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OUR SCIENCE

CASE 1

Development of Imaging Biomarkers for Translational Research

  • Kohji Abe
    Kohji Abe
    Head of Imaging Biomarker, Imaging Biomarker, Translational Research Unit, Biomarker R&D Department

Translational research, which bridges exploratory study and clinical development, is necessary for making a go or no-go decision at the earliest possible time or for implementing proof of concept (POC). The utilization of biomarkers, one of the most important methods in translational research, has now become an indispensable streamlining tool in developing pharmaceutical products like implementing a POC or POM (proof of mechanism) and patient stratification.

The imaging biomarker group investigates the pharmacokinetics and pharmacological properties of new drug candidates to estimate the optimum doses of new drugs or assess their efficacy, using imaging technologies widely used in clinical diagnoses, such as positron emission tomography (PET), single photon emission CT (SPECT), or magnetic resonance imaging (MRI). Furthermore, we are searching for new imaging biomarkers that can be used to estimate the intended patient strata or monitor their morbidity along with procedures for measuring and analyzing such markers. With PET, various radioactive compounds, which are referred to as molecular probes, help visualize the in-vivo behavior of the target molecules in a quantitative manner. Therefore, the group not only studies conventional probes, but also tries to find new molecular probes that will act on the target molecules and take measurements of receptor occupancy etc. for the compounds. In this process, based on the results of studies in animal models (ranging from rodents to primates), the utility of the new molecular probes will be assessed using human microdose studies to produce a list as development candidates. In the MRI study, methods to identify disease pathology and pharmacological action are developed for the assessment of candidate compounds. Using functional MRI, imaging markers are being investigated using neural activity or brain networks as indices, particularly in brain function imaging studies.

PET imaging in primate brain

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Rat DMN (Default Mode Network)

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bibliography

1. Kohji Abe, Nozomi Takai, Kazumi Fukumoto, Natsumi Imamoto, Misato Tonomura, Miwa Ito, Naoki Kanegawa, Katsunori Sakai, Kenji Morimoto, Kenichiro Todoroki and Osamu Inoue

In vivo imaging of reactive oxygen species in mouse brain by using [3H]Hydromethidine as a potential radical trapping radiotracer
J Cereb Blood Flow Metab. 2014 Dec;34(12):1907-13.

https://doi.org/10.1038/jcbfm.2014.160

2. Yuto Kashiwagi, Takemi Rokugawa, Tomomi Yamada, Atsushi Obata, Hiroshi Watabe, Yoshichika Yoshioka and Kohji Abe

Pharmacological MRI Response to a Selective Dopamine Transporter Inhibitor, GBR12909, in Awake and Anesthetized Rats
Synapse. 2015 Apr;69(4):203-12.

https://doi.org/10.1002/syn.21803

3. Sotaro Momosaki, Miwa Ito, Hiroko Yamato, Hitoshi Iimori, Hirokazu Sumiyoshi, Kenji Morimoto, Natsumi Imamoto, Tadashi Watabe, Eku Shimosegawa, Jun Hatazawa and Kohji Abe

Longitudinal imaging of the availability of dopamine transporter and D2 receptor in rat striatum following mild ischemia
J Cereb Blood Flow Metab. 2017 Feb;37(2):605-613.

https://doi.org/10.1177/0271678X16635183

4. Nozomi Takai, Natsumi Miyajima, Misato Tonomura, Kohji Abe

Relationship between receptor occupancy and the antinociceptive effect of mu opioid receptor agonists in male rats
Brain Res. 2018 Feb 1;1680:105-109

https://doi.org/10.1016/j.brainres.2017.12.014

5. Takemi Rokugawa, Haruyo Konishi, Miwa Ito, Hitoshi Iimori, Ryohei Nagai, Eku Shimosegawa, Jun Hatazawa and Kohji Abe

Evaluation of hepatic integrin αvβ3 expression in non-alcoholic steatohepatitis (NASH) model mouse by 18F-FPP-RGD2 PET
EJNMMI Res. 2018 31;8(1):40.

https://doi.org/10.1186/s13550-018-0394-4

CASE 2

Trojan Horse: The discovery of a new antibiotic, Cefiderocol (S-649266)

  • Yoshinori Yamano
    Yoshinori Yamano
    Chief Scientific Officer for Infectious Diseases, Drug Discovery & Disease Research Laboratory

The absence of effective anti-bacterial drugs due to the bacterial evolution of drug resistance is one of the gravest issues facing modern medicine. Particularly, carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter, and bacteria of the enteric group have been listed by the World Health Organization (WHO) as pathogenic bacteria against which the development of new anti-bacterials is most needed. To provide an answer to this problem, we developed Cefiderocol (S-649266), a new siderophore cephalosporin having two distinct properties: (1) quick transmission through the strong outer membrane barrier via an active iron uptake pathway; and (2) high stability against carbabenemase which is capable of cleaving β-lactam antibiotics, including carbapenem derivatives. We showed that Cefiderocol has high anti-bacterial activity against carbapenem-resistant bacteria. In contrast to many of the siderophore β-lactam antibiotics discovered to date, Cefiderocol was highly efficacious in clinical trials in patients with complicated urinary tract infections, and nonclinical assessment results indicate a high treatment efficacy for carbapenem-resistant gram-negative bacteria infection cases. Therefore, the drug is expected to become a new treatment option for patients with a gram-negative bacterial infection that cannot be treated with any existing antibiotics. In addition to the clinical trials for urinary tract infections, another set of clinical trials is currently in progress, and an application for approval is scheduled to be filed in the U.S. by the end of 2018.

