The erythropoietin analog ARA 290 for treatment of sarcoidosis-induced chronic neuropathic pain

Swartjes, Maarten; Heij, Lara; Brines, Michael; Cerami, Anthony; Dunne, Ann; Hoitsma, Elske; Dahan, Albert

doi:10.1517/21678707.2013.719289

Cited by 12 publications

(6 citation statements)

References 41 publications

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“…In preclinical models of injury, ARA 290 not only inhibits TNFα, but also other components of the proinflammatory cytokine cascade (25). Although ARA 290 has a short serum half-life of a few minutes (11), the peak plasma concentrations attained after the administration of 2 mg intravenously in normal human volunteers in pharmacokinetic studies reached ~50 ng/mL, exceeding the minimum effective peak concentration of ~1 ng/mL (26). ARA 290 at concentrations exceeding ~1 ng/mL activates the IRR, which functions as a molecular switch to provide long-lasting effects, similar to other effector molecules in the immune response.…”

Section: Discussionmentioning

confidence: 99%

“…The trial sample size was chosen on the basis of the robust efficacy of ARA 290 in a rodent model of neuropathy (12) and from the observations derived from a prior small nonblinded trial of 20 patients with symptoms of SFN who received ARA 290 (2 mg intravenously) for three doses every 2 d over 1 wk (11). Responses from the weekly patient questionnaires were calculated as change from baseline values.…”

Section: Methodsmentioning

confidence: 99%

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Safety and Efficacy of ARA 290 in Sarcoidosis Patients with Symptoms of Small Fiber Neuropathy: A Randomized, Double-Blind Pilot Study

Heij

Niesters

Swartjes

et al. 2012

Mol Med

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ARA 290 (a peptide designed to activate the innate repair receptor that arrests injury and initiates cytoprotection, antiinflammation and healing) reduces allodynia in preclinical neuropathy models. We studied the safety and efficacy of ARA 290 to reduce symptoms of small fiber neuropathy (SFN) in patients with sarcoidosis. A total of 22 patients diagnosed with sarcoidosis and symptoms of SFN were enrolled in a double-blind, placebo-controlled exploratory trial consisting of three times weekly intravenous dosing of ARA 290 (2 mg; n = 12) or placebo (n = 10) for 4 wks. Inclusion criteria were a diagnosis of neuropathy and a spontaneous pain score of ≥5 (Brief Pain Inventory [BPI]). Endpoints assessed were changes in pain intensity and the small fiber neuropathy screening list (SFNSL) score, quality of life (SF-36), depressive symptoms (Inventory of Depressive Symptomatology [IDS]) and fatigue (Fatigue Assessment Scale [FAS]). No safety concerns were raised by clinical or laboratory assessments. The ARA 290 group showed significant (p < 0.05) improvement at wk 4 in SFNSL score compared with placebo (Δ -11.5 ± 3.04 versus Δ -2.9 ± 3.34 [standard error of the mean]). Additionally, the ARA 290 group showed a significant change from baseline in the pain and physical functioning dimensions of the SF-36 (Δ -23.4 ± 5.5 and Δ -14.6 ± 3.9, respectively). The mean BPI and FAS scores improved significantly but equivalently in both patient groups. No change was observed in the IDS. ARA 290 appears to be safe in patients with sarcoidosis and can reduce neuropathic symptoms.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Safety and Efficacy of ARA 290 in Sarcoidosis Patients with Symptoms of Small Fiber Neuropathy: A Randomized, Double-Blind Pilot Study

Heij

Niesters

Swartjes

et al. 2012

Mol Med

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“…TGF-β has been established as the master regulator of fibrosis ( 57 ) and also an antagonist of nitric oxide production, which is implicated in the final common pathway of neuropathic pain ( 58 ). This has been evaluated in patients with sarcoidosis ( 59 ).…”

Section: Discussionmentioning

confidence: 99%

A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan

Winicki

Nanavati

Morrell

et al. 2023

Front. Cardiovasc. Med.

