bedaquiline

Its use was approved in December 2012 by the US Food and Drug Administration (FDA) for use in tuberculosis (TB) treatment, as part of a fast-track accelerated approval, for use only in cases of multidrug-resistant tuberculosis, and the more resistant extensively drug resistant tuberculosis.{{Cite press release |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm |title=FDA approves first drug to treat multi-drug resistant tuberculosis |website=U.S. Food and Drug Administration (FDA) |date=Dec 2012 |url-status=dead |archive-url=https://web.archive.org/web/20161219184517/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm |archive-date=19 December 2016 }}

{{As of|2013}}, both the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) recommend (provisionally) that bedaquiline be reserved for people with multidrug-resistant tuberculosis when an otherwise recommended regimen cannot be designed.{{cite journal | title = Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis | journal = MMWR. Recommendations and Reports | volume = 62 | issue = RR-09 | pages = 1–12 | date = October 2013 | pmid = 24157696 | author1 = Centers for Disease Control Prevention | url = https://www.cdc.gov/mmwr/pdf/rr/rr6209.pdf | access-date = 20 April 2024 | archive-date = 26 November 2022 | archive-url = https://web.archive.org/web/20221126201813/https://www.cdc.gov/mmwr/pdf/rr/rr6209.pdf | url-status = live }}{{Cite book |title=The use of bedaquiline in the treatment of multidrug-resistant tuberculosis: interim policy guidance | vauthors=((World Health Organization)) |date=February 2013 |publisher=World Health Organization (WHO) | isbn=978-92-4-150548-2 | id=WHO/HTM/TB/2013.6 | hdl=10665/84879 | hdl-access=free }}{{Update inline|date=July 2024}}

The most common side effects of bedaquiline in studies were nausea, joint and chest pain, and headache. The drug also has a black-box warning for increased risk of death and arrhythmias, as it may prolong the QT interval by blocking the hERG channel.Drugs.com: [https://www.drugs.com/sfx/sirturo-side-effects.html Sirturo Side Effects] {{webarchive|url=https://web.archive.org/web/20130923172727/http://www.drugs.com/sfx/sirturo-side-effects.html |date=23 September 2013 }} Everyone on bedaquiline should have monitoring with a baseline and repeated ECGs.

There is considerable controversy over the approval for the drug, as one of the largest studies to date had more deaths in the group receiving bedaquiline that those receiving placebo.{{cite journal | vauthors = Cox E, Laessig K | title = FDA approval of bedaquiline--the benefit-risk balance for drug-resistant tuberculosis | journal = The New England Journal of Medicine | volume = 371 | issue = 8 | pages = 689–91 | date = August 2014 | pmid = 25140952 | doi = 10.1056/NEJMp1314385 | doi-access = free }} Ten deaths occurred in the bedaquiline group out of 79, while two occurred in the placebo group, out of 81.{{cite journal | vauthors = Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, Leimane V, Andries K, Bakare N, De Marez T, Haxaire-Theeuwes M, Lounis N, Meyvisch P, De Paepe E, van Heeswijk RP, Dannemann B | title = Multidrug-resistant tuberculosis and culture conversion with bedaquiline | journal = The New England Journal of Medicine | volume = 371 | issue = 8 | pages = 723–32 | date = August 2014 | pmid = 25140958 | doi = 10.1056/NEJMoa1313865 | doi-access = free }} Of the 10 deaths on bedaquiline, one was due to a motor vehicle accident, five were judged as due to progression of the underlying tuberculosis and three were well after the person had stopped receiving bedaquiline. There remains significant concern for the higher mortality in people treated with bedaquiline, leading to the recommendation to limit its use to situations where a four drug regimen cannot otherwise be constructed, limit use with other medications that prolong the QT interval, and the placement of a prominent black box warning.

Bedaquiline should not be co-administered with other drugs that are strong inducers or inhibitors of CYP3A4, the liver enzyme responsible for oxidative metabolism of the drug. Co-administration with rifampin, a strong CYP3A4 inducer, results in a 52% decrease in the AUC of the drug. This reduces the exposure of the body to the drug and decreases the antibacterial effect. Co-administration with ketoconazole, a strong CYP3A4 inhibitor, results in a 22% increase in the AUC, and potentially an increase in the rate of adverse effects experienced.

