New potential treatment for achondroplasia by the Tsumaki lab & Astellas Pharma Inc.
ASP5878 - an FGFR inhibitor understudy for Achondroplasia
27th December 2020
The Tsumaki lab, at the Center for iPS Cell Research and Application (CiRA), Kyoto University, is leading new research for achondroplasia with ASP5878, an FGFR inhibitor, using iPS cells. This is a study in collaboration with Astellas Pharma.
Until now, diverse therapeutic strategies to treat achondroplasia have been investigated [5]. Currently, the treatment for achondroplasia that is in a more advanced stage, closer to approval by the Medicine Agencies is vosoritide. However, this treatment requires daily subcutaneous injections that burden pediatric patients, considering that treatment would last for years.
The Tsumaki lab team concluded that although ASP5878 was less effective in bone growth than vosoritide, it has the advantage that it can be administered orally, thus providing a much lighter treatment for pediatric patients. Currently, two other drugs under development for achondroplasia also have oral administration: Infigratinib from QED therapeutics, also an FGFR inhibitor and currently, in clinical trial phase 2 and Meclozine, Kyoto University, is in phase 1, also have oral administration.
The study paper published recently further concluded that ASP5878 helped bone growth in juvenile model mice at doses that were lower than those causing minimal adverse effects. [16]
Image1 and 2 - CiRA and Professor Tsumaki - Credits: Nichiryo
Many researchers around the world have conducted basic research to investigate the functions of genes important for cartilage formation and differentiation. Yet, the treatment of cartilage diseases is difficult in the field of orthopedics and has been a challenging theme for many years. The reason is that the patient's cartilage is valuable By applying cell reprogramming technology associated with iPS cell development for the findings of this basic research, it is possible to induce pure chondrocytes in vitro based on the skin cells of patients with cartilage disease.
Tsumaki did prior research with Statins for achondroplasia by using iPS cells and published this paper in 2014.
A report was presented in early 2015 in Beyond achondroplasia about this research and technology, which can be read here.
CiRa press release
22nd December 2020
The Noriyuki Tsumaki laboratory, in collaboration with Astellas Pharma Inc., reports a new candidate drug that can be taken orally to treat achondroplasia.
Achondroplasia is easily recognized by short limbs that lead to dwarfism. It is not normally associated with life-threatening conditions but does affect the quality of life and can result in stenosis that causes debilitating neurological conditions. Using mice and iPS cells, CiRA Professor Noriyuki Tsumaki and his research team, in collaboration with Astellas Pharma Inc., reports a new candidate drug they call ASP5878 for the condition.
Achondroplasia is caused by mutations in the gene encoding the fibroblast growth factor receptor FGFR3. Mice deficient in this gene show bone overgrowth, suggesting the mutation causes FGFR3 hyper-activity. Thus, researchers have targeted drug candidates that primarily reduce the strength of the FGFR3 signal during bone growth, i.e. prior to adulthood.
"Because the number of patients with achondroplasia is small because the market is small and because the development of a new drug costs a lot, the progress of research in drug discovery for rare diseases such as achondroplasia has been limited," explains Tsumaki, whose research team is using iPS cell technology to develop cell therapies and drugs to treat cartilage diseases.
Currently, the most promising treatment is vosoritide. Vosoritide is an analog of C-type natriuretic peptide (CNP) and interacts with FGFR signaling but also requires daily injections. In contrast, ASP5878 can be taken orally and directly inhibits FGFR signaling.
"Several drugs that inhibit FGFRs are currently under development as anti-cancer drugs. Since there is an abundance of patient information on these drugs, we decided to explore whether they could be repurposed for achondroplasia," he continued.
To test the benefits of ASP5878, the study first applied it to mice with a mutation in the FGFR3 gene. Femurs and tibiae grew in mice. Growth plate cartilage also grew in the two bones.
"We consider that growth in growth plate cartilage accounts for the capacity for more bone growth in the ASP5878-treated group. Cell behavior in growth plate cartilage requires more study in the future," says Tomonori Ozaki, an orthopedic surgeon and first author of the study.
What research has been done?
To test the effects on humans, the researchers reprogrammed achondroplasia patient cells into iPS cells and prepared chondrocytes from them. Unlike reprogrammed healthy cells, reprogrammed patient cells do not show cartilaginous properties under this treatment. However, this deficiency was resolved if ASP5878 was added to the differentiation protocol.
