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Home , Delamanid, Efavirenz, Pretomanid, SQ109, Sutezolid, Terizidone

New Drugs for the Treatment of

Elisa H. Ignatius, MD, MSca, Kelly E. Dooley, MD, PhDb,*

KEYWORDS  Tuberculosis     New drugs  Pharmacology

KEY POINTS  Treatment success rates for drug-susceptible tuberculosis are too low, and prognosis for drug- resistant TB remains poor.  Though shorter 9- to 12-month regimens are available for the treatment of MDR-TB, therapy is complex and often toxic.  The diarylquinoline, bedaquiline (BDQ), and the delamanid and pretomanid, have excellent preclinical and clinical data to support their use for MDR or XDR-TB. Multiple trials are centered on use of these drugs to produce well-tolerated, all-oral, short-course regimens.  Further study of new drugs is urgently needed among children, pregnant women, and people living with HIV to guide clinicians.  The pipeline now contains numerous new chemical entities from 16 drug classes with encouraging results from late preclinical or early clinical testing, the “third wave” of TB drug development.

INTRODUCTION Mycobacterium tuberculosis (M.tb.) resistant to and . Despite efforts to extend In 2014, tuberculosis (TB) surpassed HIV as the access to treatment, the prognosis for patients leading infectious cause of death. According to with MDR-TB remains poor, with only 55% treat- the World Health Organization (WHO), there ment success.1 Treatment outcomes for patients were 10 million incident cases of TB in 2017 with 1 with extensively drug-resistant (XDR) TB (MDR- 1.3 million deaths. Treatment success was TB that is also resistant to fluoroquinolones and 82%, a number that seems to be decreasing. injectable agents) are exceptionally poor, and This is alarming given that small changes in treat- now totally drug-resistant (TDR)-TB is docu- ment efficacy meaningfully affect population-level 2 mented, ushering us back to the preantibiotic incidence and mortality. The first-line regimen, era.4 In a study of patients in South Africa with developed in the 1950s to 1970s, remains lengthy “programmatically incurable tuberculosis,” many (6 months) and is unforgiving to minor lapses 3 were discharged to the community once treat- in adherence. Meanwhile, in 2017, 458,000 peo- ment options were exhausted, and community- ple developed multidrug-resistant (MDR) TB, level transmission occurred. Despite treatment

Disclosure Statement: E.H. Ignatius has no conflicts of interest to report. K.E. Dooley is principal investigator or protocol chair for trials involving BDQ, delamanid, pretomanid, , levofloxacin, high-dose isoniazid, and meropenem. Support and funding for these trials are provided by the NIH or FDA. She receives no salary support from drug companies for these studies. This work was supported by the National Institutes of Health T32-AI007291-27 to E.H. Ignatius. The content is solely the responsibility of the authors and does not neces- sarily represent the official views of the National Institutes of Health. K.E. Dooley received no support for her work on this article. a Department of Medicine, Johns Hopkins University School of Medicine, 1830 Building Room 450B, 1830 East Monument Street, Baltimore, MD 21287, USA; b Department of Medicine, Center for Tuberculosis Research, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Osler 527, Baltimore, MD, USA * Corresponding author. E-mail address: [email protected]

Clin Chest Med 40 (2019) 811–827 https://doi.org/10.1016/j.ccm.2019.08.001

0272-5231/19/Ó 2019 Elsevier Inc. All rights reserved. chestmed.theclinics.com 812 Ignatius & Dooley

