When used in combination with bedaquiline and linezolid, the newly approved pretomanid drug for MDR-TB and XDR-TB had an overall treatment success rate of about 90%. Besides better effectiveness, the duration of treatment is just six months.
Treating drug-resistant tuberculosis — multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) — got a shot in the arm on August 14 when the U.S. Food & Drug Administration (FDA) approved a new drug Pretomanid. Pretomanid is only the third anti-TB drug approved for use by the FDA in more than 40 years.
The drug was developed and tested in clinical trials by New York-based non-profit organisation TB Alliance. TB Alliance has granted a licence to Pennsylvania-based Mylan to manufacture and commercialise the drug.
Pretomanid drug is expected to be available in the U.S. by the end of this year. TB Alliance has submitted pretomanid as part of the three-drug regimen for drug approval by the European Medicines Agency (EMA). It has also provided data to the World Health Organisation (WHO) for consideration of inclusion in treatment guidelines for highly drug-resistant TB.
What makes the new drug so promising?
The duration of treatment for drug-resistant TB can be drastically cut from 18-24 months to just six-nine months when pretomanid drug is used along with two already approved drugs — bedaquiline and linezolid. The all-oral, three-drug regimen can also vastly improve the treatment success rate and potentially decrease the number of deaths due to better adherence to treatment.
According to the WHO, the treatment success in MDR-TB patients is about 54%, while it is just 30% in the case of XDR-TB patients. Most drugs are ineffective in people with XDR-TB and so a combination of eight drugs for more than a year is need for XDR-TB treatment.
According to the U.S. Centers for Disease Control and Prevention (CDC) Atlanta, treatment success in XDR-TB patients depends on many other factors — the extent of the drug resistance, the severity of the disease, whether the patient’s immune system is weakened, and adherence to treatment.
Drugs used for treating MDR-TB and XDR-TB can cause serious adverse effects such as deafness. The drugs are highly toxic thus reducing adherence to treatment.
How widespread is MDR-TB and XDR-TB?
People with TB who do not respond to at least isoniazid and rifampicin, which are first-line TB drugs are said to have MDR-TB. People who are resistant to isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs (amikacin, kanamycin, or capreomycin) are said to have XDR-TB.
As per the World Health Organisation’s Global Tuberculosis Report 2018, an estimated 4.5 lakh people across the world have MDR-TB and nearly 37,500 people have XDR-TB. India has 24% of MDR-TB cases in the world. By the end of 2017, XDR-TB had been reported from 127 countries, including India.
Which category of drug-resistant TB patients will benefit from this new drug?
Pretomanid drug along with bedaquiline and linezolid is meant for treating adults with XDR-TB. In the case of MDR-TB, the three-drug regimen containing pretomanid can be used only in those patients who cannot tolerate the MDR-TB treatment or do not respond to standard MDR-TB treatment regimen.
The three-drug regimen is meant only for treating pulmonary TB and should not be used for treating extra-pulmonary TB, drug-sensitive or latent TB.
How effective is the drug in treating XDR-TB and MDR-TB?
The three-drug regimen consisting of bedaquiline, pretomanid and linezolid — collectively referred to as the BPaL regimen — was studied in the pivotal Nix-TB trial across three sites in South Africa. The trial enrolled 109 people with XDR-TB as well as treatment-intolerant or non-responsive MDR-TB.
According to TB Alliance, 95 of the first 107 XDR-TB patients as well as treatment-intolerant or non-responsive MDR-TB were successfully treated with a six-month regimen. There was successful outcome in two other patients when the treatment duration was extended to nine months. The overall treatment success rate is about 90%.
How safe is the drug for clinical use?
Besides the Nix-TB trial, the safety and efficacy of the drug has been evaluated either alone or as part of the combination therapy in 19 clinical trials conducted in 14 countries involving 1,168 patients.
The FDA has approved the drug based on limited clinical safety and efficacy data, and so should the drug should be restricted to specific population of patients. Safety and effectiveness of the drug has been studied and established only when used in combination with bedaquiline and linezolid. Other than these two drugs, the safety of pretomanid has not been studied when used along with any other anti-TB drug.
The three-drug combination should not be used in patients for whom bedaquiline and/or linezolid drug is not recommended (contraindicated).
The drug has not been tested in pregnant women. Similarly, safety and effectiveness of the drug has not been established in children.
What are the adverse drug reactions caused by the drug?
In the Nix-trial, the three-drug regimen was reported to have caused serious adverse reactions including liver toxicity (hepatotoxicity), suppression of bone marrow activity leading to reduced production of red blood cells, while blood cells and platelets (myelosuppression), as well as peripheral and optic neuropathy.
Pretomanid drug was found to cause a reduction in the size of the testes and probably even the function (testicular atrophy) and impaired fertility in male rats. According to the prescribing information, patients should be “advised of reproductive toxicities seen in animal studies and that the potential effects on human male fertility have not been adequately evaluated”.
The drug can cause lactate to accumulate in the body leading to sharp reduction in the pH of the blood (lactic acidosis).
Prolongation of the QT interval of ECG (due to changes in the electrical activity of the heart) was reported when the three-drug regimen was used. The QT prolongation can lead to an abnormal and potentially fatal heart rhythm. The QT prolongation is caused by bedaquiline.
Other common adverse reactions seen were peripheral neuropathy, anaemia, indigestion (dyspepsia), lower respiratory tract infection, visual impairment, hypoglycaemia, abnormal loss of weight, and diarrhoea to name a few.
What is the recommended dosage for the three drugs?
All the three drugs are to be administered orally. The dosage for pretomanid is 200 mg drug once every day for 26 weeks, while 1,200 mg of linezolid once daily for up to 26 weeks. In the case of bedaquiline, the dosage and frequency change mid-course. For the first two weeks the dosage is 400 mg once daily. The dosage reduces to 200 mg three times a week with at least 48 hours gap between doses for the remaining 24 weeks.
If due to serious adverse reactions or for any other reason if either bedaquiline or pretomanid is discontinued, then intake of the entire combination should be discontinued. If linezolid is permanently discontinued during the initial four consecutive weeks of treatment, then the other two drugs should also be discontinued. On the other hand, if linezolid is discontinued after the initial four weeks of consecutive treatment,then the other two drugs — bedaquiline and pretomanid — can be continued to be administered.
If necessary, the duration of treatment can be extended beyond 26 weeks.