Delving into the Latest Updates on Bedaquiline Fumarate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

1-(6-Bromo-2-methoxy-quinolin-3-yl)-4-dimethylamino-2-naphthalen-1-yl-1-phenyl-butan-2-ol, bedaquiline, Bedaquiline fumarate (JAN/USAN)

+ [11]

Target

mycobacterial ATP synthase

Mechanism

mycobacterial ATP synthase inhibitors(mycobacterial ATP synthase inhibitors)

Therapeutic Areas

Infectious DiseasesRespiratory DiseasesOther Diseases

Active Indication

Pulmonary TuberculosisTuberculosisTuberculosis, Multidrug-Resistant+ [2]

Inactive Indication

HIV InfectionsInfectious Lung DisorderLiver Diseases+ [1]

Originator Organization

Janssen Global Services LLC

Active Organization

Janssen Research & Development LLCJanssen-Cilag International NV

Janssen Korea Ltd.

+ [3]

Inactive Organization

Janssen Infectious Diseases-Diagnostics BVTibotec Virco Virology BV

Drug Highest PhaseApproved

First Approval Date

US (28 Dec 2012),

Tuberculosis, Multidrug-Resistant

RegulationFast Track (US), Accelerated Approval (US), Orphan Drug (JP), Orphan Drug (KR), Conditional marketing approval (EU), Orphan Drug (US)

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Structure

Molecular FormulaC36H35BrN2O6

InChIKeyZLVSPMRFRHMMOY-WWCCMVHESA-N

CAS Registry845533-86-0

A Phase III, open-label, multicenter, non-inferiority trial, to compare the efficacy and safety of 4 weeks of bedaquiline (BDQ) versus a World Health Organization (WHO) -recommended regimen for preventing confirmed or probable tuberculosis disease (TBD) during 96 weeks of follow-up among people living with HIV (PLHIV) and high-risk Close Contacts (CC) of adults with Drug Susceptible (DS) or Rifampin Resistant (RR) TB.

Start Date01 Mar 2025

Sponsor / Collaborator

The Johns Hopkins University

[+1]

NCT06441006 / Not yet recruitingPhase 3IIT

Program for Rifampicin-Resistant Disease With Stratified Medicine for Tuberculosis (PRISM-TB)

PRISM-TB is an international, multicenter, open-label, randomized, controlled, pragmatic, stratified medicine, treatment shortening, noninferiority Phase 3 clinical trial for fluoroquinolone-susceptible multidrug-resistant/rifampin-resistant pulmonary tuberculosis (FQ-S MDR/RR-TB).
The trial objective is to evaluate whether stratified medicine treatment strategies for FQ-S MDR/RR-TB, defined by a pre-specified risk stratification algorithm, have noninferior efficacy to a one-size-fits-all control regimen (the local standard-of-care [SOC] regimen consistent with preferred regimen(s) in international guidelines), as measured by TB-related unfavorable outcomes at Week 73.

Start Date15 Jan 2025

Sponsor / Collaborator

The University of California, San Francisco

[+1]

NCT06192160 / Not yet recruitingPhase 2IIT

A Phase 2 Randomized, Adaptive, Dose-Ranging, Open-Label Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis

A5409/RAD-TB is an adaptive Phase 2 randomized, controlled, open-label, dose-ranging, platform protocol to evaluate the safety and efficacy of multidrug regimens for the treatment of adults with drug-susceptible pulmonary tuberculosis (TB).
A5409 hypothesizes that novel regimens for the treatment of pulmonary tuberculosis will result in superior early efficacy, as determined by longitudinal mycobacteria growth indicator tube (MGIT) liquid culture time to positivity (TTP) measurements over the first 6 weeks of treatment, and will have acceptable safety and tolerability over 8 weeks of treatment relative to standard of care [(SOC) isoniazid/rifampicin/pyrazinamide/ethambutol (HRZE)].
The study will run for 52 weeks, inclusive of 26 weeks of TB treatment comprised of 8 weeks of experimental or SOC treatment (based on treatment arm assignment) followed by 18 weeks of SOC treatment with 45 participants in each experimental treatment arm and at least 90 participants in the SOC arm.

