A novel drug combination (PaMZ) designed to treat both drug-sensitive and MDR-TB, including those who are HIV positive, is advancing to the crucial Phase III human clinical trial. If all goes well, the three-drug combination therapy will be a game changer for tuberculosis treatment. Among other things, the less toxic regimen cuts down the duration of MDR-TB treatment from 18-24 months to six months, and reduces the number of pills by 97 per cent. MDR-TB treatment is likely to be 90 per cent cheaper.
Dr. Mel Spigelman, President and Chief Executive Officer of the Global Alliance for TB Drug Development (TB Alliance), regarded as one of the world’s leading experts in tuberculosis and TB drug development explained the characteristics of the drug combination and the promise it holds in an email to me.
What phase of the trial was last studied? How many TB and MDR-TB patients were tested?
The PaMZ regimen (PA-824 + moxifloxacin + pyrazinamide) is advancing to Phase 3 study based on encouraging data from both previous clinical studies and preclinical modeling data. The most recent study of PaMZ was an eight-week study, known as NC-002. The NC-002 trial enrolled MDR-TB patients as well as drug-sensitive TB patients — the first clinical trial to do so. NC-002 enrolled more than 200 patients across seven sites in Africa. Results of NC-002 will be published later this year.
What was the duration of the STAND trial based on which you are progressing to a Phase III trial?
The [Shortening Treatments by Advancing Novel Drugs] STAND trial is now being planned. It will test PaMZ as a shorter regimen for TB and MDR-TB. Provided we can obtain the adequate funding, we expect to have top-line results for the trial in 2017.
How safe was the combination drug? Where any serious adverse effects seen? How toxic was PaMZ?
The toxicity profile of PaMZ continues to appear favorable. This is in stark contrast to existing MDR-TB treatment, which is often accompanied by severe side effects, including irreversible hearing loss.
What was the efficacy and effectiveness of the drug combination?
In July 2012, a two-week study published in The Lancet showed that PaMZ appeared to kill the patients’ bacteria more quickly than standard therapy after starting treatment. Findings from a subsequent two-month study are expected to be published later this year. While we can’t specify the exact results until publication, we are strongly encouraged by the data and feel we have the support needed to advance to the Phase 3 STAND trial. This trial will test the ability to cure TB and MDR-TB at treatment durations that last four and six months respectively.
Did PaMZ show equal efficacy, effectiveness and safety in the different populations/ethnic groups studied?
Data from previous trials showed PaMZ to be safe and efficacious across patients at various sites and with varying characteristics. More specific data will be available upon the publication of NC-002 results later this year.
Was the pharmacokinetics of all the three drugs in the regimen studied?
Yes. The pharmacokinetics of each drug has been studied individually in previous research. Additionally, pharmacokinetics of the PaMZ (the drugs when used in combination) has been studied in previous clinical trials, including NC-001 and NC-002.
If the drug is able to reduce the MDR-TB treatment duration from 18-24 months to six months, why do we see only a two-month reduction in the case of drug-sensitive TB?
As a novel regimen, PaMZ offers a new approach to treating both TB and MDR-TB. The science will determine the length of the treatment–the duration of treatment is so dramatic for MDR-TB partially because the existing treatments are so profoundly flawed.
For drug-sensitive TB, a reduction in treatment by a third would be significant, but we certainly have a ways to go in terms of achieving our ultimate goal of extremely short treatment for TB, within the order of a week or two.
How many times a day should PaMZ be taken by drug-sensitive TB and MDR-TB patients?
PaMZ projects to be a once-daily oral treatment for both drug-sensitive TB and MDR-TB.
Is it the peculiar combination and/or dosage of PaMZ that makes injectables redundant for MDR-TB patients?