failure, 90% of their sputum isolates were sensi- Table 1 tive to newer drugs, namely , BDQ, and Standard-duration therapy for MDR-TB 5 delamanid. recommended by the WHO There have been recent WHO updates to guidance for MDR-TB treatment.6 Ashort- Group Drug duration regimen, commonly referred to as the Group A: Include all 3 Levofloxacin (Lfx) Bangladesh regimen, yielded promising results OR 7 for a 9- to 12-month course, and subsequent (Mfx, M) cohort studies and a phase 3 , Bedaquiline (BDQ, B) STREAM, confirmed these impressive results.8 Linezolid (LZD) This “short-course” MDR-TB regimen still Group B: Add one or Clofazamine (CFZ) requires use of 7 drugs and is offered as a com- both medicines (Cs) OR plete regimen, with no allowance for substitu- (Trd) tions or deletions. Thus, the application of this Group C: To complete (Emb, E) regimen in some settings may be limited by regimen Delamanid (DLM, D) drug-resistance patterns.9 OR Group A or B (PZA, Fortunately, the second wave of antitubercu- cannot be used or Z) losis drug development, which included the Imipenem-cilastatin (Ipm/Cln) OR diarylquinoline, BDQ, and 2 nitroimidazoles, a delamanid and pretomanid, offers the potential meropenem (Mpm) (Am) OR for simple, shorter, all-oral regimens for MDR- (S) and XDR-TB treatment. In vitro,animal,and (Eto) OR early clinical experience with these 3 compounds (Pto) has been promising, and trials are ongoing to p-Aminosalicylic acid determine the best multidrug combinations, (PAS) including among children and persons living a with HIV (PLWH). Emerging results from the With amoxicillin-clavulanic acid. From World Health Organization (WHO). WHO Otsuka phase 3 randomized controlled trial Technical report on critical concentrations for TB drug (RCT) of delamanid, the short-course MDR-TB susceptibility testing of medicines used in the treatment regimen (STREAM Stage 1), and pediatric phar- of drug-resistant TB. Geneva; 2019. Available at: https:// macokinetic (PK) and safety studies of BDQ apps.who.int/iris/bitstream/handle/10665/311389/978924 5 and delamanid, led the WHO to release a rapid 1550529-eng.pdf?ua 1 communication in August 2018 with updated Table 1 10 guidance ( ). Standard-duration treat- It was granted approval for MDR-TB at 400 mg ment of MDR-TB now should include fluoroqui- daily for 14 days followed by 200 mg thrice nolone, BDQ, and linezolid plus or weekly for 22 weeks by the US Food and Drug cycloserine, with additional drugs such as Administration (FDA) in 2012 and by the Euro- delamanid used to comprise a 4- to 5-drug pean Medicines Agency (EMA) in 2013, making regimen. it the first drug approved for the treatment of This article outlines the history, mechanisms of TB in 40 years. Shortly thereafter, the WHO action and resistance, preclinical studies, phar- released interim guidance that BDQ could be macology, clinical evaluation, and treatment niche used in combination with second-line drugs to for new drugs for TB treatment that are licensed treat pulmonary MDR-TB.11 or in late clinical testing: BDQ, delamanid, and pretomanid. Also provided is a short summary Preclinical data of promising new chemical entities in the “third BDQ is bactericidal against M.tb.andbacterio- wave” of mycobacterial drug development, those static against other nontuberculous mycobacte- that are in earlier phases of clinical testing but ria.12,13 In mice, BDQ has sterilizing activity show great promise for shorter or less toxic superior to that of rifampicin and shortens regimens. treatment duration required for cure in multidrug regimens.14,15 BDQ-pyrazinamide (BZ) has superior activity to rifampin-pyrazinamide NEW DRUGS IN CLINICAL USE OR LATE- (RZ).16,17 Relapse rates after 3 months of BDQ- PHASE CLINICAL TESTING pyrazinamide plusrifapentine (BZP) or moxifloxa- BDQ cin (BZM) were similar to 6 months of standard BDQ is a diarylquinoline that blocks the proton treatment.18 Pyrazinamide-free regimens, BPM pump of adenosine triphosphate (ATP) synthase. or B-pretomanid (Pa)-M (BPaM), given for New Drugs for the Treatment of Tuberculosis 813

4 months showed lower relapse rate than stan- Reassuringly, large observational cohort dard 6-month treatment.16 BPaMZ cured mice studies, including a meta-analysis of 12,030 pa- in2months.19 tients with MDR-TB and studies among PLWH, have shown that BDQ decreases rather than in- Clinical pharmacology creases mortality.6,40,41 Although QT prolongation BDQ is well absorbed, and food increases bioavail- of 15 to 20 milliseconds is common, there have 20 ability 2-fold. BDQ is highly protein bound been no reports of clinically important cardiac (99.9%) and has a large volume of distribution toxicity, even with therapy up to 12 months.42,43 21 (Vd), greater than 10,000 L. BDQ is primarily Although most data are for BDQ added to MBR, metabolized by (CYP) 3A4, it also confers benefit when substituted for forming a metabolically active M2 metabolite. injectables.44 The terminal half-life of BDQ and M2 is long, w160 days.22 BDQ’s bactericidal activity is concentration dependent.23 BDQ exposures are Delamanid lower in patients of Black race or with low albu- Delamanid (OPC-67683, DLM) is a 24,25 min. Rifampicin and rifapentine reduce BDQ that inhibits synthesis of ketomycolate, a cell wall 26 concentrations substantially (70%–80%), as lipid that constitutes one-third of M.tb’s dry 27 does EFV (50%). BDQ can be given with nevira- weight.45 Delamanid was approved by EMA in pine without dose adjustment. -boosted 2014 at a dose of 100 mg twice daily for 6 months decreases BDQ clearance by 75%, so and is recommended by WHO for MDR-TB in coadministration requires caution and ECG certain circumstances. It is approved in Europe 28 monitoring. but is not yet FDA approved.