Bedaquiline blocks the proton pump for ATP synthase of mycobacteria. It is the first member of a class of drugs called the diarylquinolines.{{cite journal | vauthors = Worley MV, Estrada SJ | title = Bedaquiline: a novel antitubercular agent for the treatment of multidrug-resistant tuberculosis | journal = Pharmacotherapy | volume = 34 | issue = 11 | pages = 1187–97 | date = November 2014 | pmid = 25203970 | doi = 10.1002/phar.1482 | pmc = 5028565 }} Bedaquiline is bactericidal. ATP production is required for cellular energy production and its loss leads inhibition of mycobacterial growth within hours of the addition of bedaquiline.{{cite journal | vauthors = Koul A, Vranckx L, Dhar N, Göhlmann HW, Özdemir E, Neefs JM, Schulz M, Lu P, Mørtz E, McKinney JD, Andries K, Bald D | title = Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism | journal = Nature Communications | volume = 5 | issue = 1 | pages = 3369 | date = February 2014 | pmid = 24569628 | pmc = 3948051 | doi = 10.1038/ncomms4369 | bibcode = 2014NatCo...5.3369K }} The onset of bedaquiline-induced mycobacterial cell death does not occur until several days after treatment, but nonetheless kills consistently thereafter.

The specific part of ATP synthase affected by bedaquiline is subunit c which is encoded by the gene atpE. Mutations in atpE can lead to resistance. Mutations in drug efflux pumps have also been linked to resistance.{{cite journal | vauthors = Andries K, Villellas C, Coeck N, Thys K, Gevers T, Vranckx L, Lounis N, de Jong BC, Koul A | title = Acquired resistance of Mycobacterium tuberculosis to bedaquiline | journal = PLOS ONE | volume = 9 | issue = 7 | pages = e102135 | date = 10 July 2014 | pmid = 25010492 | pmc = 4092087 | doi = 10.1371/journal.pone.0102135 | bibcode = 2014PLoSO...9j2135A | doi-access = free }}

Bedaquiline was described for the first time in 2004 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting, after the drug had been in development for over seven years.{{cite journal | vauthors = Protopopova M, Bogatcheva E, Nikonenko B, Hundert S, Einck L, Nacy CA | title = In search of new cures for tuberculosis | journal = Medicinal Chemistry | volume = 3 | issue = 3 | pages = 301–16 | date = May 2007 | pmid = 17504204 | doi = 10.2174/157340607780620626}} It was discovered by a team led by Koen Andries at Janssen Pharmaceutica.{{cite journal | vauthors = de Jonge MR, Koymans LH, Guillemont JE, Koul A, Andries K | title = A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910 | journal = Proteins | volume = 67 | issue = 4 | pages = 971–80 | date = June 2007 | pmid = 17387738 | doi = 10.1002/prot.21376 | s2cid = 41795564 | doi-access = free }}

Bedaquiline was approved for medical use in the United States in 2012.

It is manufactured by Johnson & Johnson (J&J), who sought accelerated approval of the drug, a type of temporary approval for diseases lacking other viable treatment options.{{Cite news |title= J&J Tuberculosis Drug Gets Fast-Track Clearance |journal= Wall Street Journal |url= https://www.wsj.com/articles/SB10001424127887323320404578213421059138236 |date= 31 December 2012 | vauthors = Walker J, Tadena N |access-date= 1 January 2013 |url-status= live |archive-url= https://web.archive.org/web/20150923144004/http://www.wsj.com/articles/SB10001424127887323320404578213421059138236 |archive-date= 23 September 2015 }} By gaining approval for a drug that treats a neglected disease, J&J is now able to request expedited FDA review of a future drug.{{cite news |title= J&J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB |url= https://www.bloomberg.com/news/2012-12-31/j-j-sirturo-wins-fda-approval-to-treat-drug-resistant-tb.html |date= 31 December 2012 | vauthors = Edney A |newspaper= Bloomberg.com |publisher= Bloomberg |access-date= 1 January 2013 |url-status= live |archive-url= https://web.archive.org/web/20130104110903/http://www.bloomberg.com/news/2012-12-31/j-j-sirturo-wins-fda-approval-to-treat-drug-resistant-tb.html |archive-date= 4 January 2013 }}

