Playing catch-up: paediatric tuberculosis treatment pipeline

19 July 2014. Related: Pipeline report, Paediatric care, TB coinfection.

By Lindsay McKenna

Introduction

While the pediatric HIV drug pipeline has seen increased activity in recent years, the same cannot be said for pediatric TB. Adult-pediatric approval gaps remain an issue in HIV drug development, especially for children under two years old, including infants. [1] But HIV drugs are far ahead of TB drugs, many of which were developed over a half-century ago and still lack evidence-based dosing for children, which is critical for optimizing treatment and developing acceptable formulations, especially for very young children.

The lack of appropriate pediatric TB treatment results from the historical neglect of TB disease in children. Many TB programs, researchers, and funding agencies have not made children a priority, because they believe children do not transmit the disease and are therefore “epidemiologically insignificant.” Diagnostic challenges and resultant poor recording and reporting of TB in children have further perpetuated the perception of limited disease burden and potential market for TB treatment in children. While treatment of drug-susceptible TB (DS-TB) in children is evidence-based, fixed-dose combinations (FDCs) of first-line drugs (FLDs) are not available in appropriately dosed combinations. The current treatment of multidrug-resistant TB (MDR-TB) in children is very much a guessing game: treatment practice is guided by findings extrapolated from adult data, and unpalatable pills, designed for adults, must be split or crushed and mixed with juice or foodstuffs to administer them to children. While researchers play catch-up to generate pediatric data for existing drugs, a few studies of new drugs in children are under way or planned, though progressing slowly.

New Disease Burden Estimates

The perception of a small market for pediatric TB drugs has limited interest from developers and manufacturers. In 2013, for the second time ever, the World Health Organization (WHO) included pediatric TB incidence estimates in its annual Global Tuberculosis Report. The WHO estimated that in 2012, 530,000 children developed TB disease. [2] However, researchers from Brigham and Women’s Hospital and Harvard Medical School recently estimated that 1 million children develop TB annually—twice the number estimated by the WHO, and three times the number of children diagnosed each year—and, of those, 32,000 have MDR-TB. [3]

Existing Drugs

In 2010, the WHO released evidenced-based pediatric dosing guidelines for FLDs. Four years later, we are still waiting for appropriately dosed FLD formulations that are easy to give to children. The Global TB Alliance for Drug Development, under a grant from UNITAID, is working to speed the market introduction of pediatric FLD formulations. New pediatric FDCs for the treatment of DS-TB are expected in late 2015. For second-line drugs (SLDs), we currently lack the data necessary to develop appropriately dosed pediatric formulations, although there are plans to develop evidence-based dosing guidelines for SLDs using pharmacokinetics (PK) data from the MDR-PK study in South Africa (see table 1). [4]

New Drugs

Bedaquiline and delamanid, two new drugs recently approved for treating MDR-TB in adults, are now being studied in children. Otsuka, the sponsor of delamanid, which was approved by the European Medicines Agency (EMA) for DR-TB in April of this year, is already enrolling the second age cohort (6–11-year-olds) in its PK and safety study. [5] In stark contrast, Janssen, the sponsor of bedaquiline—which was conditionally approved by the U.S. Food and Drug Administration (FDA) in December 2012—has yet to begin its planned PK and safety study in children and adolescents. These discordant timelines are in part due to differing regulatory requirements between the EMA and FDA. The EMA, where Otsuka first registered delamanid, requires a pediatric investigational program (PIP), whereas the FDA, where Janssen first registered bedaquiline, offers pediatric study exemption for orphan drugs. While the FDA offers other incentives for research in pediatric populations, such as an additional six months of marketing exclusivity under the Best Pharmaceuticals for Children Act (BPCA), [6] a regulatory requirement for drug development in children is urgently needed, especially for neglected diseases like TB, where private-sector developers are few and investments are shrinking.