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BackgroundAging is associated with increased levels of reactive oxygen species and inflammation that disrupt proteostasis and mitochondrial function and leads to organism-wide frailty later in life. ARA290 (cibinetide), an 11-aa non-hematopoietic peptide sequence within the cardioprotective domain of erythropoietin, mediates tissue protection by reducing inflammation and fibrosis. Age-associated cardiac inflammation is linked to structural and functional changes in the heart, including mitochondrial dysfunction, impaired proteostasis, hypertrophic cardiac remodeling, and contractile dysfunction. Can ARA290 ameliorate these age-associated cardiac changes and the severity of frailty in advanced age?MethodsWe conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline. Serial echocardiography, tail blood pressure and body weight were evaluated repeatedly at 4-month intervals. A frailty index was calculated at the final timepoint (33 months of age). Tissues were harvested at 4-month intervals to define inflammatory markers and left ventricular tissue remodeling. Mitochondrial and myocardial cell health was assessed in isolated left ventricular myocytes. Kaplan–Meier survival curves were established. Mixed ANOVA tests and linear mixed regression analysis were employed to determine the effects of age, treatment, and age-treatment interactions.ResultsChronic ARA290 treatment mitigated age-related increases in the cardiac non-myocyte to myocyte ratio, infiltrating leukocytes and monocytes, pro-inflammatory cytokines, total NF-κB, and p-NF-κB. Additionally, ARA290 treatment enhanced cardiomyocyte autophagy flux and reduced cellular accumulation of lipofuscin. The cardiomyocyte mitochondrial permeability transition pore response to oxidant stress was desensitized following chronic ARA290 treatment. Concurrently, ARA290 significantly blunted the age-associated elevation in blood pressure and preserved the LV ejection fraction. Finally, ARA290 preserved body weight and significantly reduced other markers of organism-wide frailty at the end of life.ConclusionAdministration of ARA290 reduces cell and tissue inflammation, mitigates structural and functional changes within the cardiovascular system leading to amelioration of frailty and preserved healthspan.

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“…IRR signalling requires systemic concentrations of cibinetide ≥1 nM. In non-obese subjects, the peak concentration of a 4 mg subcutaneous dose in pharmacokinetic studies was~1.8 nM [37]. It is possible that peak levels of cibinetide in obese participants may have been less than the minimum activating concentration.…”

Section: Discussionmentioning

confidence: 99%

A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema

Lois

Gardner

McFarland

et al. 2020

JCM

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Purpose: Evaluating the effects of cibinetide in diabetic macular edema (DME). Methods: Phase 2 trial. Naïve patients with >400 µm central retinal thickness (CRT) DME in one/both eyes were recruited (May 2016–April 2017) at the Belfast Health and Social Care Trust. The study eye was that with best vision and lowest CRT. Patients self-administered cibinetide 4 mg/day subcutaneously for 12 weeks. Primary and secondary outcomes: mean change from baseline to week 12 in best corrected visual acuity (BCVA), CRT, central retinal sensitivity, tear production, patient-reported outcomes, adverse events and antibodies to cibinetide. Descriptive statistics were used; exploratory analyses focused on non-study eyes, diabetic control, serum cytokines and albuminuria. Results: Nine patients were recruited; eight completed the study. There was no improvement in mean change baseline-week 12 in BCVA (−2.9 + 5.0), CRT (10 + 94.6 microns), central retinal sensitivity (−0.53 + 1.9 dB) or tear production (−0.13 + 7.7 mm), but there was an improvement in National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite scores (2.7 + 3.1). Some participants experienced improvements in CRT, tear production, diabetic control and albuminuria. No serious adverse events/reactions or anti-cibinetide antibodies were seen. Conclusions: The cibinetide 12-week course was safe. Improvements in NEI VFQ-25 scores, CRT, tear production, diabetic control and albuminuria, observed in some participants, warrant further investigation. Trial Registration: EudraCT number: 2015-001940-12. ISRCTN16962255—registration date 25.06.15.

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The erythropoietin analog ARA 290 for treatment of sarcoidosis-induced chronic neuropathic pain

Cited by 12 publications

References 41 publications

Safety and Efficacy of ARA 290 in Sarcoidosis Patients with Symptoms of Small Fiber Neuropathy: A Randomized, Double-Blind Pilot Study

Safety and Efficacy of ARA 290 in Sarcoidosis Patients with Symptoms of Small Fiber Neuropathy: A Randomized, Double-Blind Pilot Study

A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan

A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema

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