The antimicrobial pipeline is ‘dry’ and that’s a problem

Antimicrobial resistance is a growing problem and one that is already claiming over a million lives per year. The situation is urgent but finding a sustainable solution is a difficult prospect, finds Ben Hargreaves.

Alexander Fleming discovered the world’s first antibiotic, penicillin, in 1928. However, the difficulty in developing a method to adequately produce sufficient levels of the product meant that the age of the antibiotic did not truly begin until the 1940s. The importance of antibiotics in the development of modern medicine is well-established; prior to their discovery minor infections were enough to kill and the average life expectancy was 47 years old. Despite all of the advancements that have occurred in medicine from antibiotics first introduction, it is estimated that a world without effective antibiotics would see a fall in life expectancy of 20 years.

The risk of a world without effective antibiotics is dramatic and yet the rise in antimicrobial resistance (AMR) is a real problem that is already responsible for approximately 1.2 million deaths each year globally. By 2050, this figure is expected grow to 10 million each year if no effective action is taken to counter the problem. The issue of the growing inefficacy of antimicrobials, including antibiotics, antivirals, antifungals, and antiparasitics, is being driven by various factors, including the natural evolution of organisms to survive attacks by medication.

There are certain influencing actions that are increasing the rate of AMR, which can be directly controlled or influence by people. This includes the misuse and overuse of antimicrobials; lack of access to clean water, sanitation and hygiene for both humans and animals; poor infection and disease prevention and control in health-care facilities and farms; poor access to quality, affordable medicines, vaccines and diagnostics; lack of awareness and knowledge; and lack of enforcement of legislation, as per the WHO.

Why AMR is a threat

The WHO has declared AMR as one of the top 10 global public health threats facing humanity. The spread of drug-resistant pathogens poses a serious problem to treat common infections. A greater threat is the emerging bacteria that are resistant to multiple or all existing anti-bacterial agents. As these bacteria spread more broadly, new antimicrobial treatments are in even greater need of development.

One of the challenges in ensuring that treatments are effective, however, is with basic education on their use. Kevin Outterson, professor of law at Boston University and executive director of CARB-X, highlighted this issue to pharmaphorum, saying, “The more we use or waste antibiotics, the faster resistance develops. Bacterial resistance proceeds inexorably.”

The latter point, wherein the greater misuse leads to an ever-worsening situation of resistance, is where education on the correct use of antimicrobials is so important. According to the Mayo Clinic, the overuse of antibiotics sees around one-third of people taking the treatments when they are neither needed nor appropriate. There is also the necessity for people to continue to taking the treatment as prescribed, as discontinuing a treatment early can promote the spread of antimicrobial resistance.

Outterson outlined the actions that are needed in the short-term to counter AMR: “First, stop wasting these drugs. Use them only when needed to protect our health. Second, prevent infections wherever possible, including with vaccines. And finally, conduct research today so we will have antibiotics tomorrow. That is our mission at CARB-X.”

Filling out the pipeline

CARB-X is a non-profit partnership organisation that aims to accelerate the development of antibacterial products, with it supporting a pipeline that includes antibiotics, vaccines, rapid diagnostics and other products. The organisation is based out of Boston University and is funded by various countries and partners, such as the Wellcome Institute, UK Aid, the US National Institute of Allergy and Infectious Diseases, and others. The work of CARB-X is necessary because, in the words of The WHO, “the clinical pipeline of new antimicrobials is dry.” In terms of support that CARB-X provides to those performing R&D on potential antimicrobials, it aims to aid early development and progress therapies to reach the phase 1 stage. Once this stage is reached, the required funding to progress to the commercialisation stage must be found through additional private or public support. This is where development can become tricky.

The reason for the lack of work being done to replenish the pipeline is complicated, but for the pharma industry the fact is that the financial return made on antimicrobials does not compare favourably to other therapeutic areas. Outterson explained, “New antibiotics are used sparingly to prevent resistance. That is wonderful advice for public health, but for the company with a new antibiotic, that spells bankruptcy. We must find a new way to pay for antibiotics, based on their value to society, not the volume of pills sold.”

Developing new strategies

This has led to several recent strategies to try to bolster development in the area, with two notable examples being pharma companies pooling their money to support early stage biotechs working in the area and countries rethinking reimbursement strategies for the products. The former saw the AMR Action Fund select two biotechs to receive funding in support of their work on treatments for drug-resistant infections. Beyond the two biotechs, the Fund plans to commit over $100 million in capital this year to companies progressing antimicrobials through the clinic.

On other side of this work is the adaptation some countries are progressing to provide alternative payments models for antimicrobials. Of which, Outterson said, “The best example I know of is the subscription program recently established in England. The proposed US version is called the PASTEUR Act, which may pass Congress this year.” The UK’s model has been likened to a ‘Netflix subscription’ for antimicrobials, which will see it pay a fixed annual fee for two new antibiotics of £10 million, regardless of how much is given to patients. The contracts given to two antibiotics, which are Pfizer’s Zavicefta (ceftazidime/avibactam) and Shionogi’s Fetcroja (cefiderocol), will have a duration of 10 years. The experiment with different, radical payment models is necessary if the pipeline of antimicrobials is to be refilled, the alternative could be far worse than the pandemic currently being endured.