Post on 07-Aug-2020
Current Adult MDR-TB Treatment Trials
XIth International Child TB Training CourseGoudini Spa, South Africa, September 12, 2017
Presented by: Kelly Dooley MD, PhD
Johns Hopkins University School of Medicine
D I V I S I O N O F
CLINICAL
PHARMACOLOGY
Global burden of TB disease: 2015
WHO Global Tuberculosis Report 2016: http://www.who.int/tb/publications/global_report/en/
In 2014, TB surpassed HIV as the #1 infectious disease killer worldwide
In 2015, 10.4M cases
Drug-Sensitive TB: Current Treatment
PHASE Drugs Duration
Intensive Phase Isoniazid (H)Rifampin (R)Pyrazinamide (Z)Ethambutol (E)
8 weeks
Continuation Phase Isoniazid (H)Rifampin (R)
16 weeks
Modern “short-course” TB treatment requires 6 months of therapy and 4 drugs
Goal: Cure without relapse, prevent resistance
INH: Early bactericidal activity, rapid reduction in organism burden
Rifampin: Unique sterilizing activity against “persisters”, key contributor to cure without relapse
Pyrazinamide: Sterilizing activity in acidic environments over the first 2 months, allowing for shortening of treatment
Ethambutol: Prevents resistance to other antibiotics
Drug-Sensitive TB: The Role of Individual Drugs in “Short Course” Therapy
MDR- and XDR-TB: Global Health Emergencies
Multidrug-resistant TB:Mycobacterium tuberculosis resistant to isoniazid and rifampin: 480,000 incident cases in 2015
Extensively drug-resistant TB:M. tuberculosis resistant to isoniazid, rifampin, fluoroquinolones, and injectable agents
5
Composition of MDR-TB regimen: standard Rx
Pick one
Pick one
Pick two
Add Z+/- E, H
Add if needed to complete a regimen
Audience response question #1
The following DOES NOT cause QT prolongation (directly or indirectly)?
A. Clofazimine
B. Amikacin
C. Bedaquiline
D. Delamanid
E. Moxifloxacin
F. Ritonavir
G. None of the above
Drugs for MDR-TB (generally 18-24 months)
Fluoroquinolones** Generally well-tolerated
Injectables (e.g. amikacin) Hearing loss, balance
Cycloserine Central nervous system toxicity
Ethionamide Nausea/vomiting
Linezolid BM toxicity, peripheral neuropathy
Clofazimine** Skin discoloration
Para-aminosalicylic acid GI toxicity, hypersensitivity, drug-induced lupus
**=cause QT prolongation8
Injectables commonly cause severe, often-irreversible toxicities in• Injectables for MDR-TB given over
prolonged periods (median 4 monthsAUC )
• Ototoxicity• > 25% (25 of 94) of children, often
irreversible [Seddon JA et al Thorax 2014;69(5):458-64]
• Significantly affects neurocognitive development, psychosocial functioning, school performance [Franck C et al, BMCID 2014;14:426.]
• Speech/ language comorbidities• Programmatic challenge
• Can develop before it is perceived (in the high frequency ranges) [Garcia-Prats A et al., Exp. Opin. Drug Safety 2016(15); 11]
• Profound source of physical and emotional suffering for children and caregivers [Isaakidis P et al, Trop. Med & Int. Health, 2013;18(9):1128-33; Seddon JA et al Thorax 2014;69(5):458-64]
Weld et al Union meeting 2016; also Lancet Resp Med 2017
New in 2016: WHO Short-Course MDR-TB Rx (9-12 months)
4-month intensive phase High-dose INH*Prothionamide/ethionamide*Kanamycin/amikacinMoxifloxacinEthambutol*Pyrazinamide*Clofazimine
5-month continuation phase Moxifloxacin Ethambutol*Pyrazinamide*Clofazimine
van Deun, et al. AJRCCM 2010:182:684-92 *Resistance likely for many MDR patients
MDR-TB treatment outcomes
WHO Global TB Report 2016
Living or Dying with MDR-TB
The Sentinel Project: http://www.treatmentactiongroup.org/tb/publications/2013/we-can-heal
Of notified cases, WHO estimates that 1 in 5 is started on treatment
“At least they gave me money for the funeral.At least this way we can finally do something nice for Thabo. We can give him a small place to rest. And to know his peace.”