Many of the problems with today’s MDR-TB treatment are due to the fact the regimens were assembled as an emergency reaction to the problem — an approach of treating patients with the “kitchen sink” of available drugs to find something that works. PaMZ projects to have such huge comparative advantages largely because it was developed from the “ground up” with the specific needs of patients and care providers in mind. Those needs include simplicity of administration, ease of storage, and low cost, therefore we choose to develop only regimens that can be fully administered orally.
It is the regimen — not just one particular drug — that shows promise.
With PaMZ regimen, would hospital stay by MDR-TB patients be required?
PaMZ projects to be much less resource-intensive on care providers, and therefore much more suitable for outpatient treatment. However, it is important to remember that on the ground, treatment practices often vary regionally.
Is the exclusion of rifampicin alone making the drug HIV friendly?
Rifampin interacts poorly with many commonly used ARV treatments for HIV. Removing it from TB treatment is a major driver of ensuring that the regimen can be taken with HIV drugs without negative interactions. In addition, studies have been conducted that show that PA-824 is not expected to have drug interactions with ARV treatments.
Can PaMZ be used in XDR-TB patients?
XDR-TB is, by definition, resistant to fluroquinolones, the class of drugs to which moxifloxacin belongs. Therefore, PaMZ does not project to be a regimen for XDR-TB. TB Alliance is working toward assembling novel regimens that could be effective against XDR-TB and expects to launch a clinical trial to test those regimens in the near future.
Despite PA-824 being a new drug candidate, how is it possible to make the combination drug cheap? Which company holds the patent for PA-824? Will Indian companies be permitted to produce generic versions of PA-824?
TB Alliance recognizes that for a new cure to have a significant impact on TB and MDR-TB, it must be affordable for those who need it. Therefore, total cost is an extremely important criterion when determining whether to develop a regimen. Existing MDR-TB therapy consists of 14,000 or more pills administered over the course of 18 months or more. PaMZ projects to reduce that number by 97 per cent; this is a significant driver of cost savings. Further, with affordability in mind, TB Alliance has invested in process chemistry efforts to help make the production of PA-824 simple and cost-effective. Moxifloxacin and pyrazinimide are available as generics. The overall cost of PaMZ for MDR-TB treatment is projected to be more than 90 per cent cheaper than today’s treatment in many countries.
Additionally, it is important to remember that the cost of drugs is only one portion of the total cost of MDR-TB therapy. Much of the true, full cost (to a health system) of treating MDR-TB is related to human and physical resources required to cure a patient. The savings potential offered by PaMZ in this realm may be even more substantial than in simple cost of treatment.
TB Alliance holds the rights to PaMZ and is committed to ensuring it is affordable and available to all who need it. However, we have licensed out the further development of PaMZ to the Council of Scientific and Industrial Research (CSIR) for continued development and commercialization in India; if the regimen is successful, CSIR will make the regimen available, affordable, and accessible to those who need it.
What was the main reason for MDR-TB patients requiring so many drugs and an injection, and prolonged duration of treatment? Was it because of the incremental benefit derived by adding one drug after another or the wrong choice of drug combination?
In practice, MDR-TB therapy embraces a bit of an approach whereby you throw what you have, flawed as it may be, at the problem and hope for the best.
This is partially why the approach behind PaMZ and additional regimens being developed by TB Alliance represents such an improvement, not only in potential but in process. These regimens are developed proactively with patients’ and providers’ needs in mind, not assembled reactively from pre-existing, flawed options. In doing so, we can realize transformative, rather than incremental, benefit.
While it is true that testing each drug individually in a trial and then going in for combinations of the drugs would entail longer time and money, is it not difficult to test the bioavilability of combination drugs, in this case three drugs plus their dosages?
A typical trial for a TB drug could take six years, or even more. If there is a three- or four-drug combination, by the time each one is developed and then added into or substituted into the regimen, it could easily take a quarter of a century to establish a novel regimen.