Resistance Preclinical data Spontaneous resistance mutations to BDQ occur DLM has an extremely low minimal inhibitory at rates comparable with rifampicin with no loss concentration (MIC) against M.tb. (0.006–0.024 29 of fitness. Given BDQ’s unique target, cross- mg/mL) and displays activity against replicating resistance was not anticipated, but a study of and dormant bacilli.46 Animal studies are limited, clofazimine-resistant isolates found coexisting although a guinea pig model of cavitary disease BDQ resistance via upregulation of the efflux demonstrated activity.47 In a mouse model, pump MmpS5-MmpL5, owing to mutations in the DLM-RZ had similar treatment efficacy at 4 months 30 transcriptional regulatory Rv0678. Clinical and as RZHE for 6 months.46 murine studies have implicated Rv0678 and Rv2535c.31,32 Although BDQ resistance generally Clinical pharmacology confers cross-resistance to clofazimine, the oppo- Delamanid’s absorption is enhanced by food site is not universally true.33 Critical concentrations and may be reduced by concomitant dosing of 0.25 mg/mL on 7H11 and 1 mg/mL on MGIT have with other .48 It displays less-than- been proposed.34 proportional PK.49 Delamanid is catalyzed to DM-6705 by a pathway that involves albumin.50 Clinical data DLM is not a substrate, inhibitor, or inducer of In humans, BDQ monotherapy has delayed early CYP . Whereas the half-life of the parent bactericidal activity (EBA), likely because of its drug is 38 hours, DM-6705 has a terminal half-life mechanism of shifting ATP use to alternative path- of 121 to 322 hours.51 There were no clinically ways such as glycolysis, leading to eventual (not significant interactions when DLM was coadmi- 35–37 immediate) cell death. In a phase 2b RCT nistered with efavirenz, lopinavir/ritonavir, or among 160 patients with pulmonary MDR-TB tenofovir.48 receiving multidrug background regimen (MBR), time to culture conversion was 83 days with BDQ Resistance versus 125 days with placebo. Twenty-four-week Both delamanid and pretomanid (see later discus- culture conversion was higher (79% vs 58%), as sion) require activation involving coenzyme F420. was cure (58% vs 32%). The BDQ arm had greater Resistance mutations have been identified in QTc prolongation and mortality, although deaths fbiA, fbiB, and fbiC (involved in F420 biosynthesis) 38 were late and of variable causes. A subsequent and fgd1 and ddn (prodrug activation). The F420 single-arm trial of 233 patients confirmed the effi- cofactor is not present in mammalian cells, cacy of 24 weeks of BDQ.39 Multiple trials involving explaining the narrow spectrum of activity.52 There BDQ as part of all-oral or treatment-shortening reg- are limited data on treatment-induced resistance, imens are currently under way in both drug- but case reports describe emergence of fgd1, sensitive and drug-resistant TB (Table 2). fbiA, fbiB, and fbiC mutants.33,53 A break point of 814 Table 2 Recent, ongoing, or upcoming trials involving BDQ, delamanid, or pretomanid

Trial Status Population Sample Description Diarylquinoline BDQ Janssen C211 Phase 1–2 India, Philippines, 60 Pediatric/adolescent PK, (NCT02354014) Enrolling Russian Federation, safety, tolerability of South Africa BDQ 1 background regimen IMPAACT P1108 Phase 1–2 Haiti, India, South 72 Pediatric PK, safety, (NCT02906007) Enrolling Africa tolerability of 24 wk BDQ 1 BR for MDR-TB in HIV-infected/ uninfected children STREAM stage 2 Phase 3 China, Ethiopia, 1155 Locally used WHO (NCT02409290) Enrolling Georgia, India, approved MDR Indonesia, Republic regimen OR 40 wk of Moldova, (Bangladesh): MXF- Mongolia, South CFZ-EMB-PZA 1 INH- Africa, Uganda, PTO-KAN (1st 16 wk) Vietnam OR 40 wk (all-oral): CFZ-EMB-PZA-LFX- BDQ 1 INH-PTO (1st 16 wk) OR 28 wk CFZ- PZA-LFX-BDQ 1 INH- KAN (1st 8 wk) TRUNCATE-TB Phase 3 Philippines, Singapore, 900 Multiarm, multistage (NCT03474198) Enrolling Thailand (MAMS) trial of ultrashort regimens in drug-sensitive TB: 8 wk RHZE, then 16 wk RH OR 8–12 wk RHZE- Lzd OR 8–12 wk RHZE- CFZ OR 8–12 wk RPT- HZ-LZD-LFX OR 8– 12 wk HZE-LZD-BDQ NExT (NCT02454205) Phase 3 South Africa 300 6–8 mo KAN-MXF-PZA- Terminated ETH-TRD, then 18 mo MXF-PZA-ETH-TRD OR 6–9 mo LZD-BDQ-LFX- PZA-TRD-ETH/INH Nitroimidazoles Delamanid Otsuka 213 Phase 3 Estonia, Latvia, 511 DLM or placebo  (NCT01424670) Complete Lithuania, Moldova, 6mo1 BR  Peru, Philippines, 18–24 mo South Africa Otsuka 232 Phase 1 Philippines, South 37 Pediatric PK, safety of (NCT01856634) Complete Africa DLM 1 BR for 10 d DLM 100 or 50 mg; pediatric formulation DLM 25, 10, or 5 mg; or optimized BR Otsuka 233 Phase 2 Philippines, South 37 Pediatric 6-mo (NCT01859923) Complete Africa tolerability, PK/PD, efficacy various doses DLM 1 BR (follow-up 232) (continued on next page) 815 Table 2 (continued)

