cibinetide

Q: What is cibinetide (ARA-290)?

Cibinetide is a lab-made copy of one short stretch of erythropoietin, the hormone that tells the body to make more red blood cells. Erythropoietin also protects tissue that has been injured, and cibinetide was built to do that second job only. There is no brand name, because no finished product has ever been approved anywhere. The clinical papers call it ARA 290, the animal papers call it pHBSP, and the material sold on the research market is labelled ARA-290 or ARA290 acetate. In full it is an 11-amino-acid peptide, Pyr-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser, modelled on the aqueous face of helix B of erythropoietin. It was engineered to bind the tissue-protective EPO receptor and beta-common receptor complex without driving the red-cell response of the parent hormone. pHBSP is short for pyroglutamate helix B surface peptide, and cibinetide is investigational everywhere.

Q: What does cibinetide do?

In animals it protects injured tissue across kidney, retina, brain, gut, islet and cardiac models, reduces allodynia, which is pain from a touch that should not hurt, and leaves haematocrit where it was. Receptor dependency has been tested twice by different methods. In people the same thing has mostly failed to show up. Most of the human testing was in patients with painful nerve damage, usually from sarcoidosis and in one trial from type 2 diabetes, checking whether the smallest nerve fibres in the skin and the surface of the eye recovered and whether the pain eased. Pain intensity did not improve more than placebo anywhere. Two of the trials' main measures did beat placebo, an imaging measure of the nerve fibres in the eye at one dose and an average blood-sugar reading in the diabetes trial. Across six published trials and roughly 130 people ever dosed, those two were corneal nerve fibre area at 4 mg in the 64-person phase 2b, p=0.012, with the 1 mg and 8 mg arms failing, and HbA1c in the 48-patient type 2 diabetes trial, p=0.002. The developers' own 2018 reanalysis of the corneal images reported no change in nerve fibre density. No group outside the originating network has reproduced any positive result.

Q: How is cibinetide administered in research?

In the published trials it was given subcutaneously at 1 to 8 mg daily for 28 days, or intravenously at 2 mg three times weekly for 4 weeks. The single longest exposure on record is 4 mg daily subcutaneously for 12 weeks in an uncontrolled 9-patient study. There is no approved dosing protocol, no drug label, and no primary human pharmacokinetic paper with Cmax, AUC or a terminal half-life table has been located.

Q: What are the side effects of cibinetide?

The record is too small to characterise. The phase 2b posted its adverse events for all four arms. Participants with at least one treatment-emergent event ran 14 of 16 at 1 mg, 11 of 16 at 4 mg, 12 of 14 at 8 mg and 12 of 16 on placebo. Serious treatment-emergent events were two in the 1 mg arm, none at 4 mg, one at 8 mg recorded as suicidal ideation, and none on placebo. The most common non-serious events were gastrointestinal, headache and fatigue. Roughly 130 people have ever been dosed and none for longer than 12 weeks, so the record is too thin to show a dose-related harm pattern either way.

Q: Is cibinetide FDA approved?

No. Queries against the FDA approvals and label endpoints return no records for cibinetide, and the EU centralised medicines register returns no authorised product. It holds two EU orphan designations, EU/3/13/1191 for sarcoidosis granted October 2013 and EU/3/16/1721 for prevention of graft loss in pancreatic islet transplantation granted August 2016. An orphan designation is a development incentive. Marketing authorisation is a separate decision, and cibinetide has never received one anywhere. Cibinetide also sits in Category 3 of the FDA's 503A compounding nomination list, the bucket for substances nominated without adequate supporting information.

Q: How much does cibinetide cost?

There is no clinical retail price because there is no approved product. In US drug-code listings cibinetide appears only as a bulk ingredient offered by API suppliers, three records, all in the bulk ingredient marketing category, with no finished dosage form and no application number. What circulates on the research market is priced by those suppliers and their resellers, and identity, concentration and contamination status are unverified unless a lot-specific certificate of analysis says otherwise.

eleven amino acids copied from erythropoietin, the hormone that tells the body to make more red blood cells. the copy keeps the half of that hormone which protects injured tissue and leaves the red cells alone. vendors label it ARA-290. six published human trials, five of them randomised, and two primary endpoints that separated.

