Rising to the challenge

Historically, pandemic diseases of bacterial origin have killed millions of people, sometimes within months. Famously, in the 14th century, the bubonic plague, a bacterial infection caused by Yersinia pestis, wiped out close to 50 million people in Europe within a matter of years. The introduction of penicillin in 1942 was regarded as a miracle by people around the world, a magical cure for diseases that had been sure death sentences. The discovery and introduction of antibiotics, starting with penicillin, is rightly considered one of the greatest medical achievements of the 20th century.

Roche was a major player in this space for many decades, developing a string of highly successful antibiotics. Literally hundreds of millions of patients have benefited from these drugs, including many generic, low-cost versions that followed. Some of Roche’s antibiotics are also part of the WHO (World Health Organisation) List of Essential Medicines, which names the most effective and safe medicines needed in a health system.

For all the ‘miraculous‘ qualities of antibiotics, a major public health problem is emerging and making headlines in tabloids and science journals alike. The acronym AMR, or antimicrobial resistance, puts it in a nutshell: antibiotics are increasingly losing their effectiveness as common microorganisms acquire drug resistance. The problem of AMR is widespread and especially troublesome for the widely used beta-lactam antibiotics such as penicillins, cephalosporins, and carbapenems. These antibiotics usually work by inhibiting bacterial cell wall synthesis. However, resistant bacterial strains produce enzymes called beta lactamases that «chew up» the active beta- lactam rings of these antibiotics, rendering them ineffective. The bacteria carrying resistance can also pass along their genetic material to other bacteria so that these become drug resistant as well.

It is estimated that by 2050, ten million people could die each year from AMR infections if things continue as they are. Weakened, immunocompromised, hospitalised patients suffering from underlying diseases are often more prone to such infections. Healthcare settings can be, and often are, a breeding ground for the spread of highly pathogenic, multidrug-resistant bacterial strains.

The spread of AMR is recognised by the WHO and other health authorities as a worldwide crisis, calling for a comprehensive effort that includes multiple players such as drug companies, hospitals and universities, as well as governments and the agricultural industry (antibiotics are overused in farm animals even more than in humans). This is an area where Roche’s contributions to society are urgently needed. Although the financial rewards are uncertain in the antibiotic space, Roche has significantly stepped up its efforts and investment.

Roche research organisations have several pre-clinical molecules and antibacterials in early clinical development: one of these is aimed for severe, hard-to-treat, gram-negative Enterobacteriaceae infections, which represent a WHO-recognised critical threat to human health. The other asset is an antibody-antibiotic conjugate aimed for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive SA. The idea is that by using an antibody-drug-conjugate technology already available in the oncology setting, the antibody tags the bacterium, and as in a ‘Trojan horse‘ scenario, would deliver the antibiotic into the infected cell compartments where it hopefully becomes activated to attack the bacteria.

Bacteria from the Enterobacteriaceae family are very adept at evading antibiotics and often cause multidrug-resistant, life-threatening, healthcare-associated infections (HAI), especially affecting the urinary tract, respiratory system (e.g. ventilator-assisted pneumonia), abdomen, and blood stream.

Professor Anna Maria Geretti, an acknowledged infectious disease expert in Roche’s Immunology, Inflammatory and Infectious Diseases (I3) Unit, explains: «Carbapenem antibiotics have traditionally been reserved for hard-to-treat gram negative bacteria such as Enterobacteriaceae. In the last few years, however, we have seen outbreaks with carbapenem-resistant Enterobacteriaceae (CRE), which have been associated with high mortality rates. In intensive care units across North America, for example, CRE currently affects up to 9% of patients. Even higher rates are reported from several healthcare settings across Europe and the rest of the world. We are working hard to develop a new antibacterial that will hopefully be successful in fighting these highly resistant strains.»

Interestingly, in the antibiotic space (unlike other therapeutic areas), the efficacy of the drug candidate can be tested outside of the human body (in vitro, in dish) with a high reliability, and the results from these tests are strongly predictive of the in vivo success or failure of a specific antibiotic drug. Therefore, the preclinical microbial testing in this area is an even stronger component of the regulatory filing package and can enable further significant acceleration of the development process.

There is a broad understanding that solutions to the challenge of AMR require collaboration and joint action from pharmaceutical and biotech companies, academia, governments and public health organisations. In an unprecedented effort, Roche – along with over 100 companies and 14 industry associations – signed the Industry Declaration on AMR at the World Economic Forum in Davos in 2016, followed by the adoption of a Roadmap by a number of pharmaceutical companies later that year. The Declaration sets out a common set of principles for global action that focus on reducing the rise of antimicrobial resistance, investing in R&D to meet public health needs, and improving access to antibiotics, vaccines and diagnostics.

Also, in September 2016, Roche entered into a multi-year, private-public-partnership with the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services. BARDA’s Broad Spectrum Antimicrobials Program aims to engage industry partners in an effort to jointly combat the rise of antibiotic resistance through development of new antibacterial drugs and point-of-care diagnostics. This strategic alliance with BARDA is providing significant funding to accelerate the development of both the above-described antibacterial drug and new diagnostic tests in the point-of-care space.

Beyond funding, what are the benefits of working with BARDA for a company like Roche? Anna Maria emphasizes: «By giving us feedback and support in terms of what data sets external agencies expect from us, the alliance with BARDA allows us to both de-risk and accelerate drug development and to engage successfully with health authorities. In the case of one of our compounds, our successful engagement with health authorities means that we have endorsement to «jump» from Phase I to Phase III. We have to learn to do things differently, and we have to manage new processes from many different angles, which can be challenging but also immensely rewarding for the team. We all have to be agile here, not only the industry but also the health authorities. Together, we’re on a steep learning curve.»