Trial Status Population Sample Description MDR-END Phase 2 Republic of Korea 238 9–12 mo DLM-LZD-LFX- (NCT02619994) Enrolling PZA vs 20–24 mo MDR-TB standard of care IMPAACT 2005 Phase 1–2 Botswana, India, South 48 PK, safety, tolerability of (NCT03141060) Enrolling Africa, Tanzania DLM 1 BR for HIV- infected/noninfected children with MDR-TB 24 wk DLM 1 BR continued ACTG A5356 Phase 2a ACTG sites globally 120 24 wk DLM-LZD 600 mg In development daily 1 BR OR 24 wk DLM-LIN 600 1 BR OR 24 wk DLM-LZD 1200 every other day ACTG 5300/IMPAACT Phase 3 Treatment of adult and 2003 (PHOENIx) Enrolling child contacts of MDR cases: 26 wk DLM OR 26 wk INH Pretomanid NC-006 STAND Phase 3 Georgia, Kenya, 1500 24 wk PaMZ (MDR or DS- (NCT02342886) Terminated Malaysia, Philippines, TB) OR 17 wk PaMZ South Africa, (DS-TB) OR 24 wk Tanzania, Uganda, RHZE (DS-TB) Zambia APT (NCT02256696) Phase 2 South Africa 183 8 wk Pa--INH- Enrolling PZA, then 4 wk Pa-Rb- INH OR 8 wk Pa-RIF- INH-PZA, then 4 wk Pa-RIF-INH OR 8 wk Pa-Rb-INH-PZA, then 4 wk Pa-Rb-INH OR 8 wk RHZE, then 4wkRH Combinations of new drugs NixTB (NCT02333799) Phase 3 South Africa 109 6–9 mo BPaLzd for XDR- Complete TB and nonresponsive MDR-TB DELIBERATE (ACTG Phase 2 Peru, South Africa 84 Cardiac (QT) safety of 5343) Complete BDQ vs DLM vs BDQ (NCT02583048) plus DLM, with BR in MDR-TB Â 24 wk NC-005 Phase 2b South Africa, Tanzania, 240 Drug-sensitive: 8 wk (NCT02193776) Complete Uganda BPaZ (with or without BDQ loading dose) OR 4HRZE/2RH Drug-resistant: 8 wk B-Pa-MXF-PZA TB-PRACTECAL Phase 2–3 Belarus, South Africa, 630 Short-course treatment, (NCT02589782) Enrolling Uzbekistan adaptive design 24 wk BDQ-Pa-LZD-MXF OR 24 wk BDQ-Pa- LZD-CFZ OR 24 wk BDQ-Pa-LZD OR local standard of care (continued on next page) 816 Ignatius & Dooley

Table 2 (continued)

Trial Status Population Sample Description endTB (NCT02754765) Phase 3 Georgia, Kazakhstan, 750 Adaptive design Enrolling Kyrgyzstan, Lesotho, 39 wk BDQ-LZD-MXF- Peru, South Africa PZA OR 39 wk BDQ- LZD-CFZ-LFX-PZA OR 39 wk BQD-DLM-LZD- LFX-PZA OR 39 wk DLM-LZD-CFZ-LFX- PZA OR 39 wk DLM- CFZ-MXF-PZA OR 86 wk local standard of care ZeNiX (NCT03086486) Phase 3 Georgia, Republic of 180 26 wk tx for XDR or Enrolling Moldova, Russian nonresponsive MDR- Federation, South TB, duration/dose Lzd Africa LZD 1200 mg  26 wk- Pa-BDQ OR LZD 1200 mg  9 wk-Pa- BDQ OR LZD 600 mg  26 wk-Pa-BDQ OR LZD 600 mg  9 wk- Pa-BDQ SimpliciTB Phase 2–3 Georgia 450 Drug-sensitive: 17 wk (NCT03338621) Enrolling BDQ-Pa-MXF-PZA OR 26 wk standard (2HRZE/4HR) Drug-resistant: 26 wk BDQ-Pa-MXF-PZA IMPAACT 2020 Phase 2 IMPAACT international 148 Children with MDR-TB In development sites 8 wk LZD 1 24 wk BDQ- DMN-LFX/FLO BEAT TB Phase 3 BDQ-DLM-LZD-CF-LFX In development for 6 mo treatment of MDR-TB

Abbreviations: BR, background regimen; CFZ, clofazimine; DLM/D, delamanid; DS, drug-sensitive; EMB, ethambutol; ETH, ethionamide; INH, isoniazid; KAN, kanamycin; LFX, levofloxacin; LZD/L, linezolid; MXF, moxifloxacin; Pa, pretomanid; PTO, prothionamide; PZA, pyrazinamide; Rb, rifabutin; RIF, rifampin; TRD, terizidone.