tier D · healing · 1 of 3 doses beat placebo

verdict

does it work: mixed. it was tested mostly in people whose smallest nerves had been damaged by sarcoidosis or by diabetes, and it never beat placebo on how much pain those people were in. two main endpoints did beat placebo across the whole human record. one was the amount of nerve visible in photographs of the eye surface, at one dose out of three, corneal nerve fibre area at 4 mg (p=0.012). the other was an average blood-sugar reading in a diabetes trial, HbA1c in type 2 diabetes (p=0.002). nobody outside the group that invented it has repeated either. roughly 130 people have ever been dosed.

if the question is simply whether it works: mixed. two endpoints beat placebo and then nobody repeated them. corneal nerve fibre area rose 697 µm² over placebo at 4 mg in the 64-person phase 2b (95% CI 159 to 1236, p=0.012), with 1 mg and 8 mg failing. HbA1c separated in the 48-patient type 2 diabetes trial, -0.21% at day 56 against +0.21% on placebo, p=0.002, with PainDetect at p=0.037. those two are the whole between-group case. no group outside the originating network has reproduced either, arms run 13 to 24 people, and nothing has started since april 2016. pain intensity failed everywhere it was measured, as did skin nerve fibre density and every objective retinal endpoint. nothing at all was measured past 28 randomised days.

if the question is whether cibinetide regrows small nerve fibres: the whole case is one imaging measure, at one dose, in one trial. the 64-person phase 2b in sarcoidosis reported corneal nerve fibre area rising 697 µm² over placebo at 4 mg (95% CI 159 to 1236, p=0.012), while 1 mg (+109 µm²) and 8 mg (+431 µm²) did not separate. regenerating GAP-43 positive skin fibres also rose in that arm (p=0.035). the same group then reanalysed those same images in 2018 and reported that corneal nerve fibre density did not change and that fibre length did not separate by ANCOVA. no group outside the originators has reproduced it.

if the question is pain: pain intensity has never separated from placebo anywhere in the published record. the 2012 pilot found the Brief Pain Inventory and the Fatigue Assessment Scale improving significantly and equally in both arms. the 2013 trial found pain intensity improving in both arms against baseline (p=0.01) with no between-group difference, though the pain interference dimension did separate, 36% against 16%, p<0.02 by the third week of dosing. in the phase 2b, pain fell in every arm including placebo, and the moderate-to-severe subgroup on 4 mg reached only p=0.157.

if the question is whether the programme is still running: it stopped. the last trial started in april 2016, ran 9 patients with diabetic macular oedema for 12 weeks, missed every objective endpoint, and terminated with the registry reason recorded as expiry of study drug with no replacement available. no phase 3 was ever registered under any spelling of the name. cibinetide holds two EU orphan designations and no marketing authorisation anywhere, and the FDA approval and label endpoints return nothing. vials sold under the ARA-290 name are selling a shelved phase 2 asset.

based on published trials, posted registry results and primary regulatory records. cibinetide is investigational and approved in no jurisdiction. not medical advice.

why D-tier

D, at the top of the band. the human record runs to six published trials, five of them randomised and placebo controlled, 218 enrolled and roughly 130 ever dosed. that count keeps cibinetide clear of C, where the mostly-preclinical compounds sit. it lands at D because of what those trials found, which comes down to replication. two between-group primary endpoints separated in the whole record. corneal nerve fibre area at 4 mg in the 64-person phase 2b (p=0.012), with 1 mg and 8 mg failing and 14 to 16 randomised per arm. HbA1c in the 48-patient type 2 diabetes trial (p=0.002, with PainDetect at p=0.037). neither repeated. the developers' own 2018 reanalysis of the phase 2b images reported no change in nerve fibre density and no ANCOVA separation on fibre length, so the most-repeated claim about this compound is walked back by the authors who made it, and the registry-posted secondaries put placebo numerically ahead on pain interference and on skin nerve fibre density. pain intensity has never separated from placebo anywhere, though the 2013 trial's pain interference dimension did (p<0.02 by week 3). the longest exposure, 12 weeks in 9 macular oedema patients, missed every objective endpoint and moved only a questionnaire. two independent reviews declined to endorse, including the 2021 ERS guideline co-authored by the phase 2b principal investigator. no group outside the originating network has replicated anything, and two supporting preclinical papers have been retracted. nothing has started since april 2016 and no phase 3 was ever registered. F is reserved for harm or for a blank file, and this is neither. the 4 mg imaging result plus the GAP-43 rise are real numbers with confidence intervals, the receptor route has been probed twice by different methods, and the posted adverse-event tables show no dose-related harm pattern. that puts it at D, where the human evidence exists, runs thin, and conflicts with itself.

