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CPTR Workshop 2016: Full Content Day 2

Welcoming Remarks

Speaker: Mel Spigelman, TB Alliance

Mel Spigelman opened the day’s program by reflecting on the changing landscape of TB drug development from a sponsor perspective. Noting that the new drugs themselves are the “beef” of the CPTR initiative, he commented that the current state of TB research has seen the retreat of some major pharmaceutical developers and the influx of more non-traditional players. This creates new dynamics and opportunities for collaboration, though resources within the field remain a significant challenge.

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TB Drug Co-Development Roundtable

Introduction

Speaker: Carl Mendel, TB Alliance

Mendel echoed Spigelman’s sentiments stressing that drug development is what CPTR is truly all about. He noted the changing complexion of the field and opened the session for representatives of various organizations with TB drugs/compounds in development to offer progress updates.

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Brief Industry Updates

Speaker: Jeffrey Hafkin, Otsuka

Jeffrey Hankin offered an update on the development of delamanid, detailing the drug’s clinical trial history and relaying the status of the ongoing Phase III study and pediatric trial. The Phase III trial has completed enrollment (511 patients). Hafkin noted that 85% of patients have either completed the study or were active and adherent in participation of the study, as of March 2016. Database lock for the trial is expected in December 2016. In the pediatric trial, enrollment of children above the age of 6 is complete, and enrollment of children from ages 3 – 5 is ongoing. Hafkin also offered learnings regarding delamanid resistance mechanisms and listed planned collaborative studies, including a drug-drug interaction study with bedaquiline. Finally, Hafkin reviewed delamanid registrations to date, noting that registrations in five additional countries – including China – are in progress, and stated that delamanid is available through the Global Drug Facility.

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Speaker: Chrispin Kambili, Janssen

Chrispin Kambili outlined bedaquiline’s clinical development to date and noted that more than 800 patients with XDR-TB or pre-XDR-TB have received bedaquiline through expanded access programs across 47 countries. Bedaquiline has been registered in 42 countries and is available through the Global Drug Facility and through a donation program, for which 111 countries are eligible. Kambili also shared learnings on acquired resistance to bedaquiline, as well as data around on acquired resistance to other drugs administered in regimens with bedaquiline, which may help to elucidate how use of bedaquiline may contribute to the prevention of resistance for other drugs.

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Speaker: Steve Murray, TB Alliance

Steve Murray reiterated TB Alliance’s goal of a fully novel regimen and referenced ongoing TB Alliance trials in the context of this goal, indicating that successive trials are testing regimens with more novel components. Murray shared the status of the Nix-TB trial, the first to test a completely novel regimen (in XDR-TB patients), explaining the trial design and remarking that it was progressing very well. The NC-005 trial of the BPaz regimen has completed enrollment and data is expected later this year. Murray also gave updates on the status of the STAND trial, which is on clinical hold, and shared that the development of the drug candidate TBA-354 has been suspended.

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Speaker: Charles Wells, Sanofi

Charles Wells provided an update on Rifapentine, for which the WHO recently issued guidelines for 3-month use for latent TB infection. Rifapentine has also been added the WHO’s Essential Medicines List. Wells also referenced a study in partnership with the CDC and TBTC that is assessing Rifapentine in a shortened regimen for active TB and recently began enrolling patients. Finally, he confirmed that plans for pediatric development of the drug are underway.

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Speaker: I.D. Rusen, International Union Against TB and Lung Disease (IUATLD)

I.D. Rusen provided updates on the STREAM trial, for both Stages 1 and 2. The last patient visit for Stage 1 of the trial, testing the “Bangladesh regimen” is scheduled for late 2017, with results expected the following year. The second Stage of the trial adds two additional regimens and enrolled its first patient in March. A large trial, which will require extensive enrollment and lengthy follow-up, its results will not be expected until 2021.

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Speaker: Michael Hölscher, University of Munich

Michael Hölscher offered an update on the TB drug compound, BTZ043, detailing the history of the compound and some of its attributes. Development of this compound is ongoing, in collaboration with the German Center for Infectious Disease Research. Hölscher outlined a plan for how development of this compound could work, including the collaborations planned/needed. It is hoped that BTZ043 can progress to human trials within a year’s time.

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Speaker: Kiyean Nam, Qurient

Nam delivered an update on the compound Q203, currently in Phase 1 trials in the U.S. He presented efficacy data from the mouse model and in vivo data on the compound in combination with various other TB drugs and drug candidates, including bedaquiline and pyrazinamide. Nam also relayed learnings stemming from dosing studies.

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Speaker: Andreas Diacon, University of Stellenbosch

Diacon reported on the beta-lactams class of TB drug candidates, presenting data from a two-week proof of concept study that showed strong results for meropenam. One of the challenges associated with this drug candidate is that it is not currently formulated for once-daily, oral administration. Diacon discussed the potential to adapt it to be more practical for use in lower resource settings.

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Speaker: David Barrios-Aguirre – GlaxoSmithKline (GSK)

Barrios -Aguirre outlined GSK’s portfolio of TB projects and emphasized GSK’s commitment to partnership-based TB drug development. He highlighted drug candidates from the LeuRS Inhibitors class, presenting efficacy data from in vivo studies of compounds GSK147 and GSK070. Additional promising properties of these compound include apparent synergy with other TB drugs, a novel mechanism of action, encouraging safety profiles, and a very low active dose in humans. Human testing is anticipated to begin in 2016.