0.016 mg/mL on 7H11 and 0.06 mg/mL on MGIT is significant difference was not detected.55 None- proposed.34 theless, given the measurable activity of the drug in the phase 2 program coupled with the Clinical data drug’s excellent safety profile, the WHO includes Phase 2a EBA trials demonstrated measurable DLM among drugs that can be used for MDR-TB. but overlapping activity of different doses of Simplified regimens including delamanid are un- 51 delamanid. In a phase 2b RCT in 481 patients der study (see Table 2). Though marketed for with MDR-TB receiving MBR, delamanid use for 6 months, it has been well tolerated for 100 mg or 200 mg twice daily given for 8 weeks up to 20 months.56,57 had higher culture conversion at 2 months (45% and 42%) than placebo (30%).49 Modest QT pro- Pretomanid longation was seen. In a nonrandomized follow- on study, longer delamanid use was associated Like delamanid, pretomanid (Pa) (PA-824) is with favorable outcomes (74.5% vs 55%) and a nitroimidazole that inhibits synthe- decreased mortality (1.0% vs 8.3%).54 In the sis in actively multiplying bacilli. In addition, phase 3 RCT of delamanid versus placebo added when it is activated by the M.tb.-specific F420- to MBR, overall treatment success at 30 months dependent nitroreductase, toxic reactive was high in both arms (>80%), so a statistically species are released, killing nonreplicating New Drugs for the Treatment of Tuberculosis 817 bacilli.58,59 A new drug application to the FDA was this regimen. Remarkably, in patients with approved in 2019. XDR-TB, thought nearly untreatable, a regimen of BDQ-pretomanid-linezolid (BPaLz) tested in the Preclinical data NixTB trial showed favorable outcomes in w90% Pretomanid’s MIC against M.tb. is between 0.015 of patients. Duration-dependent myelosuppres- m and 0.25 g/mL for drug-sensitive strains and 0.03 sion and neuropathy from linezolid are common; m 60 to 0.53 g/mL for drug-resistant strains. Preto- therefore, ZeNix was started to evaluate optimal 61 manid is active against “persisters” and under linezolid dose and duration in BPaLZ regimens.73 oxygen-poor conditions.60 Mouse models have revealed time above MIC to be the PK driver for PRACTICAL ASPECTS OF TREATMENT WITH 62 nitroimidazoles. PaMZ in mice reduced treat- NEW DRUGS ment time by 1 to 2 months compared with stan- Coadministration dard therapy,63 and the addition of BDQ (BPaMZ) cured mice in 2 months.19 There is mounting evidence to support concurrent use of BDQ and a nitroimidazole, despite initial Clinical pharmacology concerns for QT prolongation risk. Medecins Pretomanid has a half-life of 16 to 20 hours, is 94% Sans Frontie` res has endorsed judicious use of 64,65 protein bound, and has a large Vd ; PK is dose BDQ and delamanid since 2016 and has reported proportional up to 200 mg, then less-than-dose- excellent outcomes (74% conversion by 6 months) proportional. CYP3A is responsible for 20% of its and infrequent QT prolongation in a small cohort.74 metabolism.66 In a healthy volunteer trial, efavirenz Other small series have reported similar efficacy and rifampicin decreased pretomanid trough con- results,75–77 with episodes of QTc interval greater centrations by 46% and 85% and exposures (area than 500 milliseconds generally occurring only under the curve) by 35% and 66%, respectively, with concurrent moxifloxacin or clofazimine.42 raising concerns for coadministration.66 Lopina- Interim results from DELIBERATE, an AIDS Clinical vir/ritonavir did not affect pretomanid exposures Trials Group RCT, suggest no more than additive meaningfully. QT prolongation when BDQ and delamanid are combined. If BDQ and delamanid will be coadmi- Resistance nistered, considerations include: (1) repletion of Like delamanid, resistance to pretomanid can be K1 and Mg21 electrolytes; (2) measuring QTcF at related to prodrug activation (fgd1, ddn) or the baseline and serially; and (3) close attention to F420 biosynthetic pathway (fbiA, fbiB, fbiC).52 5 companion drugs (fluoroquinolones, clofazimine, Resistance is present in 1 in 10 organisms pre- ritonavir, , and all treatment. Mutations in Rv2983 in mouse models prolong QT). Pretomanid has a modest effect on disrupt F420 biosynthesis, a newly identified the QT interval, and with moxifloxacin did not mechanism of resistance yet to be identified in 71 67 cause QTc greater than 500 milliseconds. clinical samples. QTcF was prolonged by w20 milliseconds in pa- tients receiving BPaZ or BPaMZ, which is only clin- Clinical data 78 In the first EBA study of pretomanid, doses of 200 ically significant if baseline QTcF is high. to 1200 mg produced similar, measurable activ- Although the WHO recommends BDQ in the stan- ity.68 In a second EBA, 50 mg was less active dard (18–24 months) duration regimen, it is than 100 to 200 mg. Pretomanid causes dose- licensed only for 24 weeks; guidance regarding dependent increases in creatinine and modest prolonged use is awaited. QT prolongation.69 In an EBA study of multidrug Extrapulmonary Tuberculosis regimens, BPaZ had the highest microbiological activity, and 3 patients receiving regimens con- There are no data for pleural or pericardial TB taining BPa had grade 3 or 4 transaminase eleva- and only limited data for central nervous system tions.70 An 8-week study of PaMZ in drug- (CNS) TB. In one patient with MDR-TB meningitis sensitive TB showed higher 8-week culture con- (TBM), BDQ levels in cerebrospinal fluid (CSF) version (66%–71%) than HRZE (38%).71 A phase were undetectable, but collection conditions 3 RCT (STAND) opened in 2015 to investigate were not optimized for measurement of this highly PaMZ, but was put on temporary clinical hold to lipophilic drug.79,80 A study in rats using radiola- investigate cases of fatal . In the mean- beled delamanid showed lasting distribution into time, a different trial showed exceptionally high the brain.81 Recent work in a rabbit model of culture conversion rates in patients with MDR-TB TBM showed high brain but low CSF levels. Three receiving BPaMZ,72 and for this reason the patients with XDR-TBM, which is generally fatal, SimpliciTB phase 3 RCT was launched to explore who were treated with delamanid containing 818 gais&Dooley & Ignatius

