Global HealthPharmaceutical Regulations in Japan

Antimicrobial resistance (AMR)

The challenges of antimicrobial resistance (AMR), including resistance to natural and synthetic antibiotics, have a long history that dates back to the development of penicillin. In Alexander Fleming's speech accepting the 1945 Nobel Prize in Physiology or Medicine for his discovery of penicillin in 1928, he said:
“The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.”

In fact, an enzyme which inactivates penicillin named penicillinase had been discovered from penicillin-resistant bacteria in 1940, five years before the speech was given. True to Fleming's prediction, the post-war history of the rapid development of antibiotics can be described as the history of warfare waged against antimicrobial resistance (AMR). In the 1960s, as effective antibiotics against penicillin-resistant bacteria were developed one after another, including methicillin for Staphylococcus aureus, and aminopenicillin (ampicillin) and aminoglycosides (gentamicin) for Gram-negative bacteria, people gradually began to believe that bacterial infections could be defeated. With powerful weapons to fight against infectious diseases, such as vaccines and antibiotics, the leading cause of death in developed countries has shifted from infectious diseases to non-communicable diseases (NCDs), and so did the pharmaceutical trends.

The development of new antimicrobials has steadily declined since the 1980s. Meanwhile, the threat by new antimicrobial-resistant bacteria began to rise predominantly in hospital settings. It was the emergence of healthcare-associated infections (HAIs) associated with surgery and medical devices developed through the advancement of medical technologies.
These healthcare-associated infections spread also in Japan, caused by antimicrobial-resistant Gram-positive cocci including Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococci (VRE), followed by antimicrobial-resistant Gram-negative bacilli including multidrug-resistant Pseudomonas aeruginosa (MDRP) and multidrug-resistant Acinetobacter spp. (MDRA). It remains as a significant problem in medical institutions to the present day. While initially associated with medical institutions, this growing problem is now increasingly found outside the healthcare settings, called community-acquired antimicrobial-resistant infections.

Antimicrobial substances are also used for animals as veterinary antibiotics for animal disease treatment and antibiotic feed additives for effective use of nutrients contained in feeds. The development of antimicrobial-resistant bacteria in animals could reduce the efficacy of medical treatment for animals. In addition, it has been indicated that antimicrobial-resistant bacteria of animal origin have a potential to be transmitted to and cause infectious diseases in humans through livestock products, and consequently reduce the efficacy of antibiotics in humans.

Outside Japan, the rise of antimicrobial resistance is not confined to general bacterial infections. Malaria parasites have become resistant to artesunate, a drug known as a specific medicine against malaria. In addition, multidrug-resistant and extremely drug-resistant tuberculosis (acid-fast bacterium) has spread around the world.

The Jim O'Neill report which attempted to calculate the number of death as well as the cost in terms of lost global production due to AMR between now and 2050 would become an extremely disturbing 10 million every year which are more than those of cancer at present, and an enormous 100 trillion USD all over the world, respectively, if we do not take action.
These facts have led to the shared recognition that it is required to adopt a global “One Health”approach, which addresses both human and animal health together. The World Health Organization (WHO) featured antimicrobial resistance on the World Health Day 2011 and called upon the international community to devote global efforts under the One Health approach. In 2013, the G-Science Academies, the national science academies of G8 countries, issued a joint statement regarding the threat of antimicrobial resistance, followed by the first surveillance report by WHO in 2014 on the current, global state of antimicrobial resistance.

In May 2015, the World Health Assembly endorsed the Global Action Plan on Antimicrobial Resistance, and urged all Member States to develop relevant national action plans within two years. At the G7 Summit 2015 in Schloss Elmau, Germany, in the following month, antimicrobial resistance was taken up as one of the key issues. The G7 Health Ministers at the G7 Health Ministers Meeting 2015 in Berlin welcomed the formulation of the Global Action Plan by WHO and discussed the necessity of strengthening the One Health approach and of R&D for new drugs. Assuming the G7 presidency for 2016, Japan is determined to intensify its efforts in measures against AMR.

Before G7 Ise-Shima Summit was held, JPMA urged G7 countries to promote the appropriate use of antimicrobials, the development stewardship, and a One Health approach. Particular focus should be placed on the development and strengthening of surveillance programs for resistant bacteria. In addition, we would also like to underscore the critical role that vaccination plays in curbing resistance. Hence, G7 leadership should consider promoting global efforts for vaccination as an effective long-term measure against infectious diseases. JPMA who have had some distinguished drug discovery against infectious diseases will tackle the global challenge of AMR with IFPMA/PhRMA/EFPIA etc. Under the public private platform established in April 2016, our JPMA member companies will propel to develop a rapid diagnosis as well as an innovative medicine against AMR with the government and some diagnostic companies.

Initiatives by member companies
Encourage the proper use of antibiotics Shionogi considers that delivering continuously new antibiotics to medical fields is one of our missions, and also places high importance on the proper use of antibiotics to tackle antimicrobial resistance (AMR). In 2010, Shionogi established the organization named Antimicrobial Stewardship Unit in Japan and has discussed with the health care workers about the importance of not only research and development but also the proper use of antibiotics up to today.
Currently, in Taiwan, China and Singapore, Shionogi launched the same organization, respectively as in Japan to push forward the approaches involving education and awareness regarding the proper use of antibiotics.
Development of new macrolide antibiotic

Toyama Chemical has engaged in the development of "T-4288" (solithromycin).

The drug is a new macrolide antibiotic created by Cempra, Inc (Head office in North Carolina; CEO: Prabhavathi Fernandes; "Cempra"; Nasdaq: CEMP). It shows strong antibacterial activity on bacterial pneumonia and mycoplasma resistant to existing macrolide agents, and demonstrates a relatively high level of immuno-regulatory activity (anti-inflammatory activity). Cempra submitted both a New Drug Application to the U.S. Food and Drug Administration (FDA) in April 2016 and a Marketing Authorization Application to the European Medicines Agency (EMA) in June 2016 for the indication of community-acquired bacterial pneumonia (including multiple-drug-resistant isolates).

In May 2013, Toyama Chemical signed a license agreement with Cempra for the exclusive rights to develop, manufacture and market "T-4288" in Japan. Phase I and Phase II clinical trials had been completed, and Toyama Chemical confirmed T-4288's adequate efficacy and safety. Toyama Chemical is in preparation for the Phase III trials.

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