First‐time‐in‐human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification

Perelló, Joan; Joubert, P. H.; Ferrer, Miguel D.; Canals, A.; Sinha, Smeeta; Salcedo, Carolina

doi:10.1111/bcp.13752

Cited by 26 publications

(27 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the absence of clearance due to dialysis, plus the PK parameters, indicate linearity in terms of C max and AUC and allow a good PK prediction in future clinical studies. In a previous Phase 1 study with HV, it was demonstrated that the total amount of SNF472 excreted in urine accounted for <1% of the total administered dose . Since the PK profiles of HV and HD patients are similar, the lack of renal function in HD patients is not expected to affect the metabolism of SNF472.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous Phase 1 study with HV, it was demonstrated that the total amount of SNF472 excreted in urine accounted for <1% of the total administered dose . Since the PK profiles of HV and HD patients are similar, the lack of renal function in HD patients is not expected to affect the metabolism of SNF472. Mass balance and quantitative whole‐body autoradiography studies are currently being performed in rats in order to ascertain the complete metabolism and excretion of the compound, but some data on the in vivo metabolism of IP6 in rodents has been already published.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous Phase I study, the safety, tolerability and PK of IV SNF472 were evaluated following administration of single IV doses ranging from SNF472 0.5 to 12.5 mg/kg to HV and of a single dose of 9 mg/kg to HD patients. By comparing PK results from equivalent doses of SNF472 in HV and HD patients, the dialysability of the drug was assessed.…”

Section: Discussionmentioning

confidence: 99%

“…The safety, tolerability and pharmacokinetics (PK) of IV SNF472 was evaluated in healthy volunteers (HV) following administration of single IV doses ranging from 0.5 to 12.5 mg/kg and in HD patients after treatment with 1 simple dose . In that Phase I first‐time‐in‐human clinical study, the PK profile showed a C max proportionality and a relatively short half‐life.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A phase 1b randomized, placebo‐controlled clinical trial with SNF472 in haemodialysis patients

Salcedo

Joubert

Ferrer

et al. 2019

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

Aims: SNF472 is a calcification inhibitor that is being studied as a novel treatment for calciphylaxis and cardiovascular calcification (CVC). A first study showed acceptable safety and tolerability in a single ascending dose administration in healthy volunteers and a single dose administration in haemodialysis (HD) patients. This study aimed to assess the safety, tolerability, and pharmacokinetics/pharmacodynamics relationship of intravenous SNF472 in HD patients in a multiple ascending dose administration trial with 5 doses tested for 1 week (3 administrations) and 1 dose tested for 4 weeks (12 administrations).Methods: This double blind, randomized, placebo-controlled Phase 1b study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of SNF472 after repeated administrations to HD patients for up to 28 days. A pharmacodynamic assessment was performed to evaluate the potential for SNF472 to inhibit hydroxyapatite (HAP) formation. Patients were grouped into 2 cohorts, receiving multiple ascending doses for 1 week (1 to 20 mg/kg, Cohort 1) and 1 dose of 10 mg/kg for 4 weeks (Cohort 2) of intravenous SNF472.Results: Physical status, body weight, cardiorespiratory function, body temperature and laboratory parameters were in the normal range. No clinically relevant effects on heart rate or blood pressure were observed. No abnormal electrocardiogram or QTcB period were reported. The peak plasma concentration (7.6, 16.1, 46.0 and 66.9 μg/mL for 3, 5, 12.5 and 20 mg/kg, respectively) was observed at the end of the 4-hour infusion and thereafter concentrations declined rapidly with half-life between 32 and 65 min. SNF472 at 10 mg/kg inhibited dose dependently HAP crystallization in plasma samples after 28 days of treatment (78% inhibition, P < .001).Conclusions: SNF472 is safe and well tolerated in HD patients after 2 schemes: multiple ascending doses for 1 week and after repeated dosing of 10 mg/kg for 4 weeks. In both schemes, SNF472 inhibits the induction of HAP crystallization.These results provide support for the use of SNF472 as a novel treatment for CVC in end-stage renal disease.The authors confirm that the PI for this paper is Francesc Maduell and that he had direct clinical responsibility for patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A phase 1b randomized, placebo‐controlled clinical trial with SNF472 in haemodialysis patients

