MEDICAL DISCLAIMER: Educational research guidelines only. Lyophilized peptides are investigational chemical compounds and are NOT approved for human consumption, diagnosis, or therapy. Consult a licensed physician before any research application.
Ara-290 Dosage Chart, Schedule & Reconstitution Protocol
Quickstart Highlights
ARA-290 (cibinetide) is an 11-amino-acid linear peptide engineered by Anthony Cerami and Michael Brines at the Araim Pharmaceuticals program from the helix B region of erythropoietin (EPO), retaining tissue-protective activity through the heterodimeric beta-common receptor (CD131)/EPO receptor complex while lacking the homodimeric EPO receptor binding responsible for erythropoiesis. Activation of the innate repair receptor suppresses proinflammatory cytokines including TNF-alpha and IL-6, reduces leukocyte infiltration into injured tissue, and supports neuronal, endothelial, and small-fiber survival without the thrombosis, hypertension, or hemoglobin elevations that limit EPO use. Researchers study cibinetide for diabetic small-fiber neuropathy, sarcoidosis-associated neuropathic pain, sickle cell vaso-occlusive disease, post-surgical inflammatory pain, and chronic kidney disease neuropathy. Pivotal phase 2 trials in sarcoidosis and diabetes are reported in PMID 25844947 (Heij 2012) and PMID 28258049 (Dahan 2013).
Reconstitute: Add 2 mL bacteriostatic water → 8 mg/mL concentration.
Easy measuring: At 8 mg/mL, 1 unit = 0.01 mL = 0.0800 mg (80 mcg) on a U-100 insulin syringe.
Storage: Lyophilized refrigerated or frozen; reconstituted refrigerated up to 28 days.
Plasma half-life: Approximately 2 minutes by intravenous administration; tissue-protective effects nonetheless persist for 24 hours or more due to durable receptor-triggered intracellular signaling cascades.
Onset: Pain and small-fiber function endpoints typically respond over 4 to 8 weeks of daily subcutaneous dosing in phase 2 trials; acute anti-inflammatory effects on cytokine profiles are detectable within days.
Regulatory status: Not approved by FDA or EMA. Investigational across multiple phase 2 indications including sarcoidosis neuropathy, diabetic neuropathy, and sickle cell disease; phase 3 development has not been completed.
Erythropoietic safety: Unlike EPO, cibinetide does not raise hemoglobin or hematocrit in dose-ranging trials, reflecting selective signaling through the innate repair receptor rather than the classical homodimeric EPOR.
Quick Protocol Navigation
Reconstitution Instruction & Mixing Step-by-Step
Lyophilized powder must be reconstituted carefully. Agitating peptide chains can shear disulfide bonds and render the peptide biologically inert.
Draw 2.0 mL bacteriostatic water with a sterile syringe.
Inject slowly down the vial wall; avoid foaming.
Gently swirl or roll until fully dissolved (do not shake vigorously).
Inject slowly; wait a few seconds before withdrawing the needle.
Aspiration is not required for subcutaneous injections; inject slowly and steadily[13].
Interactive Ara-290 Syringe Calculator
Currently visualizing the 16 mg vial reconstituted with 2 mL bacteriostatic water. Adjust the target dose to dynamically render syringe units.
Reconstitution Calculation: 16mg dry powder in 2mL water yields 8.00 mg/mL. To evaluate a 250mcg dose, pull to 3.1 units (3 syringe ticks).
U-100 Syringe Representation
3.1 Units (3 Ticks)
Educational reference visual. Assumes standard U-100 insulin syringe where 1.0 mL volume = 100 units.
Titration & Dose Escalation Schedules
| Week | Daily Dose | Units (per injection) (mL) |
|---|---|---|
| Week 1 | 2 mg (2,000 mcg) | 25 units (0.25 mL) |
| Weeks 2–8 (or up to 16) | 4 mg (4,000 mcg) | 50 units (0.50 mL) |
Administration guidelines: Refer to guidelines | 2 mL Reconstitution
Research Supplies Quantity Planner
Scientific mathematical planning of syringes, bacteriostatic water and dry vials needed for extended research blocks using the 16 mg vial.