Table 3 New chemical entities in development for treatment of tuberculosis

Name Developer Supporting Data Preclinical/Clinical Trial Objectives Trial Design aEthylenediamine: targets Mmpl3 involved in mycolate transport and processing, disrupting incorporation into cell wall SQ109 Sequella, Inc Phase 2 EBA/safety with SQ109 EBA EBA, safety, tolerability, PK 14 d: SQ109 75, 150, 300 as gastrointestinal upset, NCT01218217 (2a, of several doses with/ monotherapy OR SQ109 no QT prolongation, published) without RIF 15, 300 1 RIF OR RIF significant decline in monotherapy exposure when MAMS-TB, NCT01785186 MAMS trial to evaluate 4 14 wk INH-RIF35 -PZA-EMB administered at 150 mg (2b, published) regimens OR INH-RIF10 -PZA-Q300 with rifampin (overcome OR INH-RIF20 -PZA-Q300 at 300 mg SQ109) OR INH-RIF20 -PZA-MXF Decreases RIF MIC; No EBA OR INH-RIF10 -PZA-EMB as monotherapy or (2b–3, complete) Additive for MDR-TB in HRZE-SQ109 OR HRZE- additive to others; No Russia placebo difference in culture conversion rate Patient with INH resistance on RHZ-SQ109 developed RIF/PZA resistance

Imidazopyridine amide: inhibits qcrB subunit of cytochrome bc1 complex Q203, Qurient Co. Ltd./LLC Mouse models NCT02530710 (1a, Safety, tolerability, PK of Doses of 10, 20, 50, 100, Telacebec "Infectex” demonstrate efficacy complete) single doses in healthy 150, 200, 400, 800 mg/kg with once daily doses adults <1 mg/kg; active NCT02858973 (1b, Safety, tolerability, PK of Q203 vs placebo intracellularly and complete) multiple doses in adults extracellularly, no NCT03563599 (2, enrolling) EBA of Q203 vs RHZE Mid, high, low doses of CYPp450 inhibition Q203 in vitro aOxaborole: Inhibits leucyl-tRNA synthetase (LeuRS), protein synthesis inhibitor GSK 070, GlaxoSmithKline Good oral , NCT03557281 (2, pending) EBA, safety, tolerability in 4 2 wk GSK3036656 or RHZE GSK3036656 low protein binding, sequential cohorts with activity comparable with DS-TB INH in mice; Active at NCT03075410 (1, complete) Safety, tolerability, PK of Single dose at 5, 25, or lower doses and wider single ascending and 100 mg intervals (48 h) than repeat doses in health Daily dosing linezolid adults Oxazolidinone: protein synthesis inhibitor, binds bacterial 23s rRNA of 50S subunit to prevent formation of 70S initiation complex , Sequella, Inc, TB Alliance In mice, shortens standard NCT01225640 (2, complete) EBA and whole blood STZ 600 mg BID, 1200 mg PNU-100480 treatment by 1 mo, activity daily or RHZE activity superior to SUDOCU (2, proposed) Sutezolid EBA and dose BDQ-DLM-MXF PLUS STZ linezolid finding study 0 mg 600 mg daily, Safety and tolerability up 1200 mg daily, 600 mg to 1000 mg in humans twice daily, OR 800 mg Highly active primary twice daily metabolite (PNU- STEP (, proposed) Safety, efficacy, exposure- 4moRhigh HZE OR 4mo 101603) at higher response of rifampin Rhigh HZhigh E OR 4–6 mo concentration than

