Tuberculosis Drug Development Hobbles Forward

July 2014

By Erica Lessem

Introduction

After forty years without new approved drug classes, tuberculosis (TB) treatment has recently advanced with the approval of two new compounds to treat multidrug-resistant TB (MDR-TB): delamanid and bedaquiline.^1,2,3 Yet with limited access to these drugs, and with no data on how they can be used to shorten or otherwise optimize MDR-TB treatment regimens, this is more an incremental step than a leap forward. Progress toward identifying shorter and better regimens for treating drug-sensitive TB is similarly slow, and there are no validated options for treating TB infection in contacts of people with MDR-TB. The TB drug pipeline features only six compounds from four different classes. The few new drugs in phase II studies have been stalled there for years; of them, only bedaquiline is likely to move to a phase III trial in the next five years. There are no TB drugs in phase I trials (see table 1).

Investments in TB drug research are paltry, totaling just US$238 million in 2012, or less than one-third of the estimated amount needed.⁴ With Pfizer and AstraZeneca’s departures from TB drug research and development (R&D) in the past year, and with Janssen’s delays in starting the pediatric and phase III trials required by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as part of bedaquiline’s accelerated approval, pharmaceutical investments in TB R&D—which fell by 22 percent in 2012—are likely to drop further.⁵ Increased investment in TB drug R&D is urgently needed to expand the pipeline and accelerate the progression of not just new compounds, but optimized regimens, through it. On the program side, improvements to patient-centered service delivery, more flexible guidelines to aid the uptake of new treatments, and better supply management are needed to ensure that people with TB receive the best possible care or, in some cases, experimental therapies.

Table 1. New Drugs in Clinical Trials for Tuberculosis

Drug	Sponsor(s)	Phase	Class
AZD5847	AstraZeneca	IIa	oxazolidinone
bedaquiline	Janssen	IIb/III	diarylquinoline
delamanid	Otsuka	III	nitroimidazole
PA-824	TB Alliance	III	nitroimidazole
SQ109	Sequella/Infectex	IIb/III	ethylenediamine
sutezolid	Sequella	IIa	oxazolidinone

Spotlight: Problems with drug purchasing and supply management

Better TB therapies will have an impact only if they are accessible to patients and doctors who need them. Commitments to affordable drug pricing, and increased funding of infrastructure and program capacity, must therefore accompany investments in TB R&D. TB programs face many serious access problems: Novartis refuses to engage meaningfully to make clofazimine available for TB patients; Pfizer’s exorbitant pricing of linezolid makes it unaffordable for most programs; and even the old, largely cheap drugs—including isoniazid, essential for preventing and treating TB—that have been on the market for decades are often subject to shortages due to poor demand forecasting and disruptions on the limited manufacturing side. With the added costs of new drugs bedaquiline and delamanid, and as more programs try to buy companion drugs such as linezolid, TB programs need additional funding from national budgets and donors to ensure that their patients can benefit from innovations in treatment. To end supply shortages, TB programs and regulatory authorities—including those in the United States—must find more resourceful ways to get the drugs and to encourage manufacturers to develop reliable supplies of cheap, quality-assured products. The Global Drug Facility (GDF) offers one mechanism for doing this globally, yet for the United States to benefit from lower prices and more stable supply, the FDA would need to welcome and ease the registration of global generic products domestically, perhaps through technical support for manufacturers, and incentives such as faster reviews and waivers or discounts for registration fees. Countries need more support and expertise in estimating demand and in managing supply chains.

LATENT TB INFECTION

Table 2. Latent Tuberculosis Infection Studies

Study/Regimen	Status	Population	Sponsor(s)
A5279 Self-administered daily rifapentine + INH for 1 month (vs. INH daily for 9 months)NCT01404312*	Enrolling	People with HIV with positive skin test/IGRA or living in high–TB prevalence regions	ACTG
A5300/TB-CHAMP Levofloxacin-based regimen to be determined (vs. placebo or INH)	Protocol in development	Household contacts (including children) of individuals with MDR-TB	ACTG, IMPAACT
iAdhere (S33) Self-administered once-weekly rifapentine + INH for 12 weeks (with and without electronic reminders)NCT01582711*	Fully enrolled	Adults with LTBI	TBTC
PREVENT TB (TBTC S26, A5259) Once-weekly rifapentine + INH for 12 weeks (directly observed)NCT00023452*	Completed	Persons with LTBI and high risk of progression, including children and people with HIV	TBTC, ACTG
4R vs. 9H 4 months daily rifampin (self-administered)NCT00931736*	Enrolling	Adults with positive skin test or QFT, including people with HIV not on ARVs whose efficacy is reduced by rifampin	McGill University, CIHR

