What Therapies Are in the Pipeline for Bronchiectasis and NTM?

David E. Griffith, MDProfessor of Medicine

University of Texas Health Science Center, Tyler, TX

∗ I was a co-investigator on Insmed protocol 112, a study of inhaled liposomal amikacin for treatment refractory M. avium complex and M. abscessus lung diseases

∗ I am a co-investigator on Insmed protocols 212 and 312 studying inhaled liposomal amikacin for treatment of M. avium complex lung disease

∗ I have served on Advisory Boards for Bayer, Insmed, and Aradigm

Real or Perceived COI

∗ “Proper management requires greater expertise than is needed for treatment of TB, first, to decide who needs to be treated, and second, to determine which drug regimens to use.”

∗ Sputum conversion rates for MAC lung disease comparable to MDR-TB

∗ Sputum conversion rates for macrolide resistant MAC lung disease comparable to XDR-TB

State of the Art: NontuberculousMycobacteria and Associated Diseases

(Wolinsky, ARRD 1979;119: 107)

NTM Drug Resistance

∗ Innate or “natural” drug resistance∗ Not readily or predictably associated with in vitro

measures of resistance such as MICs∗ Inducible macrolide resistance (erm) gene

∗ Acquired drug resistance∗ Selection of isolates with naturally occurring mutations

that confer resistance to specific antibiotics∗ The form of drug resistance most associated with TB

therapy

∗ NTM∗ Long duration of therapy required∗ Multiple potentially toxic drugs necessary∗ Ubiquitous in the environment resulting in ongoing exposure∗ Innate antibiotic resistance mechanisms*

∗ Poor correlation between in vitro susceptibility and clinical response∗ Acquired antibiotic resistance

∗ Drugs∗ Wimpy drugs∗ Frequent poor correlation between in vitro susceptibilities and clinical response

∗ Co-morbidities∗ Bronchiectasis

∗ Clinical symptoms and exacerbations∗ Predisposition for NTM reinfection with ongoing exposure∗ As yet unidentified factors inhibiting therapeutic response

Impediments to effective NTM lung disease therapy

∗ New drugs under investigation∗ Inhaled Liposomal Amikacin

∗ FDA approved drugs approved for other indications∗ Bedaquiline∗ Tedizolid∗ Clofazimine

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What’s in the NTM pipeline?New drugs

What’s in the NTM pipeline?New drugs: LAI Study 112

∗ Liposomal amikacin inhaled (LAI)∗ LAI 590 mg vs placebo for 84 days, then open label∗ Primary endpoint: reduction in NTM growth by Semi-quantitative

sputum cultures∗ Primary endpoint: not achieved∗ Sputum conversion: 32% in treated group∗ 6 min walk distance improved∗ Side effects: hoarseness, bronchospasm∗ 82.4% who achieved culture conversion after 3 to 6 months of LAI

had negative sputum culture results at 12 months after discontinuation of LAI.

∗ Olivier KN et al. Am J Respir Crit Care Med 2016;Oct 17

∗ CONVERT is a prospective, multinational, randomized, open-label study evaluating the efficacy, safety, and tolerability of LAI 590 mg administered once daily, when added to a multidrug regimen, in the treatment of refractory MAC lung disease in adult non‒cystic fibrosis patients

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LAI: CONVERT Studies212 and 312

∗ Patients randomized in a 2:1 ratio to either LAI + multidrug regimen or a multidrug regimen.

∗ The primary endpoint is the percentage of patients who achieve sputum culture conversion by Month 6 (3 consecutive negative sputum cultures collected monthly).

∗ All patients who achieved sputum culture conversion continued on their randomized treatment regimen for 12 months beginning from the first negative culture that defined culture conversion.

