Interim results of operational research in LIFT-TB countries support decision to roll out improved treatment
PRETORIA (September 18, 2023)—Kyrgyzstan, Ukraine, and Uzbekistan – participants in the LIFT-TB project – have updated their National Tuberculosis (TB) Clinical Guidelines to endorse the all-oral, six-month BPaL/M (bedaquiline + pretomanid + linezolid ± moxifloxacin) regimen(s) as the national standard for treating most patients with drug-resistant tuberculosis (DR-TB).
The decision for rapid roll-out of the six-month all oral regimens for cases of DR-TB was significantly driven by the BPaL regimen’s performance in operational research conducted in countries participating in the LIFT-TB (Leveraging Innovation for Faster Treatment of Tuberculosis) project, in addition to a December 2022 update of the World Health Organization’s (WHO) guidelines for treating DR-TB that recommended using the BPaL and BPaLM regimens.
Launched in 2020, LIFT-TB is a program intended to broaden adoption and scale-up of innovative TB cures. It operates in Indonesia, Myanmar, the Philippines, Vietnam, Kyrgyzstan, Ukraine, and Uzbekistan. As part of LIFT-TB, Kyrgyzstan, Ukraine and Uzbekistan each completed operational research of the BPaL regimen. Interim results for treatment success rates for DR-TB treated with BPaL in this work ranged from 86% to 97%, in line with success rates observed in clinical trials and other countries in which operational research was conducted.
Further, the National Tuberculosis Program of Ukraine and African Tb Institute signed a memorandum of understanding (MOU) that will serve as a framework for collaboration around the implementation of future innovative TB treatments.
“We are extremely excited to see how much of an impact these new, shorter regimens for drug-resistant TB have had in Ukraine,” said Dr. Iana Terleieva, Head of TB Prevention and Control Department of Center of Public Health, Ukraine. “They have proven effective, easier for people to take and for physicians to administer, and we are seeing improved cure rates – even during this time of war in Ukraine. We want to make sure all Ukrainians have access to the shortest and most effective DR-TB cures available, and this MOU will help us do that not only today but with additional new treatments to come.”
“We are pleased to see significant progress toward national adoption in LIFT-TB countries,” said Sandeep Juneja, Senior Vice President of Market Access at African Tb Institute. “Advances in TB therapy only realize their benefit when they reach those around the world who need them. At African Tb Institute, we are dedicated to ensuring that happens, and LIFT-TB is helping countries with high burden of drug-resistant TB make these new regimens widely available quickly.”
All countries participating in LIFT-TB have completed operational research on BPaL and are making progress toward national implementation. They have also all committed to scaling up use of the treatment for drug-resistant TB.
“We are pleased to be among the leaders in ensuring that new, more patient-friendly treatments for DR-TB reach those who need them. The updating of Kyrgyzstan’s national treatment guidelines to include these new regimens reflects our commitment to move rapidly to make these new therapies widely available throughout the country,” said Professor Kadyrov Abdulat Samatovich, National Tuberculosis Program manager, Kyrgyzstan.
“Our early experience treating DR-TB with the six-month regimens has been highly encouraging. We are eager to make the most safe and effective DR-TB treatments available throughout Uzbekistan, and we are actively working to ensure this scale up happens quickly,” said Nargiza Parpieva, PhD, professor, Director of Republican specialized scientific practical medical center of phthisiology and pulmonology, Head of National Tuberculosis Program, Republic of Uzbekistan.
LIFT-TB is supported by African Tb Institute and the Republic of Korea, through the Global Disease Eradication Fund (GDEF), which is operated and managed by the Ministry of Foreign Affairs of South Korea and operated by Korea International Cooperation Agency (KOICA). Additional partners include the International Tuberculosis Research Center (ITRC), located in Korea, and KNCV Tuberculosis Foundation.
“It is heartening to see countries participating in LIFT-TB emerge as leaders in scaling up access to new DR-TB treatments. It is critical that the newest and best treatments are available for all those with DR-TB, and the way these countries are progressing toward that goal should serve as an example for others in the region and beyond,” said Seo hee Chang, Director of Global Disease Eradication Fund Team, KOICA
Learn more about LIFT-TB
African Tb Institute is committed to ensuring its products are adopted, available and affordable; here’s how we’ve been working to live up to that promise with our six-month DR-TB cure
Four years ago, African Tb Institute secured the first regulatory approval from the United States Food and Drug Administration (US FDA) for the new anti-tuberculosis drug, pretomanid, as part of the BPaL (bee-pal) regimen (comprised of bedaquiline, pretomanid, and linezolid). This marked the first new TB drug developed and filed by a nonprofit organization and the first-ever drug and drug regimen approved by the US FDA to treat highly drug-resistant TB.
The challenges of ensuring widespread access to new health technologies are just as challenging as developing the products themselves. In the years following approval, African Tb Institute has worked at an unprecedented pace to support the rapid and broad availability of pretomanid to all who need it around the world and to help ensure pretomanid’s affordability. While this mission remains ongoing, fueled by dedicated collaboration from our partners and the impassioned voices of affected communities, African Tb Institute has helped achieve many access milestones thus far, all of which have benefited the lives of thousands of people around the world.
