KK4277 / Kyowa Kirin - LARVOL DELTA

In vitro pharmacological profile of KW-6356, a novel adenosine A receptor antagonist/inverse agonist. (PubMed, Mol Pharmacol) - "Significance Statement KW-6356 is a potent and selective adenosine A receptor antagonist/inverse agonist and exhibits insurmountable antagonism, while istradefylline, a first-generation adenosine A receptor antagonist, exhibits surmountable antagonism. Structural studies of adenosine A receptor in complex with KW-6356 and istradefylline explain the characteristic differences in the pharmacological properties of KW-6356 and istradefylline."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

Effectiveness of Long-Term Treatment with Brodalumab on Anxiety or Depressive Symptoms in Japanese Patients with Psoriasis: The ProLOGUE Study. (PubMed, Dermatol Ther (Heidelb)) - "Brodalumab treatment resulted in the reduction of the levels of self-assessed anxiety and depressive symptoms in Japanese patients with psoriasis. Unlike anxiety symptoms, depressive symptoms did not resolve completely with brodalumab treatment. Patients with psoriasis having depressive symptoms may require long-term treatment."

Journal • CNS Disorders • Dermatology • General Anxiety Disorder • Immunology • Mood Disorders • Psoriasis • Psychiatry • Rheumatology

Benefit of burosumab in adults with X-linked hypophosphataemia (XLH) is maintained with long-term treatment. (PubMed, RMD Open) - P3, P3b | "Continued treatment with burosumab appears necessary for sustained clinical benefit."

Journal • Fatigue • Immunology • Osteoarthritis • Pain • Renal Disease • Rheumatology

Screening for DAX1/EWS-FLI1 functional inhibitors identified dihydroorotate dehydrogenase as a therapeutic target for Ewing's sarcoma. (PubMed, Cancer Med) - "Taken together, the present results suggest that DHODH inhibitors can inhibit the function of DAX1/EWS-FLI1 in ESFTs and might be a therapeutic agent with potent anti-tumor activity for Ewing's sarcoma patients."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • DHODH • EWSR1 • FLI1

Data-dependent early completion of dose-finding trials for drug-combination. (PubMed, Stat Methods Med Res) - "The performance of the proposed early completion methods was similar to that of the non-early completion methods. Furthermore, the number of patients for determining early completion before the trial starts was determined and a program code for calculating the dose retainment probability was proposed."

Journal

Single-cell RNA sequencing identifies Fgf23-expressing osteocytes in response to 1,25-dihydroxyvitamin D treatment. (PubMed, Front Physiol) - "These results indicate that osteocytes are heterogeneous with respect to their responsiveness to 1,25-dihydroxyvitamin D, and sensitivity to 1,25-dihydroxyvitamin D is one of the characteristics of osteocytes with Fgf23 expression. It is likely that there is a subpopulation of osteocytes expressing several genes, including Fgf23, involved in phosphate metabolism."

Journal • CCND2 • FGF23 • IGFBP7 • PDGFA • PTPRC • TIMP1

Circulating α-Klotho counteracts TGF-β-induced sarcopenia. (PubMed, Am J Pathol) - "These findings show c-α-Klotho's potential as a circulating inhibitor counteracting TGF-β-induced sarcopenia. A novel therapy involving TGF-β blockade could thus be developed to prevent sarcopenia."

Journal • Muscular Atrophy • Sarcopenia • CDKN1A • KL • SMAD2 • TGFB1

Pitfalls in bioanalytical work with a Japanese CRO or sponsor: from a project risk management perspective. (PubMed, Bioanalysis) - No abstract available

Journal

Intranasal administration of polysulfide prevents neurodegeneration in spinal cord and rescues mice from delayed paraplegia after spinal cord ischemia. (PubMed, Redox Biol) - "Intranasal administration of polysulfides rescued mice from delayed paraplegia after transient spinal cord ischemia. The neuroprotective effects of GSSSG were associated with increased levels of polysulfides and sulfane sulfur in the lumbar spinal cord. Targeted delivery of sulfane sulfur by polysulfides may prove to be a novel approach to the treatment of neurodegenerative diseases."