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LAI: CONVERT Studies212 and 312

Bedaquiline Activity MAC

• Untreated isolates MIC90bedaquiline 0.004 – 0.008 µg/mL CLSI methods

• No difference in M. avium, M. intracellulare

______________________________Brown-Elliott et al., JCM, 2016

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CHEST 2015; 148(2):499-5062016 - New Jersey

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Preliminary Results of Bedaquiline as Salvage Therapy for Patients with NTM Lung Disease

∗ Case series of off-label use of bedaquiline for NTM lung disease, 6 MAC, 4 MAB

∗ Failed at least 12 mo Rx (MAC), 6 mo Rx (MAB)∗ Bedaquiline added to best possible companion drugs (X = 5)∗ Susceptibility of bedaquiline not allowed by company∗ All patients completed 6 months of bedaquiline therapy∗ 6/10 microbiologic response, 5/10 at least one neg culture∗ Mean Qtc interval change 2.4 msec∗ Nausea 60% (primarily in first 2 weeks of therapy)∗ Follow-up report in preparation…

Philley, et al Chest 2015

In Vitro Susceptibility Testing of Tedizolid Against Nontuberculous Mycobacteria.

Brown-Elliott BA, Wallace RJ Jr. J Clin Microbiol. 2017 Mar 22 Epub

Linezolid

∗ MAA MIC90 32 µg/ml∗ MAM MIC90 32 µg/ml

∗ MAC MIC50 32 µg/ml

∗ M. simiae MIC50 64 µg/ml

Tedizolid

∗ MAA MIC90 8 µg/ml∗ MAM MIC90 4 µg/ml

∗ MAC MIC50 8 µg/ml

∗ M. simiae MIC50 8 µg/ml

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∗ Open label trial of clofazimine with companion drugs for treating M. abscessussubsp abscessus lung disease (OHSU, UTHSCT)

∗ FDA sponsored (RO-1), randomized, placebo controlled trial of clofazimine monotherapy for nodular/bronchiectatic MAC lung disease (OHSU, UTHSCT,NJH, NIH)

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Ongoing Clofazimine TrialsKevin Winthrop M.D., MPH

Evaluation of Drug Efficacy:TB vs NTM

TB

∗ Potent bactericidal drugs∗ Strong correlation between

MIC and treatment response∗ Rapid microbiologic response∗ Established microbiologic

endpoints∗ Significant Public Health

implications∗ Established study

infrastructure and funding

NTM∗ Marginally effective drugs∗ Poor correlation between MIC

and treatment response∗ Slow microbiologic response∗ Significance of microbiologic

endpoints ∗ Evolving Public Health

Implications∗ No established study

infrastructure and funding

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∗ Monotherapy ∗ We don’t know the risk for acquired mutational resistance∗ Drugs are too wimpy to do studies similar to those done in TB

∗ Add on to failing regimen (? “monotherapy” trial)∗ Part of initial multidrug regimen/comparative trial∗ What are the most important endpoints?

∗ Sputum conversion∗ Shorter duration of therapy∗ Symptomatic improvement

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How do we test new drugs for MAC and other NTM?

∗ We must have a collaborative effort to recruit sufficient numbers of patients

∗ We need an NTM treatment consortium similar to the CDC TBTC

∗ We need better financial support

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How do we test new NTM drugs?

∗ Notice of NIAID’s Interest in Biomedical Research in non-AIDS associated, Pulmonary Non-Tuberculous Mycobacterial (NTM) Infections

∗ Notice Number: NOT-AI-17-016

∗ Release Date: March 7, 20172016 - New Jersey 19

And then….A miracle happened….

∗ And we thought designing trials for NTM disease was difficult....

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Bronchiectasis

1. Barker AF, et al. Lancet Respir Med. 2014.

“Almost all aerosol antibiotics reduce the

microbial load (including tobramycin, gentamicin, amikacin, and colistin),

yet no double-blind randomized trials

have met their primary clinical endpoint”1

Inhaled Antibiotic Therapy for Bronchiectasis:

Limited evidence to support inhaled antibiotics

Challenges with bronchiectasis clinical trial data to date

∗ Direct comparisons not possible due to differing methodologies1–5

∗ Existing trials failed to show a consistent benefit1–5

PosologyDefinitions of exacerbation

Patient inclusion criteria

Appropriate endpoint

RCTs

1. Haworth CS, et al. Am J Respir Crit Care Med 2014; 189: 975-82; 2. Barker AF,et al. Lancet Respir Med 2014; 2: 738-49; 3. O’Donnell A, et al. ATS 2016, abstract A1775; 4. Aksamit T, et al. CHEST 2015, abstract P8043; 5. De Soyza A, et al. ERS 2016, abstract OA27.

