The treatment pipeline: moving beyond “Making the most of what we’ve got”

The treatment pipeline: moving beyond “Making the most of what we’ve got”
30th November 2015 | lightspeed

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For decades, those living with tuberculosis (TB) and their care providers have operated in conditions of scarcity and neglect: inadequate funding for programmes and research, ageing infrastructure and outdated technologies, limited scientific understanding, knowledge gaps on existing treatments, low public attention, and absent political will.

The limited response to TB born of these conditions remains entrenched, even with two new drugs conditionally approved by stringent regulatory authorities,1,2 a new global strategy to end TB from the World Health Organisation (WHO) that envisions a world free of TB (with a 95 percent reduction in TB deaths and 90 percent reduction in TB incidence by 2035 compared with 2015 levels) and a relative increase in resources for TB drug development since 2006. (Though funding for TB research and development [R&D] is still grossly insufficient, investments in TB drug research, which amounted to US$243 million in 2014, have reached just one-third of the annual target set by the Global Plan to Stop TB, 2011–2015.)

To their credit, TB treatment researchers are making the most of what they have, cobbling together combinations and treatment strategies to better use existing medicines and the few new experimental drugs available, as well as exploring adjunct, host-directed therapies to improve treatment. For the first time since 2009, a new drug candidate recently entered phase I (see table 1). Studies are at last under way or coming together to test new drugs in smarter combinations to determine the safety of co-administration and optimal regimens for multidrug-resistant TB (MDR-TB). Innovative trial designs are attempting to shorten treatment for drug-sensitive TB (DS-TB), and improved preventive therapy for TB, including for MDR-TB, is progressing.

But for the most part, these research efforts won’t bear fruit for years. Drug sponsors are slow or unwilling to collaborate, pharmaceutical investment is minimal, and TB treatment trials remain lengthy. This work should have advanced long ago – but better late than never.

Table 1. New Drugs in development for tuberculosis NIAID: National Institute of Allergy and Infectious Diseases (United States). SAMRC: South African Medical Research Council. The Union: International Union Against Tuberculosis and Lung Disease

Table 1. New Drugs in development for tuberculosis NIAID: National Institute of Allergy and Infectious Diseases (United States). SAMRC: South African Medical Research Council. The Union: International Union Against Tuberculosis and Lung Disease

NIAID: National Institute of Allergy and Infectious Diseases (United States). SAMRC: South African Medical Research Council. The Union: International Union Against Tuberculosis and Lung Disease

In the meantime, TB programmes, donors, multilateral agencies, nongovernmental organisations providing technical assistance, and pharmaceutical companies have been slow and unambitious in rolling out available strategies and new technologies. Nearly half a million people develop MDR-TB a year, yet less than one in four is diagnosed, and even fewer start treatment.According to estimates based on WHO guidelines, bedaquiline or delamanid is clinically appropriate for a third of those who develop MDR-TB (160,000 people per year), yet only about 2,000 people in total have received bedaquiline or delamanid outside of a clinical trial. TB drug research and programming alike need an infusion of urgency, coordination, and funding.

TB infection

Preventing TB requires infection control to avert transmission, and preventive therapy for TB infection (often referred to as latent TB infection, or LTBI, as it is asymptomatic and is not transmissible), as an improved vaccine is years away (see Tuberculosis Vaccines Pipeline). Modelling demonstrates that rapidly reducing TB incidence and death on the path to elimination depends on treating both active TB disease and TB infection. With an estimated one-third of the world’s population infected with TB, we need a much better understanding of who is most at risk of progression from TB infection to active TB disease to target prevention efforts.

Meanwhile, efforts advance to refine prevention strategies. In 2014, the WHO issued refreshingly clear and concise guidelines on testing for and treating TB infection.11 The Temprano study had two exciting findings regarding TB prevention in people with HIV: 1) starting ART immediately reduced the risk of death and serious HIV-related illness, including TB, by 44 percent, and, 2) six months of isoniazid preventive therapy reduced the risk of severe HIV morbidity by 35 percent, with no increased risk of other adverse events. These results warrant an update to the WHO guidelines, emphasising the importance of earlier ART initiation and treatment of TB infection in those with HIV as long as active TB disease is ruled out (even in the absence of testing for TB infection).

Shortened regimens such as three months of once-weekly doses of isoniazid and rifapentine (3HP) are now recommended, and may confer advantages in some settings. But it is unclear if shorter is better in settings with high rates of transmission, such as mines in South Africa, as the protective effects of preventive therapy last only for the duration of treatment.

Strategies for preventing infection with MDR-TB from progressing to active disease are urgently needed. Three new large-scale clinical trials, Phoenix (A5300), TB CHAMP, and V QUIN, which will test either delamanid or levofloxacin, will build a much-needed evidence-based approach for treating TB infection in children and/or adults with close contact with someone with MDR-TB.