the core tension

the molecule hits its design target and misses the thing people want it for. the receptor route has been probed by two different methods, and animals repeatedly show tissue protection with red cell production left alone, which was the entire design goal. in 42 rats, five injections bought 20 weeks of reduced allodynia. then in humans, across five randomised trials, cibinetide moved a picture of the corneal nerve at one dose out of three and left pain intensity where it was.

what it is

Cibinetide is a synthetic copy of one short patch of erythropoietin, the hormone that tells the body to make more red blood cells. Erythropoietin also protects tissue that has been injured, and the copy was built to do that second job only. It runs 11 residues, Pyr-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser, mapped onto the aqueous face of helix B of erythropoietin. It also appears in the literature as ARA 290 in the clinical work and as pyroglutamate helix B surface peptide, or pHBSP, in much of the animal work. The WHO proposed the name cibinetide in 2015 and recommended it in 2017. The two jobs come apart at the receptor. Red cell mass runs through the classical receptor homodimer. Tissue protection runs through a heterocomplex of the EPO receptor with the beta-common receptor, and cibinetide was shaped to bind that second route only. It has no FDA approval and no EU marketing authorisation.

what it does

In animals it protects injured tissue in kidney, retina, brain, gut, islet and cardiac models, calms the first-response arm of the immune system, and reduces allodynia, which is pain from a touch that should not hurt. All of that happens without the haematocrit rise, the thickening of blood with red cells, that limits erythropoietin itself. In humans far less moved. One corneal imaging metric at one dose, a rise in regenerating GAP-43 positive skin fibres in that same arm, symptom-questionnaire movement in two sarcoidosis trials, and a single HbA1c reading in type 2 diabetes. The objective endpoints in the longest human study went the wrong way.

origin

Michael Brines and Anthony Cerami, who did much of the original erythropoietin tissue-protection work, described the molecule in a 2008 PNAS paper and founded Araim Pharmaceuticals to develop it. The clinical programme ran through Araim with Albert Dahan's group at Leiden University Medical Center and Daniel Culver at Cleveland Clinic. That concentration matters when reading the results. Brines, Cerami or the Leiden group appear on every positive trial, and five of the fourteen authors on the phase 2b carried an Araim affiliation. The last primary company document is a press release dated 8 May 2017.

why researchers are interested

The mechanism story is unusually clean for this market. There is a named receptor complex, a stated design goal, a founding paper that tested the separation directly, and animal work that repeatedly delivers protection while leaving red cell production where it was. The human trial count is high for a compound sold on the research market. Five randomised placebo-controlled trials is more than most peptides at this tier will ever see, and one of them met its primary endpoint.

does it work

Mixed. Two main endpoints beat placebo and nobody has repeated either. Across roughly 130 people ever dosed in six published trials, those two were corneal nerve fibre area at 4 mg in the phase 2b, p=0.012, and HbA1c in the type 2 diabetes trial, p=0.002 by repeated-measures ANOVA, with PainDetect alongside it at p=0.037. The corneal dose response peaked at the middle dose and faded at the top, with 14 to 16 randomised per arm, and the developers' own 2018 reanalysis of those images reported no change in nerve fibre density and no ANCOVA separation on fibre length. Pain intensity, skin nerve fibre density and every objective retinal endpoint were measured and failed. Durable benefit past 28 randomised days, and the HbA1c reading in any second trial, were never measured at all. A measurement that failed and a measurement nobody took are different states. Two independent reviews looked and declined to endorse, including the 2021 ERS sarcoidosis guideline, which found insufficient evidence to recommend anything for small fibre neuropathy and which the phase 2b principal investigator co-authored. Two supporting preclinical papers have been retracted. Nothing has started since 2016.

key facts

molecular formula: C₅₁H₈₄N₁₆O₂₁
molecular weight: 1257.3 g/mol
amino acids: 11
half-life: ~2 min in plasma, from a developer-authored review; no primary human PK paper located
type: erythropoietin helix B surface peptide (EPOR / beta-common receptor agonist)
CAS: 1208243-50-8
6 published human trials, five randomised
~130 people ever dosed with cibinetide
1 of 3 doses that separated in the phase 2b
0 phase 3 trials, approvals, or independent replications

frequently asked questions

What is cibinetide (ARA-290)?