Start Date10 Jan 2025

Sponsor / Collaborator

National Institute of Allergy & Infectious Diseases

[+1]

100 Clinical Results associated with Bedaquiline Fumarate

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100 Translational Medicine associated with Bedaquiline Fumarate

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100 Patents (Medical) associated with Bedaquiline Fumarate

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1,401

Literatures (Medical) associated with Bedaquiline Fumarate

01 Feb 2025·BIOORGANIC & MEDICINAL CHEMISTRY

Structural toxicity relationship (STR) of linezolid to mitigate myelosuppression and serotonergic toxicity

Review

Author: Patel, Harun ; Shaikh, Matin

Tuberculosis (TB) remains a significant global health challenge, with multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains posing severe threats to treatment efficacy. Linezolid, a key component of the BPaL (Bedaquiline, Pretomanid and Linezolid) regimen, has demonstrated substantial efficacy against MDR-TB and XDR-TB. However, its clinical utility is often limited by side effects such as myelosuppression and monoamine oxidase (MAO) inhibition, linked to its mechanism of action. This perspective centres on the structural toxicity relationship (STR) of Linezolid and its analogues, exploring modifications to the C-ring and C-5 position that aim to reduce these toxicities while maintaining or enhancing antibacterial activity. Several promising analogues have been identified that exhibit reduced myelosuppression and MAO inhibition, highlighting the potential for developing safer Linezolid derivatives. The findings underscore the importance of continued research into the structure toxicity relationships of oxazolidinones to improve the therapeutic profiles of these essential drugs in combating drug-resistant TB.

31 Dec 2024·Global health action

Low body mass index as a predictor of sputum culture conversion and treatment outcomes among patients receiving treatment for multidrug-resistant tuberculosis in Lesotho

Article

Author: Maime, Refiloe ; Kunda, Mikanda ; Makaka, Joalane ; Seung, K J ; Kanu, Makelele ; Maama, Llang ; Franke, Molly F ; Mofolo, Mabatloung ; Mpinda, Stephanie ; Oyewusi, Lawrence ; Senyo, Ninza ; Mitnick, Carole D ; Mayombo, Lwayi ; Oguntoyinbo, Bamidele ; Zeng, Chengbo ; Tamirat, Meseret

BACKGROUND:

A low body mass index (BMI) at the start of treatment for rifampicin- or multidrug-resistant tuberculosis (MDR/RR-TB) is associated with poor treatment outcomes and may contribute to delayed sputum culture conversion, thereby prolonging the period of potential transmission to others. Whether the relative importance of low BMI in predicting treatment outcomes differs by HIV status is unclear.

OBJECTIVES:

We evaluated the association between low BMI and two dependent variables, sputum culture conversion and end-of-treatment outcome, among patients receiving treatment for MDR/RR-TB in Lesotho, a setting with a high prevalence of HIV infection.

METHODS:

Secondary data from a prospective cohort of patients initiating a longer (18-20 months) treatment containing bedaquiline and/or delamanid under routine programmatic conditions in Lesotho were analysed. Risk ratios and differences were adjusted for potential confounders using multivariable logistic regression, and estimates were stratified by HIV status.

RESULTS:

Of 264 patients, 105 and 250 were eligible for culture conversion and end-of-treatment analyses, respectively. Seventy-one per cent of patients (74/105) experienced culture conversion within six months, while 74% (184/250) experienced a favourable end-of-treatment outcome. Low BMI was associated with a lower frequency of culture conversion at six months among those who were not living with HIV (relative risk [RR]: 0.50 [95% CI: 0.21, 0.79]); this association was attenuated among those living with HIV (RR: 0.88 [95% CI: 0.68, 1.23]). A low BMI was moderately associated with a lower frequency of treatment success (RR = 0.89 [95% CI: 0.77, 1.03]), regardless of HIV status.