Peptide Vials (Ara-290, 16 mg each):
- check8 weeks ≈ 14 vials
- check12 weeks ≈ 21 vials
- check16 weeks ≈ 28 vials
Insulin Syringes (U-100):
- checkPer week: 7 syringes (1/day)
- check8 weeks: 56 syringes
- check12 weeks: 84 syringes
- check16 weeks: 112 syringes
Bacteriostatic Water (10 mL bottles): Use 2.0 mL per vial for reconstitution.
- check8 weeks (14 vials): 28 mL → 3 × 10 mL bottles
- check12 weeks (21 vials): 42 mL → 5 × 10 mL bottles
- check16 weeks (28 vials): 56 mL → 6 × 10 mL bottles
Alcohol Swabs: One for the vial stopper + one for the injection site each day.
- checkPer week: 14 swabs (2/day)
- check8 weeks: 112 swabs → recommend 2 × 100-count boxes
- check12 weeks: 168 swabs → recommend 2 × 100-count boxes
- check16 weeks: 224 swabs → recommend 3 × 100-count boxes
Mechanism of Action (MOA)
Erythropoietin (EPO) was originally appreciated as a hematopoietic growth factor that binds a homodimeric EPO receptor on erythroid progenitor cells to drive red blood cell production. Brines and Cerami discovered in the early 2000s that EPO has a second, anatomically distinct tissue-protective activity mediated by a heteromeric receptor composed of an EPO receptor monomer plus the beta-common receptor (CD131), the same beta subunit shared by IL-3, IL-5, and GM-CSF receptors [1][2]. This heteromeric receptor is upregulated in injured and inflamed tissues but is absent from erythroid progenitors. ARA 290 (the structural fragment QEQLERALNSS, also known as the Helix B Surface Peptide or pyroglutamate-EPO peptide) was designed to recapitulate the surface region of EPO that interacts with the tissue-protective receptor while removing the binding interface for the homodimeric erythropoietic receptor. As a result, ARA 290 has tissue-protective and anti-inflammatory activity without driving erythropoiesis, eliminating the thrombotic and cardiovascular risks associated with high-dose recombinant EPO use [3]. Downstream signaling through the tissue-protective receptor includes activation of JAK2-STAT3, PI3K-Akt, and NF-kB pathways with net anti-inflammatory effects: reduced TNF-alpha and IL-6 release from activated macrophages, suppressed neutrophil infiltration in injury models, and enhanced survival of nerve fibers, cardiomyocytes, and renal tubular cells under stress [4]. The plasma half-life of subcutaneous ARA 290 is approximately 2 minutes, but the receptor-mediated effects on tissue protection persist for hours to days because the peptide triggers durable downstream transcriptional and protective programs. The standard research route is subcutaneous injection in the abdomen, with daily dosing for 28 days in most published trials. Common research applications include sarcoidosis-related small fiber neuropathy, diabetic peripheral neuropathy, chemotherapy-induced peripheral neuropathy, autonomic dysfunction in chronic inflammatory conditions, and exploratory work in chronic kidney disease and ischemic injury models. Outcome measures in published trials include the Small Fiber Neuropathy Screening List, the Brief Pain Inventory, corneal confocal microscopy quantification of nerve fiber density and length (which is a non-invasive surrogate for systemic small fiber neuropathy), skin biopsy quantification of intraepidermal nerve fiber density, and HbA1c and lipid panel changes in diabetic cohorts [4][5][6]. Reported benefits include statistically significant reductions in neuropathic pain in moderate-to-severe pain subgroups, increased corneal nerve fiber area on confocal microscopy after 28 days, improvements in autonomic function questionnaires, and persistence of metabolic improvements for several weeks after the end of the 28-day dosing period. The non-erythropoietic design of ARA 290 is its principal advantage over recombinant EPO and its analogs (epoetin alfa, darbepoetin), which were historically explored for neuroprotective applications but are limited by hematocrit elevation, hypertension, and thrombotic risk that reflect their erythropoietic action. By separating tissue protection from erythropoiesis through structural engineering, ARA 290 retains the therapeutic mechanism while eliminating the dose-limiting hematologic toxicity that ended large neuroprotection trials of high-dose EPO in stroke. The peptide's short plasma half-life (approximately 2 minutes) but durable downstream effects support a once-daily subcutaneous dosing schedule analogous to that used for many short-acting peptide biologics with receptor-mediated tissue retention.
