4 mg a day under the skin, in blocks of four weeks and longer
What was studied
4 mg a day under the skin for 28 days
The gap
Convention lands on a studied dose
How long it lasts
Not the useful number here. What was measured, and what the dose was actually built on, is total exposure: a crossover study in 10 healthy volunteers matched 4 mg under the skin at 59 nanogram-minutes per millilitre against 65 for the 2 mg into a vein that produced the first result. That is why the subcutaneous dose is what it is.
What it actually is
ARA-290, generic name cibinetide, is eleven amino acids in a row, molecular weight 1257.3. It is one of the few compounds in this reference whose randomised placebo controlled trials are genuinely its own, with nothing borrowed from a parent molecule. It is also not what the shorthand says. Almost every page calls it a fragment of erythropoietin, the hormone that tells the bone marrow to make red blood cells, and its sequence does not appear in that hormone anywhere.
What it is supposed to do
The design idea is that erythropoietin does two jobs through two receptors: blood making through a pair of erythropoietin receptors locked together, and tissue protection through one of them paired with a protein called CD131, which the group that built this peptide named the innate repair receptor. ARA-290 was built to switch on the second and not the first, and the European regulator describes cibinetide the same way, as activating a receptor that controls inflammatory processes. The elegant part is how it was built. Helix B of the folded hormone faces the water when erythropoietin is docked onto its blood making receptor, and the authors strung together eleven residues that sit adjacent on that surface rather than adjacent in the chain. That is closer to taking a rubbing of eleven raised studs spread across a door than to sawing a panel out of it.
What people take it for
Nerve repair, neuropathic pain and inflammation, in healthy adults. What the trials enrolled was patients with a diagnosed condition: small fibre neuropathy in sarcoidosis in the main programme, and neuropathic symptoms in type 2 diabetes in the other. Every efficacy trial ran 28 days or less except one, the longest human exposure I found anywhere was 12 weeks in nine people, and the only work I found in people who are not ill was a single 2 mg dose given to roughly 18 of 36 healthy volunteers, which reported no effect on mood.
The dose question
What circulates
4 mg a day under the skin, in blocks of four weeks and longer
What was studied
4 mg a day under the skin for 28 days
A 64 patient sarcoidosis trial, and a 10 volunteer exposure study behind the number
Lands on a studied dose
The dose is correct and vendors quote it accurately, which is rare enough here to say plainly. A crossover in 10 healthy volunteers matched 4 mg under the skin to the 2 mg into a vein that produced the first result, 59 nanogram-minutes per millilitre against 65, so the subcutaneous number reproduces the exposure of the injection that worked. The drift is population, duration and route. Every efficacy trial enrolled patients with a diagnosed condition, four of the six studies ran 28 days, and the longest exposure I found anywhere was 12 weeks in nine people. More than one guide states that under the skin is the only route in the trial literature, and the intravenous pilot is why that is wrong.
Reported because it is what people use. Nothing here recommends any amount.
How long it lasts
Not the useful number here. What was measured, and what the dose was actually built on, is total exposure: a crossover study in 10 healthy volunteers matched 4 mg under the skin at 59 nanogram-minutes per millilitre against 65 for the 2 mg into a vein that produced the first result. That is why the subcutaneous dose is what it is.
Route studied
Into a vein in the 2012 pilot, at 2 mg three times a week for four weeks, and under the skin at 4 mg a day for 28 days in the trials that followed. More than one vendor guide states that under the skin is the only route in the trial literature, and the intravenous pilot is why that is wrong.
Route used
Under the skin at 4 mg a day, which is the trial dose quoted accurately. What has drifted is who takes it, for how long, and on what schedule.
How to check you have the right molecule
Check the sequence claim yourself, because it is the one identity trap here and it runs the good way. Pull up UniProt entry P01588, strip the 27 residue signal peptide off the front, and search the mature sequence for QEQLERALNSS. It is not there. Mapped back by position the eleven residues are Q58, E62, Q65, L69, E72, R76, A79, L80, N83, S84 and S85, eight of them scattered across the twenty three positions from 58 to 80, with only A79 and L80 side by side and the last three together. So it is a designed copy of a surface rather than a piece cut out of the protein, which is why erythropoietin's own enormous literature does not transfer here. At least six names circulate, including cibinetide, the approved generic, and pHBSP, under which both retracted animal papers are filed.
The endpoint is what to read before anything else. The measure that carried this programme forward, trial after trial, was a photograph of nerve fibres in the cornea, which the largest trial's own abstract calls a surrogate. In the 2013 trial only that corneal measure moved, and both its figures are comparisons of a group against its own starting point rather than against the placebo arm the trial had gone to the trouble of recruiting, while the skin biopsy that neurologists actually use to diagnose the disease did not move. In the 2017 trial, placebo corrected change at day 28 was 109 square micrometres on 1 mg, 697 on 4 mg and 431 on 8 mg, so doubling the middle dose made the result smaller and the lowest dose did nothing, and I found no published explanation. Pain improved in every arm including the dummy. Two papers in the record are retracted for image problems, both animal work and neither touching a human trial, but one of them is the preclinical account of why a peptide that does not make blood should improve insulin sensitivity, which is what the human blood sugar number gets sold on.
What is known about harm
Everything in the human record is 28 days or less, in patients, across roughly 133 people. The 2013 sarcoidosis trial reported no serious adverse events in its 21 patients on 4 mg under the skin daily for 28 days, the 2015 diabetes trial reported four among its 24 patients on the same schedule with two judged unlikely to be related, and the phase 2b registry record gives two serious events in the 1 mg arm, one in the 8 mg arm and none in the 4 mg arm or on the dummy. Three on drug and none on the dummy is what chance produces at that size, and the three arms on drug held 48 patients against 16 on the dummy, so the two counts are not measured over the same number of people. On the central safety claim, that it does not stimulate red blood cell production, two trials report no clinically significant blood count changes but neither prints haemoglobin, haematocrit or reticulocyte numbers in the sections I read, so that property rests in humans on two statements that nothing changed, over 28 days, in fewer than 50 people between them.