In addition to Cefiderocol, Baloxavir Marboxil (S-033188), another new anti-influenza drug, was approved in Japan, and its application for approval was filed in the U.S. during the first half of fiscal 2018. This drug has a different mode of action than conventional drugs and can lead to therapeutic effects with a single administration. These drugs only represent part of the Shionogi's achievement in the discovery and development of new therapeutic drugs for infectious diseases. Our challenge to revolutionize the treatment of infectious diseases through drug discovery and development will continue.

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bibliography

1. In vitro antibacterial properties of cefiderocol, a novel siderophore cephalosporin, against Gram-negative bacteria.

Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, Kohira N, Miyagawa S, Ishibashi N, Matsumoto S, Nakamura R, Tsuji M, Yamano Y.
Antimicrob Agents Chemother. 2017 Oct 23. pii: AAC.01454-17.

http://aac.asm.org/content/62/1/e01454-17.long

2. Efficacy of Cefiderocol against Carbapenem-Resistant Gram-Negative Bacilli in Immunocompetent-Rat Respiratory Tract Infection Models Recreating Human Plasma Pharmacokinetics.

Matsumoto S, Singley CM, Hoover J, Nakamura R, Echols R, Rittenhouse S, Tsuji M, Yamano Y.
Antimicrob Agents Chemother. 2017 Aug 24;61(9). pii: e00700-17.

http://aac.asm.org/content/61/9/e00700-17.full

3. Susceptibility of Imipenem-Susceptible but Meropenem-Resistant blaIMP-6-Carrying Enterobacteriaceae to Various Antibacterials, Including the Siderophore Cephalosporin Cefiderocol.

Kanazawa S, Sato T, Kohira N, Ito-Horiyama T, Tsuji M, Yamano Y.
Antimicrob Agents Chemother. 2017 Jun 27;61(7). pii: e00576-17.

http://aac.asm.org/content/61/7/e00576-17.long

4. Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas aeruginosa.

Ito A, Nishikawa T, Matsumoto S, Yoshizawa H, Sato T, Nakamura R, Tsuji M, Yamano Y.
Antimicrob Agents Chemother. 2016 Nov 21;60(12):7396-7401.

http://aac.asm.org/content/60/12/7396.full

CASE 3

FIC Leading the World: Development of Baloxavir, a New Anti-Influenza Agent

  • Takashi Kawasuji
    Takao Shishido
    Head of Respiratory Viral Infections, Respiratory Viral Infections, Infectious diseases & Immunology, Drug Discovery & Disease Research Laboratory

Cases of influenza virus infection are reported around the world every year especially during the winter season. It claims the lives of elderly patients and causes complications such as influenza encephalopathy in babies and little children, posing a major threat to our society. Conventional neuraminidase inhibitors prevent the viruses from being released from infected cells, thereby exhibiting antiviral activity. However, some medical and hygienic problems still remain as there are only a limited number of cases demonstrating a therapeutic effect in high-risk or severely ill patients. There is also the risk of the emergence of influenza viruses with diminished sensitivity to the neuraminidase inhibitors. Moreover, oral administration of neuraminidase inhibitors requires five days, and the use of an inhalant is limited to patients who are able to inhale the medicine. Due to these difficulties associated with the mode of administration, a new anti-influenza drug that is highly effective and can be easily administered to patients is needed.

Shionogi's Infectious Disease Study Group led by Mr. Takao Shishido worked on the development of new anti-influenza agents with a completely different mechanism of action from that of conventional drugs and found S-033188 (Baloxavir Marboxil). Baloxavir Marboxil inhibits the activation of cap-dependent endonuclease, an enzyme specific to the influenza virus, which specifically interferes with the transcription of viral genomic RNA. As a result, the drug inhibits the synthesis of proteins necessary for the formation of new viral particles within the infected cells, thereby exhibiting antiviral activity.

Figure: Cocrystalline structure of activated Baloxavir Marboxil (BXA) and target protein (see Reference 1)

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In nonclinical studies using cells or mice infected with influenza viruses, Baloxavir Marboxil suppressed the replication of seasonal or highly pathogenic avian influenza viruses and reduced the mortality rate of mice. In human clinical trials, the viruses swiftly disappeared in vivo after a single oral administration of the drug, and the duration of the infection was shortened. In February 2018, Baloxavir Marboxil was approved for the treatment of influenza infection in Japan.

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bibliography

1. Omoto S, Valentina Speranzini, Hashimoto T, Noshi T, Yamaguchi H, Kawai M, Kawaguchi K, Uehara T, Shishido T, Naito A, Cusack S.

Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil.
Scientific Reports (2018) 8:9633| DOI:10.1038/s41598-018-27890-4

https://www.nature.com/articles/s41598-018-27890-4

2. Noshi T, Tachibana H, Yamamoto A, Baba K, Kawai M, Yoshida R, Sato A, Shishido T, Naito A.

S-033447/S-033188, a Novel Small Molecule Inhibitor of Cap-dependent Endonuclease of Influenza A and B Virus: In Vitro Antiviral Activity against Laboratory Strains of Influenza A and B Virus in Madin-Darby Canine Kidney Cells. P-418 OPTIONS IX. (2016)

3. Ando Y, Noshi T, Kitano M, Taniguchi K, Onishi M, Sato K, Oka R, Kawai M, Yoshida R, Sato A, Shishido T, Naito A.

2016. S-033188, an Orally Available Small Molecule Inhibitor of Cap-dependent Endonuclease of Influenza A and B Virus: In Vivo Viral Load Reduction by Single Day Oral Dosing in Mice Infected with Influenza A Virus. P-610 OPTIONS IX. (2016)