Clinical Trial Efficacy Highlights
- starHeij and colleagues conducted a randomized double-blind placebo-controlled pilot study of ARA 290 in sarcoidosis patients with small fiber neuropathy symptoms, showing reductions in neuropathic pain scores and improvements in autonomic dysfunction questionnaires over a 28-day dosing period [4].
- starThe DOSARA phase 2b trial enrolled 64 patients with sarcoidosis-related small fiber neuropathy randomized to placebo or 1, 4, or 8 mg/day subcutaneous ARA 290 for 28 days; the 4 mg/day group showed a 23 percent increase in corneal nerve fiber area on confocal microscopy versus baseline and reductions in pain intensity in the moderate-to-severe subgroup [5].
- starBrines, Dunne, and Cerami demonstrated in a randomized double-blind placebo-controlled phase 2 trial in patients with type 2 diabetes that 4 mg/day subcutaneous ARA 290 for 28 days produced improvements in HbA1c, lipid profile, and neuropathic symptoms that were sustained 4 weeks post-dosing, supporting the tissue-protective receptor mechanism [6].
- starSkin biopsies in ARA 290-treated patients have shown increases in GAP-43-positive nerve fibers, a marker of actively regenerating small sensory fibers, supporting a nerve-regenerative rather than purely analgesic mechanism [4][5].
- starPreclinical studies in rodent models of neuropathic pain demonstrated that ARA 290 produces long-term relief of mechanical allodynia coupled with suppression of spinal microglial activation, consistent with a neuroimmunomodulatory mechanism [3].
- starMechanistic studies have confirmed that ARA 290 binds the heteromeric EPO receptor/beta-common receptor with high affinity, activates JAK2-STAT3 and PI3K-Akt signaling, and produces anti-inflammatory and cytoprotective effects in macrophages, neurons, and renal tubular cells without affecting erythroid progenitor proliferation [1][7].
- starAcross approximately 200 cumulative participants in published phase 2 trials, ARA 290 has shown no hematologic effects, no blood pressure elevation, and no thrombotic events, confirming the design goal of separating tissue protection from erythropoiesis [5][6].
Side Effects & Tolerability Profile
Clinical subjects transiently report mild side effects. Slowly escalating the titration dose represents the single most effective intervention to limit side effects.
- warningARA 290 has been very well tolerated in published phase 2 trials, with adverse event rates comparable to placebo and no serious adverse events attributable to the peptide across approximately 200 cumulative treated participants.
- warningInjection site reactions including mild erythema, transient pain, and itching are the most common adverse events with subcutaneous administration, generally resolving within 24 hours.
- warningUnlike recombinant EPO, ARA 290 does not raise hemoglobin or hematocrit and has not been associated with blood pressure elevation or thromboembolic events in published trials.
- warningMild headache and transient fatigue have been reported at low frequency, particularly during the first week of dosing.
- warningLong-term safety data are limited; published exposure is restricted to 28-day courses in phase 2 trials, and chronic dosing safety, immunogenicity with repeated cycles, and effects on rare adverse events have not been characterized.
