ARA-290
Also known as: Cibinetide, ARA290, pHBSP, pyroglutamate helix B surface peptide, 1208243-50-8
Evidence: Clinical
Overview
Synthetic 11-amino-acid peptide derived from the helix-B region of erythropoietin that activates the innate repair receptor without EPO's blood-cell effects.
ARA-290 (cibinetide, pyroglutamate helix B surface peptide) is an 11-residue peptide modelled on the aqueous face of helix B of erythropoietin. It activates the innate repair receptor, a heterocomplex of the EPO receptor and the beta common receptor induced on injured tissue, without binding the EPO receptor homodimer, so it is not erythropoietic (Brines 2008). Four phase 2 trials are published. In sarcoid small fiber neuropathy, 2 mg IV three times weekly for 4 weeks (n=22) improved the symptom score against placebo (Heij 2012), 4 mg/day subcutaneously for 28 days improved symptoms, corneal nerve fiber density and 6-minute walk distance (Dahan 2013), and a 64-subject dose-ranging trial found 4 mg/day raised corneal nerve fiber area while 1 and 8 mg/day did not (Culver 2017). In type 2 diabetes, 4 mg/day for 28 days improved HbA1c, lipids and PainDetect scores (n=24; Brines 2015).
Benefits
Improved neuropathy symptom scores and corneal small nerve fiber density in phase 2 trials (human RCT, n=22 to 64); improved HbA1c and lipids in type 2 diabetes (human RCT, n=24); tissue protection in stroke, renal ischemia and nerve injury models (animal)
Dosing reference
- Research dose
- 1 to 8 mg daily subcutaneously in phase 2 trials, with 4 mg/day the dose that separated from placebo; one trial used 2 mg IV three times weekly
- Range
- 1000 to 8000 mcg, 1x daily
Subcutaneous once daily in most trials, for 28 days; one trial used 2 mg IV three times weekly for 4 weeks. The dose response is not monotonic: in the 64-subject phase 2b, 4 mg/day raised corneal nerve fiber area while 1 and 8 mg/day did not. Plasma half-life is about 2 min, yet the biological effects persist for days (Collino 2015).
Mechanism
Erythropoietin has two separable jobs through two receptors: red cell production via the EPO receptor homodimer, and tissue protection via the innate repair receptor, a heterocomplex of the EPO receptor and CD131 (the beta common receptor) that is not normally expressed but is induced by injury or inflammation. ARA-290 is an 11-residue peptide reproducing the aqueous surface of helix B, which does not contact the homodimer; it activates the innate repair receptor selectively and was tissue-protective in stroke, renal ischemia-reperfusion, retinal edema and peripheral nerve trauma models while showing no erythropoietic activity in vitro or in vivo (Brines 2008). Despite a plasma half-life of about 2 min, the receptor activation triggers effects lasting days, which the developers describe as a molecular switch rather than sustained occupancy (Collino 2015).
Evidence
Clinical: at least one published human trial or an approved drug
- An 11-residue peptide reproducing the aqueous face of EPO helix B was tissue-protective in stroke, renal ischemia-reperfusion, retinal edema and nerve trauma models and was not erythropoietic in vitro or in vivo (Brines et al., 2008)
- In sarcoidosis with small fiber neuropathy symptoms, 2 mg IV three times weekly for 4 weeks improved the neuropathy screening score against placebo (n=22, randomized double-blind; Heij et al., 2012)
- In documented small nerve fiber loss, 28 days of 4 mg/day subcutaneously improved symptoms, corneal small nerve fiber density and 6-minute walk distance against placebo (Dahan et al., 2013)
- A 64-subject phase 2b dose-ranging trial found 4 mg/day significantly increased corneal nerve fiber area (placebo-corrected +697 micrometres squared, p=0.012) while 1 and 8 mg/day did not (Culver et al., 2017)
- In type 2 diabetes with painful neuropathy, 4 mg/day for 28 days improved HbA1c, lipid profile and PainDetect scores over 56 days of observation (n=24; Brines et al., 2015)
- Human-trial status: several completed phase 2 trials, all small (n=22 to 64) and mostly in sarcoid or diabetic small fiber neuropathy. No phase 3 trial and no regulatory approval in any country
References
- Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Brines M, Patel NS, Villa P, et al., PNAS, 2008
- Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Heij L, Niesters M, Swartjes M, et al., Molecular Medicine, 2012
- ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Dahan A, Dunne A, Swartjes M, et al., Molecular Medicine, 2013
- Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain. Culver DA, Dahan A, Bajorunas D, et al., Investigative Ophthalmology and Visual Science, 2017
- ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Brines M, Dunne AN, van Velzen M, et al., Molecular Medicine, 2015
- Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin. Collino M, Thiemermann C, Cerami A, Brines M, Pharmacology and Therapeutics, 2015
Side effects
Well tolerated in small trials for neuropathic pain, where injection-site reactions were the main finding. Unlike erythropoietin it did not raise hematocrit or blood pressure in the studies conducted. Long-term safety data is limited.
Storage
- Storage
- Refrigerate 2-8°C (36-46°F)
- Lyophilized
- 2+ years at room temp, 3+ years refrigerated
- Reconstituted
- 28-30 days refrigerated
Pharmacology
- Half-life
- About 2 min (human, plasma), with biological effects lasting days (Collino 2015)
- Molecular weight
- 1257.3 Da
- Sequence
- [Pyr]-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser ([Pyr] = pyroglutamate; 11 aa)