*Clinicaltrials.gov identifier; for more details, see http://www.clinicaltrials.gov.
ACTG: AIDS Clinical Trials Group, U.S. National Institute of Allergy and Infectious Diseases (NIAID)
ARVs: antiretrovirals
CIHR: Canadian Institutes of Health Research
IGRA: interferon gamma release assay – QuantiFERON-TB Gold In-Tube (QFT) or T-SPOT TB test
IMPAACT: International Maternal Pediatric Adolescent AIDS Clinical Trials Group, NIAID
INH: isoniazid
LTBI: latent tuberculosis infection
TBTC: Tuberculosis Trials Consortium, U.S. Centers for Disease Control and Prevention

As an effective TB vaccine remains elusive (see the “Tuberculosis Vaccines Pipeline,”), treating latent TB infection (LTBI) is one of the most effective ways to prevent active TB disease and is particularly important in people with HIV and children. Yet investment in better strategies to treat LTBI has been minimal, despite the huge potential market: up to one-third of the world’s population is infected with TB. A rare advance came when the SOWETO and PREVENT TB studies demonstrated that LTBI treatment could be shortened to just 12, once-weekly doses of rifapentine and isoniazid.^6,7

An extension of the PREVENT TB randomized, open-label noninferiority study to 400 people with HIV showed this regimen to be as safe (3% vs. 4% discontinuation due to adverse drug reaction; P = .79) and effective (1.01% vs. 3.5% cumulative TB rate; 95% CI: −5.6% to +0.6%) as nine months of daily isoniazid, and with higher completion rates (89% vs. 64%; P < .001).⁸ Rifapentine and efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla) were tolerated well when coadministered, with no clinically significant impact on CD4 counts or HIV viral load. A single administration of rifapentine increased the maximum concentration of tenofovir by 23 percent, while repeated weekly dosing of rifapentine modestly reduced (by 15%) tenofovir and efavirenz minimum concentrations.⁹ Rifapentine’s sponsor, Sanofi, announced in December 2013 that it was reducing the drug’s cost in the United States by 57 percent, finally facilitating access after a year-and-a-half-long advocacy campaign.¹⁰ AIDS Clinical Trials Group Study (ACTG) A5279 is now examining a daily one-month rifapentine-based regimen in people with HIV; a substudy indicated that this regimen does not significantly affect efavirenz clearance.¹¹

Despite these advances in shortening treatment for latent, drug-susceptible TB infection, millions of people with LTBI due to exposure to MDR-TB (which, by definition, is resistant to isoniazid and rifamycins) still lack validated options for treating their infection. Observational studies, despite their limitations, suggest that preventive therapy for people thought to be latently infected with MDR-TB may be feasible, tolerable, and potentially effective. For example, during a 2008 MDR-TB outbreak in the Federated States of Micronesia, contacts with LTBI were offered treatment with one year of a fluoroquinolone with or without ethambutol or ethionamide, and followed up for two years afterwards.¹² Of the 104 who initiated treatment, none developed active disease and 89 percent completed therapy, though half reported side effects.¹³ Of 15 who refused preventive therapy, three developed MDR-TB. The ACTG (funded by the U.S. National Institutes of Health [NIH]) and International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) networks are working jointly on a planned study of levofloxacin-based MDR-TB preventive therapy.

TB DISEASE

Table 3. Active Tuberculosis Disease Studies

Study	Phase	Includes new drug(s)	May shorten DS-TB treatment	May shorten DR-TB treatment	May make DR-TB treatment more effective	For DR-TB, may reduce pill burden or improve tolerability	May have price, registration, or other access barriers
C213	III	delamanid		X	X		X
STREAM	III	bedaquiline		X	X		X
REMox NCT00864383*	III		X				X
STAND NC-006, ACTGPR682	III	PA-824	X	X	X	X	X
TBTC 31	III		X				X
NExT	III	bedaquiline		X	X	X	X
MAMS-TB-01 NCT01785186*	II	(SQ109 stopped)	X
MARVEL A5319	II	bedaquiline PA-824 delamanid (pending agreement with sponsor)		X	X	X	X
NiX-TB	II	bedaquiline PA-824		X	X	X	X
NC-005	II	bedaquiline PA-824	X	X	X	X	X
ACTG 5343	I	bedaquiline delamanid			X		X

*Clinicaltrials.gov identifier; for more details, see www.clinicaltrials.gov.
DR-TB: drug-resistant tuberculosis
DS-TB: drug-sensitive tuberculosis

Bedaquiline (brand name Sirturo; formerly known as TMC207)

