Improvement in wound healing, pain, and quality of life after 12 weeks of SNF472 treatment: a phase 2 open-label study of patients with calciphylaxis

Brandenburg, Vincent; Sinha, Smeeta; Torregrosa, José-Vicente; Garg, Rekha; Miller, Stephan; Canals, Ana-Zeralda; Bahr, Daun; Joubert, P. H.; Salcedo, Carolina; Carroll, Kevin; Gold, Alex; Perelló, Joan

doi:10.1007/s40620-019-00631-0

Cited by 35 publications

(48 citation statements)

References 31 publications

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“…Chelation of ionized calcium by 50% in saline occurred at SNF472 concentrations of 539 μM, nearly 50-fold greater than concentrations that inhibited hydroxyapatite crystallization in adapted synthetic fluid and >40-fold greater than free concentrations of SNF472 associated with a single dose of 9 mgÁkg −1 in the phase 1 clinical trial described above (Perelló et al, 2018). Doses of SNF472 in clinical development to treat cardiovascular calcification or calcific uraemic arteriolopathy (Brandenburg et al, 2019;Raggi et al, 2020) are not expected to chelate circulating calcium and hypocalcaemia was not reported in the phase 1b trial (Salcedo et al, 2019 In 157 postmenopausal women, those with low (≤0.76 μM) phytate concentrations had significantly greater bone mass loss in the lumbar spine than those with high (≥1.42 μM) phytate concentrations (López-González et al, 2013). In our experiments, the 9-month repeated dosing toxicology study in dogs showed no differences in full bone histomorphology or tartrate-resistant acid phosphatase, an osteoclast biomarker, between control animals and animals treated with SNF472.…”

Section: Effects Of Snf472 On In Vitro Osteoblast Calcificationmentioning

confidence: 99%

Mechanism of action of SNF472, a novel calcification inhibitor to treat vascular calcification and calciphylaxis

Perelló

Ferrer

Pérez

et al. 2020

British J Pharmacology

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Background and Purpose No therapy is approved for vascular calcification or calcific uraemic arteriolopathy (calciphylaxis), which increases mortality and morbidity in patients undergoing dialysis. Deposition of hydroxyapatite (HAP) crystals in arterial walls is the common pathophysiologic mechanism. The mechanism of action of SNF472 to reduce HAP deposition in arterial walls was investigated. Experimental Approach We examined SNF472 binding features (affinity, release kinetics and antagonism type) for HAP crystals in vitro, inhibition of calcification in excised vascular smooth muscle cells from rats and bone parameters in osteoblasts from dogs and rats. Key Results SNF472 bound to HAP with affinity (KD) of 1–10 μM and saturated HAP at 7.6 μM. SNF472 binding was fast (80% within 5 min) and insurmountable. SNF472 inhibited HAP crystal formation from 3.8 μM, with complete inhibition at 30.4 μM. SNF472 chelated free calcium with an EC50 of 539 μM. Chelation of free calcium was imperceptible for SNF472 1–10 μM in physiological calcium concentrations. The lowest concentration tested in vascular smooth muscle cells, 1 μM inhibited calcification by 67%. SNF472 showed no deleterious effects on bone mineralization in dogs or in rat osteoblasts. Conclusion and Implications These experiments show that SNF472 binds to HAP and inhibits further HAP crystallization. The EC50 for chelation of free calcium is 50‐fold greater than a maximally effective SNF472 dose, supporting the selectivity of SNF472 for HAP. These findings indicate that SNF472 may have a future role in the treatment of vascular calcification and calcific uraemic arteriolopathy in patients undergoing dialysis.

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Section: Effects Of Snf472 On In Vitro Osteoblast Calcificationmentioning

confidence: 99%

Mechanism of action of SNF472, a novel calcification inhibitor to treat vascular calcification and calciphylaxis

Perelló

Ferrer

Pérez

et al. 2020

British J Pharmacology

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“…It inhibits the formation and growth of hydroxyapatite microcrystals in soft tissues when administered parenterally 40,41 . Completed phase II studies in hemodialysis patients with calciphylaxis or coronary artery calcifications, respectively, showed good safety, tolerability, as well as encouraging efficacy [42][43][44] . IP6 is injected intravenously through the dialysis machine during hemodialysis sessions to allow it to reach therapeutic exposure despite its modest potency and short plasma half-life 45 .…”

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confidence: 99%

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers

et al. 2020

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Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis (phosphate), (OEG 2) 2-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG 2) 2-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG 2) 2-IP4 disrupts the nucleation and growth of pathological calcification.

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“…In addition to analgesics, treatments that may improve the underlying lesion itself are also likely to improve pain. To date, there is no approved treatment for calciphylaxis, and management is largely based on case reports and uncontrolled studies, although prospective clinical trials are under way [ 12 ]. The use of hyperbaric oxygen therapy, vitamin K and wound debridement are examples of management strategies that been reported to improve wound healing and therefore may also improve pain.…”

Section: Discussionmentioning

confidence: 99%

Pain management in patients with end-stage renal disease and calciphylaxis- a survey of clinical practices among physicians

et al. 2020

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Background Calciphylaxis is a rare condition usually seen in patients with end-stage renal disease. Pain is a hallmark of this condition and can be extremely difficult to control. Anecdotal data suggests that pain management in calciphylaxis is challenging with variable approaches across the United Kingdom (UK) and internationally. A knowledge and practice survey was conducted to establish current practice in the management of pain in patients with calciphylaxis, in the UK. Based on the results and clinical experience the authors suggest a clinical practice guideline. Methods An online questionnaire was circulated among physicians (renal and palliative care) involved in the management of pain in calciphylaxis. The questionnaire included a mix of open-ended questions and questions with drop down options. Results One hundred and six clinicians responded to the survey of which 60 (57%) respondents were from palliative medicine; the remaining 46 (43%) were from renal medicine. 31 (30%) respondents across both specialties had not encountered any patients with a diagnosis of calciphylaxis (renal-2, palliative care-29). A referral to the palliative care team was undertaken by 18% of renal physicians, 32% referred to the pain team and 50% referred to both. Only 3% of the palliative medicine respondents indicated that they had received a referral from the renal team at the time of diagnosis. Opioids were the preferred initial drug of choice for the management of all types of pain. Paracetamol was universally selected as the preferred first-choice adjuvant agent for management of all types of pain. The importance of advance care planning was highlighted with 72% undertaking advanced care planning discussions often or most of the time. Conclusion There was wide variation in the current practice of pain management in patients with calciphylaxis, with variation between renal specialists and palliative care specialists. Referral to specialists in pain management is not universal despite the severe nature of the pain experienced by patients with calciphylaxis. The data generated has facilitated the development of a clinical practice guideline to support complex pain management in a group of patients with multiple comorbidities.

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Improvement in wound healing, pain, and quality of life after 12 weeks of SNF472 treatment: a phase 2 open-label study of patients with calciphylaxis

Cited by 35 publications

References 31 publications

Mechanism of action of SNF472, a novel calcification inhibitor to treat vascular calcification and calciphylaxis

Mechanism of action of SNF472, a novel calcification inhibitor to treat vascular calcification and calciphylaxis

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers

Pain management in patients with end-stage renal disease and calciphylaxis- a survey of clinical practices among physicians

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