doses, STZ STZ-BDM OR 6 mo HRZE Tuberculosis of Treatment the for Drugs New parent NCT03237182 (4, enrolling) Gene-derived Phase 2 data: synergy with individualized drug- PZA, tmax 1–2 h (fasting), resistant TB regimens, 3 h (fed), half-life 3.4 h, including sutezolid 600 mg BID consistently higher than MIC (1200 mg was not) No heme/neuro AE, 14% patients with ALT elevation Delpazolid, LegoChem Biosciences, Inc Phase 1: tolerated to NCT02836483 (2, enrolling) EBA, safety, and PK 800 mg daily, 400 mg twice LCB01–0371 1200 mg twice daily daily, 800 mg twice daily, (though decline in heme LZD 600 mg twice daily values for daily doses >800 mg), rapid PO absorption, 100% oral bioavailability, tmax 0.5- 1 hr, half-life 1.3–2.1 h, plasma binding 37% (continued on next page) 819 820 gais&Dooley & Ignatius

Table 3 (continued)

Name Developer Supporting Data Preclinical/Clinical Trial Objectives Trial Design Contezolid, MicuRx Pharmaceuticals, Broad gram-positive NCT03033329 (1, complete) Safety, tolerability, PK with  Single IV dose 150– MRX-4 Inc activity, comparable with dose escalation (IV), 1800 mg linezolid; MRX-1 in crossover to PO  BID IV dosing for 10 d: phase 3 trials in China for 600, 900, 1200, 1500 mg skin/soft tissue, MRX-4 (prodrug of MRX-1) being studied in USA TBI-223 TB Alliance, Institute of Lower activity on NCT03758612 (1, pending) Single and multiple Materia Medica mammalian ascending dose trial mitochondrial protein synthesis; hepatocyte stability across 5 animal species, no evidence in vitro of CYP induction, half-life 3 h in mice, 8 h in rats; success in mice with BPa-TBI223 (replace linezolid); no hematologic/marrow toxicity in 14 and 28 d rat toxicity studies aDprE1 inhibitors: covalent (benzothiazinone): inhibits decaprenyl-phosphoribose epimerase (DprE1) involved in cell wall arabinan biosynthesis BTZ043 University of Munich, Superior to INH at 2 mo in NCT03590600 (1, enrolling) Ascending dose study BTZ043 125, 250, 500, 1000, Hans-Kno¨ ll Institute, mice (6 mo pending) 2000 mg or placebo Jena, German Center for No antagonism with Research (DZIF) existing drugs, apparent synergy in vivo with BDQ-RIF Low-level CYP450 interaction Macozinone, iM4TB-Innovative Highly active against NCT03776500 (1, pending) Safety, tolerability, PK at 150 mg BID OR 300 mg BID MCZ, Medicines for replicating bacteria; no multiple ascending doses OR 600 mg daily OR PBTZ169 Tuberculosis, Bill & antagonism with RHZE, 600 mg BID Melinda Gates synergy in vitro with Foundation, Nearmedic BDQ, CFZ, DLM, Plus LLC sutezolid Prior formulation with good tolerability, bactericidal activity against DS-TB at 640 mg aDprE1 inhibitor: non-covalent (OPC-167832: carbostyril, TBA-7371: azaindole): see above OPC-167832 Otsuka Pharmaceutical Activity against replicating NCT03678688 (1–2, Safety, tolerability, PK, Stage 1: 14 d of OPC- Development & and dormant enrolling) efficacy of multiple oral 167832 10 mg OR 30 mg Commercialization, Inc intracellular bacilli; doses in DS-TB OR 90 mg OR 270 mg OR active in acute and RHZE chronic murine models; Stage 2: 14 d of OPC- no antagonism with 167832Low DLM200 OR other TB drugs; additive OPC-167832High DLM200 effect with DLM OR DLM200 exceeding RHZE Tuberculosis of Treatment the for Drugs New TBA-7371 TB Alliance Efficacy in vitro and in mice NCT03199339 (1, complete) Safety, tolerability of single Single doses of 100, 250, Phase 1 trial complete on and multiple doses 500 1000, 1500 mg; food effect, optimal among healthy adults Multiple doses of 100, dose, DDI, PK, PD as 200, 400; DDI with single dose or multiple , doses Riminophenazine: Same class as CFZ TBI-166 Institute of Materia Excellent in vivo, shorter Unknown name (1, Safety, tolerability among Medica, CAMS & PUMC half-life, less enrolling) patients in China lipophilicity, less potential for skin discoloration and other toxicities of CFZ

