Considerations of the Japanese Research Working Group for the ICH S6 & Related Issues Regarding Nonclinical Safety Assessments of Oligonucleotide Therapeutics: Comparison with Those of Biopharmaceuticals.

This white paper summarizes the current consensus of the Japanese Research Working Group for the ICH S6 & Related Issues (WGS6) on strategies for the nonclinical safety assessment of oligonucleotide-based therapeutics (ONTs), specifically focused on the similarities and differences to biotechnology-derived pharmaceuticals (biopharmaceuticals). ONTs, like biopharmaceuticals, have high species and target specificities. However, ONTs have characteristic off-target effects that clearly differ from those of biopharmaceuticals. The product characteristics of ONTs necessitate specific considerations when planning nonclinical studies. Some ONTs have been approved for human use and many are currently undergoing nonclinical and/or clinical development. However, as ONTs are a rapidly evolving class of drugs, there is still much to learn to achieve optimal strategies for the development of ONTs. There are no formal specific guidelines, so safety assessments of ONTs are principally conducted by referring to published white papers and conventional guidelines for biopharmaceuticals and new chemical entities, and each ONT is assessed on a case-by-case basis. The WGS6 expects that this report will be useful in considering nonclinical safety assessments and developing appropriate guidelines specific for ONTs.

Toxicologic Pathology Forum: Current Status on the Use of Animal Models of Human Disease in the Pharmaceutical Industry in Japan in Nonclinical Safety Assessment-Opinion Paper.

In nonclinical safety studies for new drug development, healthy animals have been commonly used. However, in some cases, the use of animal models of human disease is considered to be more favorable in evaluating risks in patients. To elucidate the current status of the use of animal models for nonclinical safety assessment, an internal questionnaire from the Japan Pharmaceutical Manufacturers Association and surveys (questionnaire period: August 27 to September 30, 2015) of both common technical documents and review reports of approved drugs (approval period: May 1999 to May 2017) disclosed by the Pharmaceutical and Medical Devices Agency were conducted. Although there were some concerns and limitations raised, the survey results revealed that animal models have been used in nonclinical safety assessment on a case-by-case basis and that nonclinical safety studies using animal models were included in the data packages of several approved drugs in Japan. The survey results also revealed that nonclinical safety studies using animal models have become more frequent in the past few years. In almost all cases, useful information, such as signs of toxicity under disease conditions and mechanisms of toxic change, was obtained from the results of nonclinical studies using animal models. Note: This is an opinion article submitted to the Toxicologic Pathology Forum. It represents the views of the author(s). It does not constitute an official position of the Society of Toxicologic Pathology, British Society of Toxicological Pathology, or European Society of Toxicologic Pathology, and the views expressed might not reflect the best practices recommended by these Societies. This article should not be construed to represent the policies, positions, or opinions of their respective organizations, employers, or regulatory agencies.

[Preclinical and clinical properties of Bezlotoxumab (ZINPLAVA® 25†mg/mL concentrate for solution for infusion), novel therapeutic agent for Clostridium difficile infection].

Clostridium difficile (C. difficile), an enterobacteria, flourishes and produces potent toxins, toxin A (TcdA) and toxin B (TcdB), after the disruption of the normal colonic microbiota by antibiotic therapy. C. difficile infection (CDI) may induce life-threatening complications such as fulminant colitis through damage of the intestinal wall by the toxins, therefore the prevention of CDI recurrence is the most important in CDI treatment. Bezlotoxumab is a human monoclonal antibody that neutralizes the activity of TcdB directly. The antibody inhibited cytotoxicity by TcdB derived from various ribotypes of C. difficile at a concentration (EC50) of 1/150 or less of the serum concentration (Cmax: 169 µg/mL) in CDI patients at the clinical dose. Moreover the anti-cytotoxicity effects of the antibody were also observed against 81 clinically isolated C. difficile strains (incl. 018 [smz] and 369 [trf]: Japanese prevalent ribotypes; 027: hypervirulent ribotype) obtained in Japan and western countries. The antibody prolonged survival time of hamster and rat CDI models in a dose-dependent manner. In clinical phase III studies (MODIFY I and II), the recurrence rate of CDI up to 12 weeks after administration of the bezlotoxumab group was significantly lower (P<0.0001) than the placebo group. Bezlotoxumab is the world's first drug with an indication for reduce recurrence of CDI. In Japan, bezlotoxumab was approved for marketing in September, and launched in December in 2017. Bezlotoxumab is effective for broad ribotypes of C. difficile, therefore it expects to contribute to CDI treatment through the reduce recurrence of the CDI.

Differential localization of vasopressin- and oxytocin-immunoreactive cells and conventional neurosecretory cells in the ganglia of the earthworm Pheretima hilgendorfi.

Cells containing arginine vasopressin (AVP)- and oxytocin (OXT)-like substances were immunohistochemically visualized in the cerebral, subesophageal, and ventral nerve cord ganglia of the earthworm Pheretima hilgendorfi. Whether these anti-AVP- and anti-OXT-reactive cells are identical with classical aldehyde fuchsin (AF)-positive neurosecretory cells was tested in serial sections. In all ganglia, groups of scattered neuronal cell bodies and axons strongly reactive to AVP and OXT antisera were observed, but AF-positive cells consisting of type a (dark blue) and type b (purple) cells were predominantly present in the cerebral and subesophageal ganglia. In the cerebral and subesophageal ganglia anti-AVP- and anti-OXT-reactive cells were generally larger than AF-positive cells. Some AF-positive cells were reactive either to anti-AVP or anti-OXT serum, but some failed to react to either serum. Anti-AVP- and anti-OXT-reactive cells were not immunoreactive to OXT and AVP antisera, respectively. Electron microscopic observations showed that the granules of type a cells were larger and less electron dense than those of type b cells and anti-AVP-reactive cells. The present cytological observations clearly showed that AVP- and OXT-like substances were widely present in the ganglionic cells of the earthworm.