Apc001

Apc001：The nucleic acid aptamer targeting sclerostin (patent of the sclerostin aptamer in different countries is as follows: Chinese Patent, CN 111712573 A; International Patent, WO 2019/154410; US Patent, 1547/34 PCT/ US; Japanese Patent, 20-5563-XY; European Patent, EP3754021A1). Therapeutic antibody against sclerostin could promote bone formation and significantly reduce the risk of fracture for treatment of postmenopausal osteoporosis (POP). However, a black box warning for the potential cardiovascular risk must be included as required by the US FDA and European EMA, which strictly limited the clinical use of sclerostin antibody.While treating chronic diseases, it is necessary to avoid serious cardiovascular risksusing a new drug.In previous basic research, genetic evidence indicated that sclerostin loop3 participates in inhibiting bone formation, but not in protecting cardiovascular system. Therefore, the company research team screened, designed and synthesized a specific aptamer targeting sclerostin loop3, which was named Apc001 (Yu et al., Nat Commun 2022). Compared with sclerostin antibody, Apc001PE (PEG40k conjugated Apc001) could promote bone formation and did not increase the cardiovascular risk in animal models. Apc001PE did not induce abnormalities in all the organs examined in the healthy rats, even with ultrahigh dose of 5-times higher than the treatment dose, according to the histopathological analysis of the paraffin sections of the organs in the third-party toxicity studies. Potential indications of Apc001 included postmenopausal osteoporosis, osteogenesis imperfecta and hypophosphatemic rickets. Apc001PE was granted Orphan Drug Designation by the US FDA for the treatment of osteogenesis imperfecta in 2019 (FDA number: DRU-2019-6966) (Wang et al., Theranostics 2022). Recently, long-lasting sclerostin aptamer (Apc001OA) was granted both Rare Pediatric Disease Designation (FDA number: RPD-2022-667) and Orphan Drug Designation (FDA number: DRU-2022-9087) by the US-FDA for the treatment of OI in 2022.The Orphan Drug Designation application for the treatment of hypophosphatemic rickets will also be submitted to the US FDA in the near future.

 

Epidemic data demonstrated that circulating sclerostin level was significantly higher in postmenopausal osteoporosis  patients co-existing with type 2 diabetes (POP-T2D) compared to postmenopausal osteoporosis (POP) patients without diabetes (Li et al., Diabetes Metab Syndr Obes 2021). Sclerostin (SOST) overproduction could impair whole-body glucose and lipid metabolism (Kim et al., PNAS 2017). From the clinical data, both the company research team and clinical scientists found that glucose and lipid metabolism were improved in POP patients co-existing with newly diagnosed T2D (POP-N-T2D) with therapeutic sclerostin antibody treatment history compared to those without therapeutic sclerostin antibody treatment history. It is desirable to develop a single agent (sclerostin inhibitor) with dual therapeutic effects to promote bone anabolism and normalize glucose and lipid metabolism in POP patients co-existing with T2D. However, both US-FDA and European Medicines Agency (EMA) raised the warning of humanized therapeutic antibody against sclerostin (Romosozumab/Evenity) on cardiovascular risk in POP (FDA Press Announcements, 2019; EMA Documents, 2019). Therefore, it is an unmet need to develop a new generation of sclerostin inhibitor without increasing cardiovascular risk for not only promoting bone anabolism, but also normalizing glucose and lipid metabolism in POP-T2D. In previous studies, the company research team found that loop3 in sclerostin played an important role in inhibiting bone formation, whereas the protective effect of sclerostin on cardiovascular system was independent of loop3 (Yu et al., Nat Commun 2022). Recently, by genetic approach both in vitro and in vivo, it was found that loop3 in sclerostin played an important role in whole-body lipid and glucose metabolism impairment effects of sclerostin, including promoted lipid anabolism, inhibited lipid catabolism, impaired glucose tolerance, and decreased insulin sensitivity. Further, using Apc001, it was found that targeting sclerostin loop3 could protect against the whole-body lipid and glucose metabolism impairment in high-fat diet (HFD)-induced diabetes in mice. All the above data will provide important evidence for the clinical transformation of Apc001 to develop as a single drug that could not only promote bone anabolic potential, but also normalizing glucose and lipid metabolism (for POP patients co-existing with T2D).

