FDA Approves New Treatment For Drug-Resistant TB; Activists Call For Affordable Access

The US Food and Drug Administration (FDA) last week approved a tuberculosis (TB) treatment regimen containing a new drug, pretomanid, offering a shorter, more effective course of treatment for highly drug-resistant strains of TB, the world’s leading cause of death by infectious disease.

Pretomanid is only the third TB drug to be approved in over 50 years, and amidst the excitement from achieving this milestone, activists are calling for the developer and newly licensed producer of pretomanid to ensure that those most in need of the treatment will be able to access it.

“This newly approved regimen containing pretomanid could be a lifesaver for people with XDR-TB [extensively drug-resistant TB], but it’s not time to celebrate yet,” said Sharonann Lynch, HIV & TB Policy Advisor for Médecins Sans Frontières’ (MSF/Doctors Without Borders) 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.”

José Luis Castro, Executive Director of the International Union Against Tuberculosis and Lung Disease (The Union), commented: “The Union welcomes a new shorter all-oral regimen for XDR-TB… and we emphasise the need that it will be affordable and made available to National TB Programmes to adopt and scale up to offer effective treatment options to people with this severe form of TB.”

Drug-resistant tuberculosis patient in Mumbai, India. Photo: MSF/Atul Loke/Panos Pictures

Unlike the two other new drugs in the TB arsenal, bedaquiline and delamanid, pretomanid is the first FDA-approved TB drug to be developed and registered by a non-profit organisation, the TB Alliance.

In 2000, resistance to decades-old front-line TB drugs was becoming increasingly common, yet there were no new antibiotics in the TB development pipeline. In response to this global gap in research and development (R&D), the TB Alliance was formed as a product development partnership (PDP) dedicated to “the discovery, development, and delivery of better, faster-acting and affordable tuberculosis drugs that are available to those who need them.”

After almost 2 decades and 19 clinical trials in 14 countries, pretomanid is the first TB treatment the Alliance has successfully registered with the FDA.

Mylan, a US based pharmaceutical corporation, was granted the first license to produce, register, and supply pretomanid in April 2019. Mylan is expected to bring the drug to market by as early as January 2020, pending anticipated guidance from the World Health Organization on the new treatment regimen.

A Potentially Game-Changing New Treatment

Pretomanid is listed to be given in a 3-drug regimen known as BPaL (bedaquiline + pretomanid + high dose linezolid) based on results from the landmark Nix-TB trial in South Africa.

Although the trial only enrolled 109 participants, results showed unprecedented cure rates of 89 percent in patients with extensively drug resistant tuberculosis (XDR-TB), representing a significantly higher success rate than the historical 34 percent cure rate.

The newly approved regimen is also much shorter and easier to administer – the 6-month treatment course consists of only 5 daily pills, taken orally.

Dr. Madhukar Pai, a TB expert and advisor for TB Alliance, explained in a recent article that patients often struggle to complete their full courses of therapy for XDR-TB due to drug toxicity and the long length of treatment.

Existing treatment regimens for XDR-TB require 6-8 drugs, administered both orally and intravenously, taken for up to 2 years. The intravenous drugs can cause serious side effects such as vertigo, deafness, and visual or auditory hallucinations, and patients can be required to take up to 40 pills a day.

While there are still concerns about contraindications from the high doses of linezolid required in the new BPaL treatment course, this shorter, simpler regimen holds promise for significantly improving adherence to treatment, quality of life while on treatment, and chance of complete cure.

More studies to test whether BPaL’s treatment efficacy can be maintained at lower doses of linezolid are underway.

Questions Around Treatment Access Remain

A number of TB stakeholders are cautiously optimistic about BPaL’s approval, claiming that the drug regimen means little if it cannot be delivered to patients in need.

Historically, there have been challenges in bringing new TB tools to scale. One of the necessary drugs in the newly approved BPaL regimen, bedaquiline, was approved for use against MDR-TB in 2012, yet MSF estimates that only 20 percent of people who require the drug are able to access it.

Bedaquiline remains priced out of reach for many people in low- and middle-income countries, and a number of high-TB burden countries have not yet registered the drug to allow importation and distribution.

MSF has been advocating for Janssen Pharmaceuticals, the only producer of bedaquiline, to halve the price of the drug to US$ 1 a day. They have recommended that the price for a 6-month course of BPaL be no more than US$ 500 per person.

Mylan has yet to release its launch price for pretomanid in low- and middle-income countries, and they hold exclusive rights for producing the drug until November 2020.

However, Daniel Everitt, VP and senior medical officer at the TB Alliance, says: “In all of the lower-income countries, [TB Alliance] will be encouraging other manufacturers, generic manufacturers, to get into the market — to get competition to drive down the price as well.”

TB Alliance is also poised to receive a Priority Review Voucher (PRV) as a reward for developing pretomanid. PRVs can be sold to pharmaceutical companies for as much as US$ 350 million, and activists have urged TB Alliance to apply potential profits from sale of a PRV to efforts to increase access to pretomanid.

On the regulatory side, TB experts have been calling on the WHO and high-burden countries, such as India and Russia, to develop guidelines and policies to ensure access to BPaL once it is brought to market. India has expressed interest in starting its own pretomanid trials soon.

WHO is in the process of updating existing treatment guidelines for MDR-TB which is expected to incorporate evidence on the BPaL regimen.

WHO is currently inviting health professionals, TB patients, policy makers, and other TB stakeholders to submit comments to the MDR-TB Guideline Development Group between August 8 and August 20 2019. New treatment guidelines are set to be released in late 2019.

Current Status of XDR-TB

“By the end of 2016, XDR-TB had been reported by 123 WHO Member States. Information from countries with reliable data suggests that about 6.2% of MDR-TB cases worldwide have XDR-TB. In 2016, there were an estimated 490 000 new cases of MDR-TB worldwide,” the WHO reports.

XDR-TB is highly underreported, so the true burden of disease is likely higher than official figures indicate.

Image Credits: MSF/Atul Loke/Panos Pictures.

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