Planned Trials

Pediatric TB has recently gained momentum as a priority area for study; however, discourse often focuses on the well-characterized historical neglect of pediatric populations in research and development programs, without suggesting ways forward. This is slowly starting to change as the work of research and policy groups like the Sentinel Project for Pediatric Drug-Resistant TB, the Stop TB Partnership’s Childhood TB Subgroup, the Tuberculosis Trials Consortium Pediatric Interest Group, the U.S. National Institutes of Health (NIH) International Maternal Pediatric Adolescent AIDS Clinical Trials Group, and a new NIH-convened multi-stakeholder panel that is promoting timely pediatric safety and dosing evidence for TB drugs and regimens is helping to improve the visibility of children with TB and to advance research in this especially vulnerable population. However, a clear and prioritized research agenda remains urgently needed. Table 1 offers an overview of ongoing and planned studies for TB prevention and treatment in children.

ACTG: AIDS Clinical Trials Group, U.S. Institute of Allergy and Infectious Diseases
ART: antiretroviral therapy
ARV: antiretroviral
BMRC: British Medical Research Council
CIHR: Canadian Institutes of Health Research
DFID: Department for International Development (United Kingdom)
FDC: fixed-dose combination
FLD: first-line drug
ICMR: Indian Council of Medical Research
IMPAACT: International Maternal, Pediatric, Adolescent AIDS Clinical Trials Group, U.S. National Institutes of Health
LTBI: latent tuberculosis infection
NACO: National AIDS Control Organization (India)
NIAID: U.S. National Institute of Allergy and Infectious Diseases
NICHD: National Institute of Child Health and Human Development, U.S. National Institutes of Health
NRF: National Research Foundation (South Africa)
OBR: optimized background regimen
PI: protease inhibitor
PK: pharmacokinetics
SLD: second-line drug
TB: tuberculosis
TBTC: Tuberculosis Trials Consortium, U.S. Centers for Disease Control and Prevention
WHO: World Health Organization

Trial Results

Prevention

TBTC 26 PK/ACTG 5259

In this study of rifapentine and isoniazid, which shortens treatment for latent TB infection (LTBI) to just three months of once-weekly dosing, researchers found that higher weight-adjusted doses of rifapentine were required for children 2–11 years old to achieve exposures similar to those in adults. Higher rifapentine doses were well tolerated in children. Researchers found decreased bioavailability of rifapentine with crushed tablets compared with whole tablets, emphasizing need for the pediatric formulation currently being developed by Sanofi. [7]

MDR-TB Prevention Cohort

Six months of daily ofloxacin, ethambutol, and high-dose isoniazid was well tolerated in children with household exposure to MDR-TB, and few children developed TB or died (incident TB in 6/186 children; death in 1/186 children). Children less than one year old or HIV-positive and those with poor adherence were more likely to develop TB or die. [8] While this study was not a randomized controlled trial (RCT), the findings suggest that this three-drug regimen should be considered for preventive therapy in children exposed to MDR-TB and evaluated in a future RCT.

What’s Missing?

The WHO recommends that child contacts of DS-TB patients be treated with isoniazid preventive therapy, [9] but no such recommendation exists for child contacts of DR-TB patients. Children exposed to DR-TB by household contacts need to be rapidly identified, screened, and treated or put on prophylactic therapy. We urgently need to identify and validate TB drugs or regimens that can be used to prevent disease in child contacts of DR-TB patients.

Treatment

First-line drugs

There is a nonlinear relationship between weight and drug clearance in children. As a result, the standardized mg/kg dosing under the revised WHO guidelines for FLDs may lead to underdosing in small children. Ongoing studies will confirm that the revised FLD dose recommendations actually produce drug exposures in children (especially those younger than two years old) comparable to those observed in adults and will examine how concomitant treatment with ART affects TB and HIV drug exposure in children (see table 1: DATiC; Treat Infant TB; and PK-PTBHIV01). As dosing needs may vary significantly for infants, where immature physiological function can lead to higher exposures and toxicity, the Treat Infant TB study will confirm PK and safety of the revised FLD dosing recommendations in infants less than 12 months old, and the IMPAACT 1106 study will collect both first- and second-line drug PK data in low-birth-weight and premature infants.

Second-line drugs

Existing and forthcoming SLD PK data will eventually be combined in a systematic review, which will inform a WHO dosing recommendation required to advance the development of pediatric formulations.

