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Pretomanid and the BPaL Regimen

Now included in World Health Organization Guidelines for the Treatment of Drug-Resistant Tuberculosis

Pretomanid was developed by TB Alliance as an oral tablet formulation for the treatment of tuberculosis (TB) in combination with other anti-TB agents. Pretomanid is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines. Novel compounds are important in pursuing new TB treatments because resistance to drugs and drug classes currently used to treat TB is increasingly widespread. During early development, pretomanid was referred to as PA-824. Pretomanid has been clinically studied in more than 1,100 people who participated in 19 clinical trials evaluating the drug’s safety and efficacy. Pretomanid has been clinically studied in 14 countries. Today, more than 40 countries have procured more than 4,000 pretomanid treatment courses.

In August 2019, pretomanid received its first regulatory approval by the U.S. Food and Drug Administration (FDA) as part of a treatment regimen in combination with bedaquiline and linezolid, commonly called BPaL (bee-pal). The regimen was approved for the treatment of patients with highly drug-resistant TB.



Treating Drug-Resistant TB Globally

For the first time, almost all patients with DR-TB can be treated in six months with an all-oral regimen. Based on clinical evidence, the new World Health Organization (WHO) guidelines allow for the programmatic implementation of treating almost all forms of drug-resistant tuberculosis (DR-TB) with either BPaLM (a combination of bedaquiline, pretomanid, linezolid and moxifloxacin) or BPaL (bedaquiline, pretomanid and linezolid).

These updated guidelines allow for the implementation of BPaLM and BPaL regimens under programmatic conditions, stating:

  • “WHO suggests the use of a 6-month treatment regimen composed of bedaquiline, pretomanid, linezolid (600 mg) and moxifloxacin (BPaLM) rather than the 9-month or longer (18-month) regimens in MDR/RR-TB patients.”

The guidelines note that:

  • “Data from patients in relevant arms of [the TB-PRACTECAL and ZeNix trials] were used in each of the comparisons that led to the conclusions and final recommendation on the use of the BPaLM/BPaL regimen.”


Learn about Milestones throughout Pretomanid's Development

With critical support from funders, partners, and other stakeholders, TB Alliance developed pretomanid from a preclinical compound through regulatory approval. Our interactive timeline captures some of the major milestone's in the development of pretomanid and the BPaL regimen.

TB Alliance Timeline Graphic

BPaL has been aquired by more than 40 countries around the world

Use the tool on this page to find details on accessibility of pretomanid and the BPaL regimen in any country.

ZeNix Logo

#TBCourage Stories

Hear stories from patients who have been treated with the BPaL regimen around the world.

Mapalesa's Story of #TBCourage

Besik's Story of #TBCourage

Anna Christina's Story of #TBCourage

Panganai’s Story of #TBCourage

Mariia's Story of #TBCourage

Bongiswa's Story of #TBCourage

Data from TB Alliance clinical trials have supported the approval and extended use of BPaL

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BPaL was first studied in the Nix-TB Phase 3 clinical trial, which enrolled people with highly drug-resistant TB in South Africa. Nix-TB data, published in the New England Journal of Medicine, have demonstrated a successful outcome in 95 of the first 107 patients (90 percent) after six months of treatment with BPaL and six months of post-treatment follow-up. For two patients, treatment was extended to nine months. BPaL has been tested in DR-TB patients co-infected with HIV, including those receiving antiretrovirals (ARVs), and similar outcomes were reported in participants based on HIV status.

ZeNix Logo

The ZeNix Phase 3 clinical trial assessed six months of BPaL for treating people with highly drug-resistant TB while reducing the dosage and/or duration of linezolid. Results of the trial, published in the New England Journal of Medicine, demonstrated that the BPaL regimen remained effective against highly drug-resistant strains of TB with reduced dosage of the linezolid component of the regimen. A decrease in linezolid-associated side effects accompanied the reduction of linezolid in treatment.

Scientific Publications

Find peer-reviewed publications from TB Alliance about pretomanid and the BPaL regimen here.

Additional Resources

Find resources and materials with further details about pretomanid, BPaL, and the treatment experience around the world.

The Future of TB Treatment

Prior to the introduction of BPaL, treatment of highly DR-TB was lengthy and complex. Most extensively drug-resistant TB (XDR-TB) patients took a combination of up to eight antibiotics, some involving daily injections, for 18 months or longer. Prior to recent introduction of new drugs for drug-resistant TB, the WHO reported estimates for treatment success rates of XDR-TB therapy at approximately 43 percent and about 57 percent for multidrug-resistant TB therapy.



INDICATION | LIMITED POPULATION

Pretomanid Tablet is an antimycobacterial indicated, as part of a combination regimen with bedaquiline and linezolid for the treatment of adults with pulmonary extensively drug-resistant (XDR), treatment-intolerant or non-responsive multidrug-resistant (MDR) tuberculosis (TB). Approval of this indication is based on limited clinical safety and efficacy data. This drug is indicated for use in a limited and specific population of patients.

Limitations of Use:
  • Pretomanid Tablets are not indicated for patients with:
    • Drug-sensitive (DS) tuberculosis
    • Latent infection due to Mycobacterium tuberculosis
    • Extra-pulmonary infection due to Mycobacterium tuberculosis
    • MDR-TB that is not treatment-intolerant or non-responsive to standard therapy
  • Safety and effectiveness of Pretomanid Tablets have not been established for its use in combination with drugs other than bedaquiline and linezolid as part of the recommended dosing regimen.

IMPORTANT SAFETY INFORMATION

Contraindications

Pretomanid Tablets used in combination with bedaquiline and linezolid are contraindicated in patients for whom bedaquiline and/or linezolid is contraindicated.

Warnings and Precautions
  • Hepatic adverse reactions were reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Monitor symptoms and signs and liver related laboratory tests. Interrupt treatment with the entire regimen if evidence of liver injury occurs.
  • Myelosuppression was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Monitor complete blood counts. Decrease or interrupt linezolid dosing if significant myelosuppression develops or worsens.
  • Peripheral and optic neuropathy were reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Monitor visual function. Obtain an ophthalmologic evaluation if there are symptoms of visual impairment. Decrease or interrupt linezolid dosing if neuropathy develops or worsens.
  • QT prolongation was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops.
  • Reproductive effects: Pretomanid caused testicular atrophy and impaired fertility in male rats. Advise patients of reproductive toxicities seen in animal studies and that the potential effects on human male fertility have not been adequately evaluated.
  • Lactic acidosis was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Consider interrupting linezolid or the entire combination regimen of Pretomanid Tablets, bedaquiline, and linezolid dosing if significant lactic acidosis develops.

Adverse Reactions

The most common adverse reactions (≥10%) are peripheral neuropathy, acne, anemia, nausea, vomiting, headache, increased transaminases, dyspepsia, decreased appetite, rash, pruritus, abdominal pain, pleuritic pain, increased gamma-glutamyltransferase, lower respiratory tract infection, hyperamylasemia, hemoptysis, back pain, cough, visual impairment, hypoglycemia, abnormal loss of weight, and diarrhea.