Bedaquiline, the first new TB drug from a new drug class to receive approval in over four decades, has advanced little since its FDA approval in 2012. On the accessibility front, its sponsor, Janssen, has done well with pre-approval access and rapid registration, but poorly with pricing. Janssen’s inflexible tiered pricing system puts a course of bedaquiline at an outrageous US$26,000 in high income countries, and still unaffordable US$3,000 and US$900 for middle- and low- income countries, respectively (see table 4).¹⁴ This tiered-pricing also challenges the Global Drug Facility’s ability to pool demand to distribute the drug effectively. Bedaquiline recently obtained approval in Europe, Russia,  and South Korea.^15,16,17 Guidance on the use of bedaquiline is now available from both the U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), though the latter recommends informed consent—unusual as this requirement is not in place for other MDR-TB drugs, for which even fewer clinical trial data support their use.^18,19 Access to bedaquiline remains limited—primarily through Janssen’s commendable compassionate use program and expanded access trial. Few patients have actually benefitted from the drug’s being on the market. Despite probable approvals in more of the high-burden countries in which Janssen has filed, TB programs’ conservatism and tight budgets, coupled with the drug’s steep pricing and lack of inclusion on the WHO’s Essential Medicines List, may prove to be continuing barriers to access (see table 4).

Janssen has completely stalled on the research side. Its long-delayed study in children has been postponed yet again (see “Playing Catch-Up: The Pediatric Tuberculosis Treatment Pipeline”). A drug-drug interaction study with delamanid has yet to start. The study is needed to determine whether the two drugs are safe to give together, given that each has cardiac side effects (QT prolongation, or a disturbance in the heart’s electrical activity). Over two years after advocates began calling for this study, the ACTG is now rapidly developing A5343, which is urgently necessary as both drugs are now on the market. A phase III trial—a requirement of FDA approval, and particularly important given unexplained long-term excess mortality noted in one phase IIb trial—has still not begun.^20,21 Janssen’s phase III plans for bedaquiline now center around adding two bedaquiline-containing arms in a second stage of the ongoing STREAM MDR-TB treatment trial (see table 3). One arm will explore bedaquiline’s ability to contribute to a nine-month, all-oral regimen; the other will test whether bedaquiline can shorten treatment to six months.

Each of the two bedaquiline-containing arms, however, will be compared not with the current standard of care, but with the STREAM trial’s original experimental arm. This original experimental arm consists of a modified “Bangladesh” regimen (named after a similar regimen first introduced in Bangladesh in a poorly conceived sequential observational cohort study), which includes clofazimine, ethambutol, moxifloxacin, and pyrazinamide given for nine months, supplemented by isoniazid, kanamycin, and prothionamide in the first four months only. This design bases the whole evaluation of bedaquiline in the second stage on the risky assumption that the experimental modified Bangladesh arm will succeed in the first stage of the trial.²²

Delamanid (brand name Deltyba; formerly known as OPC67683)

Delamanid became the second new drug to receive regulatory approval to treat MDR-TB in Europe in 2014.23 In contrast to bedaquiline, delamanid is zipping through pediatric and phase III clinical trials. (Note that European approval requires an additional phase IV study to determine whether the current dosing schedule—100 mg twice daily for two months, then 200 mg daily for four months—or 400 mg daily as a single dose for six months is optimal.) These investments in research have made Otsuka the leading private-sector funder of TB R&D for seven years in a row.²⁴

Yet Otsuka’s access strategy is disappointing. The company refused to start compassionate use until its phase III trial was nearly complete and regulatory approval was ensured, defying principles of pre-approval access and denying many people with otherwise untreatable cases of MDR-TB a chance for cure. Its limited compassionate use program precludes patients from getting delamanid in conjunction with other new drugs (including bedaquiline), even though compassionate use by definition operates in a realm with incomplete safety and efficacy data, and patients are willing to accept greater risk given a lack of validated treatment alternatives. Like Janssen, Otsuka plans for a tiered-pricing approach, though details are unknown as delamanid has yet to receive marketing approval from a low- or middle- income country—a result of Otsuka’s egregious delay in submitting regulatory filings outside of rich countries; it has not filed in any of the countries where it conducted clinical trials, or in a single high–TB burden country.

No data exist on whether bedaquiline and delamanid can be used together safely to improve TB treatment regimens. Both drugs have been developed individually as additions to existing treatment schemes (though the STREAM trial and TB Alliance are exploring bedaquiline in combinations). Thus, while each may improve the efficacy of a regimen, its ability alone or in combination to shorten treatment, replace other drugs, permit all-oral regimens, or reduce pill burdens or side effects for patients remains undemonstrated. New research to inform optimal combinations—including the NIH-funded ACTG A5343 drug-drug interaction study mentioned above—needs to start soon. While A5343 is incomplete, conservative Otsuka has been slow to collaborate with researchers designing combination trials, though it may participate in the ACTG’s A5319 MARVEL trial and allow delamanid to be studied as part of regimens that include multiple new drugs if the results of A5343 are promising. However, the South African Medicine Control Council’s NExT study for people with extensively drug-resistant TB (XDR-TB), which planned to conduct a safety study of bedaquiline and delamanid before moving into a nine-month phase III study of the two drugs plus linezolid and p-aminosalicylic acid, has had to completely redesign its protocol due to unavailability of delamanid. Pivotal trials to inform better treatment for MDR- and XDR-TB must have access to both drugs together to determine their role in optimizing treatment for drug-resistant TB.