Journal • Preclinical • Cardiovascular • CNS Disorders • CASP3

Evocalcet rescues secondary hyperparathyroidism-driven cortical porosity in chronic kidney disease male rats. (PubMed, Endocrinology) - "Cell death of cultured osteocytes increased in a Pi concentration-dependent manner, and PTH administration rapidly elevated Pit1 expression and enhanced osteocytic death, indicating the possibility that the highly-concentrated serum PTH and Pi cause severe peri-lacunar osteolysis and osteocytic cell death. It is likely therefore that evocalcet not only decreases serum PTH but also reduces the exacerbation combined with PTH and Pi to the demineralization of osteocytic lacunae and osteocytic cell death, thereby protecting cortical porosity in CKD-SHPT rats."

Journal • Preclinical • Chronic Kidney Disease • Endocrine Disorders • Nephrology • Renal Disease • Secondary Hyperparathyroidism

Self-Administration of Burosumab in Children and Adults with X-Linked Hypophosphataemia in Two Open-Label, Single-Arm Clinical Studies. (PubMed, Adv Ther) - P3 | "These results indicated that the efficacy and safety of burosumab when administered either by a carer or patient are similar to that when administered by an HCP and show that self-administration is a viable option for patients with XLH."

Journal • Immunology • Renal Disease • FGF23

Safety, Tolerability, and Pharmacokinetics of the Novel Adenosine A Antagonist/Inverse Agonist KW-6356 Following Single and Multiple Oral Administration in Healthy Volunteers. (PubMed, Clin Pharmacol Drug Dev) - P1 | "The mean terminal elimination half-life of KW-6356 ranged from 18.4 to 43.1 hours following administration of single doses of 1-60 mg. There was no clear difference in the safety or pharmacokinetics of KW-6356 between healthy Japanese and White subjects."

Clinical • Journal • PK/PD data • CNS Disorders • Movement Disorders • Parkinson's Disease

Effectiveness of brodalumab in improving itching and skin pain in Japanese patients with psoriasis: The ProLOGUE study. (PubMed, J Dermatol) - "Brodalumab treatment was associated with improvement in itching and skin pain in Japanese patients with psoriasis. An Itch NRS score of 0 can be a long-term treatment goal for psoriasis (Japan Registry of Clinical Trials identifier: jRCTs031180037)."

Journal • Dermatology • Immunology • Pain • Pruritus • Psoriasis

Adjusted closed-form confidence interval formulas for network meta-analysis with a small number of studies. (PubMed, Stat Med) - "We recommend using the likelihood ratio test statistic with the restricted maximum likelihood estimator; however, just in case, we recommend applying the Bartlett-type adjustment to remove the second order bias. From demonstrations in actual studies, we confirmed that the adjusted confidence intervals improved compared with the naive confidence intervals."

Journal • Retrospective data

Impact of Off-Time on Quality of Life in Parkinson's Patients and Their Caregivers: Insights from Social Media. (PubMed, Parkinsons Dis) - "This study identified key themes that PwPD and their caregivers discuss online. These findings help signpost issues of importance to PwPD and areas in which their care may be improved."

HEOR • Journal • CNS Disorders • Depression • Mood Disorders • Movement Disorders • Parkinson's Disease • Psychiatry

An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study. (PubMed, Lancet) - P2 | "Patients treated with rocatinlimab had progressive improvements in atopic dermatitis, which was maintained in most patients after treatment discontinuation. Treatment was well tolerated."

Journal • P2b data • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Infectious Disease • Pain

Efficient production of lacto-N-fucopentaose III in engineered Escherichia coli using α1,3-fucosyltransferase from Parabacteroides goldsteinii. (PubMed, J Biotechnol) - "An E. coli strain heterologously expressing PgsFucT accumulated 3.84g/L of LNFP III after 48h of culture in a 3-L jar-fermenter. The amounts of various byproduct sugars were remarkably decreased compared with a strain expressing the previously characterized α1,3-fucT from Bacteroides fragilis."

Journal

Carer burden in rare inherited diseases: a literature review and conceptual model. (PubMed, Orphanet J Rare Dis) - "The identified burdens underscore the need for the provision of information and social support to these carers. Future research should focus on the (1) potential mediators/moderators of carers' burden, (2) needs of carers within the wider family including siblings and grandparents, (3) needs of carers of adults living with RIDs, including spouses and children, and (4) biopsychosocial effect on carers living with a RID themselves. Our conceptual model offers a potential tool for healthcare professionals to utilise during the provision of support to carers."