-Mafong Ntsibile, aunt of eight-year-old Thabo, who died of DR-TB
http://www.youtube.com/watch?v=sGfFxPkYKHM&feature=youtu.be
Surely we can do better.
How hard can it be??
Target Regimen Profile- Rifampin-Resistant TB
Priority attributes• <6 month duration
• >90% cure rate
• Serious adverse events <2%
• No requirement for lab or ECG testing for safety
• No drug interactions with first-line HIV drugs
• High barrier to emergence of resistance
http://apps.who.int/iris/bitstream/10665/250044/1/9789241511339-eng.pdf?ua=1
Existing drugs
Class Drug name
Fluoroquinolones Moxifloxacin
Riminophenazines Clofazimine
Oxazolidinones Linezolid
Nicotinic acids IsoniazidPyrazinamide
Beta-lactams/carbapenems
Meropenem, amox/clavFaropenem amox/clav
Class Drug name
ATP synthase inhibitors Bedaquiline
Nitroimidazoles PretomanidDelamanid
Oxazolidinones Sutezolid
Ethylene diamines SQ-109
Imidazopyridines Q203
3,4 carbostyril derivative OPC-167832
Benzothiazinones PBTZ169
New/investigational drugs
TB drug pipeline: what do we have to work with?
Audience response question #2
The following drug is included in every trial evaluating all-oral treatment shortening regimens for MDR-TB:
A. Clofazimine
B. Bedaquiline
C. Delamanid
D. Moxifloxacin
E. Pyrazinamide
Recent/enrolling/planned trials (for DR-TB)
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Key studies in Adults Phase Status
• A5312: INH dose-finding EBA• LIN-CL001: Linezolid EBA/safety, dose-finding (DS-TB)• OptiQ: Levofloxacin dose-finding• CLAM320B2202: Clofazimine (50 or 100) + OBR• Trial 213: Delamanid + OBR vs. placebo + OBR x 6 months
• STREAM Stage 1: 4MCEZHKPro/5MCZE (9 months) vs. SOC• STREAM Stage 2: SOC vs. MCEZHKPro (9 mo) vs. BLCEZHPro (9
months, all-oral) v. BLCZHK (6 months, incl injectable)• NC-005: B-Pa-M-Z• NIX-TB: B-Pa-LZD x 6 months (XDR-TB)• A5343: bedaquiline + delamanid added to OBR x 6 months• A5356: D+LZD+OBR (all-oral) vs. D+OBR (incl. injectable)• NExT-5001: LzBLvZ(H or Eth or Ter) vs. SOC• MDR-END: D+Lvf+Lzd+Z vs. SOC• TB-PRACTECAL: BPaMLz v BPaLzC v BPaLz vs. SOC• endTB: 9BLzMZ v 9BLzCLvZ v 9BLzDLvZ v 9DCMZ v SOC
• II• II• II• II/III• III
• III• III
• II• III• II• II• II/III• II• II/III• III
• Enrolling• In f/u• Enrolling• Premature end• In f/u
• In f/u• Enrolling
• In f/u• Enrolling • Enrolling• Planning• Enrolling• Enrolling• Enrolling• Enrolling
Key: Lz=linezolid; Lf=levofloxacin; D=delamanid; B=bedaquiline; Pa=pretomanid; C=clofazimine; Z=pyrazinamide
Goals:Shortened durationAll-OralBetter tolerabilityHigher cure rate
Bedaquiline
Bedaquiline
• First new TB drug licensed in 25 years, first drug of a new class licensed for TB in >40 years
• Novel mechanism of action: ATP synthase inhibition
• Registered for use in patients for whom there are no other good options (MDR- or XDR-TB)
Bedaquiline (J) has sterilizing activity ≥ rifampin (R) in mouse models
Proportion (%) relapsing after
stopping treatment at:
Regimen M1 M2 M3 M4
R 15/15
(100%)
13/15
(87%)
6/13
(46%)
RH 14/15
(93%)
7/13
(54%)
P 10/15
(67%)
0/15
(0%)
J 13/15
(87%)
2/14
(14%)
4/14
(28%)
Zhang et al, AJRCCM 2011
Lung CFU counts after 1 month of treatment
Relapse rates after treatment
Slide from Eric Nuermbergern.b. ‘J’ used to represent BDQ, now ‘B’ does
Clinical results: Bedaquiline in EBA (focus on EBA7-14)
Diacon et al 2012 Lancet
Bedaquiline for MDR-TB: 2 & 6 month efficacy studies
2-month culture conversion (n=44):
OBR+BDQ: 48%OBR+placebo: 9%
6-month culture results (n=132):
OBR+ BDQ: 79%OBR + placebo: 58%
*OBR=optimized background regimen
Diacon et al (2009) NEJM; Diacon et al (2012) AAC
Sirturo™ (bedaquiline) package insert
The ECG tracing
QT as a ‘surrogate’ for risk of torsades
Why assess QT in the first place?