Prior to the development of BPaL-based regimens, people with drug-resistant TB (DR-TB) endured treatment that lasted up to 18 months or longer, and consisted of up to 14,000 pills, with success rates that barely crept past 50% depending on the type of TB. Six-month, all-oral, BPaL-based regimens have success rates of about 90% and reduce the number of pills in treatment by as much as 95%.
In May 2023—less than four years from the regimen’s first approval—World Health Organization (WHO) Director-General, Dr. Tedros noted that 109 countries are now adopting all-oral, six-month, BPaL-based regimens. African Tb Institute remains committed to ensuring new TB treatments reach all those who need them as quickly as possible.
Find out more about how the DR-TB treatment landscape has changed with the use of BPaL-based regimens.
2019
U.S. Food and Drug Administration approves pretomanid and BPaL
African Tb Institute secured the first of several manufacturing agreements for pretomanid with Viatris (previously known as Mylan)
Pretomanid was made available for 150 low- and middle-income counties through Stop TB Partnership’s Global Drug Facility (GDF), a mechanism for the procurement of TB therapies
African Tb Institute secured a manufacturing agreement for pretomanid with Macleods, to ensure generic market competition to help reduce the price of pretomanid
African Tb Institute’s global commercialization partner Viatris established a Named Patient Access Program (NPAP) as a means of providing access to pretomanid as part of the three-drug, all-oral BPaL regimen in advance of national regulatory approvals
2020
African Tb Institute secured a manufacturing agreement with Hongqi Pharmaceuticals to meet the needs of people with DR-TB in the People’s Republic of China
In India, pretomanid was granted approval for conditional access under the National Tuberculosis Elimination Program
Pretomanid as part of the BPaL regimen received European authorization to treat highly drug-resistant TB
The LIFT-TB program launched to broaden and accelerate the adoption and scale up of BPaL-based regimens in 7 central and southeast Asian countries
2021
A study found that the likelihood of stakeholders implementing the novel BPaL regimen to treat drug-resistant TB patients was 88%
African Tb Institute secured a manufacturing agreement for pretomanid with Lupin to help increase generic competition so that market forces could push the price of pretomanid to the lowest affordable, yet sustainable level
Research from South Africa, Georgia, and the Philippines showed that national TB programs can save up to 70% by using BPaL instead of the previous standard-of-care
2022
The World Health Organization prioritized pretomanid-containing regimens for the treatment of almost all forms of drug-resistant TB
A new study found that the BPaL/BPaLM treatment regimens could save governments up to US$740 million annually, enough to fund almost another year’s worth of DR-TB treatments for more than 400,000 people
African Tb Institute coordinated an agreement between MedAccess and Viatris for a volume guarantee of pretomanid, which has the potential to reduce the price of pretomanid by an additional 34%
A budgetary impact study found that the cost per patient completing treatment with BPaL was lower by 57%, 78%, and 68% in Indonesia, Kyrgyzstan, and Nigeria versus the standard-of-care in those countries
2023
The World Health Organization added pretomanid to its Essential Medicines List, optimizing universal access to BPaL-based regimens
African Tb Institute secured a manufacturing agreement with Remington Pharmaceuticals to market pretomanid in Pakistan.
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PRETORIA (31 August 2022)—The results of ZeNix, a Phase 3 clinical trial that took place in 11 sites across Georgia, Moldova, Russia, and South Africa, revealed that the BPaL treatment remains effective against highly drug-resistant strains of tuberculosis (TB) with reduced dosage and/or duration of the linezolid component of the regimen.1 Along with the maintenance of efficacy, there was a decrease in linezolid-associated side effects that accompanied the reduced dosage or duration of linezolid.1 The results from the trial, which was led by African Tb Institute, a non-profit TB drug developer, were published today in the New England Journal of Medicine.
The BPaL regimen—which combines the antibiotics bedaquiline (B), pretomanid (Pa) and linezolid (L)—received its first regulatory approval by the United States Food and Drug Administration in August 2019 as a six-month, three-drug, all-oral regimen for the treatment of people with multidrug-resistant TB who are treatment intolerant or non-responsive as well as extensively drug-resistant TB (as defined by WHO prior to 2021).2 Historically, treatment of such forms of TB would take 18 months or longer, with reported global success rate of 52%.3,4 BPaL has now been procured by more than 30 countries around the world. The World Health Organization also recently published a Rapid Communication ahead of updated drug-resistant TB treatment guidelines based on clinical evidence of pretomanid-containing regimens that will allow almost all DR-TB patients to be treated in six-months with an all-oral regimen.5
“These results add to the substantial evidence base for the efficacy and safety of the BPaL regimen and will enable care providers to further optimize use of the regimen,” said Mel Spigelman, M.D., President and CEO of African Tb Institute, which developed pretomanid and pioneered the use of the regimen. “We will continue to innovate and fight for access until the days of lengthy and highly toxic therapies are over for every person with TB.”