CONCLUSIONS:

Low BMI was common and associated with the frequency of six-month culture conversion and end-of-treatment outcomes. The association with culture conversion was more pronounced among those not living with HIV. Addressing the myriad factors that drive low BMI in this setting could hasten culture conversion and improve end-of-treatment outcomes. This will require a multipronged approach focused on alleviating food insecurity and enabling prompt diagnosis and treatment of HIV and TB.

06 Dec 2024·Journal of biomolecular structure & dynamics

In silico structural and mechanical insights into bedaquiline resistance associated with high-grade non-synonymous mutations in atpE , mmpR5 , and pepQ

Article

Author: Sharma, Mukta ; Patra, Niladri ; Kori, Mahima ; Nath I.V, Ambily ; Chakraborty, Gourav ; Sheth, Jigar ; Tiwari, Avlokita

Clinical resistance against bedaquiline (BDQ) remains intractable to anti-tuberculosis therapies since its introduction to the market over a decade ago. Herein, we investigated the structural and mechanical aspects of BDQ resistance in AtpE, MmpR5, and PepQ. The known target-specific resistant single non-synonymous mutations were refined to high-grade candidates. Thus, 7 (AtpE), 5 (MmpR5), and 1 (PepQ) single nucleotide polymorphisms (SNPs) and one insertion frameshift mutation in MmpR5 were recreated at the molecular level, and these phenotypic models were then directed to stringent dynamics to define time-scaled changes. The AtpE variants destabilized the structure; mainly, L59V, E61D, and I66M were detrimental to the complex fitness, while L74V and L114P boosted the BDQ binding to MmpR5. The first three and last two alterations gave rise to loss- and gain-of-function to AtpE and MmpR5, respectively. Hence, these five mutants are functionally relevant and therapeutically targetable hotspots of BDQ resistance. There were no noticeable changes in PepQ data analysis. The present study revealed that MmpR5 mutations confer BDQ resistance, whereas AtpE and PepQ SNPs display low susceptibility. These results were tallied with the published findings, which testified to the pursued method's reliability and accuracy. We hope these data and inferences could be helpful for the futuristic design of novel TB drugs.Communicated by Ramaswamy H. Sarma.

35

News (Medical) associated with Bedaquiline Fumarate

03 Sep 2024

·www.tballiance.org

Brazil and Philippines Accelerate Availability of Shorter Drug-Resistant Tuberculosis Treatment