• QT prolongation is a surrogate for torsade – all drugs that produce Torsades prolong QT
• Torsades is, of course, rarely captured in clinical trials
Putting it in perspective
• Torsades is very rare, even with the worst offenders• Terfenadine – incidence of torsade 1/50,000
• Unacceptable for a medicine for hay fever!• Quinidine – incidence of torsade 1-2%
Bedaquiline- emerging efficacy and safety data
GDG Bedaquiline 2017: http://www.who.int/tb/publications/2017/GDGreport_Bedaquiline/en/
Clofazimine
Rationale for testing it as Rx-shortening agent
• Highly effective in mouse models • Effective in patients with drug-resistant TB
Quicker culture conversion, quicker cavity closure, better treatment outcomes when C added to background treatment
Tang CID 2015; see also Van Deun 2010 AJRCCM; Piubello IJTLD 2014; Aung IJTLD 2014
Tyagi PNAS 2015
A5362 Study Design
• Phase IIc adaptive (2-stage), double-blind, randomized, placebo-controlled trial adding CFZ to standard combination TB therapy for participants with DS-TB
2RHZE/4RH + C(50mg)
2RHZE/4RH+
C(100mg)
SOC + CFZ placeboSt
age
I Arm 1 Arm 2 Arm 3
Stag
e II
2RHZE/2RH+CFZ 50mg
2RHZE/2RH+CFZ 100mg
SOC + CFZ placebo
Arm 1 Arm 2 Arm 3
26 Weeks
Pause
76 Weeks
? ?
By A5362 study team
Delamanid
Delamanid for MDR-TB
Gler et al. 2012Skripconova et al. 2013
Two-month culture conversion
Short-term (<2 months) vs. Long-term (>6 month) treatment outcomes
31
Phase 3 completedResults pending
Pretomanid
Promising Phase 2 data
PaMZ in DR-TB
PaMZ in DS-TB, PA 100mg QD
PaMZ in DS-TB, PA 200mg QD
Revised Phase 3
Emerging data on BPaMZ
Phase 3 (STAND) temporary halt
Adults with new sputum smear-positive, drug-sensitive pulmonary TB
PA-824 200 mgIsoniazidRifampin
PyrazinamideOnce daily for 56 doses
Randomization 1:1:1
Continue TB treatment with conventional continuation phase regimen.Study visits at 4 and 6 months
PA-824 200 mgIsoniazidRifabutin
PyrazinamideOnce daily for 56 doses
ETHAMBUTOL 15 mg/kgIsoniazidRifampin
PyrazinamideOnce daily for 56 doses
PA-824 200 mgIsoniazidRifampin
Once daily for 28 doses
PA-824 200 mgIsoniazidRifabutin
Once daily for 28 doses
IsoniazidRifampin
Once daily for 28 doses
Collect sputa for solid and liquid cultures at days 0, 7, 14, 21, 28, 42, 56, 70, 84.Safety visits at Days 7, 14, 28, 42, 56, 70, 84
Semi-Intensive PK analysis at Day 14 & Sparse PK analysis at Days 28, 56, 84Ophthalmologic examination at baseline
Weeks 0-8
Weeks 9-12
Weeks 13-24
Post-treatmentPost-treatment follow-up visit at 12
months
APT: Assessing PA-824 for TB
Phase 2 trial of PA-824 with first-line drugs for drug-sensitive TB
FDA Orphan Drugs Program
Adding new drugs with potent sterilizing activity: best option for treatment shortening?How about Pretomanid (PA-824)?