∗ The study of the dosages of drugs, especially the determination of appropriate dosages

∗ From Ancient Greek πόσος (pósos, “how much?”) + -ology (“suffix indicating a branch of learning”).

∗ 1820 April, E. Milligan, “On the Doses of the Ancient Physicians”, in The Edinburgh Medical and Surgical Journal: Exhibiting a Concise View of the Latest and Most Discoveries in Medicine, Surgery, and Pharmacy, volume XVI, number LXIII, Edinburgh: The difficulty here alluded to occurs in the DOSES of medicine exhibited by the ancient physicians. These have long been observed to be very large; and it was on remarking the impossibility, according to our ideas, of exhibiting them with safety to human life, or even of escaping destruction under their influence, that my observation was first drawn to the subject of ancient posology.

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“POSOLOGY”

Inhaled antibiotic trials in bronchiectasis: Aradigm

∗ Orbit 3 and 4 trial∗ Inhaled liposomal ciprofloxacin vs placebo

∗ 6 cycles: 28 days on/28 days off∗ Enrolled only patients with chronic pseudomonas∗ Two or more exacerbations in preceding year

∗ 582 patients (pooled)∗ Improved time to first exacerbation requiring antibiotic∗ Significant reduction in annual frequency of exacerbations∗ Safe and well tolerated

∗ Haworth C et al. Am J Respir Crit Care Med 2017; 195:A7604

Inhaled antibiotic trials in bronchiectasis: Bayer

∗ Respire program∗ Ciprofloxacin DPI vs placebo

∗ 14 days on/14 days off VS 28 days on/28 days off∗ Positive pre-defined bacterial sputum culture∗ Two or more exacerbations in previous year

∗ Respire 1∗ Clinical benefit in 14 day on/14 day off arm

∗ De Soyza A et al. Eur Respir J 2016; Sept OA272

∗ Respire 2∗ Prolonged time to first exacerbation in both regimens∗ Low baseline rate

∗ Aksamit TR et al. Am J Respir Crit Care Med 2017; 195: A7642

∗ Drug was safe and well tolerated

∗ The ORBIT and RESPIRE trials share a number of common features and are more rigorous in factors, including the inclusion criteria and endpoints1

∗ Taken together, the results from the RESPIRE programme and the ORBIT 3 and 4 demonstrate potential for additional study

∗ Results for Orbit Trials to be presented at ATS on Monday, May 22, 2017 10 AM, Session B14, 10 am

∗ Results for Respire Trials to be presented at ATS May 22, 2017 215 – 415 pm WCC Center Room 144A-C

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Recent Antibiotic Trials for Bronchiectasis

∗ AZD7986: oral inhibitor of dipeptidyl peptidase 1 (cathepsin C)

∗ Enzyme catalyzes the activation of neutrophil serine proteases (NSP)

∗ Phase I study: well tolerated, effectively and reversibly inhibited DPP1 and the activation of NSP’s within maturing neutrophils

∗ Novel anti-inflammatory mechanism for a disease characterized by chronic inflammation

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Insmed: Oral DPP1 InhibitorPhase II Study in Non-CF Bronchiectasis

∗ Right now, there is arguably the greatest potential for meaningful NTM and bronchiectasis research than at ANY time before…the ducks (academia, industry, government, etc.) are finally lining up in no small part because of your voices…

∗ In spite of what you hear and see, there are really not all that many of you…We may risk “study fatigue”

∗ We need to take advantage of the current circumstances, we need everyone to help row the boat…please participate in studies, ask your physicians what studies are available, be an advocate, be a supporter, donate money if you can

∗ You, after all, are the ones with skin in the game…

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An Open Appeal to Our Patient Colleagues

∗ And, oh yeah……

∗Thank you!!

∗ “Onward Through the Fog” Oat Willie

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An Open Appeal to Our Patient Colleagues

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And the time will come when you see we're all oneAnd life flows on within you and without you

-George Harrison