The infectious disease the single-handedly kills the most humans on an annual basis today, in 2019, is tuberculosis (TB). This fact may be surprising to many who only think of tuberculosis in conjunction with the famous consumptives from artistic works such as Mimi from La Boehme, Violetta of La Traviata, or Hans Castrop from The Magic Mountain.
Fortunately, the United States is at an all-time low with tuberculosis incidences — less than 10,000 cases per year. Approximately one-third of the world’s population is infected with the tuberculosis bacterium and in 2017 an estimated 1.6 million individuals died from TB.
The tuberculosis cases that exist are sometimes very challenging to treat. This challenge, which is synergistic with all the other difficulties in tuberculosis treatment (such as multi-drug regimens, social circumstances, HIV co-infection), is antibiotic resistance. Tuberculosis is a bacterial infection and just like any other bacterial infection, the threat of antimicrobial resistance looms large.
Tuberculosis resistance can be to a single drug or to multiple drugs. The latter, when it impacts two backbone TB drugs, is termed multi-drug resistant TB (MDR-TB) and accounts for about 3.7 percent of new cases.
Within the MDR-TB class is a deadly subgroup of extremely-drug resistant tuberculosis (XDR-TB). There are no good drug regimens to treat this infection with and those that do exist are toxic, extremely cumbersome in terms of pill burden and need for intravenous therapy. And prolonged XDR-TB is often a death sentence.
Revolution in XDR-TB treatment
With that context in mind, it is easier to see why a new drug approval was grabbing headlines all over the world when a new tuberculosis antibiotic was approved by the Food and Drug Administration (FDA). The drug is called pretomanid and it will be used in combination with two other drugs previously approved (bedaquiline and linezolid in the so called BPaL regimen) in the treatment of drug-resistant tuberculosis.
The Nix-TB clinical trial that led to its approval included 109 patients with either XDR or MDR TB and involved a 6-month treatment course. Though there was no control group in this trial — an important limitation that must be kept in mind — a pathbreaking cure rate of 89 percent was achieved. This 89 percent rate was achieved with 3 medications over 6 months versus the dismal 34 percent cure rates that were the result with the historical 18-24-month 6-8 drug regimen. This type of result is extraordinary.
New pathways and incentives for anti-infectives
The approval, based on the extremely encouraging results from the clinical trial, is significant not only because it recognizes and facilitates a treatment pathway for what had been arguably the most difficult infectious disease to treat. It is also significant because its approval leveraged some of the important new FDA pathways and incentives that were created, some as part of the 21st Century Cures Act, in recognition of the fact that antimicrobial resistance and infectious diseases in general are unique in the biotech, pharmaceutical, and healthcare realm.
Antibiotics have to be used judiciously via proactive stewardship to maintain their maximum effectiveness in the face of resistance. Since they are relatively inexpensive and taken for a defined period of time, they are not major profit makers.
Returns on investment, after a billion-dollar drug development cost, are not attractive hence the movement of pharmaceutical companies away from antibiotics and the threat of bankruptcy amongst those that remain. Reflecting that reality, pretomanid was uniquely developed by a non-profit entity, the TB Alliance.
Pretomanid’s approval is an important milestone because it illustrates the additive impact of the many systems in place to incentivize infectious disease countermeasure development. Pretomanid was subject to expedited priority review and approved using a modified criterion known as the limited population pathway (LPAD).
This pathway, because it is targeted to a small population of patients with little available options, allows smaller and shorter clinical trials than would otherwise be the case. It was also designated a qualified infectious disease product (QIDP), which increases market exclusivity time before generic versions can be licensed.
Orphan drug incentives were also applied to it. Pretomanid also merited a tropical medicine priority review voucher, which can be sold very lucratively to another pharmaceutical company allowing expedited review of a different product by the FDA. Hopefully, other infectious disease products can also successfully navigate these myriad programs.
Like with each new antimicrobial, vaccine, or infectious disease diagnostic test I celebrate pretomanid’s development as a great technological advancement that enhances humankind’s resilience against ever present infectious disease threats. The advent of a real option to treat one of the deadliest forms of the top infectious disease killer is a great example of the power of the human mind. What had been an insoluble problem now has an elegant and relatively simple solution.
Dr. Amesh Adalja, board-certified in infectious disease, critical care medicine, emergency medicine and internal medicine He is a senior scholar at the Johns Hopkins Center for Health Security. Follow him on Twitter: @AmeshAA.