Testing drugs in combination presents additional scientific challenges, but holds the promise for dramatic benefits for treating TB by introducing impactful regimens. TB Alliance has worked with leading regulatory agencies around the world to determine and understand what is needed to make use of this pathway. For example, we don’t want to be giving patients more drug(s) than needed, so we must establish that each component in the regimen contributes to its efficacy. Our protocols take into account the need for additional data, and we take great efforts in selecting trial sites that can accommodate these very advanced trials.
Why was bedaquiline not included in the combination? What is the dosage of the individual drugs in the PaMZ regimen?
TB Alliance uses a preclinical regimen identification program to identify the most promising combinations of drugs, whether they are in development or already in use. PaMZ performed extremely well in combination and was selected for clinical development a number of years ago. The first clinical trial of PaMZ in combination took place in 2010; results in that and subsequent trials have continued to affirm its promise to shorten and simplify TB and MDR-TB treatment.
STAND tests the PaMZ regimen in two different dosages; only PA-824’s dose varies among the two doses. (100mg PA-824 vs. 200mg PA-824 in TB, and 200mg PA-824 in the MDR-TB version of the regimen).
While this regimen does not include bedaquiline, additional regimens in earlier stage development by TB Alliance do include it. Another promising regimen, JPaZ (bedaquiline + PA-824 + pyrazinamide) recently completed a two-week trial and is poised to continue its development. That trial was known as NC-003, and its results are expected to be published later this year.
On what basis was moxifloxacin chosen as one of the three drugs?
Moxifloxacin has proven efficacy against TB and MDR-TB; drugs of its class (fluroquinolones) are already commonly used in MDR-TB treatment on an off-label basis. It also combines synergistically with the other drugs in the regimen, as shown in earlier studies. PaMZ was identified for development because of its performance in preclinical models, as well as previously completed clinical trials.
Considering that many people, especially in South Africa, are already resistant pyrazinamide and hence will not benefit from PaMZ, is there any other drug combination being tested that will produce comparable results?
Through our preclinical regimen identification program, we have made great strides in determining which combinations of drugs are most likely to shorten TB treatment. Pyrazinamide is a drug that appears in many of the most promising regimens we have identified. However, despite its extensive use, understanding of the workings of the drug remains incomplete throughout the TB community. We know that pre-existing pyrazinamide resistance is an issue of varying concern, region by region, and have discovery projects underway, which attempt to produce new compounds that mimic pyrazinamide’s effects within a combination of drugs, but that will work in those patients who are resistant to pyrazinamide.
What percentage of people across the world is resistant to pyrazinamide?
Based on the limited data available, within high-burden settings, pyrazinamide resistance appears to be around three per cent in treatment-naïve patients, and up to 40-50 per cent in MDR-TB patients. While this may seem like a substantial figure, given the complexities and cost of today’s MDR-TB treatment, we still see this as a significant advance to the toolbox of treatments.
How many subjects will be enrolled in the Phase III trial? What will be the duration of the trial?
STAND is designed to enroll 1,500-1,800 patients. PaMZ will be tested in four and six month durations across drug-sensitive and drug-resistant TB patients respectively. Phase 3 TB drug development trials also require lengthy follow-up of patients. Top-line trial results are expected in 2017.
In how many will the drug candidate be tested and what will be the size of the control group?
The trial will include roughly 1,500 men and women, including those who are HIV-positive; about 300 of them will comprise the control group.
Are there sites in India where the Phase III trial will be conducted?
TB Alliance has granted a license to CSIR to develop and commercialize PaMZ in India. CSIR will first conduct further Phase 2 studies, which have just been launched. Following their completion, they will undertake Phase 3 studies.
This approach was taken given that, partnering with a governmental institution in India, is expected to accelerate the timeline to develop and, if successful, make available the regimen in India.
How many HIV positive subjects will be enrolled in the Phase III trial, and how many were enrolled in the earlier trial?
HIV-positive subjects are eligible for STAND, and we plan to enroll a significant number of such patients. HIV-positive patients were also eligible for and enrolled in NC-002, specific numbers will be available when NC-002 results are published later this year.