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Speaker: Andrew Phipps, Sequella

Phipps focused his presentation on SQ109, noting that 260 subjects have received the drug thus far, with no serious adverse events reported. Phipps reported on the status of an MDR-TB trial in Russia and PanACEA’s TB MAMS trial, both of which include SQ109. Phipps acknowledged the need to further investigated drug-drug interactions between SQ109 and other relevant TB drug candidates.

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Panel Discussion

The session concluded with a robust question and answer session that included all the presenters.

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Emerging TB Drug Discovery Pipeline

Overview of Anticipated Drug Discovery Pipeline for Clinical Development

Speaker: Nader Fotouhi, TB Alliance

The ultimate success of CPTR and the radical transformation of TB treatment will require the development of additional new drugs, beyond those recently introduced and currently in clinical trials. Nader Fotouhi presented on the state of the current TB drug discovery pipeline. He began by articulating some of the reasons TB drug discovery has lagged, specifically a lack of investment and incomplete understanding of M.tb biology. Fotuohi discussed some of the current drug discovery priorities and strategies, emphasizing the pursuit of novel targets and pathways and the importance of safety. He remarked on the critical role the Bill & Melinda Gates TB Drug Accelerator program has played and will continue to play in drug discovery efforts, referencing new animal models, enhanced screening capabilities, and increased investment in understanding of the TB bug. Fotouhi stated that it is expected that two new drug candidates will advance into human studies by the end of 2016. The session culminated with questions and answers.

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Consortium for TB Biomarkers (CTB2) Initiative

TB Biorepository for Identifying Biomarkers and Accelerating TB Treatments

Speaker: Payam Nahid, University of California, San Francisco

The establishment of biomarkers could prove extremely valuable in accelerating the development of new TB therapies. Payam Nahid spoke on the CTB2 biobank and key features thereof. The biobank houses robust, long-term data for adult TB patients, including multiple types of samples collected at 7 different times throughout treatment/observation. Slated to hold 1,000 patient samples when complete, the biorepository currently contains samples from 600 patients.

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Relational Sequencing TB Data Platform (ReSeq TB) Unraveling the Genetic Basis of TB Drug Resistance

Introduction

Speaker: Angela Starks, Centers for Disease Control and Prevention (CDC)

This session was opened by Angela Starks of the CDC, who set the context for the discussion of ReSeq TB and the need for improved drug sensitivity testing (DST).

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The Need for a Standardized Global Sequencing Data Platform

Speaker: Daniela Cirillo, San Raffaele Scientific Institute

Daniela Cirillo detailed the need for a platform like ReSeq TB, reminding the audience that currently only a small fraction of MDR-TB cases are correctly identified, and even fewer are properly treated. Many barriers contribute to this reality, including resource constrains, a lack of fundamental knowledge about acquired resistance, and less than perfect DST technologies. Molecular genotypic diagnostics could increase access to proper diagnosis. Cirillo noted that in Nigeria in 2014 all confirmed MDR-TB cases were diagnosed through the use of Gene Xpert, but there are still challenges to implementing these tools. In order to develop improved genotypic tests, the research community needs more complete knowledge stemming from global data. The backbone for establishing this knowledge key to improved product development is a global and standardized database.

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ReSeq TB Data Platform Pipeline Threshold Values

Speaker: Jamie Posey, Centers for Disease Control and Prevention

Jamie Posey’s presentation detailed specific technical processes and decisions relating to how data makes its way into the ReeSeq TB database, including how it is ensured that data is clean and standardized across the various inputs. Posey noted that the platform contains more than 3,700 isolates, after excluding those that failed quality checks.

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ReSeq TB Question and Answer Session 1

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ReSeq TB Data Platform Overview

Speaker: Rick Liwski, Critical Path Institute

Rick Liwski urged the workshop participants to keep this an interactive session and continue to provide feedback on ways to make ReSeq TB more useful to users. He discussed how data was acquired for the platform and suggested that there are mechanisms for additional partners to participate and contribute data, then explained several useful features for data contributors and those using the platform to access data. Liwski then looked toward the ongoing evolution of the platform noting that its use is growing and capacity expanding. ReSeq TB is currently available to CPTR partners, but will be made available to external researchers in the near future.

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Regulatory Perspective for Infectious Disease Diagnostics and FDA-ARGOS Database

Speaker: Heike Sichtig, Food and Drug Administration (FDA)

Heike Sichtig discussed FDA’s perspective, knowledge, and needs relating to validating TB diagnostics and summarized the FDA-ARGOS database to evaluate and validate diagnostics, noting that FDA is open to receiving additional isolates to help increase the scope and usefulness of the tool. Sichtig went on to detail other tools and reference materials for advancing the development of infectious disease diagnostics.

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ReSeq TB Question and Answer Session 2

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Closing Remarks

Speaker: Jan Gheuens, Bill & Melinda Gates Foundation

Gheuens closed the workshop’s second day acknowledging the role of DST in ensuring the impact of new TB treatments, and praising the growing synergies between drug and diagnostic developers.

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