Salcedo

Joubert

Ferrer

et al. 2019

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

show abstract

“…SNF472 inhibited CV calcification in adenine-induced CKD rats by up to 90% (Table 2) [20]. In ex vivo analysis using plasma from HD patients, hydroxyapatite crystallization potential was reduced by SNF472 [101,102]. The first phase 2 study CaLIPSO with 274 HD patients demonstrated attenuated progression of CAC and aortic valve calcification compared to placebo control, after 52 weeks of SNF472 treatment [21].…”

Section: Hexasodium Salt Of Myo-inositol Hexaphosphatementioning

confidence: 99%

Cardiovascular Calcification in Chronic Kidney Disease—Therapeutic Opportunities

Himmelsbach

Ciliox

Goettsch

2020

Toxins

View full text Add to dashboard Cite

Patients with chronic kidney disease (CKD) are highly susceptible to cardiovascular (CV) complications, thus suffering from clinical manifestations such as heart failure and stroke. CV calcification greatly contributes to the increased CV risk in CKD patients. However, no clinically viable therapies towards treatment and prevention of CV calcification or early biomarkers have been approved to date, which is largely attributed to the asymptomatic progression of calcification and the dearth of high-resolution imaging techniques to detect early calcification prior to the ‘point of no return’. Clearly, new intervention and management strategies are essential to reduce CV risk factors in CKD patients. In experimental rodent models, novel promising therapeutic interventions demonstrate decreased CKD-induced calcification and prevent CV complications. Potential diagnostic markers such as the serum T50 assay, which demonstrates an association of serum calcification propensity with all-cause mortality and CV death in CKD patients, have been developed. This review provides an overview of the latest observations and evaluates the potential of these new interventions in relation to CV calcification in CKD patients. To this end, potential therapeutics have been analyzed, and their properties compared via experimental rodent models, human clinical trials, and meta-analyses.

show abstract

Vascular calcification: Molecular mechanisms and therapeutic interventions

Pan

Jie

Huang

2023

MedComm

View full text Add to dashboard Cite

Vascular calcification (VC) is recognized as a pathological vascular disorder associated with various diseases, such as atherosclerosis, hypertension, aortic valve stenosis, coronary artery disease, diabetes mellitus, as well as chronic kidney disease. Therefore, it is a life‐threatening state for human health. There were several studies targeting mechanisms of VC that revealed the importance of vascular smooth muscle cells transdifferentiating, phosphorous and calcium milieu, as well as matrix vesicles on the progress of VC. However, the underlying molecular mechanisms of VC need to be elucidated. Though there is no acknowledged effective therapeutic strategy to reverse or cure VC clinically, recent evidence has proved that VC is not a passive irreversible comorbidity but an active process regulated by many factors. Some available approaches targeting the underlying molecular mechanism provide promising prospects for the therapy of VC. This review aims to summarize the novel findings on molecular mechanisms and therapeutic interventions of VC, including the role of inflammatory responses, endoplasmic reticulum stress, mitochondrial dysfunction, iron homeostasis, metabolic imbalance, and some related signaling pathways on VC progression. We also conclude some recent studies on controversial interventions in the clinical practice of VC, such as calcium channel blockers, renin–angiotensin system inhibitions, statins, bisphosphonates, denosumab, vitamins, and ion conditioning agents.

show abstract

First‐time‐in‐human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification

Cited by 26 publications

References 25 publications

A phase 1b randomized, placebo‐controlled clinical trial with SNF472 in haemodialysis patients

A phase 1b randomized, placebo‐controlled clinical trial with SNF472 in haemodialysis patients

Cardiovascular Calcification in Chronic Kidney Disease—Therapeutic Opportunities

Vascular calcification: Molecular mechanisms and therapeutic interventions

Contact Info

Product

Resources

About