Interview conducted by April Cashin-Garbutt, BA Hons (Cantab) on 24th July 2012
Please could you tell us a little bit about TB and who it affects?
TB is a leading global killer. It is the second leading infectious disease in the world, behind HIV. TB is spread through the air, so it can affect anyone, but has its worst impact on impoverished communities and those people with HIV.
How is TB currently treated and what alternative have you developed?
The treatment for TB takes too long, and is inadequate. For drug-sensitive TB, treatment includes 4 drugs taken for a period of 6 months. For drug-resistant TB, the treatment requires 6-7 drugs—one of them an injection that must be administered every day for the first 6 months—that must be taken for 18-24 months. With all these therapies, there are significant drug-drug interactions with the antiretrovirals, which is a big problem given that TB is the number one killer of people with HIV.
The Lancet study reports on the NC-001, or New Combination 1, trial, which is the first clinical study to test a novel combination of drugs. Traditionally, one new drug was developed at a time and added to or substituted into the current treatment. However, this incremental change only results in incremental benefit—and over long periods of time.
The new approach which new combinations of drugs together early in the pipeline and reported in the Lancet aims to develop dramatically improved treatments that can treat both drug-sensitive TB and drug-resistant TB, as well as HIV/TB co-infected patients, and for those treatments to be developed in a fraction of the time.
The new therapy that you have developed is called a combination drug. Please could you explain what one of these is?
The combination regimen being developed includes PA-824, a new chemical entity, moxifloxacin, an approved antibiotic that is currently under development for TB, and pyrazinimide, part of today’s established treatment regimen. Combination treatments are necessary in TB to prevent the development of resistance.
What are the benefits of this regimen?
If the results of additional trials are as we expect, there could be several benefits of this combination treatment.
The traditional definition of MDR-TB is resistance to two of the first-line drugs, isoniazid and rifampin. Because this treatment does not include those drugs, this regimen could potentially be used for treating both drug-sensitive and drug-resistant disease.
Likewise, rifampin also interacts poorly with current TB drugs, so a rifampin-sparing regimen such as PaMZ shows potential for treating HIV/TB co-infected individuals.
NC-001 study was a Phase II two-week study. However, with this data along with pre-clinical studies, the PaMZ regimen shows promise to treat both drug-sensitive and some forms of drug-resistant TB in three or four months. This would be a benefit for drug-sensitive TB, but offers a transformative change for those who could take this to treat MDR-TB—showing a reduction from 2 years of treatment to just four months with a completely oral drug combination.
Finally, the complexity and cost of today’s MDR-TB treatment is a major barrier to access, with just less than 10 percent of the people who have MDR-TB receiving proper MDR-TB treatment. The PaMZ regimen could help in the global scale-up of treatment of the disease, as it is projected to cost 90 percent less than today’s 2-year MDR-TB treatment.
At what stage is your new therapy at and when do you think that it will be available for patients?
The PaMZ regimen is in mid-stage development. NC-001, which was reported in the Lancet, was a 2 week trial that showed promising results. In March, NC-002 was launched, which will test this regimen in a 2 month trial, for which we will likely get the results in the third quarter of 2013.
If those results are positive, we will move to a Phase III in 2014.
Realistically, it will be 4-5 years until this regimen could be available. That is a long time, but considering there have been no new treatments in nearly 50 years, we’re excited about the potential for a relatively short timeline to get this treatment to patients.
It is has been announced that TB Alliance have also progressed in the pursuit of an antiretroviral-compatible TB treatment. How widespread is TB/HIV co-infection and how much of a problem are drug-drug interactions?
TB/HIV co-infection is a major problem. TB kills 1 in 4 people with HIV, and is the leading cause of death for people with AIDS. As such, to tackle HIV/AIDS, you must also tackle TB.
Today, we need to improve our approaches and tools to enable co-treatment of what’s often referred to as the “dual epidemic.” That’s important because rifampin, one of the most important drugs in today’s first line TB treatment, often has poor drug-drug interactions with the most commonly used antiretrovirals, making treatment of co-infected individuals a real challenge.
The new PaMZ regimen undergoing testing, if successful, would be a major step forward in the treatment of TB/HIV co-infected patients by providing a simpler, safer, and HIV-friendly regimen.
How do you see the future of treatment for TB progressing?
TB is an ancient disease—evidence of the disease is found as far back as in the tombs of Egyptian mummies. There have been no new treatments for nearly 50 years. However, 2 pharmaceutical companies have recently filed for new MDR-TB drugs with regulatory authorities to be used in combination with the background treatment.
If approved, these treatments should improve outcomes for those with MDR-TB.
However, moving forward, we hope to bring entirely new treatments to improve TB. These combinations should help tackle not only clinical outcomes but also the access challenges. For example, the PaMZ regimen is a shorter, simpler, and completely oral regimen that does not use injections, and will also be markedly cheaper to treat MDR-TB. These attributes will help in the scaling up of treatment.
What are TB Alliance’s plans for the future?
The results reported in the NC-001 study in the Lancet is just the first step of novel regimen development. NC-002, which began enrolling in March, is now underway to further test the PaMZ combination. Additional regimen trials of novel treatments are expected to launch later this year and next.
What hurdles do you think you will need to overcome? Will drug-resistant TB strains pose a serious problem for achieving TB Alliance’s mission of a world where no one dies of TB?
We think novel TB combinations are the next wave of treatment, but these promising regimens will only be brought to the people who need them with adequate funding from donors and governments alike. The lack of funding for new TB tools is a rate-limiting factor in achieving our mission of bringing shorter, faster TB treatments that can tackle this pandemic.
Where can readers find more information?
About Mel Spigelman
Dr. Spigelman is the President and Chief Executive Officer of the Global Alliance for TB Drug Development (TB Alliance). Prior to being appointed President and CEO in 2009, Dr. Spigelman served for five and a half years as the Director of Research and Development at the TB Alliance.
A highly regarded expert in domestic and international drug research and development, Dr. Spigelman previously spent a decade managing drug R&D at Knoll Pharmaceuticals (a division of BASF Pharma). As Vice President of R&D at Knoll for eight years, Dr. Spigelman directed clinical development and supervised all R&D activities from basic discovery to regulatory approval and Medical Affairs. He established global R&D processes as part of Knoll's senior R&D management team, oversaw a marked increase in US regulatory filings and approvals, and supervised joint R&D programs with multiple other pharmaceutical companies.
Dr. Spigelman received his undergraduate degree from Brown University and his medical degree from the Mt. Sinai School of Medicine where he specialized in Internal medicine, Neoplastic Diseases and Preventive Medicine. Dr. Spigelman holds board certifications from the American Board of Internal Medicine, the American Board's Subspecialty Board of Medical Oncology, and the American Board of Preventive Medicine and was the recipient of the American Cancer Society Clinical Oncology Career Development Award (1985-1988).
Presently, Dr. Spigelman serves on the Coordinating Board of the WHO Stop TB Partnership, is Co-chair of the Working Group on New Drugs of the WHO Stop TB Partnership, and is a member of the Governing Board of the Tres Cantos Open Lab, GlaxoSmithKline.