The Tuberculosis Treatment Pipeline: Activity, but No Answers

In the past year, the development of new tuberculosis (TB) drug candidates experienced some setbacks as well as some wise pruning, with the unexpected suspension of enrollment in STAND (a phase III combination trial that includes the new drug pretomanid), the discontinuation of candidate TBA-354 (due to signs of toxicity), and the official end of development of AZD5847 (due to lack of anti-TB activity). In a bright spot, Qurient's Q203 entered phase I, representing a new drug class and a new sponsor in TB clinical trials. But overall, the new TB drug development landscape remains parched, with just five candidates from four classes in development -- including bedaquiline and delamanid, which already have conditional marketing approval in some countries. Most of these drugs have been stalled for years. Delays across the board, from sponsors, from regulators, and from funders, are preventing nascent progress from flourishing. The phase III trial for bedaquiline has finally started enrolling -- some five years after the phase IIb trial concluded. Sutezolid is still awaiting entry into phase IIb, nearly five years after showing promise in phase IIa. Delamanid's phase III trial is chugging along dutifully, but, due to the lengthy standard-of-care background treatment and follow-up time required in TB clinical studies, won't give results till 2018.More activity is ongoing among trials testing combinations of drugs already on the market, often called repurposed drugs. But again, most will not bear fruit for several years. These various trials to optimize therapies point to creativity among researchers but also to the poor existing evidence base for use that has left the TB field reliant upon lengthy, poorly tolerated -- and, for drug-resistant TB, marginally effective -- regimens. Some exciting advances are being made in preventive therapy for TB -- these are now reported in the TB prevention chapter (see page 143) -- but this chapter will focus exclusively on the development of treatments for active TB disease.New guidelines from the World Health Organization (WHO) may help improve the treatment of multidrug-resistant TB (MDR-TB) by updating options for stronger treatments in combination regimens, though the newly recommended putative treatment-shortening approach has yet to be validated in randomized controlled trials. However, the updated WHO guidelines will help increase the use and availability of drugs of greater potency such as delamanid, bedaquiline, clofazimine, and linezolid.1 MDR-TB treatment is still inadequate, with fewer than 10% of those with the disease successfully treated worldwide, and less than 2% of those who may benefit from new drugs receiving them.2,3 Investment in new alternatives is also scandalously low; in 2014, just US$243 million out of the needed US$740 million were available for TB drug research and development (R&D).4 Recent global and national strategic plans to address antimicrobial resistance and TB, such as those from the Netherlands, the United States, and the United Kingdom, must go beyond lip service and be met with financial commitments to increase support for TB R&D.5,6,7,8 Countries with high TB burdens and large economies, such as Brazil, China, India, Indonesia, Russia, and South Africa, must contribute far more to R&D as well as to service scale-up

The Tuberculosis Diagnostics Pipeline

Over the past decade, several new options for improving TB diagnosis have become available. The past year saw considerably more progress than the previous one. However, the reality of how most TB is diagnosed -- or not -- remains largely unchanged. The world failed to detect 3.6 million of the estimated 9.6 million new cases of TB in 2014. Sputum smear microscopy -- which misses over half of TB cases and gives no indication of drug susceptibility to guide appropriate treatment -- is still the diagnostic standard in most of the world, despite the availability of the far more sensitive GeneXpert MTB/RIF for six years. Late in 2015, the World Health Organization (WHO) approved Alere's TB lipoarabinomannan (LAM) test -- a very affordable, simple, rapid, noninvasive, point-of-care (POC) rule-in test for people with HIV with very low CD4 counts -- but no country has begun to implement it yet. New versions of line probe assays -- Hain's MTBDRplus and MTBDRsl and a product from Nipro -- received WHO recommendation, facilitating rapid drug susceptibility testing (DST), but the world is still a long way from universal DST, with an estimated 59 percent of cases of multidrugresistant TB (MDR-TB) undetected.Research and development (R&D) for TB diagnostics features some promising developments since last year (see table 1). Improvements on nucleic acid amplification tests (NAATs) such as GeneXpert Omni and Ultra and Molbio's TrueNAT are being validated, positioning them for possible WHO recommendation. Further upstream, encouraging research into gene sets that can predict active TB disease and reliably distinguish it from latent TB and other infections may eventually underpin new blood tests (currently, there is no effective serological test for active TB). Incremental advances are being made to improve detection of pediatric TB (see "Extending quality," page 133).Yet, overall, with a mere US$65 million in 2014 funding out of an estimated annual need of$340 million, the pipeline for evidence-based new diagnostics has largely remained stagnant (see table 2). Dismayingly, some companies continue to move forward with marketing for their products when the data are unavailable or scream that they should not, as is the case with Epistem, which is marketing GeneDrive in India despite the test's having flopped in studies.With use of poor tests predominating, poor uptake of good extant options, poor evidence bases to support the introduction of new tests, and poor funding to support the development of better tests, it's no wonder we've made little headway in diagnosing TB