MANILA (September 3, 2024) – A delegation of experts from Brazil’s National TB Program visited Manila recently to collaborate with the Philippines to accelerate implementation of the new drug-resistant TB (DR-TB) treatment, BPaL/M. Through the Manila-based PeerLINC Knowledge Hub, Brazilian officials had in-depth scientific exchange with their peers in the Philippines – one of the first countries in the world to successfully roll out BPaL/M treatment. PeerLINC is supported by TB Alliance and offers countries like Brazil first-in-class peer support, capacity building, and technical assistance to implement the life-saving regimen in their own countries. BPaL/M – a combination of the antibiotics bedaquiline (B), pretomanid (Pa), and linezolid (L), with or without moxifloxacin (M) – are six-month DR-TB treatments with a success rate of 90% or greater. BPaL/M is recommended by the World Health Organization (WHO) for the treatment of most forms of DR-TB. Prior to the introduction of these regimens, DR-TB treatment typically consisted of 9-24 months of treatment, with a treatment success rate of approximately 60%. New regimens have the potential to improve DR-TB treatment outcomes and experiences in Brazil, while reducing costs to both health systems and individuals who seek treatment. “Brazil has decided to fast track implementation of BPaL/M,” says Dr. Fernanda Dockhorn. “We had valuable interactions with the PeerLINC team and Philippines Department of Health Disease Prevention and Control Bureau (DPCB) experts to utilize their experience as we deploy this new standard of care in our country. We are thankful to TB Alliance for supporting this interaction and DPCB for their help.” The intensive week-long programme included didactic and hands-on training with experts from PeerLINC, the Philippines Department of Health, the Lung Center of the Philippines, and the National TB Reference Laboratory (NTRL). The PeerLINC team also provides ongoing support and technical assistance as Brazil implements the new treatment regimens. “It is truly heartening and exciting to see this initiative working so well,” said Sandeep Juneja, Senior Vice President of Access at TB Alliance. “We’re seeing countries with substantial TB burdens working with the PeerLINC team and returning home with deeper knowledge, strengthened commitment, and tangible plans to expand and accelerate access to new TB cures that will benefit their people and health systems.” PeerLINC Knowledge Hub operates as a partnership between TB Alliance and the Tropical Disease Foundation, Inc. (TDF), and in close collaboration with the Department of Health (DOH), Philippines, to help countries implement best practices in the treatment of drug-resistant tuberculosis (DR-TB) and speed the worldwide programmatic implementation of innovative, more effective treatments for the disease. The initiative is funded by the Australian Government through the Partnerships for a Healthy Region initiative. Since launching in March 2024, PeerLINC has helped numerous counties define and operationalize plans to expand availability of the BPaL/M, including Brazil, Peru, Nigeria, Rwanda, and Democratic Republic of Congo. About BPaL The BPaL regimen – which combines the antibiotics bedaquiline (B), pretomanid (Pa), and linezolid (L) – was designed and clinically studied by TB Alliance. Pretomanid, as part of the BPaL regimen, received its first regulatory approval in August 2019, for use against highly drug-resistant strains of TB. Prior to the initial BPaL clinical trial, less than one-third of drug-resistant TB patients were being successfully treated. Treatment options were limited, expensive, toxic, and lengthy, requiring patients to take more than 20 pills per day for 9-20 months. About PeerLINC The PeerLINC Knowledge Hub provides practical training and technical support to help speed programmatic implementation of innovative, effective TB treatments globally. PeerLINC follows a peer-to-peer model for sharing best practices, experience, tools, and materials by connecting experts from early adopter countries with countries interested in implementing the latest TB treatments. PeerLINC, operates in partnership between the Tropical Disease Foundation, Inc. (TDF) and TB Alliance in close collaboration with the Department of Health, Philippines. PeerLINC Knowledge Hub New PeerLINC Knowledge Hub will Leverage Local Expertise and Experience to Accelerate New, More Effective TB Cures Around the World Australian Government Grants TB Alliance an Award to Help Bolster Clinical Research and Improve Access to New Treatments for Drug-Resistant TB

Drug ApprovalClinical Study

09 Jul 2024

·www.fiercepharma.com

J&J agrees to slash Sirturo price in South Africa, prompting authorities to end antitrust probe

The new price in South Africa matches the figure Johnson & Johnson charges the Global Drug Facility for Sirturo, according to South Africa's Competition Commission. A storm of scrutiny relating to Johnson & Johnson’s pricing and patenting of its tuberculosis med bedaquiline (branded as Sirturo) is clearing up after reaching a fever pitch last year. South African antitrust authorities have dropped (PDF) an investigation they opened into J&J last summer after the drugmaker and its Janssen subsidiary filed for a secondary patent that sought to fend off generics until 2027. The country’s Competition Commission decided not to move forward with a complaint after “extensive engagements” with the Sirturo maker, the commission said in a press release. Along with J&J's prior commitment to not enforce its Sirturo patent in 134 low-and middle-income countries (including South Africa), the company agreed to slash the South African government's procurement price by 40%. The new price matches the figure that J&J offers to the Stop TB Partnership’s Global Drug Facility (GDF), according to the commission. GDF supplies the med to “the majority of low-and middle-income countries,” J&J has said. Last year, J&J cut its Sirturo prices for GDF by 55% in what the organization called a “historic price reduction.” However, the GDF deal left out several countries with a high burden of multidrug-resistant tuberculosis, including South Africa, Belarus and Ukraine, global health initiative Unitaid said at the time. Soon after disclosing its GDF partnership, J&J widened its pact and pledged to not enforce Sirturo patents in certain low-and middle-income countries, allowing generics makers to sell their own versions of the med if they are “of good quality, medically acceptable” and used only in the appropriate countries. The move came after several advocacy groups, such as Unitaid and Médecins Sans Frontières, pressed the company to expand access to the drug. Sirturo scored an accelerated approval from the FDA in 2012, becoming the first tuberculosis med to offer a novel mechanism of action in more than 40 years. Since then, the drug has become a staple of worldwide tuberculosis treatment and is listed in the World Health Organization’s recommended treatment guidelines. Earlier this week, regulators in the U.S. and Europe granted Sirturo full approvals, converting their prior conditional approvals.