MDR-PK

Thee and colleagues did an interim analysis of ofloxacin (20 mg/kg) and levofloxacin (15 mg/kg) PK, safety, and tolerability data in HIV-positive and -negative children, where the drugs were used as treatment for MDR-TB disease and as prophylaxis against it. They found low drug exposures in children relative to PK and pharmacodynamic (PD) targets and to levels of exposure achieved in adults. While both drugs were well tolerated as part of long-term treatment, their optimal doses in children have yet to be determined. [10, 11, 12] In an earlier analysis of PK data for ofloxacin, researchers observed lower drug concentrations in children in the disease group compared with those in the prophylaxis group. One possible explanation is that children receiving prophylaxis were generally younger and required the tablets to be crushed, which may increase drug bioavailability. [13]

Following interim analysis of PK data for ethionamide (20 mg/kg), researchers found that younger children achieved target drug levels earlier (this again may be related to increased bioavailability when tablets are crushed); overall, however, ethionamide exposures were the same between age groups and comparable to those of adults. However, children with HIV had significantly lower levels of exposure compared with children who were HIV-negative. [14]

Contrary to what researchers found with ethionamide, children exceeded adult-target drug exposures when given 20 mg/kg of amikacin. [15] There may therefore be potential to reduce the dose or frequency of administration of amikacin in children, which could reduce the drug-related hearing loss observed in at least 20 percent of children treated with existing injectable TB drugs. [16]

Trial Status Updates

233 (delamanid)

Otsuka is currently enrolling a cohort of 6–11-year-olds in a PK and safety study in the Philippines. The study protocol was recently approved in South Africa, and enrollment is under way. Otsuka will soon begin bioequivalence studies of its dispersible minitablet, which is under development for children less than six years old. [17, 18]

P1108 (bedaquiline)

Janssen’s pediatric trials are long overdue. After nearly three years of negotiations with IMPAACT and the U.S. National Institute of Allergy and Infectious Diseases (NIAID) to complete a protocol for study P1108, Janssen decided this June that it was pulling out of the collaboration. [18a] The study had planned for 12–18-year-olds to receive the adult formulation and for younger cohorts (6–12 years, 2–6 years, 6 months–2 years, 0–6 months) to receive the pediatric formulation (dispersible tablets) currently under development. The cohorts were to be enrolled sequentially from oldest to youngest, once adequate data from the preceding cohort were available. HIV-negative children were to be enrolled first in each age cohort, and similar numbers of HIV-positive children 12–17 years old would follow. Enrollment for this study was expected to begin in the first quarter of 2013, and revised to the first quarter of 2015 before Janssen’s withdrawal. [19] IMPAACT may still go ahead with this or a modified design. As this report goes to press, Janssen has yet to announce plans for an alternative pediatric trial, despite its being a requirement of EMA approval. Janssen’s delays in developing the protocol with IMPAACT and NIAID, and its recent withdrawal from the collaboration, have squandered public resources and investigators’ effort, and needlessly slowed the collection of critical data on bedaquiline in children.

PA-824

While the Global TB Alliance for Drug Development will advance the new drug, PA-824, to phase III trials in adults, its pediatric program is not expected to start until 2016. This delay could be related to toxicology study findings that some rats receiving high doses of PA-824 over three to six months developed cataracts. [20]

What’s Missing?

Data detailed above suggest that crushing and mixing TB medicines to facilitate their administration to young children may have an affect on drug bioavailability. The Sentinel Project on Pediatric Drug-Resistant Tuberculosis is conducting a laboratory-based study to evaluate the stability and availability of SLDs when mixed with different foods. Its study includes ethionamide, cycloserine, levofloxacin, and linezolid in Plumpy’Nut (a nutrient-dense peanut-based paste), milk, vitamin syrup, and crushed banana. [21] Results, expected this summer, will inform the design of a study proposed by researchers at Stellenbosch University to examine taste and practical preferences and how different foods and food products affect drug PK. [22]

The current development model for pediatric TB drugs is similar to that for adult therapies: researchers study individual drugs sequentially and often as additions to existing regimens. Yet, what we actually need is new, shorter, all-oral regimens that are effective against all forms of TB and available in pediatric formulations (preferably dispersible tablets). The ongoing PK study in South Africa will fill many of the existing data gaps for the use of SLDs in children. However, once we have adequate PK information, we will still lack data on the optimal role of each drug in pediatric TB treatment. For example, if moxifloxacin-containing regimens (see “Tuberculosis Drug Development Hobbles Forward,” p. 197) show favorable results, we will still lack a pediatric formulation for moxifloxacin (the tablet is not scored and is bitter when crushed). In addition, we lack data and consensus on the role of fluoroquinolones in treatment shortening for pediatric DS-TB.