Table 4. Bedaquiline and Delamanid: Research and Access

	Bedaquiline	Delamanid
RESEARCH
Pediatrics (see “Playing Catch-Up”)	Trial not yet started	Trial started June 2013
Phase III trial	Trial not yet started (two arms to be added to STREAM trial early 2015)	Enrollment completed November 2013; results expected end of 2014
ACCESS
Compassionate use	Started first quarter of 2011 342 patients enrolled (as of March 5, 2014)	Started first quarter of 2014 3 patients enrolled (as of March 24, 2014)
Expanded access trials	Started 2011 in China, Lithuania, Russia	none
Approvals	United States (2012), Russia (2013), Europe (2014), South Korea (2014)	Europe (2014)
Additional registrations (decision pending)	China, Colombia, India, Kazakhstan, South Africa, Thailand, Vietnam, Philippines	Japan
WHO Essential Medicines List inclusion	none	none
Pricing	Tiered pricing by country income level (per-pill price: high US$159.57; middle US$15.96; low US$4.79)	Tiered pricing by country income level (details unannounced)

Oxazolidinones

Remaining optimism for the TB drug pipeline centers around the oxazolidinone drug class. As additional drugs are urgently needed to accompany bedaquiline and delamanid, researchers and clinicians are increasingly interested in three drugs: linezolid—a drug approved for other bacterial infections and used off-label to treat difficult cases of drug-resistant TB—and its new chemical relatives, sutezolid and AZD5847. Yet data to support linezolid’s clinical efficacy and safety remain limited. Follow-up data from a 2012 study analyzing posttreatment relapses are still pending, but earlier analyses showed potential efficacy, but high rates of adverse events.²⁵

Sutezolid and AZD5847 are moving very slowly through the pipeline after their respective sponsors, Pfizer and AstraZeneca, withdrew from TB R&D. Pfizer sold its rights to sutezolid to the small company Sequella without providing adequate resources to develop the drug; Sequella lacks both the active pharmaceutical ingredient and the funds to process sutezolid into pill form for use in studies. After inexplicable delay, Pfizer finally published the results of a phase IIa study of sutezolid in a peer-reviewed journal.²⁶ In a two-week study of its early bactericidal activity in patients with smear-positive pulmonary TB, sutezolid was safe and well tolerated at either 600 mg twice daily or 1,200 mg once daily, and significantly reduced the number of TB bacteria in sputum (daily log change of −0.088 colony-forming units; 90% CI: −0.112 to −0.065, P < .0001 for the 600 mg twice-daily dose; and daily log change of −0.068 colony-forming units; 90% CI: −0.090 to −0.045, P < .0001 for the 1,200 mg once-daily dose), demonstrating that the drug is active in humans.²⁷

The NIH recently completed a phase IIa trial of AZD5847; results are pending.

New combinations

The TB Alliance’s development of new drugs in combination is a good model for the field. The TB Alliance has been developing PA-824 (in the same drug class—nitroimidazoles—as delamanid) in various combinations of new and existing drugs. Study NC-003 compared the bactericidal activity and safety of several combinations of new and existing drugs given for two weeks to people with drug-sensitive TB. It found that a combination of bedaquiline, PA-824, and pyrazinamide (PZA) was the best at reducing the amount of TB bacteria in sputum (0.167 colony-forming units; 95% CI: 0.078–0.256), similar to standard first-line treatment (0.151 colony-forming units; 95% CI: 0.070–0.231), but moderately prolonged cardiac conduction. Clofazimine alone had no early bactericidal activity and did not add to that of the studied combinations.²⁸ The TB Alliance now plans to bring bedaquiline, PA-824, and PZA (with the addition of moxifloxacin for patients with MDR-TB) into a two-month study (NC-005). Some consider the inclusion of bedaquiline in studies of people with DS-TB controversial, given concerns about the drug’s safety. Community groups have offered guidance on what additional information is needed for developers to ethically study bedaquiline in DS-TB.²⁹ The TB Alliance is also planning the NiX-TB study of bedaquiline, PA-824, and linezolid for people with XDR-TB. The ACTG A5319 MARVEL study currently plans to study bedaquiline, PA-824, and PZA given with either linezolid or levofloxacin in people with MDR-TB.