2016 Pipeline Report Tuberculosis Edition

Over the past decade, several new options for improving TB diagnosis have become available. The past year saw considerably more progress than the previous one. However, the reality of how most TB is diagnosed—or not—remains largely unchanged. The world failed to detect 3.6 million of the estimated 9.6 million new cases of TB in 2014. Sputum smear microscopy—which misses over half of TB cases and gives no indication of drug susceptibility to guide appropriate treatment—is still the diagnostic standard in most of the world, despite the availability of the far more sensitive GeneXpert MTB/RIF for six years. Late in 2015, the World Health Organization (WHO) approved Alere's TB lipoarabinomannan (LAM) test—a very affordable, simple, rapid, noninvasive, point-of-care (POC) rule-in test for people with HIV with very low CD4 counts—but no country has begun to implement it yet. New versions of line probe assays—Hain's MTBDRplus and MTBDRsl and a product from Nipro—received WHO recommendation, facilitating rapid drug susceptibility testing (DST), but the world is still a long way from universal DST, with an estimated 59 percent of cases of multidrugresistant TB (MDR-TB) undetected.Research and development (R&D) for TB diagnostics features some promising developments since last year (see table 1). Improvements on nucleic acid amplification tests (NAATs) such as GeneXpert Omni and Ultra and Molbio's TrueNAT are being validated, positioning them for possible WHO recommendation. Further upstream, encouraging research into gene sets that can predict active TB disease and reliably distinguish it from latent TB and other infections may eventually underpin new blood tests (currently, there is no effective serological test for active TB). Incremental advances are being made to improve detection of pediatric TB (see "Extending quality," page 133).Yet, overall, with a mere US$65 million in 2014 funding out of an estimated annual need of$340 million, the pipeline for evidence-based new diagnostics has largely remained stagnant (see table 2). Dismayingly, some companies continue to move forward with marketing for their products when the data are unavailable or scream that they should not, as is the case with Epistem, which is marketing GeneDrive in India despite the test's having flopped in studies.With use of poor tests predominating, poor uptake of good extant options, poor evidence bases to support the introduction of new tests, and poor funding to support the development of better tests, it's no wonder we've made little headway in diagnosing TB

2016 Pipeline Report HIV and TB

HIV and TB: Drugs, Diagnostics, Vaccines, Preventive Technologies, Research Toward a Cure, and Immune-Based and Gene Therapies in Developmen

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis.

Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues

Towards early inclusion of children in tuberculosis drugs trials : a consensus statement

Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally eff ective, are hampered by high pill burden, long duration of treatment, coexistent toxic eff ects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.National Institute of Allergy and Infectious Diseases and National Institute of Health.Department of Health and Human Services.http://www.thelancet.com/infection2016-06-30hb201

Public investments in the clinical development of bedaquiline.

IntroductionIn 2012, bedaquiline became the first new treatment from a novel class to be approved for tuberculosis in nearly five decades and is now a core component of the standard of care for multidrug-resistant tuberculosis. In addition to the originator pharmaceutical company, Janssen, a range of governmental and non-profit entities have contributed to the development of bedaquiline.Materials and methodsWe identified various avenues of public investments in the development of bedaquiline: direct funding of clinical trials and a donation programme, tax credits and deductions, and revenues resulting from the priority review voucher (PRV) awarded to the originator. Data on investments were gathered through contact with study leads and/or funders; for non-responses, published average costs were substituted. The originator company's expenses were estimated by similar methods. Tax credits and deductions were calculated based on estimated originator trial costs and donation expenses. The value of the PRV was estimated by application of a published model.ResultsPublic contributions through clinical trials funding were estimated at US$109-252 million, tax credits at US$22-36 million, tax deductions at US$8-27 million, administration of a donation programme at US$5 million, PRV revenues at US$300-400 million. Total public investments were US$455-747 million and originator investments were US$90-240 million (if capitalized and risk-adjusted, US$647-1,201 million and US$292-772 million, respectively).ConclusionsEstimating the investments in the development of a medicine can inform discussions regarding fair pricing and future drug development. We estimated that total public investments exceeded the originator's by a factor of 1.6-5.1

Global Progress and Challenges in Implementing New Medications for Treating Multidrug-Resistant Tuberculosis

Two new drugs—bedaquiline and delamanid—have recently been approved by stringent regulatory authorities to treat multidrug-resistant tuberculosis (TB) and recommended by the World Health Organization for use under defined programmatic conditions. Introducing the medications in TB programs worldwide has not kept pace with the need for these drugs. In response, the DR-TB STAT (Drug-Resistant TB Scale-up Treatment Action Team) task force was formed in April 2015 to monitor progress and help overcome challenges. Information was collected from multiple sources and assessed monthly. Some progress has been made in introducing bedaquiline: as of October 2015, a total of 1,258 persons were on the medication under programmatic conditions. For delamanid, >100 patients, but few under programmatic conditions, have received the medication. Coordinated global action might help assist making these medications accessible for persons who need them most

Access to new medications for the treatment of drug-resistant tuberculosis: Patient, provider and community perspectives

Multidrug-resistant tuberculosis (MDR-TB) is on the rise, and is difficult to treat. The approval of two new drugs, bedaquiline and delamanid, and growing evidence for the use of linezolid, offer renewed hope for addressing MDR-TB. However, access to these medicines remains a significant challenge. These drugs have not been registered for TB in most settings; barriers to preapproval access persist; and high pricing and intellectual property restrictions limit access. Many unanswered research questions about optimal use of these drugs also limit access, particularly for vulnerable populations. This review outlines challenges in accessing drugs encountered from the perspective of clinicians, patients and affected communities, and offers potential solutions