FDA approves new drug for one of the deadliest forms of drug resistant tuberculosis

Pretomanid, developed by the non-profit TB Alliance, has received U.S. approval for people with XDR-TB or treatment-intolerant/non-responsive MDR-TB.

On August 14th, the U.S. Food and Drug Administration approved Pretomanid Tablets in combination with bedaquiline and linezolid intended to treat a certain type of highly treatment-resistant tuberculosis.

TB Alliance, the drug developer, is happy about approval

Pretomanid, a novel compound developed by the non-profit organization TB Alliance, was approved by the U.S. Food & Drug Administration (FDA) for treating some of the most drug-resistant forms of tuberculosis (TB). Pretomanid is only the third new anti-TB drug the FDA has approved for use in more than 40 years; it is the first to be developed and registered by a not-for-profit organization.

The new drug was approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD pathway).  It is part of a three-drug, six-month, all-oral regimen used to treat patients with extensive drug-resistant TB (XDR-TB) or multidrug-resistant TB (MDR-TB) who are also treatment-intolerant or non-responsive. The collective term for this condition is “highly drug-resistant TB”.

“FDA approval of this treatment represents a victory for the people suffering from these highly drug-resistant forms of the world’s deadliest infectious disease,” said Mel Spigelman, MD, president and CEO of the TB Alliance. “The associated novel regimen will hopefully provide a shorter, more easily manageable and highly efficacious treatment for those in need.”

While developing Pretomanid, TB Alliance received significant support from numerous governments, academic and philanthropic institutions, the private sector, civil society organizations and other partners.

“The threat of antimicrobial-resistant infections is a key challenge we face as a public health agency,” said FDA Principal Deputy Commissioner Amy Abernethy, M.D., Ph.D. “The bacterium that causes tuberculosis can develop resistance to the antibiotics used to treat it. Multidrug-resistant TB and extensively drug-resistant TB are public health threats due to limited treatment options. New treatments are important to meet patient national and global health needs. That’s why, among our other efforts to address antimicrobial resistance, we’re focused on facilitating the development of safe and effective new treatments to give patients more options to fight life-threatening infections.”

About Tuberculosis and multi drug resistant tuberculosis

Tuberculosis is a worldwide disease, affecting populations in every country of the world. An airborne disease, it can be spread by coughing or sneezing.  It is highly dangerous, especially since latent carriers do not have any symptoms, but can carry the disease for years before it becomes active.  

• Tuberculosis (TB) is one of the top 10 causes of death worldwide.

• In 2017, 10 million people fell ill with TB, and 1.6 million died from it (among those 0.3 million had been diagnosed with HIV).

• An estimated 1 million children became ill with TB in 2017; 230,000 children died of it (including children with HIV associated TB).

• Multidrug-resistant TB (MDR-TB) continues to be a public health crisis and a health security threat.  The World Health Organization (WHO) estimates that there were 558,000 new cases with resistance to Rifampicin – the most effective first-line drug, of which – 82% had MDR-TB.

• An estimated 54 million lives were saved through TB diagnosis and treatment between 2000 and 2017.

Multidrug-resistant tuberculosis (MDR-TB) is a form of TB in which infection is worsened by bacteria unresponsive to Isoniazid and Rifampicin, the two most powerful first-line anti-TB drugs. MDR-TB is treatable and curable by using second-line drugs. Second-line treatment options are limited and require extensive chemotherapy (up to two years of treatment) with medicines that are expensive and toxic.

The drug has been tested in 19 clinical trials 

Treatment for all forms of TB requires a combination of drugs.  The most drug-sensitive forms of TB involve six months of treatment using four anti-TB drugs. Treatment of XDR-TB or treatment intolerant/non-responsive MDR-TB has historically been lengthy and complex.  Currently, treatment for most XDR-TB patients includes a combination of as many as eight antibiotics, some of which involve daily injections. Treatment can last for 18 months or longer.

The newly approved  three-drug regimen consisting of Bedaquiline, Pretomanid and Linezolid – collectively referred to as the BPaL regimen – was studied in South Africa, at three different sites, during the pivotal Nix-TB trial which enrolled 109 people with XDR-TB as well as treatment-intolerant or non-responsive MDR-TB.

Outcomes of the trial were very encouraging.  Nix-TB data show that 95 of the first 107 patients demonstrated a successful outcome after six months of treatment with BPaL and six months of post-treatment follow-up. The treatment was extended to nine months for only two of the patients. The new drug application is based on data gathered from 1,168 people who have received pretomanid in 19 clinical trials evaluating the drug’s safety and efficacy. Pretomanid has been clinically studied in 14 countries.

How the new treatment works and who it can help

Before the more recent introduction of new drugs for drug-resistant TB, treatment success rates of XDR-TB therapy and MDR-TB therapy were at 34 and 55 percent success rates, respectively, as reported by the WHO.

“Until very recently, people infected with highly drug-resistant TB had poor treatment options and a poor prognosis,” said Dr. Francesca Conradie, principal investigator of the Nix-TB trial. “This new regimen provides hope with 9 out of 10 patients achieving culture negative status at 6 months post-treatment with this short, all-oral regimen.”

Pretomanid is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines. TB Alliance acquired the rights to develop the formula in 2002, and has been working on it ever since.This oral tablet formulation for the treatment of TB was developed to be used in combination with Bedaquiline and Linezolid, two other anti-TB agents, and is now indicated for use in a limited and specific population of patients.

Adverse reactions reported during the Nix-TB trial of the BPaL regimen include hepatotoxicity, myelosuppression, as well as peripheral and optic neuropathy. 

It is expected that Pretomanid will become available in the United States by the end of this year. TB Alliance has also submitted Pretomanid as part of the BPaL regimen for review by the European Medicines Agency and has provided data to the WHO for consideration of inclusion in treatment guidelines for highly drug-resistant TB.

Contraindications

Pretomanid tablets used in combination with Bedaquiline and Linezolid are contraindicated in patients for whom Bedaquiline and/or Linezolid is contraindicated.

Adverse Reactions

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.

About TB Alliance

TB Alliance (The Global Alliance for TB Drug Development, Inc.) is a not-for-profit organization dedicated to finding faster-acting and affordable drug regimens to fight TB. Through innovative science and with partners around the globe, They aim to ensure equitable access to faster, better TB cures that will advance global health and prosperity. TB Alliance operates with support from Australia’s Department of Foreign Affairs and Trade, the Bill & Melinda Gates Foundation, Cystic Fibrosis Foundation, European & Developing Countries Clinical Trials Partnership, Germany’s Federal Ministry of Education and Research through KfW, Global Health Innovative Technology Fund, Indonesia Health Fund, Irish Aid, Medical Research Council (United Kingdom), National Institute of Allergy and Infectious Disease, Netherlands Ministry of Foreign Affairs, United Kingdom Department for International Development, and the United States Agency for International Development.