africa and Lesotho. “To treat someone with more effective drugs, and faster, would radically change things."
The two companies, along with advocacy groups, governments and doctors, are doing their best to get the pills to those who need them.
Last year, Janssen requested so-called “accelerated approval” for bedaquiline in MDR TB patients from the American Food and Drug Administration (FDA), and “conditional marketing approval” from the European Medicines Agency (EMA). Both allow approval and use based on promising phase II trial results. However, phase III studies, which further confirm safety and effectiveness in a larger group of people and which are normally required for approval, must still be conducted.
In December 2012, the FDA granted accelerated approval for bedaquiline. Although this only allows bedaquiline to be sold in the United States, it could provide an impetus for early approval to be granted in other countries as well. Already a few South African patients with extensively drug-resistant (XDR) TB, an extremely deadly form of the disease for which there is even less treatment than MDR TB, have received bedaquiline. Others will receive it later this year because of an expanded access programme. This was approved by South Africa’s Medicines Control Council (MCC) within days of FDA accelerated approval. The World Health Organisation (WHO) posits that the MCC may approve bedaquiline by the end of this year.
But Janssen's submission to the FDA did include some worrying data. In one study of bedaquiline, 10 patients who received the drug on top of a normal course of MDR TB treatment died, versus only two who died who had received normal treatment. Considering the relatively high mortality data and citing safety concerns, an American advocacy group, Public Citizen, condemned the FDA approval.
It’s too early to tell whether this data is a real cause for concern or simply a fluke, says Andreas Diacon, a professor at Stellenbosch University’s department of biomedical sciences.
Diacon oversaw bedaquiline phase II trials and is now responsible for delamanid phase III trials at Cape Town’s Brooklyn Chest Hospital for TB patients. He also presented evidence at the FDA hearing.
“It's impossible to find some common denominator [for] all the patients that died. “Some … died from TB …one of them fell out of a window, another one died in a car accident, another one was an alcoholic who died from an alcohol-related disease … There's no pattern that would let one think that there's something that the drug is doing.”
Diacon says that the small sample size included in a phase II study makes it impossible to look for trends. Phase III trials, just getting under way, will help to expose a potential pattern of death or illness connected to the drug, if there is one.
Van Cutsem still sees the drug as hugely promising, especially in light of the dismal outcomes that patients’ face today. “If I had the choice of dying of MDR TB or taking bedaquiline, I would take bedaquiline, definitely.
“These people have a 20% chance of survival without bedaquiline. There's nothing in bedaquiline that can make those odds worse,” he says.
Potentially at fault is the drug's effect on patients' QT interval, or the time between heartbeats: bedaquiline has been shown to lengthen the interval, which could, in theory, lead to a heart attack. Studies have shown that delamanid may also affect patients’ QT interval, a worrying fact given that doctors are hoping to use the two new drugs together.
Currently all forms of TB, drug-resistant and otherwise, are treated using many drugs together. Whether using bedaquiline and delamanid in conjunction will add, multiply or have no impact on QT prolongation is not yet known.
Van Cutsem says more research is needed to understand how the drugs should be used in real life.
“We have these new drugs, which are potentially incredible … but we don’t know how to use them,” he says.
No studies on drug-to-drug interactions between bedaquiline and delamanid have been done, but both companies are co-operating with the American government’s National Institutes of Health, which will conduct a drug-to-drug interaction study later this year.
Additionally, both have been tested with some of the most commonly used antiretrovirals in treating HIV, with no seriously harmful interactions found.
The WHO is expected to release guidelines on bedaquiline use in the first half of this year.
But the MSF warns that, even with more data and guidelines, there’s no guarantee that South African patients will benefit from the drugs.
Neither Janssen nor Otsuka has submitted a public price for their medicines. An American price for bedaquiline is expected when it comes on the market in the US in March, but Otsuka will not give a price unless it is granted approval by the EMA.
The cost of new drugs is a major concern. Linezolid, an antibiotic that has been shown to be effective in treating drug-resistant TB, is R282 a pill in the public sector and R593 a pill in the private sector.
Patients require one pill a day for at least six months. Generic versions of the medicine are available for as little as R10 a pill in India but a patent granted in South Africa bars them from being marketed here.
“This isn’t just about bedaquiline or delamanid; this is about getting new TB drugs to patients who need them,” says Oliver Moldenhauer of the MSF’s access campaign, who advocates for generic production of the new medicines in low- and middle-income countries.
“Having them come on the market isn’t a wonder solution but it is a big step forward."
Priority review - does it work?
Beginning in the 1990s— at the height of the HIV crisis, when few drugs were available— the FDA instituted several programmes that allow for expedited approval of potentially important new medicines.
Once such programme is accelerated approval, which was granted to Janssen for bedaquiline. In many regards, the programmes have been a success, allowing for several important HIV medicines to come onto market months to years earlier than expected.
But the US government accounting office, responsible for oversight of government agencies, has also found that the accelerated approval system is open to abuse, citing cases of companies who do not finish phase III trials, as required, going unpunished. While the programme is in part designed to allow for patients and doctors to advocate for the drugs they need most, there have been cases of patient advocates pushing for early registration of medicines that turn out to be ineffective, or worse, harmful, and/or rallying against FDA attempts to revoke approval on the basis of poor data.
Utilising new models to create TB drugs
The FDA voucher system was instituted in 2007 under former president George W. Bush, and allows for a company who has gained approval for a neglected disease drug to put forward a separate drug of their choice for priority review.
Priority review is normally saved for medicines that offer major advances in treatment, or provide a treatment where no adequate therapy exists, and cuts time to approval by nearly half. A 2006 paper published in the journal Health Affairs suggested that the system also be used to reward companies who had invested in otherwise unprofitable drugs, and two US senators subsequently suggested legislation in the hopes that it would incentivise new drug development for neglected diseases.
Janssen insists that the FDA voucher system did not impact their work on bedaquiline, given that research on the drug started nearly a decade ago, long before the voucher system came to play. But the company does stand to benefit from early approval of the drug: they have now received the voucher for priority review of a drug of their choice years before if they had waited to submit phase III data for normal regularity approval.
Janssen says that it has not yet decided which drug it will put forth for priority review as part of the voucher system.
The voucher is part of a trend of creative “push” and “pull” mechanisms that help to incentivize or reward drug and diagnostic development that may not otherwise occur. Increasingly, such programmes require partnership between several sectors, including government, private companies, nonprofit organisations, foundations, and academia.
Such collaboration has been essential for TB drug development. For example, while bedaquiline will be marketed by Janssen for treatment of MDR-TB, the TB Alliance is bringing the drug forward for drug-sensitive (DS) TB.
The alliance is a product development partnership—a non-profit organisation that brings together public and private resources—and is currently responsible for managing 20 projects, including those investigating new drug candidates and new TB treatment regimens.
Because of its connection with multiple drug producers, the group is able to test new compounds in conjunction with one another to make sure that there are no adverse effects, and to see which drugs work best in combination, a process that rarely happens if left up to the companies alone.
PDPs are becoming increasingly popular, with over 140 drugs, diagnostic, and vaccine projects taking place under the guise of such programmes worldwide.
Shyam Goswami contributed research and reporting for this article.
This story was produced with the support of the Open Society Foundation. Details of the drug regulatory process and incentives for neglected diseases, see mg.co.za/health