The TB Alliance NC-002 study evaluated PA-824 at doses of 100 and 200 mg daily with moxifloxacin and PZA for two months in people with both drug-susceptible and multidrug-resistant TB; both new combinations of PA-824, moxifloxacin, and PZA resulted in significantly higher rates of sputum culture conversion at eight weeks than did the standard of care. The TB Alliance will test the efficacy of PA-824 at either dose, moxifloxacin, and PZA given for either four or six months in the phase III STAND, or NC-006, trial.³⁰ The STAND trial will also include an open-label MDR-TB arm. While shortening treatment to six months for some MDR-TB patients would represent a major advance, the lack of randomization and control for this arm will make it difficult to judge the suitability of this regimen, which also requires widespread drug susceptibility testing, as 38–54 percent of people with MDR-TB are resistant to PZA.^31,32

SQ109, the last new compound in the meager TB pipeline, is in development by Sequella. The drug was included in the publicly funded study MAMS-TB-01—despite its lack of prior clinical data demonstrating any activity in patients with TB. SQ-109 has no early bactericidal activity.^33,34 The adaptive design of MAMS-TB-01 incorporated a planned interim analysis to allow for early termination of arms showing little treatment-shortening potential. While the SQ109-containing arms had no safety or inferiority signals, there was no evidence that either arm was superior to the standard regimen in shortening the time to a negative culture (used as a proxy for predicting the ability to shorten treatment). As such, the two SQ109 arms were discontinued.³⁵ Sequella previously sold the rights to SQ109 in Russia to Infectex, which in late 2012 began what Russian regulators deemed a phase III registration trial, despite the company’s enrolling just 80 participants and the drug’s apparent lack of clinical efficacy.³⁶

Rifamycins

Many recent studies have explored the safety and potential efficacy of higher doses of drugs in the rifamycin class, especially rifampin (also commonly known as rifampicin) and the longer-acting rifapentine, to shorten treatment for DS-TB (see table 3). The HIGHRIF1 study, funded by the European and Developing Countries Clinical Trials Partnership (EDCTP) and conducted by the Pan-African Consortium for Evaluation of Anti-tuberculosis Antibiotics (PanACEA), compared increasing rifampin doses up to 35 mg/kg against the standard dose of 10 mg/kg for bactericidal activity and safety over fourteen days. The 35 mg/kg dose appeared well tolerated, safe and showed greater bactericidal activity with higher doses, though results have not yet been published in a peer-reviewed publication.³⁷ An extension of this study to examine use of 40 mg/kg
of rifampin for 14 days ended in May 2014; the study team has approval to test arms containing 45 mg/kg, 50 mg/kg, and 55 mg/kg of rifampin, but needs more funding to do so.³⁸ The HIGHRIF 2 study ended in November 2013; results will be presented in October 2014. Antimicrobial activity data are being analyzed, but this study found no serious adverse events for two months of rifampin at 15 and 20 mg/kg.³⁹ The RIFATOX trial found that rifampin at 15 and 20 mg/kg for the first four months of the standard six-month regimen was safe, with no increase in serious adverse events. However, these slightly higher doses of rifampin did not lead to a significant increase in culture conversion (participants’ sputum testing negative for TB) at eight weeks.⁴⁰ Doses of rifampin up to 35 mg/kg are being tested for longer periods (eight weeks) in the ongoing MAMS-TB-01 study to determine their potential for treatment shortening.⁴¹ If long-term data support safety and efficacy, rifampin’s widespread availability and accessibility could facilitate its incorporation into a treatment-shortening regimen for drug-sensitive TB.

Rifapentine, which has a longer half-life than rifampin and is more potent against the TB bacterium, is being explored in higher doses for its treatment-shortening capacity. TBTC study 29X, which gave daily doses of rifapentine (with or without a boiled egg, as fatty food increases absorption) up to 20 mg/kg, showed that doses as high as 1,200 mg given daily for eight weeks were safe and well tolerated. Of those receiving 20 mg/kg, 11.1% permanently discontinued their regimens, and only one experienced a serious adverse event, compared with a 12.9% discontinuation rate and two serious adverse events in those receiving standard-dose rifampin.⁴² Of those receiving 20 mg/kg of rifapentine, 94.7% tested negative for TB on solid culture at eight weeks, versus 81.3% of those receiving standard rifampin (P < .05).⁴³ Study 29X, a phase I pharmacokinetic trial in healthy volunteers, showed that body weight did not affect rifapentine clearance from the body, meaning that weight-based dosing for rifapentine is not necessary. ACTG Study A5311 stopped early after 20 of 44 subjects discontinued treatment, 12 with grade 3 or higher toxicity.⁴⁴ These participants received daily single or divided doses of up to 2,400 mg of rifapentine. It is unclear whether the increased toxicity was related to higher exposures or to more robust responses from healthy volunteers. The Johns Hopkins–sponsored RioMAR trial, which gave two months of rifapentine (7.5 mg/kg) and moxifloxacin together, stopped early for administrative reasons, with just over half of the target population enrolled. Analyses indicate that participants in the experimental arm were slightly more likely to discontinue treatment due to study withdrawal (5% vs. 2%), loss to follow-up or default (5% vs. 0%), or toxicity (6% vs. 3%), but were more likely to have negative liquid cultures at the end of the intensive phase of treatment (94.4% vs. 71.4%; P = .01 in the per-protocol analysis).⁴⁵