We need a pediatric TB treatment research agenda that analyzes planned and ongoing studies in adults, determines what pediatric data remain to be gathered, and identifies adult studies where adolescents can and should be included. Until such an agenda is established, children will remain an afterthought, and researchers will be stuck in a never-ending game of catch-up.

Recommendations

1. Integrate adult and pediatric TB drug research.The existing model, in which TB treatment research in adults and children is conducted sequentially, needs to shift toward integration. Failing to study, or delaying the study of, TB treatments in children leaves us with no safety or efficacy data and no guidelines for dosing: every child remains an experiment. [23]
2. Mandate earlier inclusion of children in TB drug development.The earlier inclusion of children in TB research is critical to developing appropriately dosed and formulated drugs for children. In a forthcoming consensus document, an NIH-convened group of experts recommends a parallel development pathway for pediatric TB drugs. The development of pediatric formulations should follow phase IIa studies so that once efficacy and adequate safety have been established in adults (phase IIb studies), PK, safety, and tolerability studies in children can begin. [24]
3. Include adolescents in phase III TB drug trials.Adolescents more than 10 years old who can tolerate adult formulations should be included in phase III trials. The protocol for TBTC phase III study 31, currently in development (see “Tuberculosis Drug Development Hobbles Forward,” table 3, p. 201), will include adolescents more than 13 years old. [25] Individual site Institutional Review Boards (IRBs) may pose a barrier to the inclusion of adolescents in phase III trials on the basis of age. Differing expertise and populations between sites may also affect the recruitment of adolescents. It is important that local IRB decisions be driven by community consultation.
4. Conduct progressive clinical trials to speed research on and access to TB drugs for children.For studies in children less than 10 years old, cohorts should be recruited in parallel, as sequential enrollment does not necessarily offer any additional protection for the younger age groups, whose physiology differs from that of older children. [26] However, enrollment of older cohorts should not be delayed while pediatric formulations are developed; it should start early on.TBTC study 35 (see table 1), will recruit all age cohorts in parallel. Janssen should follow the TBTC and Sanofi’s lead as it revises its pediatric trial plans following its sudden withdrawal from the collaboration with IMPAACT and NIAID. If IMPAACT moves forward with its plans to study bedaquiline in children independent of Janssen, it should revise the protocol for P1108 to recruit all age cohorts in parallel. If Janssen and IMPAACT go ahead with plans for sequential enrollment, it will only further delay the gathering of data urgently needed to inform the inclusion of bedaquiline in pediatric DR-TB regimens.
5. Develop a pediatric TB treatment research agenda.We need a pediatric TB treatment research agenda that analyzes planned and ongoing studies in adults, determines what pediatric data are missing, and identifies adult studies where adolescents can and should be included.
6. Increase funding for pediatric TB drug development.Greatly increased funding is critical to hastening the development of correctly dosed formulations of new and existing TB drugs designed for use in children.The recently published Roadmap for Childhood Tuberculosis, which outlines key actions and investments needed to address pediatric TB, estimates that US$200 million between 2011 and 2015 is needed for research and development (R&D) projects to provide new tools to prevent, diagnose, and treat TB in children. [27] Yet, in 2012, TAG reported only US$10.3 million in pediatric TB R&D investments from 14 donors—just two percent of the US$627.4 million that 84 funders invested in overall TB R&D in 2012. [28] Out of US$237.8 million in total TB drug R&D funding, only US$3.8 million was invested in pediatric TB drug development. Pediatric TB R&D investments follow the larger trend of decline in TB R&D funding overall described in TAG’s 2013 Report on Tuberculosis Research Funding Trends, 2005–2012. [29]
7. Mandate the development of pediatric TB drugs.While the FDA offers some incentive for research in pediatric populations (six months’ additional marketing exclusivity under the BPCA), a regulatory requirement is urgently needed for sponsors seeking approval for new TB drugs, especially as private-sector developers are few and investments are shrinking. Under the Pediatric Research Equity Act of 2003, the FDA can require that companies conduct pediatric studies after receiving marketing approval; however, drugs with orphan status (for diseases that affect <200,000 people in the U.S., like TB) are exempt from this requirement. Other stringent regulatory authorities should also consider mandating pediatric investigational program submissions alongside new drug applications as has been done successfully by the EMA.