Potent combinations of new drugs
36
B, Pa, Z and M containing regimens
Participants with newly diagnosed smear positive DS- and MDR-TB
B(200mg daily) - Pa - Z
Rifafour
B(200mg daily) - Pa - Z - M
B(registered dosing) - Pa - Z
Z=pyrazinamide (1500mg daily), M = moxifloxacin 400mg daily, Pa = PA-824 200mg daily , J(registered dosing) =
bedaquiline 400mg for 14 days then 200mg three times a week, J(200mg daily) = bedaquiline 200mg daily
60 per DS groupUp to 60 MDR
DS
Randomize 8 Weeks
Serial 16 hour pooled sputum samples for TTP/CFU Count
MDR
Primary Analysis
2 Years
Survival Follow-up Visits at 6, 12, 18 and 24 Months
NC-005 – 8 week SSCC Study of B-Pa-Z-M
www.tbvi.eu/wp-content/uploads/2017/03/TBVI-February-2017.pptx
37
Overnight Overnight
B(loading)PaZ 66% 89%
B(200mg)PaZ 75%* 84%
BPaMZ (MDR) Z-sensitive 96%* 100%*
BPaMZ (MDR) Z-resistant 78%* 95%*
HRZE control 51% 86%
Growth Medium Liquid Solid
Percent of Patients Culture Negative at 2 MonthsKaplan-Meyer Analysis
* statistically significant vs HRZE
www.tbvi.eu/wp-content/uploads/2017/03/TBVI-February-2017.pptx
Patients with XDR-TB or Who Have Failed MDR-TB Treatment
Nix-TB Trial in XDR-TB
Pretomanid 200 mg
Bedaquiline 200 mg tiw after 2 week load
Linezolid 1200 mg qd**
Sites: Sizwe and Brooklyn Chest, South Africa
6 months of treatment
Additional 3 months if sputum culture positive at 4 months
XDR-TB
Follow up for relapse-free cure over 24 months
**Just amended from 600 mg bid strategy www.tbvi.eu/wp-content/uploads/2017/03/TBVI-February-
2017.pptx
Pretomanid + BDQ + LZD
39
• 67 participants enrolled as of 23 January 2017– 60% male, 40% female; 49% HIV infected– 79% XDR-TB; 21% MDR failures or intolerant
• 36 completed therapy– None required longer than 6 months of treatment– 20 followed through 6 months after completion of treatment with final results
of sputum cultures; 30 completed 6 months f/u (sputum cultures pending on final months in approximately 10)
– Total of 4 died (all in 2015, within first 7 weeks of start of treatment)• Causes:• Severe pulmonary tuberculosis and disseminated tuberculosis• Upper gastrointestinal bleeding• Acute severe worsening of tuberculosis• Multi-organ failure
• One microbiological relapse or reinfection to date – 56 yo w/XDR-TB, HIV+ - Clinically well but cultures MTB+ at 3 mos f/u after end
of 6 months of drug regimen therapy – genome sequencing not yet available
Update on Ongoing Participants
What about Bedaquiline & Delamanid?
Why are these ‘add-on’ drugs?