When it was approved by the FDA in December 2012, it was the first new medicine for TB in more than 40 years.{{cite web|title=FDA Approves 1st New Tuberculosis Drug in 40 Years|url=https://abcnews.go.com/Health/wireStory/fda-approves-tuberculosis-40-years-18100650|work=ABC News|access-date=31 December 2012|url-status=live|archive-url=https://web.archive.org/web/20130104001025/https://abcnews.go.com/Health/wireStory/fda-approves-tuberculosis-40-years-18100650#.UOIPT-RQWe0|archive-date=4 January 2013}}{{Cite news|title=F.D.A. Approves New Tuberculosis Drug|journal=The New York Times|url=https://www.nytimes.com/2013/01/01/business/fda-approves-new-tuberculosis-drug.html|access-date=31 December 2012|url-status=live|archive-url=https://web.archive.org/web/20130108021805/http://www.nytimes.com/2013/01/01/business/fda-approves-new-tuberculosis-drug.html?_r=0|archive-date=8 January 2013|date=31 December 2012| vauthors = Thomas K }}

In 2016, the WHO came under criticism for recommending it as an essential medicine.{{Cite web |url=https://www.arte.tv/de/videos/061650-000-A/die-who-im-griff-der-lobbyisten/ |title=Die WHO - Im Griff der Lobbyisten? |vauthors=Pinzler J, Mischke T |date=2016 |website=Arte TV |access-date=8 April 2020 |archive-date=24 April 2020 |archive-url=https://web.archive.org/web/20200424174149/https://www.arte.tv/de/videos/061650-000-A/die-who-im-griff-der-lobbyisten/ |url-status=dead }}

The WHO TB program director has pointed out that Janssen will donate $30{{nbsp}}million worth (30,000 treatment courses) of bedaquiline over a four-year period.{{Cite web |url=http://www.stoptb.org/gdf/drugsupply/bedaquilineDonation.asp |title=Stop TB Partnership, Global Drug Facility (GDF), The Bedaquiline Donation Program |last=UNOPS |date=2015 |website=www.stoptb.org |access-date=8 April 2020 |archive-date=11 June 2020 |archive-url=https://web.archive.org/web/20200611073256/http://www.stoptb.org/gdf/drugsupply/bedaquilineDonation.asp |url-status=dead }}

In 2023, a request to extend the patent on bedaquiline until 2027, was rejected by the Indian patent office.{{Cite news |last=Dhillon |first=Amrit |date=29 March 2023 |title=Victory over big pharma opens door to cheaper tuberculosis drugs |work=The Guardian |url=https://www.theguardian.com/global-development/2023/mar/29/victory-over-big-pharma-opens-door-to-cheaper-tuberculosis-drugs-india |access-date=11 July 2023 |issn=0261-3077 |archive-date=21 February 2024 |archive-url=https://web.archive.org/web/20240221210847/https://www.theguardian.com/global-development/2023/mar/29/victory-over-big-pharma-opens-door-to-cheaper-tuberculosis-drugs-india |url-status=live }} The patent was supposed to expire in July 2023, but J&J's evergreening practices will not allow the distribution of generics in several countries heavily afflicted by tuberculosis.{{Cite web |date=26 April 2023 |title=MSF demands J&J give up its patent monopoly on TB drug to put lives over profits |url=https://www.msfaccess.org/msf-demands-jj-give-its-patent-monopoly-tb-drug-put-lives-over-profits |access-date=11 July 2023 |website=Médecins Sans Frontières Access Campaign |archive-date=17 December 2023 |archive-url=https://web.archive.org/web/20231217051940/https://www.msfaccess.org/msf-demands-jj-give-its-patent-monopoly-tb-drug-put-lives-over-profits |url-status=live }}

In July 2023, the WHO's Stop TB program and Johnson & Johnson came to an agreement allowing for Stop TB Partnership's Global Drug Facility to produce generic bedaquiline for the majority of low and middle income countries.{{cite web | url=https://www.stoptb.org/news/global-drug-facility-update-access-to-bedaquiline | title=Global Drug Facility Update on Access to Bedaquiline | website=Stop TB Partnership | date=13 July 2023 | access-date=13 July 2023 | archive-date=9 March 2024 | archive-url=https://web.archive.org/web/20240309022632/https://www.stoptb.org/news/global-drug-facility-update-access-to-bedaquiline | url-status=live }}