Abbreviations: EBA, early bactericidal activity; RIF or R, rifampin/rifampicin; MIC, minimal inhibitory concentration; PZA or Z, pyrazinamide; PK, ; INH or H, isoniazid; EMB or E, ethambutol; Q, SQ109; STZ, sutezolid; BDQ or B, bedaquiline; DLM or D, delamanid; MXF or M, moxifloxacin; LZD, linezolid; PO, per oral; Pa, pretomanid; CYP, cytochrome p450; d, day; mg, milligram; DDI, drug-drug interaction; BID, twice daily; PD, pharmacodynamic; CFZ, clofazamine. a Denotes novel class. Adapted from Working Group on New TB Drugs (https://www.newtbdrugs.org/pipeline/clinical) as of January 2019. 821 822 Ignatius & Dooley

regimens displayed marked clinical improvement now approved for use in combination with LZD despite very low delamanid CSF/plasma ratios.82 and BDQ in patients with highly resistant TB. In In rats, pretomanid seems to cross the blood- addition, nitroimidazoles may have brain pene- brain barrier and penetrate into the brain, although tration that allows for use in CNS TB, but clinical clinical correlation is needed.83 data are lacking. Now that the WHO has listed BDQ and delamanid among the options for Children and Pregnant Women MDR-TB in the newest guidelines, access to these drugs will improve. Lastly, the third wave Initial results from Otsuka trials 232/233 demon- of TB drug discovery offers exciting new com- strated acceptable PK and safety of delamanid in pounds with numerous mechanisms of action HIV-uninfected children 3 years old; therefore, that may expand the arsenal not only for MDR- the WHO now recommends DLM for that age TB but for ultrashort combination regimens for group. The WHO recommends BDQ in children drug-sensitive TB. with MDR-TB aged 6 to 17 years.84 Trials are ongoing to optimize pediatric dosing (BDQ: Jans- sen C211, IMPAACT P1008; delamanid: Otsuka REFERENCES 233, 234, IMPAACT 2005). There is not yet a pedi- 1. World Health Organization (WHO). Global tubercu- atric formulation of BDQ, but suspension or crush- losis report 2018. WHO; 2018. Geneva (Switzerland). ing gives similar bioavailability to whole tablets.85 2. Kendall EA, Shrestha S, Cohen T, et al. Priority- Dispersible formulations of BDQ and delamanid setting for novel drug regimens to treat tubercu- are in development. Safety and efficacy of these losis: an epidemiologic model. PLoS Med 2017; drugs in children seem similar to those in adults, 14(1):e1002202. although data are limited.86–88 The pediatric inves- 3. Imperial MZ, Nahid P, Phillips PPJ, et al. A patient- tigation plan for pretomanid is progressing. There level pooled analysis of treatment-shortening regi- exist little data about use of these drugs in preg- mens for drug-susceptible pulmonary tuberculosis. nancy89; given that these drugs are life-saving in Nat Med 2018;24(11):1708–15. MDR-TB, PK and safety studies in this population 4. Slomski A. South Africa warns of emergence of are needed. “totally” drug-resistant tuberculosis. JAMA 2013; 309(11):1097–8. THE DRUG DEVELOPMENT PIPELINE 5. Dheda K, Limberis JD, Pietersen E, et al. The “third wave” of TB drug development is now Outcomes, infectiousness, and transmission dy- here (Table 3). Some compounds are from drug namics of patients with extensively drug-resistant classes already in clinical use for TB but have tuberculosis and home-discharged patients with been redesigned to optimize bioavailability, po- programmatically incurable tuberculosis: a pro- tency, safety, or activity against resistant strains spective cohort study. Lancet Respir Med 2017; (fluoroquinolones, diarylquinolines, riminophena- 5(4):269–81. zines, carbapenems, oxazolidinones, nitroimida- 6. Ahmad N, Ahuja SD, Akkerman OW, et al. zoles). Many are from new classes with novel Treatment correlates of successful outcomes in mechanisms of action (eg, inhibitors of DprE1, pulmonary multidrug-resistant tuberculosis: an in- leucyl-tRNA synthetase, catabolism). dividual patient data meta-analysis. Lancet 2018; Many of these compounds are now in phase 1 or 392(10150):821–34. phase 2 trials.90–117 7. Van Deun A, Maug AKJ, Salim MAH, et al. Short, highly effective, and inexpensive standardized SUMMARY treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2010;182(5):684–92. BDQ is proven to reduce mortality in MDR-TB, 8. Tre´bucq A, Schwoebel V, Kashongwe Z, et al. and it is recommended for use as a first-line Treatment outcome with a short multidrug- agent for patients with MDR-TB. Best practices resistant tuberculosis regimen in nine African coun- for ECG monitoring, dosing in children, and HIV tries. Int J Tuberc Lung Dis 2018;22(1):17–25. cotreatment are emerging. Delamanid, despite 9. Sotgiu G, Tiberi S, D’Ambrosio L, et al. Faster for disappointing phase 3 results, has a role as a less: the new “shorter” regimen for multidrug- companion drug in all-oral regimens for MDR- resistant tuberculosis. Eur Respir J 2016;48(5): TB. It is well tolerated, and rational dosing 1503–7. recommendations and formulations for children 10. World Health Organization. Rapid communication : are coming soon. Pretomanid, in combination key changes to treatment of multidrug- and with linezolid and BDQ, displayed exceptional ef- rifampicin-resistant tuberculosis (MDR/RR-TB). ficacy among patients with XDR-TB, and it is Geneva (Switzerland): WHO; 2018. New Drugs for the Treatment of Tuberculosis 823

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