Drug ApprovalAccelerated Approval

09 Jul 2024

·firstwordpharma.com

J&J averts South African antitrust action with TB drug price cut

South Africa's Competition Commission has decided not to move ahead with prosecuting allegations of anticompetitive conduct against Johnson & Johnson and its Janssen unit after the company agreed to cut the price of its tuberculosis (TB) drug Sirturo (bedaquiline) by about 40% in the country.The probe, which began last September, examined accusations that Johnson & Johnson had filed a secondary patent for Sirturo, potentially restricting generic competition until 2027 and enabling the company to charge "excessive" prices to South Africa's National Department of Health."The decision to non-refer the complaint of alleged anti-competitive conduct... to the Competition Tribunal for prosecution, follows extensive engagements with the two companies," according to a statement by the Competition Commission. "The companies, in turn, have agreed not to enforce the bedaquiline patent in 134 low- and middle-income countries, including South Africa."After backlash from advocacy groups against the decision to enforce patents on Sirtuto in several markets, the drugmaker confirmed its intention last year to forgo patents in those countries.South Africa's Competition Commission noted that the discounted price aligns with what Johnson & Johnson offers to the Global Drug Facility, the world's largest procurer of TB medicines and diagnostics.The decision coincides with a pair of regulatory milestones for Sirturo. Earlier this month, the drug received full approval in the US and EU for the treatment of multidrug-resistant pulmonary tuberculosis in adults and children aged 5 and older.

Drug Approval

100 Deals associated with Bedaquiline Fumarate

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External Link

KEGG	Wiki	ATC	Drug Bank
D09873	Bedaquiline Fumarate	J04AK05	DB08903

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Pulmonary Tuberculosis	JP	Janssen Pharmaceutical KK	19 Jan 2018
Tuberculosis	KR	Janssen Korea Ltd.	21 Mar 2014
Tuberculosis, Multidrug-Resistant	US	Janssen Therapeutics, Inc.	28 Dec 2012

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Mycobacterium Avium-Intracellulare Infection	Phase 3	JP	Janssen Pharmaceuticals, Inc.	08 Jan 2021
Mycobacterium Avium-Intracellulare Infection	Phase 3	KR	Janssen Pharmaceuticals, Inc.	08 Jan 2021
Mycobacterium Avium-Intracellulare Infection	Phase 3	TW	Janssen Pharmaceuticals, Inc.	08 Jan 2021
Infectious Lung Disorder	Phase 3	CN	Janssen Infectious Diseases-Diagnostics BV	01 Mar 2014
Infectious Lung Disorder	Phase 3	BR	Janssen Infectious Diseases-Diagnostics BV	01 Mar 2014
Infectious Lung Disorder	Phase 3	KH	Janssen Infectious Diseases-Diagnostics BV	01 Mar 2014
Infectious Lung Disorder	Phase 3	EE	Janssen Infectious Diseases-Diagnostics BV	01 Mar 2014
Infectious Lung Disorder	Phase 3	ET	Janssen Infectious Diseases-Diagnostics BV	01 Mar 2014
Infectious Lung Disorder	Phase 3	GE	Janssen Infectious Diseases-Diagnostics BV	01 Mar 2014
Infectious Lung Disorder	Phase 3	LV	Janssen Infectious Diseases-Diagnostics BV	01 Mar 2014