Acknowledgments

Dr. Anneke Hesseling was instrumental in constructing the table of ongoing and planned pediatric trials. Dr. Jennifer Furin and Polly Clayden deserve special thanks for their patience and generosity in reviewing early drafts of the chapter.

Endnotes

1. Clayden P, Harrington M. Seven ways to speed up the pipeline. In: Clayden P, Collins S, Daniels C, et al.; i-Base/Treatment Action Group. 2013 pipeline report. Edited by Andrea Benzacar. New York: Treatment Action Group; 2013. p. 1–26. Available from:
   http://www.pipelinereport.org/2013/seven-ways. (Accessed 2014 March 15)
2. World Health Organization. Global tuberculosis report 2013. Geneva: World Health Organization; 2013. Available from:
   http://www.who.int/tb/publications/global_report/en/. (Accessed 2014 March 15)
3. Jenkins HE, Tolman AW, Yuen CM, et al. Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates. Lancet. 2014 May 3;383(9928):1572–9. doi: 10.1016/S0140-6736(14)60195-1.
4. NIH Research Portfolio Online Reporting Tools (U.S.) [Internet]. Bethesda (MD). Project 5R01HD069169-04: Pharmacokinetics and toxicity of 2nd line anti-TB drugs in HIV-infected children. [modified 2014 June 9; cited 2014 June 4]. Available from:
   projectreporter.nih.gov/project_info_description.cfm?aid=8653974&icde=0.
5. Destito, Marc (Otsuka, Geneva, Switzerland). Personal communication with: Erica Lessem (Treatment Action Group, New York, NY). 2014 February 24.
6. Food and Drug Administration (U.S.). Best Pharmaceuticals for Children Act (BPCA) of 2002, Public Law 107–109. Sect. 10 (2002). Available from:
   http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/ucm148011.htm.
7. Weiner M, Radojka M, Savic WR, et al. Rifapentine pharmacokinetics and tolerability in children and adults treated once weekly with rifapentine and isoniazid for latent tuberculosis infection. J Pediatric Infect Dis Soc. 2014 Jan 16. doi:10.1093/jpids/pit077.
8. Seddon JA, Hesseling AC, Finlayson H, et al. Preventive therapy for child contacts of multidrug-resistant tuberculosis: a prospective cohort study. Clin Infect Dis. 2013 Dec;57(12):1676–84. doi: 10.1093/cid/cit655.
9. World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children. 2nd ed. Geneva: World Health Organization; 2014. Available from:
   http://www.who.int/tb/publications/childtb_guidelines/en/. (Accessed 2014 June 9)
10. Garcia-Prats AJ, Thee S, Draper HR, McIlleron HM, Schaaf HS, Hesseling AC. The pharmacokinetics and safety of the fluoroquinolones for the treatment and prevention of drug-resistant tuberculosis in HIV-infected and -uninfected children. Paper presented at: MDR-TB in Children and Adolescent TB Issues Symposium at the 44th Union World Conference on Lung Health; 2013 November 1; Paris, France.
11. Thee, Stephanie. The pharmacokinetics of ofloxacin and levofloxacin in HIV-infected and -uninfected children with tuberculosis (Abstract OP-212-02). Paper presented at: Novel Concept in the Diagnosis and Treatment of Tuberculosis and Children Oral Abstract Session at the 44th Union World Conference on Lung Health; 2013 November 2; Paris, France.
12. Thee S, Garcia-Prats AJ, McIlleron HM, et al. Pharmacokinetics of ofloxacin and levofloxacin for prevention and treatment of multidrug-resistant tuberculosis in children. Antimicrob Agents Chemother. 2014 May;58(5):2948–51. doi: 10.1128/AAC.02755-13.
