The Global Alliance for TB Drug Development (TB Alliance) announced on February 19, 2015 the start of the first human study of a new TB drug candidate TBA-354-the first new potential TB drug to begin a Phase 1 clinical study in 6 years since 2009. “There is a critical gap of new compounds for TB,” said Mel Spigelman, MD, President and CEO of TB Alliance. “The advancement of TBA-354 into clinical testing is a major milestone, not only because of the potential it shows for improving TB treatment, but because it is the first new potential TB drug to begin a Phase 1 clinical trial in six years.”
HOW DOES THIS NEW CANDIDATE COMPARE WITH THE LAST ONE?
Dr. Stephen Murray, Senior Medical Officer at TB Alliance, told Citizen News Service – CNS, that, the last drug to cross from preclinical development to clinical development was Astra Zeneca’s AZD5847, which entered clinical development in December of 2009. AZD5847 is a member of the oxazolidinone class, which includes drugs such as linezolid, while TBA-354 is a nitroimidazole, which includes pretomanid and Deltyba (delamanid).
“The best comparator for TBA-354 is Pretomanid, TB Alliance’s late stage drug candidate that is a component of many of the most advanced new regimens in development, such as ‘PaMZ’ (Pretomanid + Moxifloxacin + Pyrazinamide) and ‘BPaZ’ (Bedaquiline + Pretomanid + Pyrazinamide). TBA-354 is from the same chemical class as Pretomanid, but has demonstrated more potent anti-bactericidal and sterilizing activity, as compared to Pretomanid, in pre-clinical studies. TBA-354 is a novel drug, and therefore projects to be effective against drug sensitive and drug-resistant TB. However the stage to begin that kind of testing is yet to be reached.”
WHO ARE THE STUDY PARTICIPANTS AND WHAT IS THE TIMELINE?
“The upcoming study of TBA-354 will be the drug candidate’s first exposure to humans – a Phase 1 study whose main goal is to establish that the drug is safe, which includes being safe to be tested in people who are already sick. It would enroll healthy, adult volunteers in order to minimize risk. Recruitment is underway to enroll nearly 50 U.S. volunteers for the randomized, double-blind Phase 1 study, which will evaluate the safety, tolerability, pharmacokinetics, and dosing of TBA-354. This Phase 1 programme includes 2 clinical studies- a single ascending dose study and a multiple ascending dose study-and is expected to be complete in 2016,” Dr Murray said.
According to the data of the World Health Organization 1.5 million people die every year from TB, and more than 9 million are diagnosed with the disease. Lack of short, simple, and effective treatments is a significant obstacle to TB control. However, because there is little economic incentive to develop new tools, there are not enough promising drugs in the pipeline, and this could hinder efforts to develop the appropriate treatments needed to combat the TB epidemic.
In fact, as per a 2014 Report by Treatment Action Group, pharmaceutical companies are shedding their TB portfolios and continue to disband TB research programmes for development of new drugs and vaccines. While Pfizer’s exited in 2012, AstraZeneca and Novartis announced the closures of their TB drug discovery programmes in 2013 and 2014, respectively. The private sector now spends less than $100 million on TB R&D annually. As more and more private-sector companies pull out of TB R&D, the onus of responsibility falls increasingly on public institutions and country governments. Public institutions contributed 60% (about $400 million) of total TB R&D spending in 2013, with 62% of this public funding coming from USA alone.
Industry cuts have been especially harmful to TB drug development, with major companies no longer filling the pipeline with new TB leads. Commenting on this problem, Dr Mary Moran of Policy Cures said “With drug resistance on the rise, this is particularly worrying. New medicines can take a decade or more to develop. Without a strong backfill of fresh leads, there are worrying consequences for TB control in the future.”
Indeed, the TB world had to wait for 45 years between the introduction of rifampicin (in 1967) and the approval of the next new class drug bedaquiline (in 2012). Over 120 years elapsed between the advent of smear microscopy and the introduction of GeneXpert for the diagnosis of TB. And we are still waiting for a vaccine that can replace/improve the BCG vaccine introduced in 1921.
According to Dr Murray – “As TB was brought under adequate control in most of the developed world, innovation in tools to diagnose, treat, and prevent TB stalled. However, TB continued to be a leading killer in poorer regions. As AIDS emerged, TB exploded and received renewed attention as a global health threat. This led to resurgence in TB drug development, including the launch of TB Alliance in 2000.”
“In the last few years, we have seen the introduction of two new drugs – Sirturo (bedaquiline) and Deltyba (delamanid). However, these drugs have only been approved for use against MDR-TB and we are yet to see their major impact on the disease. What is needed is therapy that can transform TB treatment, making it short, simple, effective, and affordable for all. New regimens in development, such as PaMZ, are believed to be able to usher in a new age of TB treatment and have major impact on the TB pandemic.” TBA-354 was identified in collaboration with partners – University of Auckland and University of Illinois Chicago. Once identified, TB Alliance further advanced TBA-354 through pre-clinical development and is now the sponsor of this Phase 1 study.