Journal • Review • CNS Disorders • Cognitive Disorders • Depression • Genetic Disorders • Metabolic Disorders • Mood Disorders • Psychiatry • Rare Diseases

A novel monoclonal antibody with improved FcγR blocking ability demonstrated non-inferior efficacy compared to IVIG in cynomolgus monkey ITP model at considerably lower dose. (PubMed, Clin Exp Immunol) - "Furthermore, we successfully established a novel cynomolgus monkey ITP model and demonstrated that the anti-Hp antibody exerted its effect in this model with only a single dose. This Fc-modified anti-Hp monoclonal antibody could be a valuable therapeutic replacement for IVIG for the treatment of ITP."

Journal • Preclinical • Hematological Disorders • Immunology • Inflammation • Thrombocytopenic Purpura • HP

Comprehensive analyses of the intracellular and in vivo disposition of Fab-siRNA conjugate to identify key issues to improve its in vivo activity. (PubMed, Drug Metab Dispos) - "Comprehensive analyses of intracellular disposition and in vivo pharmacokinetics were performed for small interfering RNA (siRNA) conjugated with the Fab fragment of Panitumumab, a fully humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody...This study clearly shows that improvements in siRNA stability in lysosomes, blood and tumor are needed for target gene knockdown in tumors. The major metabolic pathway of Fab-siRNA is 3' exonuclease degradation, suggesting that optimization of the conjugation site to Fab might help improve stability."

Journal • Preclinical • Oncology

Efficacy and exploratory biomarker analysis of entinostat plus exemestane in advanced or recurrent breast cancer: phase II randomized controlled trial. (PubMed, Jpn J Clin Oncol) - P2 | "In Japanese patients, the safety of entinostat plus exemestane was acceptable and progression-free survival was prolonged, although not significantly. Exploratory analyses identified potential biomarkers, including lysine acetylation, of efficacy."

Biomarker • Journal • P2 data • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Immune Modulation • Inflammation • Oncology • Respiratory Diseases • Solid Tumor • CD4 • CD86 • ER

Evaluation of the reproducibility and positive controls of cellular immortality test for the detection of immortalized cellular impurities in human cell-processed therapeutic products. (PubMed, Regen Ther) - "The growth rate of hMSCs supplemented with HEK293 cells increased with passage and remained high, whereas that of hMSCs supplemented with MRC-5 cells eventually decreased, as in the case of hMSCs alone. These results indicate that the cellular immortality test is reproducible and can detect immortalized (i.e., potentially tumorigenic) cells such as HEK293 cells with a lower growth rate than HeLa cells by discriminating against normal cells, which could contribute to ensuring the safety and quality of hCTPs."

Journal • Oncology

Safety and effectiveness of istradefylline as add-on therapy to levodopa in patients with Parkinson's disease: Final report of a post-marketing surveillance study in Japan. (PubMed, J Neurol Sci) - "Istradefylline safely and effectively improves motor symptoms in PD patients experiencing the wearing-off phenomenon with levodopa therapy in the real-world setting."

Journal • P4 data • CNS Disorders • Movement Disorders • Parkinson's Disease • Psychiatry

Treatment with brodalumab is not associated with improved sleep problems in real-life patients with plaque psoriasis: Results of the ProLOGUE study. (PubMed, J Dermatol) - "The SPI-II score and MOS Sleep-R subscale scores, except the Snoring score (p = 0.0319), did not significantly change from baseline to week 12 of brodalumab treatment. In conclusion, treatment with brodalumab did not improve overall sleep problems in real-life patients with plaque psoriasis, suggesting that sleep problems require attention in daily clinical practice (Japan Registry of Clinical Trials identifier, jRCTs031180037)."

Journal • Dermatology • Immunology • Pain • Psoriasis • Sleep Disorder

Non-clinical safety evaluations of next-generation therapeutic antibodies (PubMed, Nihon Yakurigaku Zasshi) - "On the other hand, there is still plenty of room for improvement in these technologies which sometimes occur unexpected toxicity, so the safety of drugs applying these technologies should be carefully evaluated. Here some important considerations for the non-clinical safety evaluations of bispecific antibodies and antibody-drug conjugates are discussed based on a literature review of these types of antibody drugs (approved or terminated due to toxicity)."

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