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#WAAW: A glimpse of hope in tackling antibiotic resistance

Klebsiella Photo NIAID

Norwegian start-up company AdjuTec’s novel antibiotic resistance breakers may help to facilitate reduced use of antibiotics.

If there is one positive thing about the COVID-19 pandemic, it could perhaps be our increased awareness of infectious diseases.

“The COVID-19 pandemic has been a mind-opener to society’s vulnerability for infectious diseases in general. This includes the importance of having a well-equipped tool-box with antibiotics and adjuvants to keep antimicrobial resistance (AMR) at bay,” says Pål Rongved, professor at the Department of Pharmacy at the University of Oslo (UiO) and CEO/CSO of AdjuTec Pharma. The company focuses on developing adjuvant products to be combined with antibiotics to protect them against bacteria antibiotic resistant enzymes.

“The COVID-19 pandemic has been a mind-opener to society’s vulnerability for infectious diseases in general. This includes the importance of having a well equipped tool-box with antibiotics and adjuvants to keep antimicrobial resistance (AMR) at bay.”

“If vaccine programs soon will take society back to “normal”, development of our lead product, APC148, will not be negatively affected. On the contrary, we see that viral pandemic patients often suffer from bacterial secondary lung infections. If these infections resist treatment with marketed antibiotics, this is an opportunity to help with our technology.”

 

MRSA NIAID and Pål Rongved AdjuTec

LEFT: SCANNING ELECTRON MICROGRAPH OF METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (MRSA) AND A DEAD HUMAN NEUTROPHIL. CREDIT: NIAID. RIGHT: PÅL RONGVED, CEO/CSO, ADJUTEC PHARMA

Novel antibiotic resistance breakers

AdjuTec began as an oncology project in 2009, but the substances studied early on showed remarkable effects in hundreds of resistant bacterial strains, describes Rongved. At first the research project was funded by private (e.g., Novo Nordisk) and public grants (e.g., the Norwegian Research Council), supporting the preclinical studies.

In order to attract further funding, with help from Oslo Cancer Cluster Incubator, Rongved and coworkers decided to establish AdjuTec Pharma in 2019. “It was necessary to establish a team to drive development of the company forward,” says Rongved.

“New antibiotics nearly always suffer from bacteria developing resistance mechanisms for protection. Initial studies do not indicate that this is the case with APC148, possibly because it has no effect on the bacteria itself, only on their defense enzymes.”

The company’s vision is to develop and provide a platform of novel antibiotic resistance breakers in order to retain efficacy and facilitate reduced use of antibiotics. Their lead product, a metallo-β-lactamase resistance breaker, APC148, inactivates bacterial resistance enzymes, making the bacteria sensitive to traditional antibiotics again. In more detail, it destroys vital bacterial carbapenem-resistance mechanisms (beta-lactamases) and prevents the bacteria from defending themselves against the antibiotic. Zinc-containing enzymes, the metallo-β-lactamases (MBLs), are emerging as the most alarming resistance mechanisms. There are currently no marketed, clinically efficient available agents active against carbapenem-destroying MBLs.

“New antibiotics nearly always suffer from bacteria developing resistance mechanisms for protection. Initial studies in meropenem resistant bacteria strains do not indicate that this is the case with the combination of APC148 and meropenem, no new resistance genes for the adjuvant was found. This possibly relates to the fact that APC148 has no effect on the bacteria themselves, only on their defence enzymes. In addition, initial efficacy and safety data, both in-vitro and in-vivo, show good efficacy on clinical resistant bacteria strains and with an excellent safety profile,” says Rongved.

 

Klebsiella Photo NIAID

COLORIZED SCANNING ELECTRON MICROGRAPH SHOWING CARBAPENEM-RESISTANT KLEBSIELLA PNEUMONIAE INTERACTING WITH A HUMAN NEUTROPHIL. PHOTO: NIAID

 

An urgent need

The need for new technologies to fight AMR is urgent. Resistance to carbapenem antibiotics, the last line of defense for many patients, is increasing globally.

“It is alarming. This silent pandemic is estimated to take an increasing number of lives, from 700,000 today to possibly ten million deaths annually by 2050.”

“It is alarming. This silent pandemic is estimated to take an increasing number of lives, from 700,000 today to possibly ten million deaths annually by 2050 according to global reports (O’Neill, 2017),” says Rongved.

The most important measure, he believes, will be to reduce misuse of antibiotics, both in agriculture and human medicine. “In addition, development and commercialization of new therapeutics needs to be incentivized to broaden the armament of society to fight bacteria resistance,” he adds.

He believes emerging adjuvant technologies, like AdjuTec’s, will become important products in combination with marketed antibiotics. “Market research shows that these technologies are more attractive to investors than traditional new antibiotics,” he says.

The global antibiotic market is estimated to reach USD 62.06 billion in 2026, with the largest market in North America but the fastest growing market in Asia Pacific.

Reduce the risk of beginner mistakes

Pål Rongved is not new to the start-up process. He has 22 years of previous leading positions in R&D/IPR at Nycomed Imaging/GE HealthCare and as advisor in Birkeland Innovation (now Inven2) in Oslo.

“In addition, to reduce the risk of beginner mistakes and to point out the best direction of development, early advice from key opinion leaders (KOL) is very important.”

“As an entrepreneur, access to funding is a necessity, as well as mentorship when it comes to rigging a company and establishing a team to commercialize your lead,” he says. It was essential to get external competence from TTO/incubators, including patenting and identifying investors, management and board, he continues.

“In addition, to reduce the risk of beginner mistakes and to point out the best direction of development, early advice from key opinion leaders (KOL) is very important. Also, be sure to have negotiated an unlimited freedom to handle your IP to attract investors.”

Norway has a flourishing life science community with available public grants for projects and start-ups, according to Rongved.

“During the last 30 years Norwegian investors, traditionally coming from shipping, petroleum and fish farming, have seen the opportunity in healthcare that benefits an increasing number of start-ups.”

“During the last 30 years Norwegian investors, traditionally coming from shipping, petroleum and fish farming, have seen the opportunity in healthcare that benefits an increasing number of start-ups.”

He also says that antimicrobial resistance is an area of priority in the new Life Science Campus being built by UiO and Oslo University Hospital, as part of a larger plan for developing Oslo Science City.

As for future plans, Pål Rongved and his colleagues both in Adjutec Pharma and in the research group SYNFAS are committed to continuing their development of AMR products based on their novel technologies.

“Our research resulting in the bio startup Adjutec Pharma has developed a technology platform, now creating pipeline innovations based on resistance-breaker thinking, rather than classic broad-spectrum oral antibiotics. That era is now diminishing. We will attract funding to develop our products to clinical proof-of-concept or to registration, when partnering with international specialty pharma for distribution,” he concludes.