These data cumulatively indicate that doses of rifapentine up to 1,200 mg are well tolerated in people with TB, and warrant further study as they may help shorten treatment. A planned phase III trial, TBTC 31, will explore whether 1,200 mg daily of rifapentine, with or without moxifloxacin, can allow treatment to be shortened to just four months in people with and without HIV. Posttrial access to rifapentine, however, may prove challenging, as the drug is registered only in the United States, and despite the recent price reduction, remains much more costly than rifampin.
Both rifampin and rifapentine interact with a number of drugs that are metabolized by the liver, including antiretrovirals and methadone, important for treating people with HIV or on opiate substitution therapy. A study is under way to see if rifampin interacts with buprenorphine, used for opioid substitution therapy. It is unclear how increasing doses of rifamycins may affect these known drug-drug interactions. Further research is needed.

Fluoroquinolones

Fluoroquinolones, currently one of the backbones of MDR-TB treatment, continue to be explored for their potential to shorten treatment for drug-sensitive TB. Currently, there is little resistance to fluoroquinolones among patients with newly diagnosed TB, but resistance in re-treatment TB is increasing, and the widespread use of this class for other indications raises concerns about emerging resistance. A debate has emerged as to whether the potential impact of treatment shortening outweighs concerns over the risk of “losing” the fluoroquinolone class for MDR-TB treatment.^46,47 This debate has so far been theoretical, as data from fluoroquinolone-based treatment-shortening trials are pending or negative. The OFLOTUB study failed to show that a four-month gatifloxacin-containing regimen was noninferior to—no worse than—the standard six-month treatment regimen.⁴⁸ Participants in the gatifloxacin arm were 3.8% more likely to have an “unfavorable outcome” (relapse, treatment failure, death, or loss to follow-up) than those in the control arm (95% CI: −0.3% to 8.0%, with noninferiority bounds set to 6%), but patients treated with gatifloxacin in this trial were much more likely to experience relapse (14.6% vs. 6.9%).⁴⁹

Results from the REMox TB trial, due to be released soon, will provide further evidence on the potential for fluoroquinolones to shorten treatment of drug-sensitive TB. REMox studied four months of daily moxifloxacin, a fluoroquinolone that is more effective than other drugs in that class against the few but persistent TB bacteria that survive even when antibiotics wipe out most of them.⁵⁰ The future role of moxifloxacin and the fluoroquinolone class in the treatment of drug-susceptible TB will depend on the outcome of REMox and TBTC Study 31(see table 3). Fortunately, moxifloxacin’s formerly high price is dropping as quality-assured generics enter the market.⁵¹

CONCLUSIONS AND RECOMMENDATIONS

TB drug development has undoubtedly advanced, but progress is slow, the number of new compounds limited, and knowledge insufficient to dramatically improve cure rates, reduce treatment duration, and make treatment more tolerable. To resolve this:

