Médecins Sans Frontières (MSF) welcomed today's approval by the US Food and Drug Administration (FDA) of a combination regimen containing a new drug, pretomanid, for the treatment of extensively drug-resistant tuberculosis (XDR-TB). As the third new drug developed for TB in over half a century, and the first to be developed as part of a ready-to-use treatment regimen, pretomanid's approval represents another potent tool for tackling difficult-to-treat drug-resistant forms of TB. MSF stressed that the drug must be made affordable to everyone who needs it, especially considering the substantial taxpayer and philanthropic contributions that went into its development.
The three-drug regimen (BPaL: bedaquiline + pretomanid + high-dose linezolid) was approved yesterday for adult patients with XDR, treatment-intolerant, or nonresponsive multidrug-resistant pulmonary TB. This new regimen could dramatically shorten treatment length to between six and nine months, greatly reduce the number of pills required, and help to increase XDR-TB cure rates from the abysmal historical figure of 34%. While the new regimen will be shorter and simpler to administer, optimism around BPaL is balanced against the need for intensive monitoring for side effects from the high doses of linezolid required. Separate clinical trials run by MSF and TB Alliance are underway to further evaluate pretomanid-containing regimens to try to identify safer future treatment options.
"The treatment of XDR-TB has been dire ever since this form of the disease was discovered," said Jay Achar, Infectious Disease Specialist and TB Medical Advisor at MSF. "Having access to effective treatment regimens will give people hope of a cure, and help programmes limit transmission of this deadly bacteria. While safer, simpler regimens are still needed, the shorter treatment duration of this novel regimen is an important step in the right direction."
Pretomanid was developed by TB Alliance, a not-for-profit organisation, funded by governments (e.g. Australia, Germany, the UK and the US) and philanthropic sources, with the expectation that the organisation would hold true to its stated mission, that they are "dedicated to the discovery, development and delivery of better, faster-acting and affordable tuberculosis drugs that are available to those who need them." In addition, TB Alliance stands to be granted a tropical disease priority review voucher (PRV)*, which it can sell for a substantial amount: PRVs have previously been sold for US$67-350 million. MSF calls for TB Alliance to use this financial reward to ensure that the drug gets registered and made available at an affordable price, faster.
"This newly approved regimen containing pretomanid could be a lifesaver for people with XDR-TB, but it's not time to celebrate yet," said Sharonann Lynch, HIV & TB Policy Advisor for MSF's Access Campaign. "The approval of this new regimen by the US FDA is just the first step. We now need pretomanid to be registered and available at an affordable price in all countries, prioritising those with the highest TB burden."
In April this year, TB Alliance granted the first license to the US pharmaceutical corporation Mylan to manufacture, register and supply pretomanid. To date, TB Alliance and Mylan have not made the price of pretomanid public. It has been estimated that generic versions of pretomanid could be produced and sold at a profit for between US$0.36 and US$1.14 per day.The lowest global prices for the other two drugs in the regimen, bedaquiline and linezolid, already run at around US$3 per day; people needing this treatment regimen would have to take it for between six and nine months, amounting to a total price of US$548 to US$776, before considering the additional price of pretomanid. MSF has called for treatment of drug-resistant TB to be no higher than US$500 per person for a complete treatment course.
But four months on, neither Mylan nor TB Alliance has made the licensing agreement public, despite calls from civil society for transparency on the terms and conditions that will ultimately impact people's access to this drug globally. Mylan is expected to bring pretomanid to market by January 2020. However, this is dependent on World Health Organization guidance on using the drug, and on Mylan filing for registration in countries with the highest DR-TB burden.
"TB Alliance and Mylan must not squander this opportunity. They must make good on TB Alliance's mandate to deliver affordable treatment – which is why they received the support of government and philanthropic funding that went into the development of pretomanid and this combination – and provide the drug at an affordable price because when it comes to people with resistant forms of TB, it's a matter of life or death," said Lynch.
Pretomanid is part of the same class of drugs (nitroimidazoles) as delamanid—one of the two other newer TB drugs approved in the last half century—developed by pharmaceutical corporation Otsuka. Delamanid is fraught with access issues: the drug is patented in many countries until 2023, including in India, and the price of a six-month treatment course remains very high (the lowest global price is US$1,700), with many people needing the drug for up to 20 months, taking the price much higher. If pretomanid is affordable compared to delamanid, it has the important potential to spark competition and reduce prices for this class of drugs.
*Priority Review Voucher (PRV)
Under the neglected disease priority review voucher (PRV) program, when the FDA approves an eligible neglected disease product—a medicine or vaccine—the developer is awarded a PRV. This voucher can then be used to accelerate the FDA review of any of the developer's drugs or vaccines. Alternatively, the developer can choose to sell their voucher to another entity, as has been done previously for as much as US$350 million.
TB is an ancient disease and is the number one infectious disease killer worldwide, with 95% of deaths in developing countries. The TB epidemic is exacerbated by the rise of drug-resistant TB (DR-TB), which in 2014 was declared by the World Health Organization (WHO) as a global health emergency. An estimated 558,000 people developed DR-TB in 2017. Highly resistant forms of the disease are particularly hard to treat: in 2015 only 34% of people with extensively drug-resistant TB (XDR-TB) were successfully treated.
Currently, WHO recommends 18-20 months of treatment for DR-TB with four-drug regimens that combine bedaquiline and linezolid with older and repurposed TB drugs. Unfortunately, despite updated WHO recommendations, many countries have not implemented these new recommendations, and patients continue to receive old and toxic regimens, containing injectable agents that lead to severe side effects. BPaL (bedaquiline + pretomanid + high-dose linezolid), a shorter and simpler regimen, could therefore substantially improve the treatment of XDR-TB.
MSF and tuberculosis
MSF has been involved in TB care for 30 years, often working alongside national health authorities to treat people in a wide variety of settings, including chronic conflict zones, urban slums, prisons, refugee camps, and rural areas. In 2018, MSF provided TB treatment to 19,400 people, including 2,840 people with drug-resistant forms of TB. As of September 2018, across MSF projects in 14 countries, more than 2,000 people have been treated with the other newer drugs, including 633 with delamanid, 1,530 with bedaquiline, and 227 with a combination of both medicines.
MSF and BPaL
In addition to providing DR-TB treatment in various settings, MSF is conducting research together with partner organisations to develop the evidence base for the therapeutic value of newer DR-TB treatments. In 2017, MSF launched the TB PRACTECALtrial (ClinicalTrials.gov Identifier: NCT02589782), a randomised, controlled, multicentre, Phase II/III adaptive trial to evaluate the safety and efficacy of six-month regimens that contain bedaquiline, pretomanid and linezolid (standard dose) with or without moxifloxacin or clofazimine, for the treatment of adolescents and adults with multidrug-resistant (MDR)-TB or XDR-TB. This trial should help inform which combinations of bedaquiline, linezolid and pretomanid-based regimens are effective and safe for the treatment of MDR-TB. The trial is sponsored by MSF and is being conducted in seven sites in Belarus, South Africa and Uzbekistan. Outcomes from this trial are expected in early 2022.