Active TB disease

For the first time in six years, a new drug candidate for TB has entered phase I clinical trials.17 TBA-354, the newest nitroimidazole under study, is in the same class of drugs as delamanid and pretomanid (formerly PA-824).

Little progress has been made on other early-stage candidates. For example, there is still no evidence to suggest that SQ109 has clinical activity in persons with TB disease, and AZD5847 is no longer in development for TB.

he resulting small number of plausible new compounds (five) and narrow diversity of new drug classes (two, as linezolid from the oxazolidinones is already on the market) for TB treatment remain a serious concern (see table 1). For most of these products, progress remains glacially slow. We urgently need more investment and collaboration to bring them forward, as well as new candidates to come through preclinical development. With so few options, researchers are focusing on repurposing what’s available, for both drug-sensitive (DS-) and drug-resistant TB (DR-TB). Efforts are also picking up to evaluate the utility and safety of host-directed therapy.

DS-TB

The quest for shorter treatments for DS-TB continues, with a commitment to optimising the use of older treatments and some creative thinking on how to use new ones. Better use of rifamycins, whose potent anti-TB activity and likely current underdosing offer promise, could potentially be one avenue for shortening DS-TB treatment. The potential efficacy benefits and safety of higher doses of rifampicin appear promising so far (PanACEA MAMS-TB-01). More studies are planned to look at rifampicin and rifapentine in higher doses to shorten treatment. These approaches to optimise rifamycins – some with the addition of moxifloxacin – are among the most straightforward options for potentially shortening DS-TB treatment using existing drugs, since REMox and OFLOTUB clearly showed that exchanging one standard first-line TB drug with moxifloxacin or gatifloxacin is not enough to meaningfully reduce treatment duration without a much greater risk of relapse than the six-month standard of care. The APT study will examine the role of new drug pretomanid, in DS-TB treatment. There are also plans to study clofazimine in DS-TB.

TRUNCATE-TB is aiming to take a different approach, by seeking to produce relapse-free cure in most patients, while accepting that in a clinical trial there may be more relapses than with the current standard of care. TRUNCATE-TB will use an adaptive design to test several two-month DS-TB regimens including new and repurposed drugs (including high-dose rifampin, linezolid, clofazimine, delamanid, and bedaquiline); it will also attempt to identify who may be at increased risk of relapse.

Studies for DS-TB and some forms of DR-TB

Two new trials are looking at using new drugs to treat DS-TB, in addition to some forms of DR-TB: the phase III STAND-TB trial, designed to evaluate four- and six-month regimens of pretomanid, moxifloxacin, and pyrazinamide, has started.25 NC-005, a two-month phase II study looking at pretomanid, bedaquiline, and pyrazinamide, has also begun (this trial will also include moxifloxacin in an arm for people with MDR-TB).26 Both trials offer hope for the tremendous advantage of all-oral regimens with greatly reduced pill burdens, fewer drugs (and potentially fewer side effects), and shorter treatment for DS-TB and some MDR-TB, but also raise troubling questions about trial design, the management of drug-resistance, and the wisdom of moving into combination drug development without robust data on individual new drugs.

DR-TB

While Otsuka completes its phase III trial that adds delamanid to the current standard of care for MDR-TB, investigators are struggling to advance trials to understand how to better use delamanid and bedaquiline as part of optimised regimens for MDR-TB, in trials such as STREAM II, NExT, Nix-TB, A5343, endTB, and TB-PRACTECAL. A few other trials, such as STREAM I, Opti-Q, and studies on clofazimine and linezolid, seek to improve MDR-TB treatment without new drugs.

Conclusions and recommendations

With few new drugs to work with, inadequate investment from drug sponsors, and limited funding, TB treatment researchers are in the difficult position of trying to do more with less. To ensure the development and availability of improved treatment strategies for TB, we must:

  • Move promising preclinical drug candidates into clinical development more quickly.
  • Revitalise research on compounds languishing in early-stage clinical development.
  • Increase funding for TB R&D.
  • Invest existing resources wisely.
  • Design studies with high scientific rigor.
  • Make new drugs available for pragmatic and investigator-initiated research.
  • Plan for access earlier and ensure early/emergency access when needed before approval.
  • Improve regulatory structures and harmonise them regionally.
  • Support robust postmarketing safety monitoring without making it a barrier to rollout.

We have a long way to go. But we are building political will to address the structural, financial, and scientific deficits that sustain and encourage this epidemic. And with two new drugs, shorter treatment for TB infection, and potentially dramatically shorter treatment regimens for MDR-TB infection and active DS-TB and DR-TB disease under study, there is potential to do more than ever to treat, cure, and ultimately end TB. Let us not squander this unprecedented and all-too-rare opportunity.