1. Pharmaceutical companies, public agencies and research institutions, and philanthropies must invest more in TB drug research to speed the progress of the drugs that are in development and to bring additional compounds into development. Existing public research funders such as the NIH, the CDC, the U.S. Agency for International Development, the British Medical Research Council, the French National Agency for Research on AIDS and Viral Hepatitis, and the EDCTP can invest more. High–TB burden countries also need to fund TB R&D.⁵² Additional investment in optimal strategies for treating latent TB infection is especially critical.
2. Drug sponsors and clinical trials groups must collaborate to ensure the development not just of individual agents but also of new and better regimens. The ACTG should expedite its study of delamanid and bedaquiline to inform the use of the two together. Sequella needs to make sutezolid available for studies with potential partners. Janssen must commit to adequate funding for its phase III program to ensure that the STREAM trial is conducted to the highest scientific and ethical standards, including that the standard-of-care arm continues to enroll throughout the trial duration. Research on drug-drug interactions is essential for bringing new regimens forward.
3. More research must be conducted in populations disproportionately affected by TB, including people with HIV, people who use drugs or alcohol, people with HCV coinfection, children, and pregnant and lactating women. Research in these groups is important for all new TB drugs and regimens, especially in light of their historical lack of representation in clinical trials.
4. Trial sponsors must include community representatives throughout the research process, from early development to registration, to ensure that planned studies reflect community interests and needs.⁵³
5. Regulatory authorities must ensure that postmarketing requirements are enforced so that adequate safety and efficacy data are available to support the use of new tools to fight TB, particularly ones that are approved under early review mechanisms.Limitations in research are paralleled by those on the access side, where patients, doctors, and TB programs are unable to access new and old drugs alike due to high costs, supply problems, and lack of registrations.
6. Sponsors of new drugs must plan early on for pre-approval access programs as soon as sufficient safety and preliminary efficacy data (phase II) are available; this includes both individual patient compassionate use programs, and expanded access trials in countries that do not have a legal mechanism to allow for compassionate use (e.g., China, Lithuania, Moldova, Russia). Otsuka has been negligent in its already late and limited compassionate use program. The TB Alliance should develop and implement a compassionate use strategy for PA-824 as it enters into phase III trials.
7. Sponsors of new drugs must rapidly file for registration in trial-site countries and other high–TB burden settings. Otsuka must immediately file in countries other than the high-income, low-burden settings it has been targeting for years. Similarly, Sanofi should file for approval for rifapentine in the numerous countries where its trials have been conducted, such as South Africa and Brazil; it is unethical not to have done so years after rifapentine received approval in the United States.
8. Drug companies must commit to affordable pricing. Community groups have lambasted the tiered-pricing approach that does little to promote fair drug prices,⁵⁴ yet Janssen and Otsuka are insisting on this approach. Many activists advocate instead for voluntary licensing and other plans that allow competition to drive down prices and expand access in low- and middle-income countries, while tiered pricing locks in fixed, often high, prices.⁵⁵
9. TB programs and regulatory authorities must prepare for the registration of new drugs and regimens early, considering risks and benefits thoroughly, and strategizing for the roll-out of numerous, rather than individual, changes to guidelines for patient care. As many treatment-shortening first-line studies are under way, programs should carefully weigh what evidence would be required to change a long-established standard of care, and to mitigate the risk of resistance when fluoroquinolones or new drugs are included.
10. National programs and donors must finance better drug procurement, supply-chain management, and universal access to ensure access to both old and new treatment options. Drug shortages are preventable and therefore unacceptable; better forecasting is needed to assist manufacturers in creating a stable supply; regulatory incentives may also be required. In particular, the FDA and CDC should move quickly to find ways to take advantage of the GDF model. In parallel, drug procurement budgets need expansion to enable the best treatment to reach those in need at no cost to the patient.The World Health Organization must update its Essential Medicines List. In particular, bedaquiline, clofazimine, delamanid, linezolid, and rifapentine must be included on the list. Countries need these drugs urgently for the treatment of LTBI and active drug-resistant TB disease; their addition to the WHO’s Essential Medicines List would provide critical guidance to countries to purchase these drugs.

While TB treatment and prevention research and implementation are moving forward, they are a long way from where we need them to be. With political will, commitment from the public sector and industry, smarter science, and guidance from and engagement with all affected communities, we can get there. We must.

Acknowledgments

Many thanks to all the investigators and sponsors who provided information and feedback that aided the development of this report. Special gratitude is owed to Dr. Michael Vjecha for his thoughtful review, and to Dr. Richard Chaisson for his editing expertise.

 