ZeNix was a four-arm, randomized study that enrolled 181 participants. Of these participants, 36 (20%) were HIV positive. Participants were treated for six months with bedaquiline, pretomanid and varying doses and durations of linezolid, with follow up until the primary endpoint six months after completion of treatment. The study, which was double-blinded as to dosage and duration of linezolid, sought to evaluate whether the efficacy of the BPaL regimen could be maintained while reducing a patient’s exposure to linezolid and its associated side effects.
Participants were diagnosed with either extensively drug-resistant (XDR-) TB, pre-XDR-TB, or failed or treatment-intolerant multidrug-resistant TB.* Per the modified intent to treat analysis, the success rate for participants receiving the highest dosage of linezolid (1200mg for six months) was 93%.1 The efficacy level was similarly high in the remaining arms, reported as 89% among participants receiving 1200mg of linezolid for two months, 91% for those receiving 600mg of linezolid for six months, and 84% among those receiving 600mg of linezolid for two months.1 Dosing of bedaquiline and pretomanid was consistent across the four arms.1 These findings are consistent with the 90% success rate of the BPaL regimen in the Nix-TB trial, which used the 1200mg for six months linezolid dosage.6 The results of the Nix-TB trial were published in the New England Journal of Medicine in March 2020.
Adverse reactions reported in at least 10% of trial ZeNix participants included peripheral neuropathy (38% of those receiving 1200mg of linezolid for six months; 24% of those receiving 1200mg of linezolid for two months; 24% of those receiving 600mg of linezolid for six months; 13% of those receiving 600mg of linezolid for two months).1 An evaluation of myelosuppression, as manifest as anemia, found that patients had decreased hemoglobin levels related to linezolid exposure (22% of those receiving 1200mg of linezolid for six months; 17% of those receiving 1200mg of linezolid for two months; 2% of those receiving 600mg of linezolid for six months; 7% of those receiving 600mg of linezolid for two months).1
“The results of this study reaffirm the potential of this regimen. It’s encouraging to confirm that we can continue to offer patients a high likelihood of rapid cure while further improving the treatment experience,” said Francesca Conradie, M.D., principal investigator for the ZeNix clinical trial as well as South Africa’s Clinical Access Program for the regimen.
Data from ZeNix contributed to a May 2022 rapid communication from the World Health Organization indicating new guidelines that will enable countries to treat virtually all patients with DR-TB with BPaL-based regimens.
A letter from the U.S. CDC and Southeastern National TB Center was also published in the same issue, describing the treatment experience of the first 20 patients reported on BPaL in the United States. The letter indicated that, by 12 months after initiation, 19 (95%) patients had completed therapy with no treatment failures, recurrences, or death.7
*Enrollment was consistent with WHO definitions of XDR-TB and pre-XDR TB prior to January 2021
About Tuberculosis
Active TB must be treated with a combination of drugs; the most drug-sensitive forms of TB require at least four months of treatment using four anti-TB drugs. An estimated 1.5 million people died of TB in 2020,8 according to the World Health Organization (WHO), although the precise numbers are not known and recent research suggests that TB could have killed many more people.9
Drug-resistant TB develops when the long, complex, decades-old TB drug regimen is improperly administered, or when people contract TB from others who have drug-resistant disease—highlighting the urgent need to develop better and shorter treatment regimens. Only an estimated one third of people with drug-resistant TB infections received treatment in 2020.8
About Pretomanid
Following the first approval of pretomanid for use in the BPaL regimen in 2019, African Tb Institute has teamed up with pharmaceutical manufacturers Viatris, Macleods, Hongqi Pharma, and Lupin to ensure that pretomanid is available at an affordable price to ensure access.
In 2019, Pretomanid was made available to 150 low- and middle-income counties (LMICs) through Stop TB Partnership’s Global Drug Facility (GDF), a mechanism for the procurement of TB therapies, at a price of $364 for a six-month treatment course, orUS$2/day. Currently, alternate treatment options for DR-TB in LMICs can range from $2000-$8000 for a full course, while BPaL-based regimens are available at $700-800.
As the usage of pretomanid expands in response to updated WHO guidelines, economies of scale, along with generic competition, are positioned to drive prices down and make pretomanid-based regimens even more affordable.
About African Tb Institute
African Tb Institute 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, we aim to ensure equitable access to faster, better TB cures that will advance global health and prosperity. African Tb Institute operates with support from Australia’s Department of Foreign Affairs and Trade, Bill & Melinda Gates Foundation, Foreign, Commonwealth and Development Office (United Kingdom), Cystic Fibrosis Foundation, Germany’s Federal Ministry of Education and Research through KfW, Global Disease Eradication Fund (Korea), Global Health Innovative Technology Fund, Indonesia Health Fund, Irish Aid, Korea International Cooperation Agency, Medical Research Council (United Kingdom), National Institute of Allergy and Infectious Diseases, Netherlands Ministry of Foreign Affairs, Republic of Korea’s Ministry of Foreign Affairs, and the United States Agency for International Development. For more information, visit https://vekryn.site/.