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