BDQ+DLM-- A5343: Background & Rationale• Delamanid and bedaquiline are the first drugs of new classes
licensed for treatment of TB in over 40 years; different mechanisms of action
• Neither induces or inhibits metabolizing enzymes appreciably, so low risk of metabolic drug interaction
• Both are oral agents that could potentially contribute to an injectable-free regimen for MDR-TB in the future, improved pre-XDR or XDR Rx
• Each prolongs the QT interval (10-15 msec). They are likely to be (sometimes are) used together for drug-resistant TB in the clinic
Study Schema: the DELIBERATE trial
Weeks 1-24: Study treatment Weeks 25+: Standard MDR-TB Treatment
BaselineECGs
Week 2 Week 8 Week 24
Multidrug Background Treatment
Bedaquiline + MBT
Bedaquiline + Delamanid + MBT
Delamanid + MBT Multidrug Background Treatment
ECG assessments, sparse PK sampling
= intensive PK
ECG and sparse PK every 2 weeksto 24 weeks, then once at 28 weeks
http://www.tb-symposium.org/documents/en/3_NEXT_STEPS/carole_mitnick_endtb.pdf
enrolling
TB-Practecal
https://www.msf.org.uk/content/tb-practecal
STREAM-2
9-monthFully oral
6-month, With Injectable
Circling back…
46
Key studies in Adults Phase Status
• A5312: INH dose-finding EBA• LIN-CL001: Linezolid EBA/safety, dose-finding (DS-TB)• OptiQ: Levofloxacin dose-finding• CLAM320B2202: Clofazimine (50 or 100) + OBR• Trial 213: Delamanid + OBR vs. placebo + OBR x 6 months
• STREAM Stage 1: 4MCEZHKPro/5MCZE (9 months) vs. SOC• STREAM Stage 2: SOC vs. MCEZHKPro (9 mo) vs. BLCEZHPro (9
months, all-oral) v. BLCZHK (6 months, incl injectable)• NC-005: B-Pa-M-Z• NIX-TB: B-Pa-LZD x 6 months (XDR-TB)• A5343: bedaquiline + delamanid added to OBR x 6 months• A5356: D+LZD+OBR (all-oral) vs. D+OBR (incl. injectable)• NExT-5001: LzBLvZ(H or Eth or Ter) vs. SOC• MDR-END: D+Lvf+Lzd+Z vs. SOC• TB-PRACTECAL: BPaMLz v BPaLzC v BPaLz vs. SOC• endTB: 9BLzMZ v 9BLzCLvZ v 9BLzDLvZ v 9DCMZ v SOC
• II• II• II• II/III• III
• III• III
• II• III• II• II• II/III• II• II/III• III
• Enrolling• In f/u• Enrolling• Premature end• In f/u
• In f/u• Enrolling
• In f/u• Enrolling • Enrolling• Planning• Enrolling• Enrolling• Enrolling• Enrolling
Key: Lz=linezolid; Lf=levofloxacin; D=delamanid; B=bedaquiline; Pa=pretomanid; C=clofazimine; Z=pyrazinamide
Goals:Shortened durationAll-OralBetter tolerabilityHigher cure rate
Summary
• Treatment for drug-resistant TB is long, toxic, and poorly efficacious
• Several trials are ongoing or planned in MDR- or XDR-TB with goals of:• Dose optimization• Treatment shortening• Improving tolerability• Increasing treatment success• Advancing an injectable-free regimen
• Overlapping toxicities and drug interactions add challenges
• Backbones: BCZ, BPaM, BDe, BPaLz
• Extending promising regimens to children as soon as is feasible and appropriate is a high priority
Acknowledgements
• Johns Hopkins University• Center for TB Research
• Richard Chaisson, Eric Nuermberger, (Susan Dorman), Jonathan Golub, Amita Gupta
• Division of Clinical Pharmacology• Lisa Wolf, Grace Barnes, Craig Hendrix,
Charles Flexner, Theresa Shapiro, Mark Marzinke
• Clinical Trials Networks• Tuberculosis Trials Consortium
• AIDS Clinical Trials Group
• IMPAACT Network
• Partners• TB Alliance, Sanofi, ViiV, Janssen,
Otsuka, Pfizer
• Mats Karlsson (Uppsala),
Rada Savic (UCSF)– pharmacometrics
• NIRT, BJGMC, UNC/Malawi Project
• Stellenbosch, UCT
• Funding• R01FD004794 (FDA)
• R01HD074944 (NICHD)
• R01AI111992 (NIAID)
• R01FD005724 (FDA)
• TBTC/CDC, ACTG/DAIDS
Thank you.
WHO. Roadmap for Childhood Tuberculosis: Towards Zero Deaths