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ENDNOTES

1. Otsuka (Press Release). Otsuka wins European marketing authorization for Deltyba™ (delamanid). 2014 April 30. Available from: http://www.otsuka.co.jp/en/company/release/2014/0430_01.html. (Accessed 2014 May 2)
2. Food and Drug Administration (U.S.) (Press Release). FDA approves first drug to treat multi-drug resistant tuberculosis. 2012 December 31. Available from:mhttp://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm. (Accessed 2014 April 1)
3. Johnson and Johnson (Press Release). SIRTURO (bedaquiline) receives conditional approval in the European Union for the treatment of multi-drug resistant tuberculosis. 2014 March 6. Available from: http://www.jnj.com/news/all/SIRTURO-bedaquiline-Receives-Conditional-Approval-in-the-European-Union-for-the-Treatment-of-Multi-Drug-Resistant-Tuberculosis. (Accessed 2014 April 1)
4. Frick M. 2013 Report on tuberculosis research funding trends, 2005–2012. New York: Treatment Action Group and Stop TB Partnership; 2013. Available from: https://www.treatmentactiongroup.org/tbrd2013. (Accessed 2014 March 19)
5. Ibid.
6. Martinson NA, Barnes GL, Moulton LH, et al. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med. 2011 Jul 7;365:11–20. doi: 10.1056/NEJMoa1005136.
7. Sterling TR, Villarino ME, Borisov AS, et al. N Engl J Med. 2011 Dec 8;365:2155–66. doi: 10.1056/NEJMoa1104875.
8. Sterling T, Benson C, Scott N, et al. Three months of weekly rifapentine and isoniazid for M. tuberculosis infection in HIV-infected persons (Poster 817). Poster session presented at: 2014 Conference on Retroviruses and Opportunistic Infections; 2014 March 5; Boston, MA.
9. Farenc C, Doroumian S, Cantalloube C, et al. Rifapentine once-weekly dosing effect on efavirenz, emtricitabine and tenofovir PKs (Poster 493). Poster session presented at: 2014 Conference on Retroviruses and Opportunistic Infections; 2014 March 4; Boston, MA.
10. Treatment Action Group (Press Release). CRAG, TAG welcome Sanofi U.S. commitment to reduce the price of tuberculosis drug rifapentine. 2013 December 12. Available from: https://www.treatmentactiongroup.org/tb/press/2013/crag-tag-welcome-sanofi-us-commitment-reduce-price-tuberculosis-drug-rifapentine. (Accessed 2014 April 1)
11. Podany AT, Bao Y, Chaisson RE, et al. Efavirenz pharmacokinetics in HIV+ persons receiving rifapentine and isoniazid for TB prevention (Poster 105). Poster session presented at: 2014 Conference on Retroviruses and Opportunistic Infections; 2014 March 5; Boston, MA.
12. Bamrah S, Brostrom R, Fred D, et al. Treatment for multidrug-resistant latent tuberculosis infection—Federated States of Micronesia, 2009–2012. Int J Tuberc Lung Dis. Forthcoming 2014.
13. Ibid.
14. Médecins Sans Frontières and the International Union Against Tuberculosis and Lung Disease. DR-TB drugs under the microscope: 2nd edition. Geneva: Médecins Sans Frontières; 2012. Available from: http://www.msfaccess.org/content/dr-tb-drugs-under-microscope-2nd-edition. (Accessed 2014 April 4)
15. Johnson and Johnson. Bedaquiline receives approval in European Union.
16. Federal Service on Surveillance in Healthcare (Russia). Sirturo registration certificate. 2013 October 22. Available from: http://grls.rosminzdrav.ru/Grls_View.aspx?idReg=38726&isOld=1&t=3f524e27-35c9-43c4-9187-c74048c8aac3. (Accessed 2014 May 16).
17. Ministry of Food and Drug Safety (Korea). Drug library online: bedaquiline fumarate. 2014 March 21. Available from: http://drug.mfds.go.kr/html/bxsSearchDrugProduct.jsp?item_Seq=201401310. (Accessed 2014 May 16).
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23. Otsuka. European marketing authorization for Deltyba
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25. Myungsun L, Jongseok L, Matthew W, et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med. 2012 Oct 18;367(16):1508–18. doi: 10.1056/NEJMoa1201964.
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27. Ibid.
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29. Ruiz Mingote L, Namutamba D, Apina F, et al. The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from TB-affected communities. Lancet. Forthcoming 2014.
30. Mendel, Carl (TB Alliance, New York, United States). Personal communication with: Erica Lessem (Treatment Action Group, New York, NY). 2014 April 16.
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35. PanACEA(Press Release). MAMS study has completed first interim analysis. 2014 March 10. Available from: http://panacea-tb.net/mams-study-has-completed-first-interim-analysis/. (Accessed 2014 April 4)
36. Infectex, Maxwell Biotech Venture Fund, Sequella Incorporated (Press Release). Maxwell Biotech Venture Fund’s portfolio company, Infectex, enrolls first multi-drug resistant tuberculosis (MDR-TB) patients in pivotal clinical trial of SQ109, licensed from Sequella. 2012 December 19. Available from: http://www.sequella.com/docs/Sequella_Infectex_Release_19Dec2012.pdf. (Accessed 2014 April 1)
37. Boeree M. The High Rif trials of the PanACEA Group. Presentation at: 44th Union World Conference on Lung Health; 2013 October 30–November 3; Paris, France.
38. Boeree, Martin (PanACEA Consortium, Nijmegen, Netherlands). Personal communication with: Erica Lessem (Treatment Action Group, New York, NY). 2014 June 5.
39. Boeree, Martin (PanACEA Consortium, Nijmegen, Netherlands). Personal communication with: Erica Lessem (Treatment Action Group, New York, NY). 2014 March 25.
40. Jindani A, Shrestha B, Westernmann de Patino I, et al. A multicentre randomised controlled clinical trial to evaluate the toxicity of high dose rifampicin in the treatment of pulmonary tuberculosis (RIFATOX). Presentation at: 44th Union World Conference on Lung Health; 2013 30 October–November 3; Paris, France.
41. PanACEA. MAMS study completed interim analysis.
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43. Ibid.
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49. Ibid.
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51. Médecins Sans Frontières and the International Union Against Tuberculosis and Lung Disease. DR-TB drugs under microscope.
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54. Milanga, Maureen (AIDS Law Project, Nairobi, Kenya). E-mail with: Mark Dybul (Global Fund, Washington, DC). 2013 December 20.
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