Clinical trials for ASP5878 were conducted on adults suffering from one of several types of cancers including those affecting the liver, lung, and urethra, providing information on its side effects and safe dosage levels. At the same time, the exclusive study is needed on the patient group who would use the drug for achondroplasia, namely children and juveniles.
Furthermore, although the mouse experiments show that the effectiveness of ASP5878 is less than vosoritide, researchers and clinicians like Tsumaki expect that patients are more likely to follow a regimen in which a drug that can be taken orally than a regimen that requires daily injections.
"We need more data on its effects and toxicity on juveniles in preclinical tests, but this is a starting point to repurpose drugs for cartilage diseases," he says.
Note: Currently, there is no available information on the Astellas Pharma website on this research. Let's see when further steps are presented.
Sources:
CiRa
1. Ornitz, D.M.&LegeaiMallet,L. Achondroplasia: Development, pathogenesis and therapy. Dev. Dyn. 246, 291–309. https://doi. org/10.1002/dvdy.24479 (2017).
2. Horton, W. A., Hall, J. G. & Hecht, J. T. Achondroplasia. Lancet 370, 162–172. https://doi.org/10.1016/S0140-6736(07)61090-3 (2007).
3. Tavormina, P. L. et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat. Genet. 9, 321–328. https://doi.org/10.1038/ng0395-321 (1995).
4. Mortier, G. R. et al. Nosology and classification of genetic skeletal disorders : 2019 revision. Am. J. Med. Genet. A https://doi. org/10.1002/ajmg.a.61366 (2019).
5. Laederich, M. B. & Horton, W. A. Achondroplasia: Pathogenesis and implications for future treatment. Curr. Opin. Pediatr. 22, 516–523. https://doi.org/10.1097/MOP.0b013e32833b7a69 (2010).
6. Yasoda, A. et al. Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology 150, 3138–3144. https://doi.org/10.1210/en.2008-1676 (2009).
7. Lorget, F. et al. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am. J. Hum. Genet. 91, 1108–1114. https://doi.org/10.1016/j.ajhg.2012.10.014 (2012).
8. Wendt, D. J. et al. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J. Pharmacol. Exp. Ther. 353, 132–149. https://doi.org/10.1124/ jpet.114.218560 (2015).
9. Xie,Y.etal.IntermittentPTH(1–34)injectionrescuestheretardedskeletaldevelopmentandpostnatallethalityofmicemimicking human achondroplasia and thanatophoric dysplasia. Hum. Mol. Genet. 21, 3941–3955. https://doi.org/10.1093/hmg/dds181 (2012).
10. Jin, M. et al. A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia. Hum. Mol. Genet. 21, 5443–5455. https://doi.org/10.1093/hmg/dds390 (2012).
11. Garcia,S.Etal.PostnatalsolubleFGFR3therapyrescuesachondroplasiasymptomsandrestoresbonegrowthinmice.Sci.Transl. Med. 5,203ra124. https://doi.org/10.1126/scitranslmed.3006247 (2013).
12. Matsushita,M.Etal.Meclozinepromoteslongitudinalskeletalgrowthintransgenicmicewithachondroplasiacarryingagain-of-function mutation in the FGFR3 gene. Endocrinology 156, 548–554. https://doi.org/10.1210/en.2014-1914 (2015).
13. Yamashita,A.Etal.StatintreatmentrescuesFGFR3skeletaldysplasiaphenotypes.Nature513,507–511.https://doi.org/10.1038/ nature13775 (2014).
14. Komla-Ebri, D. et al. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J. Clin. Invest. 126, 1871–1884. https://doi.org/10.1172/jci83926 (2016).
15. Futami, T. et al. ASP5878, a novel inhibitor of FGFR1, 2, 3, and 4, inhibits the growth of FGF19-expressing hepatocellular carci- noma. Mol. Cancer Ther. 16, 68–75. https://doi.org/10.1158/1535-7163.mct-16-0188 (2017).
16. Ozaki, T., Kawamoto, T., Iimori, Y. et al. Evaluation of FGFR inhibitor ASP5878 as a drug candidate for achondroplasia. Sci Rep 10, 20915 (2020). https://doi.org/10.1038/s41598-020-77345-y
17. Yamamoto,N.etal.Aphase1studyoforalASP5878,aselectivesmall-moleculeinhibitoroffibroblastgrowthfactorreceptors1-4, as a single dose and multiple doses in patients with solid malignancies. Invest. New Drugs 38, 445–456. https://doi.org/10.1007/ s10637-019-00780-w (2020).
