No rest in the hunt for novel antibiotics

Antibiotics have provided protection against life-threatening bacterial infections for nearly 100 years. However, multi-drug resistance is on the rise. The need for novel antibiotics is now greater than ever.

In 2017, the World Health Organization (WHO) published a list of 12 families of priority pathogens for which new antibiotics are urgently needed. The list highlights the serious and rapidly emerging global health threat posed by pathogens known as Gram-negative bacteria, that are difficult to treat and, in some cases, resistant to several classes of antibiotics.

The priority pathogens include Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae (e.g. Escherichia coli, Klebsiella species). While these pathogens can affect anyone, they pose the greatest risk to immunocompromised patients and those in hospital environments - causing life-threatening infections. To counter this urgent global health threat, Roche has a comprehensive strategy for antibiotic research and development that aims to overcome the scientific and economic challenges standing in the way of bringing new, effective treatments to patients in need.

Speaking of the economic challenges, they cannot be understated. The expected return on investment for novel antibiotics is low relative to medicines in other disease areas, and because most new agents will be reserved for use only when other drugs have failed.

According to John Young, Global Head of Infectious Diseases for Roche Pharma Research & Early Development (pRED), these roadblocks do not deter Roche’s commitment. He says, “as one of very few large pharmaceutical companies remaining in anti­biotics research and development, Roche is embracing the challenge and endeavouring to deliver novel antibiotics to patients in need. Tackling the global crisis of antimicrobial resistance requires joint action from pharmaceutical companies, academia, governments and public health organisations, as well as an ‘all hands on deck’ approach within Roche.”

Roche is strongly committed to the AMR Action Fund, a groundbreaking collective venture organised by the International Federation of Pharmaceutical Manufacturers and Associations. The Fund invests into the development of novel antibiotics and works with partners to ensure that there will be a sustainable pipeline of new antibiotics to fight drug-resistant infections.

Resistance is persistent

With their introduction during the first half of the 20th century, antibiotics ushered in a new era for mankind – saving lives on a massive scale. In essence, common bacterial infections that once proved deadly could finally be cured: from strep throat to bloodstream infections, earaches to tuberculosis. But over time, nature began to strike back.

Bacteria evolve in response to antibiotics and in doing so, slowly chip away at the efficacy of treatments. It is an issue for which we see only the tip of the iceberg in high-income countries but that already disproportionately impacts low- and middle-income countries, where public health infrastructure is less robust. According to the World Health Organization,1 drug-resistant bacteria account for an estimated 700,000 deaths a year worldwide, including 33,000 in Europe alone.

Medical practice reveals the individual stories behind these numbers, says Michael Lobritz, who worked as a physician at Massachusetts General Hospital in Boston before joining Roche pRED as a translational scientist in the Infectious Diseases group: “There was a turning point in my career when I saw a woman suffering from pneumonia. It was caused by the very common pathogen Klebsiella pneumoniae. However, her infection was resistant to almost every single drug except for a last-resort treatment that is only given in serious emergencies as it can cause kidney failure. This patient was flown in from Greece in search of a life-saving cure, but no new options were available,” he remembers.

Eventually, Michael had to accept a difficult reality, and his patient succumbed to her infection several days later. “For me, this one patient encapsulates the entire problem. Antibiotics have played such an important role for so long that we take for granted how powerful they are. Transplantations, chemotherapy and surgery – they are all based on the ability to treat complications resulting from infections. We have had this innate belief in antibiotics. Now, this fundamental trust is fading.”

A quick glance at the pipeline

Besides the search for broad-spectrum antibiotics, Roche also pursues a pathogen-focused approach, targeting the top three bacteria on the WHO pathogen list. Several Roche preclinical antibiotic molecules have now been discovered and are advancing toward the clinic. Genentech, a member of the Roche Group, also has an active program for the development of antibiotics aligned with the overarching strategy.

Partners within Roche

Antibiotics discovery and development is a unique therapeutic area at Roche, in which scientists across the entire Group are working together to leverage their preclinical and clinical expertise to transform molecules from lab to bedside.

Will Stubbings, Head of Clinical Science Innovation - I2O, Product Development highlights the immense challenges that antibiotic research entails, especially when it comes to clinical development. “We need to focus on strategic planning at a very early stage. Development pathways and trial designs need to be tailor-made, especially for pathogen-­focused ­antibiotics, he says.

Will points out that “this comes with a unique set of challenges that require early planning of the full development plan up to registration. We also aim to have smaller, more focused clinical trials at the later stage, in order to move quickly while providing evidence that the drug works in the target patient population. Health authorities like the European Medicines Agency and the US Food and Drug Administration support this approach and have been valued partners in creating development pathways which are scientifically robust and streamlined.”

The right diagnostics can make the difference

When it comes to using existing antibiotics and novel agents appropriately, diagnostics also play an important role. The medical community desperately needs to detect bacteria quickly and reliably to ensure that appropriate drugs are only used when needed, thereby conserving their efficacy in the longer term. “Moreover, the faster patients get the right treatment, the higher the likelihood of a positive outcome,'' says Subita Sudershana of Roche Molecular Systems.

Today’s standard methods, such as culture enrichment, take between two and five days to show results. Molecular tests are faster but only detect the specific bacterial genotype they are designed for and have to be constantly updated to keep up with the evolving microorganisms.

Roche Diagnostics has therefore invested in a technology to rapidly detect not only the type of bacteria, but also its response to antibiotics. This is achieved by packaging DNA into delivery bioparticles that bind to receptors on the surface of bacteria, ultimately causing resistant bacteria to produce light and enabling rapid detection.

Subita highlights the advantages of the simple but elegant technology: “Not only can Smarticles-­based diagnostics reduce the test time from days to hours, it also offers the chance to measure the bacteria’s response to antibiotics. Since the tailor-made Smarticles remain the same, assays can be easily adapted to work for many antibiotics. Determining bacterial resistance or susceptibility not only guides clinicians to use the appropriate therapy, but also reduces inappropriate antibiotic use which is a major driver of multi-drug resistance acquisition by bacteria.”

The role of diagnostics in mitigating antimicrobial resistance is further enhanced by digital solutions that provide clinical laboratory inter-connectivity and interpretation. Artificial intelligence has matured to the point where localised factors can be modeled to provide therapeutic guidance tailored to individual health care institutions. “By coupling local epidemiological information with rapid and holistic guidance to clinicians it becomes possible to ensure antibiotics are used appropriately, safeguarding our most effective tools for future generations,” says Brett Hanson, Research Leader, Smarticles Research.

Revolutionary prospects

Does Roche stand a chance of finding the next breakthrough antibiotic? Ken Bradley, Head of Discovery Infectious Diseases, Roche pRED is quick to answer “Absolutely! We were part of the golden age of antibiotics in the 1950s and 60s when the world saw a true explosion of new classes of antibiotics. Roche developed a series of highly successful antibiotics, including variations of the original molecules in order to overcome the developing resistance. As there has not been a new mechanism to treat Gram-negative bacteria since 1967, a single novel medicine could be revolutionary. I am proud to work on something here at Roche that could help millions of people now and in the future.”


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