Safety, pharmacokinetics and pharmacodynamics of the anti‐hepcidin Spiegelmer lexaptepid pegol in healthy subjects

Boyce, Malcolm; Warrington, Steve; Cortezi, B; Zöllner, Stefan; Vauléon, S; Swinkels, Dorine W.; Summo, Luciana; Schwoebel, Frank; Riecke, Kai

doi:10.1111/bph.13433

Cited by 60 publications

(41 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Conversely, therapeutics that bind to and inactivate hepcidin have been developed and studied for the treatment of anaemia of inflammation and chronic disease. Such hepcidin-binding agents include humanized monoclonal antibodies (LY2787106, discontinued after phase 1 in 2015, Eli Lilly163; and 12B9m, Amgen Inc164), an anticalin (PRS-080, Pieris Pharmaceutical)165 and a L-RNA spiegelmer (Lexaptepid pegol (NOX-H94), NOXXON Pharma)166,167.…”

Section: Iron Metabolism As a Therapeutic Targetmentioning

confidence: 99%

Targeting iron metabolism in drug discovery and delivery

Crielaard

Lammers

Rivella

2017

Nat Rev Drug Discov

279

205

View full text Add to dashboard Cite

Iron fulfils a central role in many essential biochemical processes in human physiology, which makes proper processing of iron crucial. Although iron metabolism is subject to relatively strict physiological control, in recent years numerous disorders, such as cancer and neurodegenerative diseases, have been linked to deregulated iron homeostasis. Because of its involvement in the pathogenesis of these diseases, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents will likely have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are often available.

show abstract

Section: Iron Metabolism As a Therapeutic Targetmentioning

confidence: 99%

Targeting iron metabolism in drug discovery and delivery

Crielaard

Lammers

Rivella

2017

Nat Rev Drug Discov

279

205

View full text Add to dashboard Cite

show abstract

“…Nox-H94, a PEGylated anti-hepcidin L-RNA aptamer, has been shown to minimise hepcidin-induced FPN degradation and ferritin expression in cynomolgus monkeys [91]. A human study involving healthy adults investigated the safety, pharmacokinetics and pharmacodynamics of Nox-H94 and showed no serious adverse health effects [92] while resulting in an increase in serum iron and transferrin saturation levels [92] (Table 1).…”

Section: Hepcidin-binding L-rna Aptamers (Spiegelmers)mentioning

confidence: 99%

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis

et al. 2019

View full text Add to dashboard Cite

The interaction between hepcidin and ferroportin is the key mechanism involved in regulation of systemic iron homeostasis. This axis can be affected by multiple stimuli including plasma iron levels, inflammation and erythropoietic demand. Genetic defects or prolonged inflammatory stimuli results in dysregulation of this axis, which can lead to several disorders including hereditary hemochromatosis and anaemia of chronic disease. An imbalance in iron homeostasis is increasingly being associated with worse disease outcomes in many clinical conditions including multiple cancers and neurological disorders. Currently, there are limited treatment options for regulating iron levels in patients and thus significant efforts are being made to uncover approaches to regulate hepcidin and ferroportin expression. These approaches either target these molecules directly or regulatory steps which mediate hepcidin or ferroportin expression. This review examines the current status of hepcidin and ferroportin agonists and antagonists, as well as inducers and inhibitors of these proteins and their regulatory pathways.

show abstract

“…Recent investigations have presented the effects of antihepcidin agents, and phase 2 clinical trials are being conducted in patients receiving HD. Hitomi et al developed human‐induced pluripotent stem (iPS) cells producing erythropoietin, and demonstrated that transplantation of these human iPS cells into mice with CKD improved hemoglobin levels to the normal range.…”

Section: Novel Therapeutic Approach For Renal Anemia In Patients Undementioning

confidence: 99%

Anemia in conventional hemodialysis: Finding the optimal treatment balance

Hasegawa

Koiwa

Akizawa

2018

Seminars in Dialysis

View full text Add to dashboard Cite

Renal anemia is a serious and common complication in hemodialysis (HD) patients.The introduction of erythropoiesis-stimulating agents (ESAs) has dramatically improved hemoglobin levels and outcomes. Several interventional studies reported that excessive correction of anemia and the massive use of ESA can trigger cardiovascular disease (CVD), and consequently may worsen the prognosis of patients undergoing HD. Therefore, it has been widely recognized that large doses of ESA should be used with caution. An effective use of iron preparations is required to yield the optimal effect of ESA. It is well-known that iron utilization is inhibited under pathological conditions, such as chronic inflammation, resulting in ESA resistance. It is postulated that a new class of therapeutic agents for renal anemia, hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitors, will have beneficial treatment effects in patients on HD. HIF is induced by hypoxia and promotes erythropoietin production. In the absence of a hypoxic state, HIF is decomposed by the HIF catabolic enzyme. HIF-PH inhibitors inhibit this degrading enzyme and stimulate endogenous erythropoietin production via HIF induction. Additionally, HIF-PH inhibitors promote effective utilization of iron and raise erythropoietin to physiological concentrations. Accordingly, HIF-PH inhibitors improve anemia and iron metabolism. It appears that this effect persists irrespective of chronic inflammatory conditions. HIF-PH inhibitors do not overshoot erythropoietin above physiological concentrations like ESAs. Therefore, it is hypothesized that HIF-PH inhibitors would not increase the risk of CVD in patients undergoing HD.

show abstract

Safety, pharmacokinetics and pharmacodynamics of the anti‐hepcidin Spiegelmer lexaptepid pegol in healthy subjects

Cited by 60 publications

References 32 publications

Targeting iron metabolism in drug discovery and delivery

Targeting iron metabolism in drug discovery and delivery

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis

Anemia in conventional hemodialysis: Finding the optimal treatment balance

Contact Info

Product

Resources

About