Last year, at the UN High Level Meeting on Tuberculosis, I spoke about the need to “science the shit out of TB.” Without innovation and ambition, we will continue to use century-old tools to fight the most important infectious killer of humans. Thankfully, innovative scientific research and partnerships are delivering us, for the first time, substantially shorter and safer drug treatments for TB.
In the past few months, landmark clinical trials have demonstrated that we can now treat latent TB infection with effective, safe, short treatments which include 4 months of rifampicin, or a combination of isoniazid and rifapentine for 1 month. This is remarkable progress when compared to the conventional standard of 6-9 months of just isoniazid.
This week, a major breakthrough has been made in shortening the duration of extensively drug resistant (XDR-TB), a deadly form of TB that poses a major threat to global health and security. The US FDA approved a new drug called Pretomanid, in combination with another relatively new drug called bedaquiline, along with linezolid, a drug already used for infections such as vancomycin-resistant enterococcus.
The three-drug regimen (referred to as the BPaL regimen) was studied in the pivotal Nix-TB trial across three sites in South Africa. The trial enrolled 109 people with XDR-TB as well as treatment-intolerant or non-responsive MDR-TB. All drugs were given orally, for a total duration of 6 months. Of the 107 patients who were evaluated six months after the end of therapy, 95 (89%) were deemed to have a successful outcome. This is vastly superior to historic data which show treatment success of under 30% for patients with XDR-TB.
By eliminating toxic injectable drugs, the BPaL regimen offers an all-oral option for patients. However, the regimen, especially linezolid, does have important adverse effects that need to be anticipated and carefully managed. Trials are underway to check whether the efficacy of the BPaL regimen can be maintained, while reducing toxicity by testing a lower dose and shorter duration of linezolid.
Pretomanid is only the third new anti-TB drug approved for use by FDA in more than 40 years. Bedaquiline and delamanid are the other two new TB drugs. Pretomanid was granted Priority Review, Qualified Infectious Disease Product, and Orphan Drug status by the US FDA.
Unlike bedaquiline and delamanid, pretomanid was developed by a non-profit, product development partnership called TB Alliance, which received significant support from governments, academia, philanthropic institutions (notably, the Bill & Melinda Gates Foundation), the private sector, and other partners. [Disclosure: I am a member of the Access Advisory Committee of TB Alliance, but have no financial interests in pretomanid, or any other drug/company].
Why shorter and safer TB treatments are needed?
The long duration of TB treatment and drug toxicity are key reasons why persons with TB struggle to complete the therapy. This is true for all forms of TB, but especially true for drug-resistant disease. Drug-resistant TB is a nightmare for patients, families, and doctors. Patients have to endure a prolonged (up to 2 years) and treatment with more than 14000 pills, including painful, daily injections for 6 months. Every year, nearly half a million people struggle to fight drug-resistant TB.
New treatments will not deliver themselves
While there is great excitement about new drugs and shorter regimens, they will not deliver themselves. There is a need for planning, coordination, and alignment of several key stakeholders.
Unlike the HIV/AIDS community, national TB programs in high-burden countries are typically under-funded, and have an unimpressive track record of absorbing innovative technologies. A good case study is the rather slow scale-up of Xpert MTB/RIF, the best-in-class molecular TB test endorsed by WHO in 2010.
Scale-up of bedaquiline has also been a challenge, with with fewer than 20% of those in need of the drug being able to access it. While pretomanid is only registered by the FDA so far, bedaquiline and rifapentine are yet to be registered in most high-burden countries, despite being on the market for over 5 years. And cost has been a concern. Similar concerns have already been raised with pretomanid, which will be manufactured and commercialized by Mylan, under license from TB Alliance (pricing details awaited).
Clearly, we need to address the big gap between innovation and access in TB. After all, TB innovations mean little, if they cannot save lives.
Pathfinder countries must set an example
Countries must be more proactive and anticipate the introduction of new regimens, pave the way for their rapid regulatory approval, and offer early access to their patients who urgently need them.
South Africa is a role model for other high-burden countries. The country was an early adopter of Xpert MTB/RIF and bedaquiline, and has successfully scaled-up both tools, after conducting evaluation studies. South Africa has leveraged its strong capacity for conducting trials of new diagnostics, drugs and vaccines. Hopefully, since the Nix-TB trial included South African patients, the country will make sure the new regimen is registered quickly and made easily available.
India is also stepping up in the area of TB innovation and delivery, especially with the high-level political commitment from Prime Minister Modi, indigenous development of new TB tools (e.g. molecular tests and AI-based x-ray software), strong TB research capacity, and the creation of an India TB Research Consortium. Where India can do better is a less bureaucratic, more streamlined process for running clinical trials of new TB drugs and vaccines.
Stronger and responsive policies matter
The slow pace of policy change (globally as well as in high TB burden countries) is another reason why TB innovations don’t reach scale. Since WHO endorsement is critical for many countries, WHO can play a big role by rapidly publishing evidence-based policies that are bold and ambitious. Policies will also need to be updated on a regular basis, and engage civil society and a broader range of stakeholders. This is already happening, but can be enhanced by the newly created Science Division, led by Soumya Swaminathan.
Drug manufactures must go beyond donation programs
Given the high mortality of drug-resistant TB, drug developers have an obligation to make new regimens more affordable and accessible, especially when public and/or philanthropic funding was used to support the R&D process. The current model of heavy reliance on drug donation program is simply not working. There is a growing momentum towards demanding greater transparency in R&D and drug pricing.
Sleeping regulators need to wake up
Regulatory agencies are known for their legendary bureaucracy, but have a role to play in ensuring timely access to life-saving medicines. The US FDA has done well in the TB space. Pretomanid is the second drug to be approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs pathway to advance development and approval of antibacterial and antifungal drugs to treat serious or life-threatening infections in patients with unmet needs. If stringent regulatory agencies (e.g. FDA) have approved new TB medicines, these could be used to expedite reviews within countries, thus avoiding the need for repetitive, expensive clinical trials.
While governments step up, donors can support innovations
There is no question that ending TB will require high burden country governments to take the lead, step up their investments in TB as well as universal health coverage (UHC), and make sure the best tools are made accessible via publicly-funded systems. This is already happening with the strong push for UHC. Until then, donors have a big role to play.
This year marks the Sixth Replenishment of the Global Fund, which seeks to raise at least US$14 billion to help save 16 million lives, avert 234 million infections and help the world get back on track to end TB, HIV, and malaria. Successful replenishment of the Global Fund can help ensure greater access to the best tools we have for these infectious diseases. Other donors such as USAID, Unitaid, PEPFAR, and the Bill & Melinda Gates Foundation can and are supporting scale-up of new technologies. Of course, better coordination among them will help.
We need a unified, collaborative TB community
Lastly, it is critical for all people and agencies working in TB to be more unified (stronger ties), cohesive, and cooperative. When disagreements arise, it just might help to focus on the real enemy here – Mycobacterium tuberculosis.
Note: I have no financial or industry conflicts to disclose. I serve on the Access Advisory Committee of TB Alliance, a not-for-profit organization dedicated to the discovery, development and delivery of better, faster-acting and affordable tuberculosis drugs that are available to those who need them.
Original Source: https://www.forbes.com/sites/madhukarpai/2019/08/15/better-therapies-for-tb-are-here-but-they-will-not-deliver-themselves/#2b42738c272c