In July 2024, the Indian Patent Office’s rejected Johnson & Johnson's application for a pediatric version of bedaquiline, paving the way for more affordable generic alternatives, potentially reducing treatment costs by 80% beyond the primary patent’s expiration in July 2023.{{cite news |title=India paves way for a cheaper anti-tuberculosis drug for kids |url=https://www.hindustantimes.com/india-news/india-paves-way-for-a-cheaper-anti-tuberculosis-drug-for-kids-101721590824223.html?utm_campaign=pharmalittle&utm_medium=email&_hsenc=p2ANqtz-8mcqtRVDIG5NK-c-jNH-VOwAZqqFlxtHX_BPp1bEmNdcOKayssd2elHqo-D9ZeiwQlPloAetxu_W_ljDemLxfQuuC49A&_hsmi=316758759&utm_content=316758759&utm_source=hs_email |publisher=Hindustan Times |date=22 July 2024 |access-date=22 July 2024 |archive-date=26 July 2024 |archive-url=https://web.archive.org/web/20240726164425/https://www.hindustantimes.com/india-news/india-paves-way-for-a-cheaper-anti-tuberculosis-drug-for-kids-101721590824223.html?_hsenc=p2ANqtz-8mcqtRVDIG5NK-c-jNH-VOwAZqqFlxtHX_BPp1bEmNdcOKayssd2elHqo-D9ZeiwQlPloAetxu_W_ljDemLxfQuuC49A&_hsmi=316758759 |url-status=live }}

The cost for six months is approximately {{US$|900}} in low-income countries, $3,000 in middle-income countries, and $30,000 in high-income countries.{{cite book | vauthors = ((World Health Organization)) | year = 2015 | title = The selection and use of essential medicines. Twentieth report of the WHO Expert Committee 2015 (including 19th WHO Model List of Essential Medicines and 5th WHO Model List of Essential Medicines for Children) | publisher = World Health Organization | location = Geneva | author-link = World Health Organization | hdl = 10665/189763 | id = WHO technical report series;994 | hdl-access=free | isbn = 9789241209946 | issn = 0512-3054 | pages=26–30 }}

The public sector invested $455–747{{nbsp}}million in developing bedaquiline. This is thought to be 1.6x to 5.1x what the owner, Janssen Biotech, invested (estimated at $90–240{{nbsp}}million). If capitalized and risk-adjusted, these costs become $647–1,201{{nbsp}}million and $292–772{{nbsp}}million, respectively.{{cite journal | vauthors = Gotham D, McKenna L, Frick M, Lessem E | title = Public investments in the clinical development of bedaquiline | journal = PLOS ONE | volume = 15 | issue = 9 | pages = e0239118 | date = 18 September 2020 | pmid = 32946474 | pmc = 7500616 | doi = 10.1371/journal.pone.0239118 | bibcode = 2020PLoSO..1539118G | doi-access = free }}

In vitro experiments have indicated that bedaquiline may also target the mitochondrial ATP synthase of malignant mammalian cells and reduce the rate of metastasis.{{cite journal | vauthors = Fiorillo M, Scatena C, Naccarato AG, Sotgia F, Lisanti MP | title = Bedaquiline, an FDA-approved drug, inhibits mitochondrial ATP production and metastasis in vivo, by targeting the gamma subunit (ATP5F1C) of the ATP synthase | journal = Cell Death and Differentiation | volume = 28| issue = 9| pages = 2797–2817| date = May 2021 | pmid = 33986463 | doi = 10.1038/s41418-021-00788-x | pmc = 8408289 | s2cid = 234496165 | doi-access = free | title-link = doi }}

Bedaquiline has been studied in phase IIb studies for the treatment of multidrug-resistant tuberculosis while phase III studies are currently underway.{{cite journal | vauthors = Field SK | title = Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment? | journal = Therapeutic Advances in Chronic Disease | volume = 6 | issue = 4 | pages = 170–84 | date = July 2015 | pmid = 26137207 | pmc = 4480545 | doi = 10.1177/2040622315582325 }} It has been shown to improve cure rates of smear-positive multidrug-resistant tuberculosis, though with some concern for increased rates of death.

Small studies have also examined its use as salvage therapy for non-tuberculous mycobacterial infections.

It is a component of the experimental BPaMZ combination treatment (bedaquiline + pretomanid + moxifloxacin + pyrazinamide).{{Cite web|url=https://www.tballiance.org/portfolio/regimen/bpamz|archiveurl=https://web.archive.org/web/20170219100904/https://www.tballiance.org/portfolio/regimen/bpamz|url-status=dead|title=BPaMZ|date=12 July 2016|archivedate=19 February 2017|website=TB Alliance}}{{Cite web|url=https://www.newscientist.com/article/2121354-two-new-drug-therapies-might-cure-every-form-of-tuberculosis/|archiveurl=https://web.archive.org/web/20170220094956/https://www.newscientist.com/article/2121354-two-new-drug-therapies-might-cure-every-form-of-tuberculosis/|url-status=dead|title=Two new drug therapies might cure every form of tuberculosis|archivedate=20 February 2017|website=New Scientist}}

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