Cibinetide is a lab-made copy of one short stretch of erythropoietin, the hormone that tells the body to make more red blood cells. Erythropoietin also protects tissue that has been injured, and cibinetide was built to do that second job only. There is no brand name, because no finished product has ever been approved anywhere. The clinical papers call it ARA 290, the animal papers call it pHBSP, and the material sold on the research market is labelled ARA-290 or ARA290 acetate. In full it is an 11-amino-acid peptide, Pyr-Glu-Gln-Leu-Glu-Arg-Ala-Leu-Asn-Ser-Ser, modelled on the aqueous face of helix B of erythropoietin. It was engineered to bind the tissue-protective EPO receptor and beta-common receptor complex without driving the red-cell response of the parent hormone. pHBSP is short for pyroglutamate helix B surface peptide, and cibinetide is investigational everywhere.

What does cibinetide do?

In animals it protects injured tissue across kidney, retina, brain, gut, islet and cardiac models, reduces allodynia, which is pain from a touch that should not hurt, and leaves haematocrit where it was. Receptor dependency has been tested twice by different methods. In people the same thing has mostly failed to show up. Most of the human testing was in patients with painful nerve damage, usually from sarcoidosis and in one trial from type 2 diabetes, checking whether the smallest nerve fibres in the skin and the surface of the eye recovered and whether the pain eased. Pain intensity did not improve more than placebo anywhere. Two of the trials' main measures did beat placebo, an imaging measure of the nerve fibres in the eye at one dose and an average blood-sugar reading in the diabetes trial. Across six published trials and roughly 130 people ever dosed, those two were corneal nerve fibre area at 4 mg in the 64-person phase 2b, p=0.012, with the 1 mg and 8 mg arms failing, and HbA1c in the 48-patient type 2 diabetes trial, p=0.002. The developers' own 2018 reanalysis of the corneal images reported no change in nerve fibre density. No group outside the originating network has reproduced any positive result.

How is cibinetide administered in research?

In the published trials it was given subcutaneously at 1 to 8 mg daily for 28 days, or intravenously at 2 mg three times weekly for 4 weeks. The single longest exposure on record is 4 mg daily subcutaneously for 12 weeks in an uncontrolled 9-patient study. There is no approved dosing protocol, no drug label, and no primary human pharmacokinetic paper with Cmax, AUC or a terminal half-life table has been located.

What are the side effects of cibinetide?

The record is too small to characterise. The phase 2b posted its adverse events for all four arms. Participants with at least one treatment-emergent event ran 14 of 16 at 1 mg, 11 of 16 at 4 mg, 12 of 14 at 8 mg and 12 of 16 on placebo. Serious treatment-emergent events were two in the 1 mg arm, none at 4 mg, one at 8 mg recorded as suicidal ideation, and none on placebo. The most common non-serious events were gastrointestinal, headache and fatigue. Roughly 130 people have ever been dosed and none for longer than 12 weeks, so the record is too thin to show a dose-related harm pattern either way.

Is cibinetide FDA approved?

No. Queries against the FDA approvals and label endpoints return no records for cibinetide, and the EU centralised medicines register returns no authorised product. It holds two EU orphan designations, EU/3/13/1191 for sarcoidosis granted October 2013 and EU/3/16/1721 for prevention of graft loss in pancreatic islet transplantation granted August 2016. An orphan designation is a development incentive. Marketing authorisation is a separate decision, and cibinetide has never received one anywhere. Cibinetide also sits in Category 3 of the FDA's 503A compounding nomination list, the bucket for substances nominated without adequate supporting information.

How much does cibinetide cost?

There is no clinical retail price because there is no approved product. In US drug-code listings cibinetide appears only as a bulk ingredient offered by API suppliers, three records, all in the bulk ingredient marketing category, with no finished dosage form and no application number. What circulates on the research market is priced by those suppliers and their resellers, and identity, concentration and contamination status are unverified unless a lot-specific certificate of analysis says otherwise.

related peptides

ss-31: the other tissue-protection peptide graded on mechanism versus outcome
bpc-157: the healing peptide with the opposite problem: huge animal base, almost no trials
kpv: anti-inflammatory peptide studied in overlapping innate-immune models

reptides grades the research record and cites the literature behind every call. research reference only; not medical advice.