13. Hesseling AC. Pharmacokinetics of second-line TB therapy in children. Paper presented at: State of the Art on Childhood TB Treatment and Diagnostics Symposium at the 43rd Union World Conference on Lung Health; 2012 November 16; Kuala Lumpur, Malaysia.
14. Ibid.
15. Hesseling AC. Pharmacokinetics of second-line TB therapy in children.
16. Seddon J, Thee S, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS. Hearing loss in children treated for multidrug-resistant tuberculosis. J Infect. 2013 Apr;66(4):320–9. doi: 10.1016/j.jinf.2012.09.002.
17. Destito, Marc (Otsuka Pharmaceutical Co., Geneva, Switzerland). Personal communication with: Erica Lessem (Treatment Action Group, New York, NY). 2014 February 24.
18. Ibid.18a De Marez, Tine (Janssen Infectious Diseases, Titusville, NJ). Personal communication with: Lindsay McKenna (Treatment Action Group, New York, NY). 2014 June 13.
19. Lessem E. The tuberculosis treatment pipeline. In: Clayden P, Collins S, Daniels C, et al.; i-Base/Treatment Action Group. 2012 pipeline report. Edited by Andrea Benzacar. New York: Treatment Action Group; 2012. Available from:
    http://www.treatmentactiongroup.org/pipeline-report/2012. (Accessed 2014 June 4)
20. Winter H, Egizi E, Erondu N, et al. Evaluation of pharmacokinetic interaction between PA-824 and midazolam in healthy adult subjects. Antimicrob Agents Chemother. 2013 Aug;57(8):3699–703. doi: 10.1128/AC.02632-12.
21. Becerra, Mercedes (Harvard Medical School, Boston, MA). E-mail with: Lindsay McKenna (Treatment Action Group, New York, NY). 2014 March 14.
22. Furin, Jennifer (Case Western Reserve University, Cleveland, OH). E-mail with: Lindsay McKenna (Treatment Action Group, New York, NY). 2013 April 17.
23. Friedman RL. Children in medical research: access versus protection. New York: Oxford University Press; c2006. p. 25.
24. Nachman S, Ahmed A, Amanullah F, et al. Towards earlier inclusion of children in tuberculosis (TB) drug trials: consensus from an expert panel. 2014. 31 p.
25. Nahid P, Dorman S. Report from phase III RCT (study 31) protocol team. Presented at: 34th Semi-annual Tuberculosis Trials Consortium (TBTC) Meeting; 2014 March 19; Atlanta, GA.
26. Mendel CM, Murray SR, van Niekerk C, et al. A framework for evaluating novel MDR-TB regimens in children. Paper presented at: MDR-TB in Children and Adolescent TB Issues Symposium at the 44th Union World Conference on Lung Health; 2013 November 1; Paris, France.
27. World Health Organization, Stop TB Partnership, Treatment Action Group, International Union Against Tuberculosis and Lung Disease, U.S. Agency for International Development, U.S. Centers for Disease Control and Prevention, and UNICEF. Roadmap for childhood tuberculosis. Geneva: World Health Organization; 2013. Available from:
    http://www.who.int/tb/challenges/children/en/. (Accessed 2014 March 15)
28. Lessem E, Jimenez-Levi E. Funding for pediatric TB research, 2012: supplement to the 2013 report on tuberculosis research funding trends, 2005–2012. New York: Treatment Action Group; 2013. Available from:
    http://www.treatmentactiongroup.org/tbrd2013. (Accessed 2014 March 15)
29. Frick M, Jimenez-Levi E. 2013 Report on tuberculosis research funding trends, 2005–2012. New York: Treatment Action Group; 2013. Available from:
    http://www.treatmentactiongroup.org/tbrd2013. (Accessed 2014 March 15)