- warningUse in pregnancy, lactation, and pediatric populations has not been studied; theoretical concerns about effects on fetal hematopoiesis exist despite the non-erythropoietic design.
- warningDrug-drug interactions have not been formally characterized; the peptide does not interact with cytochrome P450 enzymes, but pharmacodynamic interactions with immunomodulators are theoretically possible.
Subcutaneous Injection Technique
Most research peptides require subcutaneous injection into fatty tissue. Never inject directly into a blood vessel or deep muscle tissue unless clinically detailed.
1. Site Selection
Common locations include the abdomen (2 inches from navel), outer upper arms, or thighs.
2. Sanitization
Thoroughly clean the selected site, stopper and vial top using 70% isopropyl alcohol prep swabs.
3. Angle & Push
Pinch the skin and insert the needle at a 45 to 90-degree angle. Depress plunger smoothly.
4. Site Rotation
Rotate injection sites continuously to avoid lipodystrophy or tissue scarring.
Frequently Asked Questions
What is the typical ARA 290 dosage?expand_more
Research protocols use 1 to 8 mg/day subcutaneously for 28 days, with 4 mg/day emerging as the preferred dose in published phase 2 trials. Longer dosing cycles and maintenance regimens have not been formally evaluated in published clinical studies.
How is ARA 290 used in research protocols?expand_more
Primary applications include sarcoidosis-related small fiber neuropathy, diabetic peripheral neuropathy, and chemotherapy-induced peripheral neuropathy. Outcome measures include validated pain scales, autonomic symptom questionnaires, corneal confocal microscopy, skin biopsy nerve fiber density, and metabolic parameters.
Can ARA 290 be combined with other peptides?expand_more
Combinations with conventional neuropathic pain pharmacotherapy (gabapentinoids, SNRIs) have been used in research cohorts. Combinations with other regenerative peptides have not been formally studied; the mechanism is distinct from BPC-157 or TB-500 and offers complementary anti-inflammatory and nerve-protective activity.
What are the side effects of ARA 290?expand_more
ARA 290 has been very well tolerated in phase 2 trials with adverse event rates similar to placebo. Mild injection site reactions and occasional headache or fatigue are the most common. Unlike EPO, ARA 290 does not raise hemoglobin or cause thrombosis.
Is ARA 290 FDA approved?expand_more
No. ARA 290 (cibinetide) is not approved by the FDA, EMA, or other major regulators. It remains an investigational agent under development by Araim Pharmaceuticals for neuropathic pain and tissue-protective indications.
Academic References & Study Citations
Brines M, Patel NS, Villa P, et al. Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A. 2008;105(31):10925-10930. View Scientific Paper →
Brines M, Cerami A. The receptor that tames the innate immune response. Mol Med. 2012;18(1):486-496. View Scientific Paper →
Swartjes M, Morariu A, Niesters M, et al. ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response. Mol Pain. 2014;10:13. View Scientific Paper →
Heij L, Niesters M, Swartjes M, et al. Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Mol Med. 2012;18(1):1430-1436. View Scientific Paper →
Culver DA, Dahan A, Bajorunas D, et al. Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. Invest Ophthalmol Vis Sci. 2017;58(6):BIO52-BIO60. View Scientific Paper →
Brines M, Dunne AN, van Velzen M, et al. ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol Med. 2015;20(1):658-666. View Scientific Paper →
Brines M, Grasso G, Fiordaliso F, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A. 2004;101(41):14907-14912. View Scientific Paper →
Niesters M, Swartjes M, Heij L, et al. The erythropoietin analogue ARA 290 for treatment of sarcoidosis-induced chronic neuropathic pain. Expert Opin Orphan Drugs. 2013;1(1):77-87. View Scientific Paper →
Dahan A, Brines M, Niesters M, Cerami A, van Velzen M. Targeting the innate repair receptor to treat neuropathy. Pain Rep. 2016;1(1):e566. View Scientific Paper →