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05406479 (BE-PEOPLE P2, CTgov)	Phase 2	Leprosy	313	BE-PEP (Bedaquiline) (BE-PEP (Bedaquiline Post-Exposure Prophylaxis))	fptiaufcuh(qkseodmhuz) = cypepsqkuf egirnqvdyd (zbmuweeoyi, kqbgsnftmp - nowgfrjwae) View more	-	28 Aug 2024
				SDR-PEP (SDR-PEP (Single-Dose Rifampicin Post-Exposure Prophylaxis))	fptiaufcuh(qkseodmhuz) = qmoucsxtcd egirnqvdyd (zbmuweeoyi, xyibuoxouf - nwrnzulfew) View more
NCT02589782 (TB-PRACTECAL, Pubmed) Manual	Phase 2/3	Extensively Drug-Resistant Tuberculosis	552	rifampicin (Standard care)	milowwhllb(trlslorrxu) = hzqwgxfmur ruzbocqiwo (gpdiilfkza ) View more	Positive	01 Feb 2024
				rifampbedaquilinepretomanidlinezolidmoxifloxacin (BPaLM)	milowwhllb(trlslorrxu) = cbbhtgpmjc ruzbocqiwo (gpdiilfkza ) View more
ATS2023	Not Applicable	Lung Diseases	-	Bedaquiline	tcmvuokneh(qyblykyxbg) = tvhswujkzb xfnxfomcmy (nwymoagyqq, +20.9)	-	21 May 2023
NCT02454205 (NExT, Pubmed \| Am J Respir Crit Care Med) Manual	Phase 2/3	Tuberculosis, Multidrug-Resistant	93	Levofloxacin+Bedaquiline+Linezolid	kcxinijsxm(xeiodearja) = aaauudastk vwuslilclq (meaverbeqp ) View more	Positive	17 Feb 2022
				SOC	kcxinijsxm(xeiodearja) = cvxpmuqllk vwuslilclq (meaverbeqp ) View more
NCT02754765 (Pubmed \| Clin Infect Dis)	Phase 3	Pulmonary Tuberculosis \| Tuberculosis, Multidrug-Resistant	2,296	Bedaquiline and/or Delamanid	ubnjbrfyaz(sxaamngooa) = occurred in 36.8% or 72.8 (95%CI: 66.0-80.0) times/1000 person-months of injectable drug exposure tlbjbsqmtm (fkdkqheyvu ) View more	-	13 Jan 2022
				Linezolid
ERS2021	Not Applicable	Soft Tissue Infections	-	Bedaquiline	rjsxccqept(ttdtncppoe) = Side effects included corrected QT prolongation xaeqoysyvb (vqbudngmwu ) View more	-	05 Sep 2021
ERS2021	Not Applicable	Extensively Drug-Resistant Tuberculosis	87	Bedaquiline and fluoroquinolone-based treatment regimens	qpqaumtyoy(punqvhqrwi) = bakaltacxt gjvxijkqcf (rmhpjkhlpt ) View more	-	05 Sep 2021
NCT02354014 (TMC207-C211, Pubmed) Manual	Phase 2	Tuberculosis	30	Bedaquiline	jifgosdkmn(rczcqsajpr) = Few yzwkngdnhh (dltrlzkpuq ) View more	Positive	01 Sep 2021
				Bedaquiline (≥12-<18 years)
NCT02583048 (ACTG A5343, Pubmed \| Lancet Infect Dis)	Phase 2	Rifampicin resistant tuberculosis	84	Bedaquiline	zluzwuimbq(zanrvfvkuy) = rilmgbaxgt hbmzuanklg (phjzgtjxbm, 71 - 97)	Positive	12 Feb 2021
				Delamanid	zluzwuimbq(zanrvfvkuy) = uccxyfljhy hbmzuanklg (phjzgtjxbm, 65 - 95)
ZeNix (IAS2021)	Not Applicable	Tuberculosis	181	Bedaquiline (B)	ggucfpylel(mfejmtcuvu) = ojvczhrpst lfrfkbhsev (qwnarwzptj )	-	01 Jan 2021