 

In 2021, anti-PD-1 antibody Keytruda was newly approved by US FDA for the first-line treatment of PDL-1-positive triple-negative breast cancer (TNBC) patients. However, the PDL-1 expression in TNBC patients is limited, which leaves a majority of TNBC patients with no PDL-1 expression still lacks effective immunotherapy (Keenan & Tolaney et al., J Natl Compr Canc Netw 2020). The systemic analysis of clinical data showed that higher sclerostin is expressed in TNBC tissues when compared to normal breast tissues. In addition, higher sclerostin expression in TNBC tissues is correlated with lower survival. Further,the genetic animal studies demonstrated that sclerostin plays an important role in tumor progression and exhibited excellent anti-tumor activities in mice inoculated with PDL-1-deficient TNBC cell lines. The above-said accumulative results provide important evidence for clinical translation of Apc001 in PDL-1-negative TNBC patients with low response to Keytruda.

 

It was reported that the NASA might consider the therapeutic sclerostin antibody a viable drug intervention to protect astronauts from bone loss on their 2030s Mars mission (Elizondo et al., J Bone Miner Res 2019). However, the cardiovascular monitoring data of the astronauts on mission showed that their carotid arteries stiffness was significantly increased after long-term staying on the International Space Station, which was equivalent to the 10-20 years of aging changes in general populations on the ground (Hughson et al., Am J Physiol Heart Circ Physiol 2016). On the other hand, humanized therapeutic sclerostin antibody romosozumab for POP-imposed severe cardiac ischemic events in clinical trials (Saag et al., N Engl J Med 2017; Lewiecki et al., J Clin Endocrinol Metab 2018). Accordingly, the cardiovascular safety of sclerostin antibody for counteracting bone formation recution during spaceflight could not be controlled. Thus, whether the therapeutic sclerostin antibody would be enrolled into NASA 2030s Mars mission is still not confirmed. Recently, the company research teamfound that sclerostin loop3 deficiency could counteract simulate weightlessness-induced bone formation reduction and bone loss, while it doesn't have influence in the arteries of mice under the same condition. Hence, it provides important evidence supporting translation for the development of the sclerostin inhibitor Apc001 with cardiovascular safety to counteract bone loss of astronauts under spatial weightlessness condition.

 

Large scale clinical studies showed that the ratio of glycosylated hemoglobin (HbA1c) in at least 60% of patients with type II diabetes could not be controlled below 7% after treatment with DPP4 small molecule inhibitors, and they are classified as the group of patients with low response to DPP4 inhibitors (Raz et al., Diabetologia 2006; Ferrannini et al., Diabetes Care 2013). Recently, both the company research team and clinical scientists found that high circulating sclerostin level was in association with high circulating DPP4 activity in newly diagnosed Type 2 diabetes patients, which was consistently observed in our high-fat diet-induced diabetic mice. Meanwhile, the serum sclerostin level of the group of patients with low response to DPP4 inhibitors before treatment was significantly higher than that of patients with high response to DPP4 inhibitors. Our data from both sclerostin knock-in mice and sclerostin knock-out mice further demonstrated that sclerostin could augment circulating DPP4 activity, lower circulating intact GLP-1 level and reduce the therapeutic effect of DPP4 inhibitors. Through the structural prediction of the binding interface between sclerostin, DPP4, and GLP-1 by the AlphaFold-Multimer protein complex platform (Richard et al., biorxiv 2021) and molecular dynamics simulation, it was suggested that sclerostin could augment the DPP4 activity on degrading GLP-1. On the other hand, it was implied that sclerostin might impair the inhibitory effect of DPP4 small-molecule inhibitors on DPP4 activity. Subsequently, the above prediction was experimentally verified by the company research team both in vitro and in vivo through a combination of genetic and pharmacological approaches. At the level of specific structural regions of sclerostin protein, the company research team further showed that either genetic depletion or Apc001-mediated pharmacological inhibition of sclerostin loop3 weakened the above effects of sclerostin, suggesting that sclerostin loop3 could contribute to the sclerostin-related augment of DPP4 activity and impairment of DPP4 inhibition by DPP4 inhibitors.Taken together, all these critical evidence would facilitate the clinical translation of Apc001 in treating diabetic patients with low response to DPP4 inhibitors.


Reference

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  2. Wang, L., Yu, Y., Ni, S., Li, D., Liu, J., Xie, D., Chu, HY., Ren, Q., Zhong, C., Zhang, N., Li, N., Sun, M., Zhang, Z., Zhuo, Z., Zhang, H., Zhang, Shu., Li, M., Xia, W., Zhang, Z., Chen, L., Shang, P., Pan, X., Lu, AP., Zhang, BT., Zhang G. Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice. Thearanostics. 12(13), 5645.

  3. Elizondo, J., Lenfest, S., Sihra, S., Kosniewski, J., Black, J., Kohn, Z., Brezicha, J., Bloomfield, S., Hogan, H. (2019). Pretreatment with anti-sclerostin antibody has lasting osteogenic effects on the femur of unloaded male rats. J Bone Miner Res. 34(S1): 65-66.

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